MSCCH09

MScCH-09
Vardhman Mahaveer Open University, Kota
Drugs and Pharmaceuticals

MScCH-09
Drugs and Pharmaceuticals

Course Development Committee
Chair Person
Prof. Ashok Sharma
Vice-Chancellor
Coordinator and Members
Coordinator
SANDEEP HOODA
Assistant Professor of Zoology
School of Science & Technology
Prof L.R. Gurjar Dr. Arvind Pareek
Director Academic Director Regional Centre-Bharatpur
VMOU Kota VMOU Kota
Dr. Anuradha Dubey Dr. Sunil kumar Jangir
Deputy Director,SOST Convener Chemistry
VMOU Kota VMOU Kota
Prof. P.S. Verma (Retd.) Prof. Pahup Singh (Retd.)
Department of Chemistry Department of Chemistry
University of Raj, Jaipur University of Raj, Jaipur
Prof. P.D. Sharma (Retd.) Prof. Ashu Rani
University of Raj, Jaipur University of Kota, Kota
Dr. R.L. Pilaliya, (Retd.) Dr. Sapna Sharma
Department of Chemistry, Govt. College Department of Chemistry
Bikaner JECRC,university Jaipur
Dr. Sanjay Kumar Sharma Dr. Sushil Kumar Sharma
JECRC,university Jaipur University of Kota, Kota
Editing and Course Writing
Editor
Dr. M. P. Khinchi Dr. Sushil Kumar Sharma
Principal Assistant Professor, Department of Pure
and Applied Chemistry
Kota College of Pharmacy, Kota
University of Kota, Kota
Writers:
Dr. M. P. Khinchi 1,2,6,9,13 Mrs. Samiksha Sharma 5,10,14
Principal Assistant Professor
Kota College of Pharmacy, Kota College Of Pharmacy
Kota
Mr. Gaurav Sanadya 15,18,20 Mr. Mohd. Shahid 12,16,17
Assistant Professor Assistant Professor
Kota College of Pharmacy, Kota College Of Pharmacy
Kota
Mr. Abhishek Namdev 4,7,19 Mr. Lokesh Gupta 3,8,11
Assistant Professor Senior Research Fellow
Kota College of Pharmacy, Central University Of
Kota Rajasthan , Kishangargh,
Ajmer
Academic and Administrative Management

Prof. Ashok Sharma Prof. L.R. Gurjar
Vice-Chancellor Director (Academic)
Vardhman Mahaveer Open University, Kota Vardhman Mahaveer Open University, Kota
Prof. Karan Singh Dr. Subodh Kumar
Director (MP&D) Additional Director (MP&D)
Vardhman Mahaveer Open University, Kota Vardhman Mahaveer Open University, Kota
ISBN :
All Right reserved. No part of this Book may be reproduced in any form by mimeograph or any other means
without permission in writing from V.M. Open University, Kota.
Printed and Published on behalf of the Registrar, V.M. Open University, Kota.
Printed by :
MScCH-09
Index
Unit No. Unit Name Page
No.
Unit -1 Drug Discovery, Design and Developme 1
Unit -2 Structure Activity Relationship 20
Unit -3 Theories of Drug Activity 37
Unit -4 Quantitative Structure Activity Relationship 54
Unit -5 Concepts of drug receptors 70
Unit -6 Pharmacokinetic I 86
Unit -7 Pharmacokinetic-II 103
Unit -8 Pharmacodynamics-I 119
Unit -9 Pharmacodynamics – II 140
Unit -10 Antineoplastic agents 157
Unit -11 Synthesis Antineoplastic agents 174
Unit -12 Cardiovascular Drugs 191
Unit -13 Synthesis of Cardiovascular Drugs 210
Unit -14 Local Anti-infective Drugs 225
Unit -15 Synthesis of Local Anti-Infective Drugs 248
Unit -16 Psychoactive Drugs 262
Unit -17 Antipsychotic Drugs 282
Unit -18 Synthesis Of Antipsychotic Drugs 301
Unit -19 Antibiotics 315
Unit -20 Synthesis of Antibiotics 331
MScCH-09
Preface
The present book entitled “Drugs and Pharmaceuticals ” has been designed so as to
cover the unit-wise syllabus of MScCH-09 course for M.Sc. Chemistry (Final)
students of Vardhman Mahaveer Open University, Kota. The basic principles and
theory have been explained in simple, concise and lucid manner. Adequate
examples, diagrammes , photographs and self-learning exercises have also been
included to enable the students to grasp the subject easily. The unit writers have
consulted various standard books and internet as their reference on the subject and
they are thankful to the authors of these reference books.
Unit-1
Drug Discovery, Design and Developme
Structure of Unit:
1.1 Objectives
1.2 Introduction
1.3 Development of new drugs
1.4 Procedures followed in drug design
1.5 Concept of lead compounds and lead modification
1.6 Concepts of prodrug and soft drugs
1.7 Summary
1.8 Glossary
1.9 Review questions /comprehensive questions
1.10 References and suggested readings
1.1 Objectives
In this unit the students will be able to understand
 Drug Discovery with and without lead
 Identification of the active Part: The Pharmacophore
 Functional Group Modification
 Structural Activity Relationships
 Quantitative Structure activity Relationships
 About Pro-drugs and soft drugs
1.2 Introduction: Drug Discovery, Design, and Development
Medicinal chemistry is the scientific discipline that makes such drugs available
through either discovery or design processes. Therapeutic agents are chemicals
that prevent disease, assist in restoring health to the diseased, or alleviate
symptoms associated with disease conditions.
1
Medicinal
Chemistry Applied Chemistry

Chemistry
Medicines
Fig.1.1: Relation Cycle of Applied Chemistry

Drug discovery is part luck and part structured investigation. In the twentieth
century, a very large number of biologically active natural products were
structurally modified in order to optimize their pharmacology, and novel drugs
were prepared by use of increasingly advanced synthetic methods. Moreover,
the rapidly growing understanding of the nature of disease mechanisms, how
cells function, and how drugs interact with cellular processes has led to the
rational design, synthesis, and pharmacological evaluation of new drug
candidates. Most recently, new dimensions and opportunities have emerged
from a deeper understanding of cell biology and genetics.
Drug design aims at developing a drug with high degree of chemotherapeutic
index and specific action.
Drug design seeks to explain:
 Effects of biological compounds on the basis of molecular interaction in
terms of molecular structures or precisely the physico-chemical
properties of the molecules involved.
 Various processes by which the drugs usually produce their
pharmacological effects.
 How the drugs specifically react with the protoplasm to elicit a
particular pharmacological response.
 How the drugs usually get modified or detoxicated, metabolized or
eliminated by the organism.
 Probable relationship between biological activities with chemical
structure.
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1.3 Development of new drugs
Drug development normally refers to the process of taking a compound that has
been identified from the drug discovery process described above through the
subsequent steps necessary to bring it to market. Typically, these additional
major steps include preclinical development, clinical development, and
regulatory approval.
The ‘drug design’ in a broader sense implies random evaluation of synthetic as
well as natural products in bioassay systems, creation of newer drug molecules
based on biologically-active-prototypes derived from either plant or animal
kingdom, synthesis of congeners displaying interesting biological actions, the
basic concept of isosterism and bioisosterism, and finally precise design of a
drug to enable it to interact with a receptor site efficaciously.
Fig.1.2: The general steps in the design of a new drug

Factors governing drug-design
 The smaller the expenditure of human and material resources involved
evolving a new drug of a particular value, the more viable is the design
of the programme.
 Experimental animal and clinical screening operations of the new drugs.
 Relationships between chemical features and biolgoical properties need
to be established retrospectively.
 Quantitative structure-activity relationships (QSARs) vary to an
appreciable extent in depth and sophistication based on the nature of
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evaluation of structure or activity. A purposeful relation of structural
variables must include steric factors, electronic features of component
functional groups and, in general, the molecule as a whole.
 The trend to synthesize a huge number of newer medicinal compounds
indiscriminately for exploratory evaluation still prevails which
exclusively reflects the creative genuineness and conceptual functions of
a highly individualized expression of novelty by a medicinal chemist.
 Introduction of functional groups in a molecule that need not essentially
resemble metabolites, but are capable of undergoing bonding
interactions with important functional groups of biochemical
components of living organisms affords an important basis for
exploration.
 Disease etiologies and various biochemical processes involved prove
useful.
1.4 Procedures followed in drug design
1.4.1 Drugs discovered without rational design
(a) Medicinal chemistry folklore
Medicinal chemistry, in its crudest sense, has been practiced for several
thousand years. Man has searched for cures of illnesses by chewing herbs,
berries, roots, and barks. Some of these early clinical trials were quite
successful; however, not until the last 100–150 years has knowledge of the
active constituents of these natural sources been known. The earliest written
records of the Chinese, Indian, South American, and Mediterranean cultures
described the therapeutic effects of various plant concoctions. Eg. Ephedra
sinica, Papaver somniferum, Rauwolfia serpentine, Colchicum autumnal,
Digitalis purpurea etc.
4
(b) Discovery of Penicillins
In 1928, Alexander Fleming noticed a green mold growing in a culture of
Staphylococcus aureus, and where the two had converged, the bacteria were
lysed. This led to the discovery of penicillin, which was produced by the mold.
The original mold was Penicillium notatum, a strain that gave a relatively low
yield of penicillin. It was replaced by Penicillium chrysogenum. Two reasons
for the delay in the universal utilization of penicillin were the emergence of the
sulfonamide antibacterials (sulfa drugs)
(C) Discovery of Drugs through Metabolism Studies

During drug metabolism studies, metabolites (drug degradation products
generated in vivo) that are isolated are screened to determine if the activity
observed is derived from the drug candidate or from a metabolite. For example,
the anti-inflammatory drug sulindac is not the active agent; the metabolic
reduction product is responsible for the activity.
5
(d) Discovery of Drugs through Clinical Observations
Sometimes a drug candidate during clinical trials will exhibit more than one
pharmacological activity, that is, it may produce a side effect. This compound,
then, can be used as a lead (or, with luck, as a drug) for the secondary activity.
The impotence drug sildenafil citrate (Viagra) was designed for the treatment of
angina and hypertension by blocking the enzyme phosphodiesterase-5, which
hydrolyzes cyclic guanosine monophosphate (cGMP), a vasodilator that allows
increased blood flow. In Phase II clinical trials, it was not as effective against
angina as Pfizer had hoped, so it went back to Phase I clinical trials to see how
high of a dose could be tolerated. It was during that clinical trial that the
volunteers reported increased erectile function. Given the weak activity against
angina, it was an easy decision to try to determine its effectiveness as the first
treatment for erectile dysfunction.
Fig.1.3: Mechanism of action of Sildenafil (Viagra)

1.4.2 Rational approach to drug design
A rational approach to drug design may be viewed from different angles,
namely:
(a) Quantum Mechanical Approach
Quantum mechanics (or wave mechanics) is composed of certain vital
principles derived from fundamental assumptions describing the natural
phenomena effectively. The properties of protons, neutrons and electrons are
adequately explained under quantum mechanics. The electronic features of the
molecules responsible for chemical alterations form the basis of drug molecule
phenomena.
(b) Molecular Orbital Approach
The molecular orbital approach shows dependence on electronic charge as
evidenced by the study of three volatile inhalation anaesthetics, and also on
molecular conformation as studied with respect to acetylcholine by such
6
parameters as bond lengths and angles including torsional angles. Molecular
orbital calculations are achievable by sophisticated computers, and after
meticulous interpretations of results the molecular structure in respect of
structure-activity analysis is established.
(c) Molecular Connectivity Approach
This approach establishes the presence of structural features like cyclization,
unsaturation, skeletal branching, and the position and presence of heteroatom in
molecules with the aid of a series of numerical indices. For example: an index
was determined to possess a correlative factor in the SAR study of
amphetamine-type hallucinogenic drugs. Molecular connectivity approach has
some definite limitations, such as: electronegativity variance between atoms,
non-distinguishable entity of cis-trans isomerism.
(d) Linear Free-Energy Approaches
This method establishes the vital link between the proper selections of
physicochemical parameters with a specific biological phenomenon. However,
such a correlation may not guarantee and allow a direct interpretation with
regard to molecular structure, but may positively offer a possible clue towards
the selection of candidate molecules for synthesis.
(e) Drug Design through Disjunction
Disjunction comes in where there is the systematic formulation of analogues of
a prototype agent, in general, toward structurally simpler products, which may
be viewed as partial or quasi-replicas of the prototype agent.
The method of disjunction is usually employed in three different manners,
namely:
 Unjoining of certain bonds
 Substitution of aromatic cyclic system for saturated bonds
 Diminution of the size of the hydrocarbon portion of the
 parent molecule.
(f) Drug Design through Conjunction
This is known as the systematic formulation of analogues of a prototype agent,
in general, toward structurally more complex products, which may be viewed as
structures embodying, in a general or specific way, certain or all of the features
of the prototype. In this type of drug-design, the main principle involved is the
‘principle of mixed moieties’. A drug molecule is essentially made up with two
or more pharmacophoric moieties embedded into a single molecule.
7
Example. Acetylcholine is an effective postganglionic parasympathetic
stimulant in doses that afford no appreciable changes in the ganglionic function;
whereas hexamethonium possesses only a slight action at postganglionic
parasympathetic endings in doses that produce a high degree of ganglionic
blockade.
1.5 Concept of lead compounds and lead modification
Drugs are generally not discovered, lead compounds are discovered. In the
modern drug discovery paradigm that we are discussing, a lead compound
typically has most or all of the following characteristics:
 It interacts with the target in a manner consistent with that needed to
achieve the desired effect.
 It is amenable to synthetic modifications needed to improve properties.
 It possesses, or can be modified to possess, physical properties
consistent with its ability to reach the target after administration by a
suitable route.
Interestingly, the ‘drug discovery process’ may be categorized into four distinct
heads, namely:
 Target identification and selection,
 Target optimization,
 Lead identification, and
 Lead optimization.
The concerted efforts encompassing various intangible and critical
methodologies that ultimately relate to the activities, expertise, wisdom and
integration of the individual scientist directly or indirectly involved in ‘drug
discovery process’ virtually leads to advance drug discovery profiles.
Common sources of lead compounds are the following:
 The natural ligand or substrate for the target of interest. For example,
dopamine is the natural ligand for the family of dopamine receptors.
 Another substance already known to interact with the target of interest.
For example, the plant alkaloid cytisine was known to interact with
nicotinic acetylcholine receptors.
 Comparing the three structures, one can also imagine that the structure
of nicotine inspired some of the ideas for the modifications of cytisine
on the way to the discovery of varenicline.
8
 Random or targeted screening- Screening refers to the exercise of
conducting a biological assay on a large collection of compounds to
identify those compounds that have the desired activity. Assays that
rapidly measure binding affinities to targets of interest, called high-
throughput screens, have been commonly used for this purpose.
 Fragment-based screening. Several screening methods using, for
example, X-ray crystallography or NMR spectrometry have been
developed to identify simple molecules (fragments) possessing typically
modest affinity for a target, with the intent of connecting two or more of
these fragments to create a useful lead compound.
 Computational approaches. Given knowledge of the binding site on the
target (for example through X-ray crystallography) or of the structure of
several known ligands, computational approaches may be used to design
potential lead compounds.
Lead Modification (Lead Optimization)

Once one or more lead compounds have been identified, the most notable
parameters that may need to be optimized include: potency; selectivity;
absorption, distribution, metabolism, and excretion (ADME); and intellectual
property position. This process normally involves synthesizing modified
versions (analogs) of the lead compound and assessing the new substances
against a battery of relevant tests. It is not uncommon to synthesize and test
hundreds of analogs in the lead optimization process before a drug candidate (a
compound worthy of extensive animal testing) is identified.
(a) Potency: Potency refers to the strength of the biological effect, or put
another way, how much (what concentration) of the compound is required
to achieve a defined level of effectiveness.
(b) Selectivity: Unintended sites of action, noted above, refer to interactions
with unidentified or unexpected targets. In addition, there may be off-
targets that are related to the intended target, with which it would be
disadvantageous for the drug to interact.
9
(c) Absorption, Distribution, Metabolism, and Excretion (ADME): Absorption
refers to the process by which a drug reaches the bloodstream from its site
of administration. Distribution refers to what “compartments” in the body
the drug goes. Metabolism refers to the action of specific enzymes on a
drug to convert it to one or more new molecules (called metabolites).
Excretion refers to means by which the body eliminates an unchanged
drug or its metabolites through urine, feces, exhalation and other
secretions.
(d) Intellectual Property Position: Discovering a new drug and bringing it to
market is an exceptionally expensive endeavor, to recover the costs and
also be able to appropriately compensate investors who are financing the
research (and incentivize potential new investors), it is imperative to
obtain a patent on a drug that is progressing toward drug development.
The patent gives the patent holder the legal means to prevent others from
making, selling, or importing the drug, effectively granting the holder a
monopoly, for a limited period of time, on selling the drug.
1.6 Concept of prodrugs and soft drugs
The term “prodrug” or “proagent” was introduced by A. Albert in 1958 to
describe compounds that undergo biotransformation prior to eliciting a
pharmacological effect. The formation of a prodrug provides a transient change
of physicochemical and biological properties thereby altering or eliminating
undesirable properties of the parent drug molecule. This prodrug to drug
biotransformation may take place before absorption, during absorption,
immediately after absorption, or at a specific site of action. The conversion of
prodrugs to the active parent drug molecule can take place through various
reactions such as hydrolytic cleavage either as a spontaneous or enzyme-
mediated reaction.
10
Fig.1.4: Prodrug principle
The prodrug approach has been successfully utilized to overcome significant
barriers for many drugs aiming
1. To improve the oral bioavailability by increasing aqueous solubility, by
increasing biomembrane permeability, and/or by improving (metabolic)
stability
2. To increase the duration of pharmacological action
3. To decrease toxicity or adverse reactions
4. To obtain drug targeting using site-specific biotransformation or site
specific transporters.
Types of Prodrugs-
(a) A carrier-linked prodrug is a compound that contains an active drug
linked to a carrier group that can be removed enzymatically, such as
an ester, which is hydrolyzed to an active carboxylic acid-containing
drug.
(b) A bioprecursor prodrug is a compound that is metabolized by molecular
modification into a new compound, which is the active principle or
which can be metabolized further to the active drug. For example, if
the drug contains a carboxylic acid group, the bioprecursor may be a
primary amine, which is metabolized by oxidation to the aldehyde and
then further metabolized to the carboxylic acid drug.
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Fig.1.5: Protecting group analogy for a prodrug
Design of prodrugs: chemical considerations-
Prodrugs are most often taken into consideration after identification of a
pharmacological active lead compound or structure.
 The first step in prodrug design is identification of functional groups such
as hydroxyl, carboxyl, carbonyl, amide, NH-acidic, and/or amino groups in
the active compound that are available for chemical derivatization.
 Potentially bioreversible derivatives such as esters, N-acyl, N-
hydroxymethyl, or N-acyloxyalkyl derivatives, N-Mannich bases,
enaminones, and lactones may be synthesized and subjected to further
testing.
 The most important requirement for a prodrug is its ability to adequately
regenerate the active drug in-vivo.
 It must be chemically stable in the bulk form and together with common
excipients used in drug formulation leading to an acceptable shelf-life and,
finally, the toxicity of the promoiety and the prodrug itself must be
acceptable.
Prodrugs transformed by enzymatic reactions
The most common prodrugs are those requiring hydrolytic cleavage mediated
by enzymatic catalysis. Drugs containing hydroxyl, carboxyl, or amino
functional groups can be converted into prodrug esters or amides from which
the active forms are readily regenerated by hydrolytic enzymes such as
esterases, amidases, peptidases, or phosphatases.
Less often prodrugs are designed to undergo reductive or oxidative processes
mediated by enzymes such as cytochrome P450, monoamine oxidases,
azoreductases, or nitroreductases.
12
Fig.1.6: Schematic examples of prodrugs designed to undergo enzymatic-
mediated hydrolysis
Prodrugs transformed by spontaneous reactions
As an alternative to the enzymatic-mediated bioconversion, prodrugs may be
designed to undergo spontaneous (or chemical) transformation dictated by the
physicochemical environment such as the pH in various parts of the human
body.
Some important examples of prodrugs biotransformed by nonenzymatic-
mediated reactions are hydroxymethyl derivatives of NH-acidic drug molecules
such as 5-fl uorouracil, phenytoin, N-Mannich bases derived from drugs
containing amino or amide functions (e.g., tetracycline, carbamazepine) and
ring-opened derivatives of cyclic drugs e.g. pilocarpine.
Figure 1.7: Prodrugs transformed by spontaneous reactions

Design of Prodrugs: application of the prodrug principle-
13
The prodrug principle offers an opportunity for optimization of drug therapy for
a variety of reasons. The intention of this section is to illustrate important
features of the principle by providing selected examples of achievements by
prodrug design and development.
(a) Design of prodrugs with improved bioavailability
The oral bioavailability (F) of a compound is determined by a number of
parameters such as aqueous solubility (determines the amount of drug available
at the site of absorption), permeability (the ability of the molecule to permeate
biological membranes), and stability in the gastrointestinal tract.
Fick’s first law of diffusion that describes the rate of diffusion across a (bio)
membrane:
dQ/dt = Papp × A × (C – Co )
where dQ/dt is the mass flux across the membrane, A is the membrane surface
area, C − Co determines the initial concentration gradient between the apical &
basolateral side of the epithelium and Papp is the permeability coefficient.
Thus, optimization of the fl ux and thereby the absorption potential is a balance
between high aqueous solubility and adequate permeability characteristics. This
has been successfully obtained by using the prodrug approach.
a. Improved Aqueous Solubility: For compounds suffering from
dissolution rate or solubility limited absorption due to low aqueous
solubility and/or high therapeutic dose introduction of a hydrophilic
moiety may prove beneficial for the oral bioavailability. Example-
Amprenavir phosphate (protease inhibitor) to fosamprenavir (ester
prodrug).
b. Improved Biomembrane Permeability (Passive Diffusion): Due to the
large surface area of the gastrointestinal epithelium, transcellular
(passive) diffusion is a very important absorption principle for drug
molecules. Thus, the ability of a compound to permeate this epithelium is
of vital importance for the absorption of the drug. Example-
Pivampicillin, talampicillin, and bacampicillin are the
pivaloyloxymethyl, the phthalidyl, and the ethoxycarbonyloxyethyl
esters, respectively, of the parent penicillin ampicillin.
c. Improved Transporter-Mediated Permeability: Various active
transport mechanisms for amino acids, small peptides, monocarboxylic
acids, monosaccharides, and nucleosides exist in the human body and it
is generally recognized that such mechanisms play a major role in the
absorption of many drug molecules. This has been used in prodrug
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design attempting to provide chemical bioreversible modifi cations
mimicking natural substrates for various active transporters with the aim
of improving intestinal absorption of various drugs. Example- Levodopa
(or l-dopa) is a prodrug of the neurotransmitter dopamine
d. Increased Stability in the Gastrointestinal Tract: The poor
absorption of carbenicillin after oral administration can to a large
extent be attributed to fast acid-catalyzed degradation in the
gastrointestinal tract. More acid resistant Prodrugs such as
carindacillin and carfecillin have been shown to signifi cantly
increase the bioavailability of cabenicillin.
e. Improved Metabolic Stability: the prodrug approach can be applied to
protect a drug against presystemic metabolism by directly blocking the
susceptible part of the molecule or by blocking at an alternative position
of the molecule. In both cases, a prodrug that is not a substrate for the
metabolizing enzyme may be obtained. Example- Bioactivation of N-(N-
acetyl- l-methionyl)-O,O-biscarbonyl dopamine.
Fig.1.8: Design of prodrugs with improved bioavailability

(b) Design of prodrugs for prolonged drug action
15
The utility of prodrugs as a means to achieve prolonged pharmacological action
of a drug has been effective mainly in terms of intramuscular (IM) injection
preparations and other local administrations.
(i) Intramuscular Depot Injections: The principle has provided long-term (1–
4 weeks) delivery of neuroleptic drugs such as haloperidole, flupentixole, and
fluphenazine by IM preparations of highly lipophilic prodrug derivatives such
as decanoate and other long-chain fatty acid esters formulated in oily vehicles.
This has offered a significant increase in patient compliance and, thus,
treatment of patients suffering from psychiatric disorders.
(ii) Macromolecular Prodrugs: Conjugation of small drug molecules to high

molecular weight promoieties such as polyethylene glycols (PEGs),
polysaccharides such as dextrans or other polymers may be used to obtain
prolonged drug action. Example- anticancer drugs such as paclitaxel.
(c) Design of produgs for drug targeting
Drug targeting by site-specific bioactivation was achieved using intelligent
prodrug design of the blockbuster drug omeprazole, which is widely used in the
treatment of gastric ulcers. Omeprazole specifically inhibits the enzyme gastric
H+-K+-ATPase that is responsible for the gastric acid production and is located
in the secretory membranes of parietal cells. Omeprazole itself does not inhibit
this enzyme but is biotransformed within the acid compartments of the parietal
cells into the active inhibitor cyclic sulfonamide, which reacts with cysteine
thiol groups of the enzyme thereby inactivating it.
16
Fig.1.9: Bioconversion and mechanism of action of Omeprazole
1.7 Summary
Brief overview and synopsis of points in drug discovery and development from
screening and target identification through to drug approval and the potential
for generics Armed with their understanding of the disease, scientists are ready
to begin looking for a drug. They search for a molecule, or “lead compound,”
that may act on their target to alter the disease course. If successful over long
odds and years of testing, the lead compound can ultimately become a new
medicine. Lead compounds that survive the initial screening are then
“optimized,” or altered to make them more effective and safer. By changing the
structure of a compound, scientists can give it different properties. For example,
they can make it less likely to interact with other chemical pathways in the
body, thus reducing the potential for side effects. For the purpose of this
summary, drug development is defined as those activities required for
advancing a biomedical concept to a medical product in commerce.
1. 10 Glossary
 Drug design is the approach of finding drugs by design, based on their
biological targets. Typically a drug target is a key molecule involved in a
particular metabolic or signalling pathway that is specific to a disease
condition or pathology, or to the infectivity or survival of a microbial
pathogen.
 Drug development or preclinical development is defined in many
pharmaceutical companies as the process of taking a new chemical lead
through the stages necessary to allow it to be tested in human clinical trials,
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although a broader definition would encompass the entire process of drug
discovery and clinical testing of novel drug candidates.
 Computer Assisted Drug Design (CADD) is a three-dimensional puzzle
where small drug molecules, ligands, are adjusted to the binding site of a
protein.
 The process of drug discovery involves the identification of candidates,
synthesis, characterization, screening, and assays for therapeutic efficacy.
 Ideal drug: Given by mouth and has a beneficial effect (safe & efficacious)
in only-50%
 Promising drug candidate: Most site specific with best combination of target
affinity, highest bioavailability and lowest toxicity.
 Membrane transport is mediated by specific integral membrane proteins –
ion channels, porins, transporters (passive), pumps (active)
 Drug delivery is the method or process of administering a pharmaceutical
compound to achieve a therapeutic effect in humans or animals.
1.11 Review questions / Comprehensive Questions
1. Define drug design. Jutify the following statements :Drug design aims at
developing a drug with high degree of chemotherapeutic index and specific
action.
2. Enumerate various steps of drug design. And development.
3. Discuss the various ‘factors governing drug-design’.
4. Eloborate the ‘rational approach to drug design’.
5. Describe Drug discovery without rational design.
6. ‘Tailoring of Drugs’ is the outcome of anunique blend of skill involving
various configurational and stereochemical changes attributing its flexibility
and overall dimension. Explain.
7. Discuss in detail Concept of lead compounds and lead modification.
8. Discuss the various possible approaches in designing newer drugs.
9. Discuss the basic concepts of ‘prodrugs’ with the help of suitable examples
of parent drug molecule(s).
10. Write various applications of Prodrug.
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1.12 References and Suggested readings
1. Povl Krogsgaard-Larsen, Kristian Stromgaard & Ulf Madsen; “Textbook of
Drug Design and Discovery” 4th edition 2010; CRC Press, Taylor & Francis
Group.
2. Richard B. Silverman & Mark W. Holladay; “The Organic Chemistry of
Drug Design and Drug Action” 3rd edition 2014; Academic Press, Elsevier.
3. Donald J. Abraham; “Burger’s Medicinal Chemistry and Drug Discovery”
6th Edition 1988; A John Wiley and Sons, Inc. Publication
4. H. Gerhard Vogel; “Drug Discovery and Evaluation: Pharmacological
Assays” 2nd edition 2002; Springer-Verlag Berlin Heidelberg, New York
5. Gareth Thomas; “Fundamentals of Medicinal Chemistry” edition 2003;
John Wiley & Sons Ltd, England
6. John H. Block John M. Beale Jr.; “Wilson & Gisvold's Textbook of Organic
Medicinal and Pharmaceutical Chemistry” 11th edition 2004; Lippincott
Williams & Wilkins
7. Graham L. Patrick; “An Introduction to Medicinal Chemistry” edition 1995;
Oxford University Press, Oxford
8. Ashutosh Kar; “Medicinal Chemistry” 4th and revised edition 2007; New
Age International (P) Ltd. Publishers.
9. Donald Cairns; “Essentials of Pharmaceutical Chemistry”, 3rd edition 2008;
Pharmaceutical Press, An imprint of RPS Publishing.
19
Unit-2
Structure Activity Relationship
Structure of Unit:
2.1 Objectives
2.2 Introduction: Structure Activity Relationship
2.3 Ferguson Principle
2.4 Factors affecting bioactivity: Resonance effect
2.6 Inductive effect
2.7 Stereochemistry
2.8 Isosterism
2.9 Bioisosterism
2.10 Summary
2.11 Glossary
2.1 Objectives
 Structure activity relationship
 Ferguson principle
 Factors affecting biological activity
 Resonance and inductive effect
 Stereochemistry and its type
 Concept of isosterism and bioisoterism
2.2 Introduction: Structure Activity Relationship
A Structure-Activity Relationship (SAR) is the relationship between
the chemical or 3D structure of a molecule and its biological activity. The aim
of SAR is to identify the physicochemical properties of a drug and to see
whether any of these properties has an effect on the drug’s biological activity. If
such a relationship holds true, an equation can be drawn up which identifies the
relationship and allows the medical chemist to say with confidence that the
property (or properties) has an important role in pharmacokinetics or
20
mechanism of action of drug. It also allows the medical chemist to some level
of prediction. By identifying physicochemical properties, it should be possible
to calculate in advance what the biological activity of novel analogue might be.
There are two advantages of this. First, it allows the medical chemist to target
efforts on analogues which should have improved activity and thus cut out the
number of analogue that has to be made. Second, it allows modification of the
effect or the potency of a bioactive compound (typically a drug) by changing
its chemical structure. Medicinal chemists use the techniques of chemical
synthesis to insert new chemical groups into the biomedical compound and test
the modifications for their biological effects.
In an effort to interpret the SAR of a drug, two main approaches have emerged
via (1) The group and moiety approach and (2) Integral approach.
The former places emphasis on significance of certain chemical groups in the
drug molecule as a whole and particularly concerned with overall physico-
chemical properties. Modulating the structure of drug implies introduction,
elimination or substitution of certain groups in the drug. This may lead to the
development of parallel drug with characteristics similar to the lead compound
like vitamin analogues and hormone analogues. Hence the activity is
maintained, although structure is changed. This can be expressed by an idea of
bio-isosteric groups which generally have similar biological activity. The
spectrum of action of the existing compound may be changed or side effects
can be changed to main effects. E j. Ariens mentioned the following physico-
chemicals parameters affecting drug-activity. The chemical properties of a drug
are determinant for its biological action and activity. The various physico-
chemical properties of bioactive compound in general, are parameters related to
the interaction of the drug with its environment.
2.3 Ferguson Principle
Pharmacologically active compounds can be divided into two major groups:
(a) Structurally specific and
(b) Structurally non specific.
The structurally specific drugs bring about their effects by combining with a
specific receptor. The SAR of such groups can only be varied with relatively
narrow limits.
The structurally non specific drugs do not act on specific receptor. Instead, they
penetrate into the cell or accumulate in cellular membranes, where they
interfere by chemical or physical means, with some of the fundamental cellular
21
processes e.g. general anaesthetics, hypnotics, volatile insecticide and certain
bacterial agents. The biological effect of such drugs is more closely correlated
with the physical properties of the molecule than with the chemical structure
e.g. cyclopropane, diethyl ether and chloroform, though having different
structures, good general anaesthetics.
Ferguson suggest in 1939, that the potency of structurally none specific drugs
was determined by their thermodynamic activity. His quantity is a measure of
the proportion of the molecules which are free to react with enzymes system,
nerve membranes and similar biologically important sites. The molecule which
are not free to act in this way, are reacting with one another, with molecule of
other solutes. It follows, therefore, that the thermodynamic activity of a drug in
solution is not determine entirely by its concentration. In the case of volatile
anaesthetics administer with air or oxygen, the thermodynamic activity is
proportional to the relative saturation of a drug.
Ferguson theory predicts that the anaesthetic agents will show the same degree
of biological activity if there concentrations are adjusted so that there
thermodynamic activities are equal. This theory is also applicable to substances
other than anaesthetics and it was originally applied to insecticides and
antibacterial substances.
The physico-chemical parameters can be divided into three categories.
1) Parameters which are an expression of the hydrophobic aggregation
forces at site of action :
These include partition coefficient, surface activity, Rf value and the
partial vapour pressure of the solution. Hydrophobic groups and
hydrophobic aggregation forces represented by these parameters give
relatively large contribution to binding energy. They allow, by variation
in size of groups, a gradual change in lipid water balance which rules
distribution by passive transport.
2) Parameters which are an expression of the charge distribution in
the molecule and thus of electrostatic force at site of action:
These include the redox potential, the base or acid dissociation
constants, the electronic polarization, dipole moments, the inductive
field effect and the resonance effect, especially in conjugated systems,
the capacity of chelate formation, and H-bond formation and finally the
characteristics in IR and NMR spectra. Electrostatic forces represented
by theses parameters give a relatively low contribution to binding
energy. They contribute more to the selectivity in drug-receptor
22
interaction and are essentially involved in substrate activation in
enzymes and conformational skeletal important for induction of a
stimulus in the macromolecular receptor molecules.
3) Parameters which are an expression of spatial arrangement of the
molecule:
These parameters represent spatial arrangement of various groups in the
molecule and play a role in the possible steric hindrance on the
intramolecular level. The location, size, volume and charge of particular
group play a role here.
The intensity of pharmacological response elicited by many drugs is probably
directly related to the concentration or activity of a drug in the immediate
vicinity of the receptor site in the body. Since it is not possible to measure this
concentration directly, the study of physico-chemical parameters presents a
picture of indirect measurement of concentration of a drug at receptor site. It
follows, therefore, that drug molecules exert their effect by influencing receptor
sites in living systems through their physico-chemical properties.
2.4 Factors affecting bioactivity: Resonance Effect
Factor affecting bioactivity:
Various aspect of bioactivity applies to any chemical or synthetic origin. The
aspect will be dealt as follows:
 Physicochemical properties: These are related to the transport of bioactive
compound to its site of action, usually a receptor or other biomolecule at
the cellular level. Under experimental conditions, either in vivo or clinical,
or real life conditions, the extent to which a drug passes through semi-
permeable membranes before reaching its site of action depends on its
solubility. After the bioactive molecular entity has been identiﬁed, detailed
data on solubility, partition coeficients and the electrolytic behaviour can
be determined.
 Chemical parameters: The structural features of a compound can be related
to its pharmacological properties, either qualitatively or quantitatively. The
principles, concepts and numerical rules governing qualitative and
quantitative relationships between structure and activity help explain the
pharmacological activity of a new compound. It is important to evaluate the
structure of a newly isolated plant compound. The basic aspect of
molecular structures involved in bioactivity include: Resonance and
Inductive effect.
23
 Resonance is a phenomena that a molecule can be represented by two or
more structures that differ only in their electron but not atomic
arrangement. The electron density and electron distribution patterns explain
the molecules activity.
 Inductive effect is a electro static phenomena caused by actual electron
shifter displacements along chemical bonds. Both negative and positive
inductive effects can lead to change bioactivity.
 Types of bonding: The phenomenon of biological activity is concerned
with covalent and non-covalent interactions. Covalent bonds are formed
enzymatically and are common to all biomolecules. Hydrogen bonds, ionic
forces, hydrophobic bonding, charge-transfer interactions, all representing
non-covalent interactions are also common to functional life processes.
 Spatial arrangement of the molecule : In terms of activity, it is important to
have a good steric and electronic complementary between ligand and target
bio molecule. Bioactive compounds interact with enzymes by fitting
sterically into a binding pocket the space sterically provided by these
targets.
 Thus the molecular dimensions, inter atomic distances, arrangements of
electrons and the stereochemical properties of both ligand and target are
decisive in determining biological activity
Resonance Effect
It has been observed that ‘resonance’ give rise to an altogether different
distribution of electron density than would be the situation if there existed
absolutely no resonance.
Example: The resonance effects, as observed in two electron donating
functional moieties, such as: - (a) NH2 (amino); and (b) –OH (hydroxyl),
attached to an aromatic nucleus.
(a) Resonance structure of aniline
24
(b) Resonance structure of phenol
Explanation
For Resonance Structures of Aniline (a): In case, the first structure is the
actual structure of aniline, the two unshared electrons of the N- atom would
certainly reside exclusively on that particular atom. However, in true sense and
real perspective the first structure is not the ideal and only structure for aniline
but a hybrid one which essentially includes contribution from several canonical
forms as shown, wherein the density of electrons of the unshared pair does not
reside necessarily on the N-atom but get spread out around the phenyl ring. In
nut shell, this observed density of electrons at one particular position (with a
corresponding enhancement elsewhere) is invariably known as the ‘resonance’
or ‘mesomeric effect’.
For Resonance Structure of Phenol (b): Here, the influence of R at the para
position, and the electron-donating effect due to resonance is more marked,
pronounced and significant as compared to the electron withdrawing influence
due to induction.
Inductive Effect
The electronic effect of various substituents will clearly have an effect on a
drug’s ionization or polarity. This in turn may have an effect on how a drug can
pass through cell membranes or how strongly it can interact with a binding site.
It is therefore necessary to measure inductive effect of a substituent. Hammett
substitution constant (σ) measures the electron withdrawing or electron
donating ability of a substituent, and with reference to a specific substituent is
usually defined by following equation:
σX = log KX = log KX/KH – log KH
Hammett substitution constant may be determined conveniently by actual
measurement of the dissociation of a series of substituted benzoic acids
compared to the dissociation of benzoic acid itself. Benzoic acid is a weak acid
and only partially ionizes in water. An equilibrium is setup between the ionized
25
and non-ionized forms, where the relative proportions of these species are
known as equilibrium or dissociation constant KH (the subscript H signifies that
there are no substituents on the aromatic ring).
KH = [PhCO-2]
[PhCO2H]
When a substituent is present on the aromatic ring, this equilibrium is affected.

Electron-withdrawing group, such as NO2, CN, COOH, CONH2, CONHR,
CONR2, CHO, COR SO2R, SO2OR, NO; results in aromatic ring having a
strong electron withdrawing and stabilizing influence on the carboxylate anion.
The equilibrium will therefore shift more to the ionized form such that the
substituted benzoic acid is a stronger acid and has a larger KX value.
If the substitution X is an electron-donating group, such as R, Ar, F, Cl, I, Br,
SH, O-, S-, NR2, NHR, NHCOR, OR, OH, OCOR; then the aromatic ring is less
able to stabilize the carboxylate ion. The equilibrium shifts to the left and a
weaker acid is obtained with a smaller KX value.
Benzoic acids containing electron-withdrawing substituents will have larger KX

values than benzoic acid itself (KH) and therefore the value of σX for an
electron-withdrawing substituents will be positive.
Benzoic acids containing electron-donating substituents will have smaller KX
values than benzoic acid itself (KH) and therefore the value of σX for an
electron-donating substituents will be negative.
2.6 Stereochemistry
Stereoisomers are compounds containing the same number and kind of atoms,
the same arrangement of bonds, but different three-dimensional structures; in
other words, they only differ in the three-dimensional arrangements of atoms in
26
space. Stereo isomers are subdivided into two types, enantiomers and
diastereoisomers.
Enantiomers
Enantiomers are the compounds whose 3-D arrangement of atoms is such that
they are nonsuperimposible mirror images. These are also termed as chiral
compounds, enantiomers or antipode. These compounds posses identical
physical as well as chemical properties except their ability to rotate plane
polarized light in just opposite directions with almost equal magnitude,
quantum and extent. Predominantly, when enantiomeric features are introduced
strategically right into either a chiral environment or an asymmetric one, for
instance: the human body, enantiomers shell evidently show marked and
pronounced variant physical chemical properties thereby exhibiting appreciable
and significant differences in their respective pharmacokinetic and
pharmacodynamic behaviour.
Thus, the presence of variant biological activities based on their diverse
enantiomeric features in a drug substance may lead to:
 adverse side effects,
 toxicity caused due to one of the isomer,
 exhibit appreciable difference in absorbtion,
 show significant variation in serum protein binding,
 extent /degree of metabolism,
 conversion into a toxic substance (impaired metabolism),
 influence the metabolism of an altogether another drug.
For example naproxen sodium shows that the priority sequence in (S)-(+)
naproxen sodium is to the left; and it exhibit activity as an antipyretic, analgesic
and anti-inflammatory drug. In contrast, the (R)-(-) naproxen sodium is an
inactive.
27
Diastereoisomers
Distereoisomers are all stereoisomeric compound which are not enantiomers.
Thus, the term “diastereoisomer” includes compound containing both ring
systems and double bonds simultaneously. Unlike enantiomers,
diastereoisomers exhibit different physico-chemical properties, including
melting point, boiling point, solubility and chromatographic behavior. These
differences in physico-chemical properties allow the separation of
diastereoisomers from mixtures utilizing standard chemical separation
techniques such as column chromatography or crystallization. These isomers
have different physico-chemical properties; thus, differences in biological
activity.
Compound containing more than one chiral centre probably are the most
common type of diastereoisomers used as drugs e.g. ephedrine and
pesudoephrdrine. In (-) pseudoephrdine the two H-atoms are on the opposite
side of the plane of the ring. However, in (-) ephedrine the said to two H-atoms
are located on the same side i.e., beneath the ring plane; and hence, it shows
biological activities (CNS-stimulatory actions).
Diastereoisomers also can be found in cyclic compounds. For example, the

cyclic alkane 1,2-dimethylcyclohexane can exist as cis/trans- diastereoisomer,
and trans isomer also can exist as an enantiomeric pair. Each of trans-
enantiomorphs are depicited in the two possible chair conformation for the
cyclohexane ring. Cyclohexane ring can exhibit significant conformational
freedom that allows for the possibility of conformational isomers.
28
Conformational Isomers
It is a dynamic process i.e, isomerization take place by rotation about one or
more single bonds. Such bond rotation results in nonidentical spatial
arrangement of atoms in molecule. This results in different conformation,
whereas conversion of one enantiomer into another requires breaking of bonds,
which has a higher energy requirement than rotation about single bond. For
example, acetylcholine, each single bond within acetylcholine molecule is
capable of undergoing rotation, and at room temperature, such rotation readily
occur.
29
2.7 Isosterism
When a lead compound is first discovered for a particular disease state, it often
lacks the required potency and pharmacokinetic suitable for making it a viable
clinical candidate. The medical chemist therefore must modify the compound
reduce the undesirable features without losing the desired biological activity.
Replacement or modification of functional group with other groups having
similar properties is known as ‘isosteric’ or ‘biosteric replacement’.
Langmuir suggested that any two ions or molecules possessing essentially an
identical number and arrangement of electrons must exhibit similar
characteristics; e.g. CO and N; CO2 and NO2; and N-3 and NCO- . Such isosteres
which are isoelectric in nature must show good similarity in properties. To
account for similarities between groups with the same number of valance
electron but different numbers of atoms, Grimm developed his hydride
displacement law which shows similar physical properties among closely
related functional groups. Instead of considering only partial structures,
Hinsberg applied the concept of isosterism to entire molecule and developed the
concept of “ring equivalents” –that is, groups that can be exchanged for one
another in a aromatic ring systems without drastic changes in physiochemical
properties relative to the parent structure. Benzene and thiopene and pyridene
illustrate this concept. A –CH=CH-group in benzene is replaced by divalent
sulphur, -S, in thiophene, and a –CH= is replaced by trivalent –N= to give
pyridine. The physical properties of benzene and thiopene are very similar than
that of pyridine. For e.g., boiling point of benzene is 81.1oC, thiophene is
84.4oC while that of pyridine is 116oC. Hinsberg therefore concluded that
divalent ether -S must resemble –C=C in shape, these groups were considerd to
be isosteric.
2.8 Bioisosterism
Bioisosteres are compounds or groups that essentially posses equal or near
equal molecular shapes and volumes, approximately the same distribution of
electrons and that exhibit similar physical characteristics such as
hydrophobicity. Bioisostereic compounds affect the same biochemically
associated systems as agonists and antagonists and thereby produce biological
properties that are related to each other. It may be classified under two
categories –classical and non-classical bioiosteres.
30
I. Classical bioisosteres
a) Monovalent atoms and groups
F, H, OH, NH, F, OH, NH OR CH3 for SH, OH, Cl, Br, CF3
b) Divalent atoms and groups

-C=S, -C=O, -C=NH, -C=C-
c) Trivalent atoms and groups

-C=, -N=, -P=, -As=
d) Tetrasubstituted atoms
e) Ring equivalents
II. Non-classical bioisosteres

a) Exchangeable groups
b) Ring versus noncyclic structure
I. Classical bioisosteres
Functional groups that satisfy the original conditions of Langmuir and Grimm
are referred to as classical bioisosteres. Substitution of hydrogen by fluorine is
one of the most common
Monovalent isosteric replacement. A classical example of hydrogen
replacement nby fluorine is development of antineoplastic agent 5-fluorouracil
from uracil.
31
II. Non-classical bioisosteres
Non-classical bioisosteres do not obey electronic and steric definitions of
classical bioisosteres and donot necessarily have the same number of atoms as
the substituent they have the same of atoms as the substituent they replace. For
example, non classical replacement of a sulphonamide group for a phenol in
catecholamines. In this, steric factor appears to have less influence on receptor
binding than acidity and hydrogen bonding potential of functional group on
aromatic ring. Both groups are weakly acidic and capable of losing a proton and
interacting with the receptor as anions or hydrogen bond donars at receptor.
Another example is the use of double bond to position essential functional

groups in spatial configuration critical for activity this is shown with the
naturally occurring hormone estradiol and the synthetic analogue
diethylstilbestrol. The trans isomer of diethylstilbestrol has the same potency as
estrsdiol, where cis isomer is only one-fourteenth as active. In trans
32
configuration, the phenolic hydroxyl group group mimic the correct orientation
of the phenol and alcohol in estradiol. This is not possible with the cis isomer,
and more flexible analogues have little or no activity.
2.9 Spatial arrangement

1. Planarity
It has been known that a series of closely related compounds differing in
relative planarity are adsorbed on non biological medial to different extents. For
example, in the case of three geometrical isomers of 1,4-diphenylbutadiene, the
order of elution from an aluminium oxide column was the Z, Z isomer followed
by the E, Z isomer and finally E, E isomer. In other words, the greatest
absorbtion occurred with the most planar compound. Thus it was reasoned that
differences in planarity may account for differences in bioactivities in closely
related compounds.
33
In some cases coplanarity of important functional groups is associated with
marked bioactivities, e.g., certain antihistaminic compounds, and in the case of
Bipyridine herbicides. On the other hand, examples may be found where a lack
of coplanarity of important groups is necessary for significant biological
activity, e.g., cinnamic acids are useful as plant growth hormones and clonidine
and related compounds.
For example in certain antihismatic drugs in isomer (A) the 2-pyridyl function
is coplanar with the olefinic double bond, whereas in isomer (B) there is no
planarity of these two groups. The isomer (A) is far more active as an
antihistaminic and this principle of coplanarity of the olefinic double bond and
the heterocycle is found through this series of compounds.
(2) Cinnamic acids:

They are useful as plant growth hormones and in the series of compounds, the
aryl ring and the COOH group must not be coplanar. For example, E-cinnamic
acid which is a planar moleculeis inactive.
34
E- Planner molecule Z- Non planner molecule
(inactive) (active)
Delocalized chemical bonding involves resonance for which conjugation is
must. The resonance depends upon the substituent’s at aromatic system.
Hyperconjugation increases the stability of intermediates i.e. Carbocation and
free radicals. Tautomers are isomers of a compound which differ only in the
position of the protons. Keto form is more stable than enol form. Tautomerism
mechanism observed in acid as well as in basic medium. Due to difference in
electronegativities between two atoms forming an σ- bond gives Inductive
effect.
2.10 Summary
Medicinal chemistry involves the discovery of new chemical entites for the
treatment of disease and the systematic study of SARs of these compounds.
Such studies provide the basis for development of better medicinal agents from
lead compounds found via random screening, and rational design. The role of
medicinal chemist is to increase the potency and duration of action of newly
discovered compounds and to decrease adverse side effects. Without a thorough
understanding of physico-chemical properties of organic functional groups that
compromises any given structure. For a pharmacist, it is also important to
understanding physico-chemical properties of medicinal agents that is to be
dispensed. Such knowledge will help the practicing pharmacist not only to
better understand the clinical properties of these compounds and also of that
which are appearing in market.
2.11 Glossary
 A Structure-Activity Relationship (SAR) is the relationship between
the chemical or 3D structure of a molecule and its biological activity.
 The SAR of a drug has two main approaches via (1) The group and
moiety approach and (2) Integral approach.
35
 Pharmacologically active compounds can be divided into two major
groups:
(a) Structurally specific and, (b) Structurally non specific.
 The structurally specific drugs bring about their effects by combining
with a specific receptor while structurally non specific drugs do not act
on specific receptor. Instead, they penetrate into the cell or accumulate
in cellular membranes, where they interfere by chemical or physical
means, with some of the fundamental cellular processes
 Resonance gives rise to an altogether different distribution of electron
density.
 The electronic effect of various substituents has an effect on a drug’s
ionization or polarity.
 Hammett substitution constant (σ) measures the electron withdrawing or
electron donating ability of a substituent, and with reference to a specific
substituent alkyl groups give +I effect while other electronegative
groups give –I effect. The Hammett constant take into account both
resonance and inductive effects.
 Stereoisomers are compounds containing the same number and kind of
atoms, the same arrangement of bonds, but different three-dimensional
structures.
 Enantiomers are the compounds whose 3-D arrangement of atoms is
such that they are nonsuperimposible mirror images. These are also
termed as chiral compounds, enantiomers or antipode.
 Distereoisomers are all stereoisomeric compound which are not
enantiomers. Thus, the term “diastereoisomer” includes compound
containing both ring systems and double bonds simultaneously. Unlike
enantiomers, diastereoisomers exhibit different physico-chemical
properties, including melting point, boiling point, solubility and
chromatographic behavior.
 Replacement or modification of functional group with other groups
having similar properties is known as isosteric or biosteric replacement.
 Bioisosteres are compounds or groups that essentially posses equal or
near equal molecular shapes and volumes, approximately the same
distribution of electrons and that exhibit similar physical characteristics
36
 It may be classified under two categories –classical and non-classical
bioiosteres.
 Functional groups that satisfy the original conditions of Langmuir and
Grimm are referred to as classical bioisosteres.
 Non-classical bioisosteres do not obey electronic and steric definitions
of classical bioisosteres and donot necessarily have the same number of
atoms as the substituent they have the same of atoms as the substituent
they replace.
 a series of closely related compounds differing in relative planarity are
adsorbed on non biological medial to different extents.
1. Define structure activity relationship.
2. Explain the Ferguson principle.
3. What is cross conjugation? Explain with example.
4. What is resonance? How it effect the biological activity?
5. Explain the inductive effect.
6. Explain the types of stereoisomers with examples.
7. How spatial arrangement of compounds effects biological activity of
compounds?
8. Give a comprehensive account of importance of ‘Isosterism and
Bioisosterism’ in drug design.
 Foyes Principle of Medicinal Chemistry (6th ed.)- Thomas L Lemke and DA

Williams (Lipincott Williams & Wilkins).
 An Introduction to Medicinal Chemistry- Graham L. Patrick (Oxford
University Press) 2006.
 Medicinal Chemistry (5th ed.)- Ashutosh Kar (New Age International
Publisher) 2007.
 Principle of Medicinal Chemistry (18th ed.)- SS Kadam, KR Mahadik and
KG Bothra (Nirali Prakashan) 2007.
 An Introduction to Drug Design- S.N. Pnadey and J.R. Dimmock (New
Age International Publisher) 2011.
37
Unit-3
Theories of Drug Activity
Structure of Unit:
3.1 Objectives
3.2 Introduction: Theories of Drug Activity
3.3 Drug–Receptor Complex
3.4 Theories for Drug–Receptor Interactions
3.5 Occupancy Theory
3.6 Rate Theory
3.7 Induced-Fit Theory
3.8 Other Theories & models of Drug–Receptor Interactions
3.9 Summary
3.10 Glossary
3.1 Objectives
 Drug-Receptor Theory
 The Operational Model of Receptor Function
 Important Interactions (Forces) Involved in the Drug–Receptor Complex
 Determination of Drug–Receptor Interactions
 The Use of Mathematical Models in Pharmacology
 Pharmacodynamics of general receptors
3.2 Introduction: Theories of Drug Activity
Principles of drug action
Drugs (except those gene based) do not impart new functions to any system,
organ or cell; they only alter the pace of ongoing activity. The basic types of
drug action can be broadly classed as:
38
1. Stimulation refers to selective enhancement of the level of activity of
specialized cells, e.g. adrenaline stimulates heart, pilocarpine stimulates
salivary glands.
2. Depression means selective diminution of activity of specialized cells,
e.g. barbiturates depress CNS, quinidine depresses heart.
3. Irritation connotes a nonselective, often noxious effect and is
particularly applied to less specialized cells (epithelium, connective
tissue).
4. Replacement refers to the use of natural metabolites, hormones or their
congeners in deficiency states, e.g. levodopa in parkinsonism, insulin in
diabetes mellitus, iron in anaemia.
5. Cytotoxic action for invading parasites or cancer cells, attenuating them
without significantly affecting the host cells is utilized for
cure/palliation of infections and neoplasms, e.g. penicillin, chloroquine,
zidovudine, cyclophosphamide, etc.
Majority of drugs produce their action by interacting with a discrete target
biomolecule, which usually is a protein. Such mechanism confers selectivity of
action to the drug. Functional proteins that are targets of drug action can be
grouped into four major categories, viz. enzymes, ion channels, transporters and
receptors.
The largest number of drugs does not bind directly to the effectors, viz.
enzymes, channels, transporters, structural proteins, template biomolecules, etc.
but act through specific regulatory macromolecules which control the above
listed effectors. These regulatory macromolecules or the sites on them which
bind and interact with the drug are called 'receptors'.
Receptor is defined as a macromolecule or binding site located on the surface or
inside the effector cell that serves to recognize the signal molecule/ drug and
initiate the response to it, but itself has no other function. Though, in a broad
sense all types of target biomolecules, including the effectors (enzymes,
channels, transporters, etc.) with which a drug can bind to produce its action
have been denoted as 'receptors' by some authors, such designation tends to
steal the specific meaning of this important term.
Receptors have been divided into four major superfamilies: GPCRs, ligand-
gated ion channels, tyrosine kinase receptors, and nuclear receptors. The first
three receptor superfamilies are located in the cell membrane and the latter
39
family is located intracellularly. GPCRs are the largest class of receptors
known; about 800 different human genes (∼4% of the human genome) are
predicted to be members of the GPCR family.
Pharmacological stimulation or inhibition of the earlier mentioned synaptic
mechanisms are, however, likely to affect the function of the entire
neurotransmitter system. Activation of neurotransmitter receptors may, in
principle, represent the most direct and selective approach to the stimulation of
a particular neurotransmitter system.
Fig. 3.1: Generalized schematic illustration of processes and mechanisms

associated with an axosomatic synapse in the CNS. E, enzymes; EM, metabolic;
EB, biosynthetic; ED, degradation; ESM, second messenger; (.) neurotransmitter.
3.3 Drug–Receptor Complex

To appreciate the mechanisms of drug action, it is important to understand the
forces of interaction that bind drugs to their receptors. Because of the low
concentration of drugs and receptors in the bloodstream and other biological
fluids, the law of mass action alone cannot account for the ability of small doses
of structurally specific drugs to elicit a total response by combination with all,
or practically all, of the appropriate receptors. The enlightening calculation
shown below supports the notion that something more than mass action is
required to get the desired drug–receptor interaction.
One mole of a drug contains 6.02 × 1023 molecules (Avogadro’s number). If the
molecular weight of an average drug is 300 g/mol, then 15 mg (an effective
dose for many drugs) will contain 6.02 × 1023(15 × 10−3)/300 = 3 × 1019
40
molecules of drug. The human organism is composed of about 3 × 1013 cells.
Therefore, each cell will be acted upon by 3 × 1019/3 × 1013 = 106 drug
molecules. One erythrocyte cell contains about 1010 molecules. On the
assumption that the same number of molecules is found uniformly in all cells,
then for each drug molecule, there are 1010/106 = 104 molecules of the human
body! With this ratio of human molecules to drug molecules, Le Chatelier
would have a difficult time explaining how the drug could interact and form a
stable complex with the desired receptor.
The driving force for the drug–receptor interaction can be considered as a low
energy state of the drug–receptor complex (Scheme given below), where kon is
the rate constant for formation of the drug–receptor complex, which depends on
the concentrations of the drug and the receptor, and koff is the rate constant for
breakdown of the complex, which depends on the concentration of the drug–
receptor complex as well as other forces. The biological activity of a drug is
related to its affinity for the receptor, i.e., the stability of the drug–receptor
complex. This stability is commonly measured by how difficult it is for the
complex to dissociate, which is represented by its Kd, the dissociation constant
for the drug–receptor complex at equilibrium.
Because Kd is a dissociation constant, the smaller the Kd, the larger the
concentration of the drug–receptor complex, the more stable is that complex,
and the greater is the affinity of the drug for the receptor. Kd roughly represents
the concentration of the drug required to reach an equilibrium of 50% in the
drug–receptor complex.
Formation of the drug–receptor complex involves an elaborate equilibrium.

Solvated ligands (such as drugs) and solvated proteins (such as receptors)
generally exist as an equilibrium mixture of several conformers each. To form a
complex, solvent molecules that occupy the binding site of the receptor must be
displaced by the drug to produce a solvated complex; interactions between the
drug and the receptor are stronger than the interactions between the drug and
receptor with the solvent molecules. Drug–receptor complex formation is also
entropically unfavorable; it causes a loss in conformational degrees of freedom
for both the protein and the ligand, as well as the loss of three rotational and
three translational degrees of freedom. Therefore, highly favorable enthalpic
41
contacts (interactions) between the receptor and the drug must compensate for
the entropic loss.
Important Interactions (Forces) Involved in the Drug–Receptor Complex
Interactions involved in the drug–receptor complex are the same forces
experienced by all interacting organic molecules and include covalent bonding,
ionic (electrostatic) interactions, ion–dipole and dipole–dipole interactions,
hydrogen bonding, charge-transfer interactions, hydrophobic interactions,
cation–π interactions, halogen bonding, and van-der-waals interactions.
The spontaneous formation of a bond between atoms occurs with a decrease in
free energy, that is, a noncovalent bond will occur only when there is a negative
ΔG, which is the sum of an enthalpic term (ΔH) and an entropic term (−TΔS).
The change in free energy (binding energy) is related to the binding equilibrium
constant (Keq) according to Equation. Therefore, at physiological temperature
(37°C), changes in free energy of a few kilocalories per mole can have a major
effect on the establishment of good secondary interactions. In fact, if the Keq
were only 0.01 (i.e., 1% of the equilibrium mixture in the form of the drug–
receptor complex), then a ΔG0 of interaction of −5.45 kcal/mol would shift the
binding equilibrium constant to 100 (i.e., 99% in the form of the drug–receptor
complex).
The bonds formed between a drug and receptors are following:

1. The covalent bond is the strongest bond, generally worth anywhere from
−40 to −110 kcal/mol in stability. It is seldom formed by a drug–
receptor interaction, except with enzymes and DNA.
2. Drug and receptor groups will be mutually attracted provided they have
opposite charges. This ionic interaction can be effective at distances
farther than those required for other types of interactions, and they can
persist longer. A simple ionic interaction can provide a ΔG0 = −5
kcal/mol, which declines by the square of the distance between the
charges.
3. As a result of the greater electronegativity of atoms, asymmetric
distribution of electrons produces electronic dipoles. These dipoles in a
drug molecule can be attracted by ions (ion–dipole interaction) or by
42
other dipoles (dipole–dipole interaction) in the receptor, provided
charges of opposite sign are properly aligned.
4. Hydrogen bonds are a type of dipole–dipole interaction formed between
the proton of a group X–H, where X is an electronegative atom, and one
or more other electronegative atoms (Y) containing a pair of nonbonded
electrons.
5. When a molecule (or group) that is a good electron donor comes into
contact with a molecule (or group) that is a good electron acceptor, the
donor may transfer some of its charge to the acceptor. This forms a
charge-transfer complex, which, in effect, is a molecular dipole–dipole
interaction.
6. When two nonpolar groups, such as a lipophilic group on a drug and a
nonpolar receptor group, each surrounded by ordered water molecules,
approach each other, these water molecules become disordered in an
attempt to associate with each other. This increase in entropy, therefore,
results in a decrease in the free energy (ΔG = ΔH − TΔS), which
stabilizes the drug– receptor complex. This stabilization is known as a
hydrophobic interaction.
7. In proteins, the most common aromatic group involved in a cation–π
interaction is tryptophan (although phenylalanine, tyrosine, and
histidine also participate), and the most common cation is arginine
(although lysine is also important).
8. A covalently bonded halogen atom can act as an electron acceptor
(Lewis acid) to undergo halogen bonding with an electron-rich donor
atom, such as O, N, or S. The strength of these interactions is in the
order H ≈ I > Br > Cl >> F.
9. As atoms from different molecules (such as a drug and a receptor)
approach each other, the temporary dipoles of one molecule induce
opposite dipoles in the approaching molecule, intermolecular attractions,
known as van der Waals forces.
43
Fig. 3.2: Examples of forces involved in the Drug–Receptor Complex (Wavy
line represents the receptor cavity)
3.4 Theories for Drug–Receptor Interactions
Before learning drug-receptor interactions, we should aware about following
terms are used in describing drug-receptor interaction:
 Agonist: An agent which activates a receptor to produce an effect similar to
that of the physiological signal molecule.
 Inverse agonist: An agent which activates a receptor to produce an effect in
the opposite direction to that of the agonist.
44
 Antagonist: An agent which prevents the action of an agonist on a receptor
or the subsequent response, but does not have any effect of its own.
 Partial agonist: An agent which activates a receptor to produce submaximal
effect but antagonizes the action of a full agonist.
 Ligand: (Latin: ligare-to bind) Any molecule which attaches selectively to
particular receptors or sites. The term only indicates affinity or binding
without regard to functional change: agonists and competitive antagonists
are both ligands of the same receptor.
 There are two general categories of compounds that interact with receptors:
compounds that occur naturally within the body, such as hormones,
neurotransmitters, and other agents that modify cellular activity autocoids
and xenobiotics, compounds that are foreign to the body.
Over the years a number of hypotheses have been proposed to account for the
ability of a drug to interact with a receptor and elicit a biological response.
Several of the more important proposals are listed below.
 Occupancy Theory
 Rate Theory
 Induced-Fit Theory
 Macromolecular Perturbation Theory
 Activation - Aggregation Theory
 The Two-State (Multistate) Model of Receptor Activation
 The operational model of receptor function
 Classical model of receptor function
 The extended ternary complex model
 The ternary complex model
 Constitutive receptor activity
 Multistate receptor models and probabilistic theory
 Inactivation Theory
3.5 Occupancy Theory
After studying quantitative aspects of drug action, Clark (1937) propounded a
theory of drug action based on occupation of receptors by specific drugs and
that the pace of a cellular function can be altered by interaction of these
45
receptors with drugs which, in fact, are small molecular ligands. He perceived
the interaction between the two molecular species, viz. drug (D) and receptor
(R) to be governed by the law of mass action, and the effect (E) to be a direct
function of the drug-receptor complex (DR) formed:
K1
D+R DR E
K2
Subsequently, it has been realized that occupation of the receptor is essential

but not itself sufficient to elicit a response; the agonist must also be able to
activate (induce a conformational change in) the receptor. The ability to bind
with the receptor designated as affinity, and the capacity to induce a functional
change in the receptor designated as intrinsic activity (IA) or efficacy are
independent properties. Competitive antagonists occupy the receptor but do not
activate it. Moreover, certain drugs are partial agonists which occupy and sub-
maximally activate the receptor. An all or none action is not a must at the
receptor. A theoretical quantity(S) denoting strength of stimulus imparted to the
cell was interposed in the Clark's equation:
K1 S E
D+R DR
K2
Depending on the agonist, DR could generate a stronger or weaker S, probably

as a function of the conformational change brought about by the agonist in the
receptor. Accordingly:
Agonists have both affinity and maximal intrinsic activity (IA = 1), e.g.
adrenaline, histamine, morphine. Competitive antagonists have affinity but no
intrinsic activity (IA = 0), e.g. propranolol, atropine, chlorpheniramine,
naloxone. Partial agonists have affinity and submaximal intrinsic activity (IA
between 0 and 1), e.g. dichloroisoproterenol (on β adrenergic receptor). Inverse
agonists have affinity but intrinsic activity with a minus sign (IA between 0 and
-1), e.g. DMCM (on benzodiazepine receptor). It has also been demonstrated
that many full agonists can produce maximal response even while occupying
<1% of the available receptors. A large receptor reserve exists in their case, or a
number of spare receptors are present.
The modified occupancy theory accounts for the existence of partial agonists
and antagonists, but it does not account for why two drugs that can occupy the
46
same receptor can act differently, i.e., one as an agonist, the other as an
antagonist.
Example of affinity and efficacy are given in following figure. Figure-A shows
the theoretical dose–response curves for five drugs with the same affinity for
the receptor (pKD = 8), but having efficacies varying from 100% of the
maximum to 20% of the maximum. The drug with 100% efficacy is a full
agonist; the others are partial agonists. Figure-B shows dose–response curves
for four drugs with the same efficacy (all full agonists), but having different
affinities varying from a pKD of 9 to 6.
Fig. 3.3: Theoretical dose–response curves illustrate (A) drugs with equal
affinities and different efficacies (the top compound is a full agonist, and the
others are partial agonists) and (B) drugs with equal efficacies (all full agonists)
but different affinities
3. 6 Rate Theory
As an alternative to the occupancy theory, Paton proposed that the activation of
receptors is proportional to the total number of encounters of the drug with its
receptor per unit time. Therefore, the rate theory suggests that the
pharmacological activity is a function of the rate of association and dissociation
of the drug with the receptor and not the number of occupied receptors. Each
47
association would produce a quantum of stimulus. In the case of agonists, the
rates of both association and dissociation would be fast (the latter faster than the
former). The rate of association of an antagonist with a receptor would be fast,
but the dissociation would be slow. Partial agonists would have intermediate
drug–receptor complex dissociation rates. At equilibrium, the occupancy and
rate theories are mathematically equivalent. As in the case of the occupancy
theory, the rate theory does not rationalize why the different types of
compounds exhibit the characteristics that they do.
3. 7 Induced-Fit Theory
The induced-fit theory of Koshland was originally proposed for the action of
substrates with enzymes, but it could apply to drug–receptor interactions as
well. According to this theory, the receptor need not necessarily exist in the
appropriate conformation required to bind the drug. As the drug approaches the
receptor, a conformational change is induced, which orients the essential
binding sites (Figure below). The conformational change in the receptor could
be responsible for the initiation of the biological response (movement of
residues to interact with the substrate). The receptor (enzyme) was suggested to
be elastic, and could return to its original conformation after the drug (product)
was released. The conformational change need not occur only in the receptor
(enzyme); the drug (substrate) also could undergo deformation, even if this
resulted in strain in the drug (substrate). According to this theory, an agonist
would induce a conformational change and elicit a response, an antagonist
would bind without a conformational change, and a partial agonist would cause
a partial conformational change. The induced fit theory can be adapted to the
rate theory. An agonist would induce a conformational change in the receptor,
resulting in a conformation to which the agonist binds less tightly and from
which it can dissociate more easily. If drug–receptor complexation does not
cause a conformational change in the receptor, then the drug–receptor complex
will be stable, and an antagonist will result. Other theories evolved from the
induced-fit theory, such as the macromolecular perturbation theory, the
activation– aggregation theory, and multistate models.
48
Fig. 3.4: Schematic of the induced-fit theory
(Koshland et. al.)
3. 8 Other theories & models of drug–receptor interactions

Macromolecular Perturbation Theory
Having considered the conformational flexibility of receptors, Belleau
suggested that in the interaction of a drug with a receptor two general types of
macromolecular perturbations could result: a specific conformational
perturbation makes possible the binding of certain molecules that produce a
biological response (an agonist) and a nonspecific conformational perturbation
accommodates other types of molecules that do not elicit a response (e.g., an
antagonist). If the drug contributes to both macromolecular perturbations, a
mixture of two complexes will result (a partial agonist). This theory offers a
physicochemical basis for the rationalization of molecular phenomena that
involve receptors, but does not address the concept of inverse agonism.
Activation - Aggregation Theory
An extension of the macromolecular perturbation theory (which also is based
on the induced-fit theory) is the activation–aggregation theory of Monad,
Wyman, and Changeux and Karlin. According to this theory, even in the
49
absence of drugs, a receptor is in a state of dynamic equilibrium between an
activated form (Ro), which is responsible for the biological response, and an
inactive form (To). Using this theory, agonists bind to the Ro form and shift the
equilibrium to the activated form, antagonists bind to the inactive form (To),
and partial agonists bind to both conformations.
The Two-State (Multistate) Model of Receptor Activation
The revised two-state model of receptor activation proposes that, in the absence
of the natural ligand or agonist, receptors exist in equilibrium (defined by
equilibrium constant L) between an active state (R*), which is able to initiate a
biological response, and a resting state (R), which cannot. In the absence of a
natural ligand or agonist, the equilibrium between R* and R defines the basal
activity of the receptor. A drug can bind to one or both of these conformational
states, according to equilibrium constants Kd and Kd* for formation of the drug–
receptor complex with the resting (D-R) and active (D-R*) states, respectively.
Fig. 3.5: Two-state model of receptor activation. D is the drug, R is the

receptor, and L is the equilibrium between the resting (R) and the active (R*)
state of the receptor
3. 9 Summary
It is emphasized that drug activity is observed through a translation process
controlled by cells. Different drugs have different inherent capacities to induce
response (intrinsic efficacy). Thus, equal cellular responses can be achieved by
different fractional receptor occupancies of these drugs. The ability to reduce
stimulus-response mechanisms to single monotonic functions allows relative
cellular response to yield receptor-specific drug parameters. It has been shown
that most receptors can activate several different signaling pathways, which
may also be selectively activated/ inhibited by drugs.
50
3. 10 Glossary
 Receptor is defined as a macromolecule or binding site located on the
surface or inside the effector cell that serves to recognize the signal
molecule/ drug and initiate the response to it, but itself has no other
function.
 Agonist: An agent which activates a receptor to produce an effect similar to
that of the physiological signal molecule.
 Inverse agonist: An agent which activates a receptor to produce an effect in
the opposite direction to that of the agonist.
 Antagonist: An agent which prevents the action of an agonist on a receptor
or the subsequent response, but does not have any effect of its own.
 Partial agonist: An agent which activates a receptor to produce submaximal
effect but antagonizes the action of a full agonist.
 Ligand: (Latin: ligare-to bind) Any molecule which attaches selectively to
particular receptors or sites.
 Affinity: The ability to bind with the receptor designated as affinity.
 Intrinsic activity or Efficacy: The capacity to induce a functional change in
the receptor designated as intrinsic activity (IA) or efficacy.
 Agonists have both affinity and maximal intrinsic activity.
 Competitive antagonists have affinity but no intrinsic activity.
 Partial agonists have affinity and submaximal intrinsic activity.
 Inverse agonists have affinity but intrinsic activity with a minus sign.
1. What is receptor? Give brief description about receptor.
2. What are different principles of drug action?
3. Discuss about Drug-Receptor complex.
4. Write different interactions/ forces involved in the drug–receptor complex.
5. What do you know about receptor theory? Enumerate different theories of
drug–receptor interactions.
6. Discuss about Occupancy Theory.
7. Discuss about Rate Theory.
8. Discuss about Induced-Fit Theory
9. What is the importance of receptor theory in drug design?
51
10. Indicate what drug–receptor interactions are involved at every arrow shown.
More than one kind of interaction is possible for each letter (A, B, C, D and
E).

 Povl Krogsgaard-Larsen, Kristian Stromgaard & Ulf Madsen; “Textbook of
Drug Design and Discovery” 4th edition 2010; CRC Press, Taylor &
Francis Group.
 Richard B. Silverman & Mark W. Holladay; “The Organic Chemistry of
 Donald J. Abraham; “Burger’s Medicinal Chemistry and Drug Discovery”
 K.D. Tripathi; “Essentials of Medical Pharmacology” 6th edition 2008;
Jaypee Brothers Medical Publishers (P) Ltd New Delhi.
 John H. Block John M. Beale Jr.; “Wilson & Gisvold's Textbook of Organic
Williams & Wilkins
 Ashutosh Kar; “Medicinal Chemistry” 4th and revised edition 2007; New
 Donald Cairns; “Essentials of Pharmaceutical Chemistry”, 3rd edition 2008;
52
 Alfonso R. Gennaro; “Remington: The Science and Practice of Pharmacy”
20th edition 2001; Lippincott Williams & Wilkins
53
Unit - 4
Quantitative Structure Activity
Relationship
Structure of Unit:
4.1 Objectives
4.2 History
4.3 Introduction
4.4 QSAR Parameters
4.5 Physicochemical parameters
4.6 Hydrophobicity of the molecule
4.7 Electronic parameters
4.8 Steric parameters
4.9 Methods used in QSAR studies
4.10 Hansch analysis (Theoretical method)
4.11 Free and Wilson analysis
4.12 Advantages of QSAR
4.13 Limitation of QSAR
4.14 Summary
4.15 Glossary
4.1 Objective
 Aim of drug design is developing a drug with high degree of
chemotherapeutic index and specific action.
 To design a drug on the basis as possible as reducing the minimum trial
and error approach.
54
 To target the dedicated screening approach, is more or less random in
nature and involves greater efficacy of therapeutic targets.
4.2 History
Drugs are not designed. Brown and Fraser in 1869 showed biological activity
could be related to its structure convulsant action of naturally occurring
alkaloids was lost after reaction with CH3I. Ehrlich’s big achievement in 1909
is the discovery of the specific cure for the treatment of syphilis. The random
screening for a new chemical led to discovery of many important new drugs.
The most convincing demonstration that is random screening plus systematic
modification of the active compounds. The independent observation of Meyor
and Overtone that in a rough way the narcotic potency of simple natural organic
compounds parallels the lipophilicity was the enormous importance of the
hydrophobic interaction in biology.
4.3 Introduction
The drug design aspect often involves molecular modeling and the use of
quantitative structure activity relationship (QSAR) to better define the
physicochemical properties that the crucial for biological activity. For
identifying the effect, testing is usually done with specific receptor system or
enzymes. The various approaches used in drug design include:
 Random screening of synthetic compounds or chemicals and natural
products by bioassay procedures.
 Novel compounds preparation based on the known structures of
biologically active, natural substance of the plant and animal origin.
 Preparation of structure analogues of lead with increasing biological
activity.
There are number of procedures involved in drug design, the first step is the
detection of some biological action in a group of compounds so as to serve as a
lead. This is followed by molecular manipulations to increase or modify the
activity. Identification of a lead nucleus depends upon the consideration of the
following points:
1. Molecular structure of the drug
2. Behavior of the drug in the biophase
3. Geometric of the receptor
4. Drug-receptor interaction
55
5. Change in the structure on binding and
6. The observed biological response.
After following such a tedious process only fewer drug can reach to the level of
clinical applicability. Such compounds have to be given extensive trials before
they are tried on humans. This adds to the cost of research for new drugs.
Broadly, this means that if the development of new drug is to remain
economically feasible. The ratio of output to input must be increased.
The lead is a prototype compound that has the desired biological or
pharmacological activity but may have many undesirable characteristics such as
high toxicity, other biological activities, insolubility or metabolic problems.
QSAR is the study of how the physicochemical properties of a series of
compounds affect their biological activity. Drug receptor interactions are a
subset of structure- property correlation in which a variety of chemical and
physical molecular property is employed to define the association between
structure and properties. Quantitative values are measured or calculated for the
physical features and these are related to biological activities using
mathematical equations.
QSAR techniques employ powerful computers, molecular graphics and
sophisticated software: they may be of enormous assistance to those trying to
generate the large data bases resulting from the massive efforts in the drug
research. QSAR is essentially a computerized statistically method which tries to
explain the observed variance in the biological effect of certain classes of
compounds as a function of molecular changes caused by the substituents. It
assumed that potency of a certain biological activity exerted by a series of
congeneric compounds is a function of various physicochemical parameters of
the compounds.
The ability to examine multiple relationships between physical property and
biological activity is given in Figure 4.1
56
4.4 QSAR parameters
Physical organic chemistry deals with characterization of the structure and
prediction of the structure and prediction of the properties are usually found
experimentally. Some property depends on the set of the selected descriptors.
The structural information is coded in these properties. Therefore, good
correlation of physicochemical properties with a particular set of indices may
help in understanding the contribution of these invariants in determining the
property.
Fig. 4.1: The relationship between physical property and biological activity
4.5 Physicochemical parameters

Biological activity reflects the fundamental physicochemical properties of the
bioactive compounds. For example enantiomers are related physico chemically
very closely but they differ only by sterically. Various physicochemical
parameters are used in QSAR studies are shown in Table 4.1
Table 4.1 Various physicochemical parameters and symbol used in QSAR
study
S.No. Physicochemical Parameters Symbol
1. Hydrophobic parameters
57
 Partition coefficients Log p
 Pie substituent constant π
S
 Solubility
2. Electronic parameters
 Ionization constant pKa
R
 Resonance effect
 Inductive effect (field F
effect)
 Ionization potential I
3. Steric parameters
 Taft’s steric substituent ES
constant
 Vander Waal radii R
MR
 Molar refractivity
MV
 Molar volume
The physicochemical properties of a compound impact on the biological
activity. The overall hydrophobic character of a compound influences how
efficiency it can cross the cell membrane. The hydrophobic character and size
of molecule may influence how well the compound interact fits into its binding
site. While the electronic character of the substituent can influence the basicity
of the compound, affecting both absorption and receptor binding.
There are many software programs that help in deriving equations but it is upto
the medicinal chemist to decide what data to put in. the biological activity of
each compound has to be included, but the chemist has to decide which
physical feature might be more important to biological activity.
It is usually best to derive an initial equation based on only one or two physical
features. The initial equation will give calculated activities close to the
experimentally measured activities. The medicinal chemist can study these
molecules and try to identify a physical feature with these molecules which
have the others do not then search includes that property.
58
4.6 Hydrophobicity of the molecule
Hydrophobicity of a molecule is measured by log P value where P is known as
the partition coefficient. Hydrophobicity of a drug is measured by distribution
of compound between an aqueous and non aqueous solvent. Aqueous solution
is water and non aqueous solution is n-octanol. Now P is the ratio of
concentration of compound in n-octanol to concentration of compound in water.
P=
If greater proportions of drug dissolve in organic layer than higher the value of
log P. higher value of log P and it indicates the higher in vivo activity. This is
the indication that increasing hydrophobicity allow easier passage of drug
through cell membrane in order to reach target site.
Most of the QSAR experiments are carried out on compounds that have a
limited range of log P values.
Log activity = - K1 (log P)2 + K2 (log P) + K3
K1, K2 and K3 are constant
In above equation –(log P)2 give negative impact on activity where as log P
give positive effect when P is low, log P is more important than – (log P)2.
Substituent Hydrophobicity of the molecule
The partition coefficient describe the overall hydrophobicity of a molecule, but
it is also possible to quantify the hydrophobic character of individual
substituent that give hydrophobicity constant ( ) for each substituent.
The substituent hydrophobicity constant is a measure of how hydrophobic
substituent is related to hydrogen. The value is measured experimentally by
comparing the log P values of a compound with and without the substituents.
The hydrophobicity constant ( ) for the substituents (x) are obtained using the
following equation:
= log PX – log PH
PH is the partition coefficient for standard compound and PX is the partition
coefficient for analogue containing the substituent X. If is the positive then
the substituents are more hydrophobic than hydrogen. If is negative then the
substituent is less hydrophobic than hydrogen.
59
Hydrophobicity constant can be used to calculate log P values for different
compound avoiding the need to measure each log P value experimentally. For
example log P value for parabromoanisol can be calculated as 2.97, given the
log P value for benzene (2.13) and constant for bromine and methoxy is 0.86
and -0.02 respectively. The relationship between biological activity and
partition coefficient is given in Figure 4.2
Fig. 4.2: Parabolic relationship between biologic activity (log 1/C)

and partition coefficient (log P)
4.7 Electronic parameters
Electronic parameters mainly indicate the influence of polar characters of the
drug on its biological activity. They affect:
 Metabolism and elimination pattern of the drug
 The drug receptor interaction
Hammet introduced constants as a quantitative measure of the electronic effects
of substituents of aromatic rings on on reaction rates and equillibria. Hammet
postulated that the electronic effect of a set of substituents on different organic
reactions should be similar. The most commonly used electronic parameter is
Hammet substituent constant σ which can be obtained from the dissociation
constants KX and KH of the benzoic acids X-Ph-COOH and Ph-COOH
respectively.
Electronic parameters mainly indicate the influence of polar characters of the
drug on its biological activity. The electronic properties of aromatic substituents
are describe by the Hammet substitution constant ( ). Hammet postulated that
60
the electronic effect of particular substituents in different organic reactions
should be similar. He selected banzoic acid as a standard system to develop the
numerical constant value.
Banzoic acid is a weak acid and partially ionizes in water. Equilibrium is attain
between ionize and unionize form. The equilibrium dissociation constant KH is
showing the relative proportion of ionize or unionize proportion.
KH = [PhCOO-]
[PhCOOH]
The subscript H signifies that there are no substituents on the aromatic ring.
Substituent on the aromatic ring affects this equilibrium. If electronic
withdrawing group attached to benzene ring that will stabilize the carboxylate
anion (stability 1/ amount of charge) and equilibrium will shift to ionize form
and result in larger equilibrium constant. If an electron donating group is
attached to ring than it destabilized the carboxylate anion and equilibrium will
shift to left side results in smaller equilibrium constant.
The Hammet substituent constant ( X) for a particular substituent (X) is
defined by the following equation:
X = log = log KX – log KH
These constant are accurate for the molecular structures from which they are
derived. Electron withdrawing group such as –Cl, -CN, -CF3 have positive
values while electronic donating group such as –CH3, -CH2CH3 have negative
value.
The value of the Hammet substituents depends upon the substituent’s inductive
effects and resonance effects and value also depends on the substituent position
that is meta or para or rest of the molecule.
For example m for phenol group is 0.12 it means electon withdrawing
influence felt at the meta position due to induction. When phenol group is at the
61
para position ( P is –0.37) it means the group is electron donating at that
position due to resonance. It should be noted that substitution at ortho position
can have steric as well as electronic effect.
Inductive effect of phenol is predominates at meta position.
Other constant which separately quantify the Inductive/field effect (F) or the
Resonance effect (R) of aromatic substituent. Aliphatic electronic substituents
constants have been obtained by measuring the rate of hydrolysis which is a
measure of substituent’s electronic effect which arises purely from inductive
effect.
Electron donating groups reduce the rate of hydrolysis and have negative value.
Electron donating groups increase the rate of hydrolysis and have positive
values. Large substituents may also have a steric effect of hydrolysis by
shielding the ester from attack.
Steric and electronic factors are separate out by measuring rate of hydrolysis is
acidic and basic condition. Under basic condition steric and electronic factors
are important whereas under acidic condition only steric factor are important.
4.8 Steric parameters
Steric substitution constant:
Steric features of drug markedly affect the drug receptor interaction reflecting
the change in the onset and duration of biological action. Various parameters
are used to describe the steric features of the substituents.
62
1. Taft’s constant (ES): which is derived from acid hydrolysis of aliphatic
esters.
Log (K/K0) = ES
K= rate of acid hydrolysis of substituted ester
K0 = rate of hydrolysis of parent ester
This parameter is useful in studying intra molecular steric effect.
Generally, ES is standardized to the methyl group so that ES for the CH3 group
is equal to zero. It is possible to standardize this parameter to hydrogen i.e. ES
(H) = 0.00 and adding 1.23 to every additional methyl group. Greater the
positive value of ES, the greater the steric effect. Greater steric effect affecting
intra molecular and inter molecular hinderance to drug receptor interaction.
2. Molar refractivity: It is expressed by Lorentz equation
(n2-1) MW
MR=
(n2 + 2) d
n = index of refraction at the sodium line

MW = molecular weight of the compound, and
d = density of compound
Greater the value of MR means the steric contribution of substituents.
3. Molecular connectivity index ( ):
It indicates the degree of branching in a given structure. Molecular connectivity
describes the molecular structures in topological terms for calculation of
connectivity index. The structural formula of the compound is written as
skeleton formula without the hydrogen atom. It is known as hydrogen
suppressed graph. Then valence number (δi) is indicated the atoms attached to
each atom.
Such valence numbers of adjacent atoms are multiplied and the bond
contribution is calculated by taking the reciprocal square root of the product
δiδj.
= ∑( δiδj)-1/2
63
Correlation of the physical properties with the variation in the structure depends
not only on number of atoms in the structure but also upon arrangements of
these atoms. Since size and shape of the molecule determines mainly many of
the physical parameters govern the biological activity of drug, molecular
connectivity index helps to quantify the effect of size and shape on the
biological response.
Molecular connectivity index represents sub-structure environment, degree of
branching, unsaturation, hetro-atoms and their position and presence of cyclic
structures. The close correlation of molecular connectivity with partition
coefficients and molar refractivity shows that connectivity index can be taken
as measure of the lipophilic feature as well as polar interaction between the
molecules. Hence, molecular connectivity index is such a parameter that
expresses both, lipophilicity as well as steric feature of the drug molecule.
Effect of electronic and steric parameters on lipophilicity:
Inductive effect influences the overall lipophilicity of the molecule. In general,
electron withdrawing groups increase value when a hydrogen bonding group
is involved. Thus in an aromatic skeleton having either nitro group or a
hydroxyl group, the electron withdrawing inductive effects of the phenyl ring
and the nitro group make the non bonded electrons on the hydroxyl group less
available for H- bonding. It leads to a decrease in the affinity of this functional
group for the aqueous phase. This then increases the log P or value.
Similarly delocalization of unbounded electrons (i.e. resonance effect) into
aromatic systems decreases their availability for H-bonding with the aqueous
phase. It leads to an increase in the log P or value. Similarly, if a group
stericaly shields non bonded electrons, then aqueous interactions will decreases
and the value will increase. However, crowding of functional groups
involved in hydrophobic interactions will have the opposite effect.
Conformational effects also can affect the value.
4.9 Methods used in QSAR studies
Various methods used in QSAR analysis are as follows:
1. Free energy models
 Hansch method
 Free Wilson mathematical model
2. Other statistical methods
64
 Discriminant analysis
 Factor analysis
 Cluster analysis
3. Pattern recognition
4. Topological methods
5. Quantum mechanical methods
6. Molecular modeling
4.10 Hansch analysis (Theoretical method)
Hansch equation is widely used theoretically method in drug design. This
method relates biological activity and physicochemical properties for example,
degree of ionizations, molecular size or lipid solubility. Most common
parameters are included in Hansch equation such as log P, , σ, F, MR and ES.
Hansch proposed that the action of drug depending on two processes.
 First the journey from the point of entry in the body to the site of action.
 Secondly the interaction with the receptor site.
A typical Hansch equation would be represented as:
Log 1/C = K1 (log P)2 + K2 log P + K3 σ + K4 ES + K5

Log 1/C = potency
K1, K2, K3, K4 and K5 are constants.
These constant would be determined by computer in order to get the best fitting
line. Activity is often measured by 1/C where C is the concentration of drug
required to produce a specific effect. The more active the drug, the smaller the
concentration required and larger value of 1/C.
It should be appreciated that a QSAR equation is only as good as the data that
has been entered. Usually a range of compounds are synthesized to quantify the
effect that two or three physical parameters have on biological activity. Hansch
analysis may serve both to guide the medicinal chemist in future synthesis and
testing of other compound in series and to the role of hydrophobic, electronic
and steric factors in drug receptor interactions.
65
4.11 Free and Wilson analysis
Free and Wilson developed an approach to SAR. This method is based upon an
additive mathematical model in which a particular substituent in a specific
position is assumed to make an additive and contribution to biological activity
of a molecule in a series of chemically related molecules. This method is based
on the assumption that the introduction of a particular substituent at particular
position that gives a quantitatively similar effect on biological potency of the
whole molecule. Biological activity is expressed as:
Log (biological activity) = contribution of unsubstituted parent compound +
contribution of corresponding substituent
This method is preferred when nothing is known about the mode of action or
when the physicochemical properties of the substituents used are unknown.
Best results with the free Wilson method are obtained in series with several
positions are available for substitution and only if each substituent any location
is present in at least two compound in a series.
4.12 Advantages of QSAR
QSAR helps to understand the forces that govern the activity in a series of
compounds. It thus helps to reduce the work in drug design and ensure that
every drug synthesized and pharmacologically tested is as meaningful as
possible. The main area where QSAR provides:
1. Forcasting of biological activity: innumerable applications of QSAR has
been reported where successful prediction of biological activity played an
important role. Through the regression analysis, parameters or nature and
position of substituent which may increase the activity can be guessed. The
advanced techniques using computerized programs even give the structural
features of the most possible active compound of the series.
2. Selection of proper substituents: Proper selection of substituents to
develop a series leads to a decrease in the average number of analogs
required to investigate the relationship between substituent parameters and
the biological activity. Planning gives a good chance of finding out what
combinations of parameters will optimized the potency.
3. Bioisosterism: With the introduction of QSAR, the qualitative concept of
bioisosterism has turned to be more quantitative and constitutive. QSAR also
helps to decide an isoester which will give better pharmacokinetic and
pharmacodyanamic properties to lead molecule.
66
4. Drug-receptor interactions: In a series of compounds, QSAR studies help
to predict in quantitative terms, the force involved in the drug receptor
interaction if the substitution are involved in non-essential part of the drug
molecule. If selection of parameter is proper, QSAR may also suggest at
which position of the receptor, increased lipophilicity of the drug increase
binding.
5. Pharmacokinetic information: The correlation between various types of
parameter and the pharmacokinetic features of the drug can be done using
QSAR.
4.13 Limitation of QSAR
The application of QSAR analysis may result in statistically valid equations. It
is often difficult to interpret the relationship in biochemical terms. Failure of
regression analysis in the prediction of biological activity of analogs results
mainly due to
 A poorly designed series
 Improper condition of the biological testing
 Multiple mode of action
The most serious problem in QSAR is the lack of fundamental understanding of
how to quantitatively describe substituent effect on drug-receptor interactions.
A successful QSAR can provide only indirect (ES, MV, MR) information about
the three dimensional aspect of drug-receptor interactions.
Other effects (electronic or steric) have their own influences on the overall
lipophilicity of the molecule. This may result in wrong correlation and
interpretation of activity in a series that mainly depends upon lipophilicity for
biological action. Electronic effect of a substituent may change both, the degree
of ionization and the charge distribution.
Since the biological activity determination process is susceptible to
considerable experimental variations, a non linear scatter may be observed
during correlation of biological activity with physicochemical parameters.
QSAR fails to explain this built in scatter mathematically.
Similarly, physiological active compounds on their way from the site of
administration to the target sites, are known to undergo diverse chemical and
biochemical and biochemical transformations. It is likely that they act
differently on different bio-targets to exert same kind of activity.
67
4.14 Summary
Medicinal chemistry involves the discovery of new chemical entities for the
treatment of disease and systematic study of the structure activity relationships
of these compounds. Such studies provide the basis for development of better
medicinal agents from lead compounds found via random screening, systemic
screening and rational design. The role of the medicinal chemist is that of
increasing the potency and duration of action of newly discovered compounds
as well as decreasing adverse effects.
QSAR for drug receptor interactions are subset of structure property correlation
in which a variety of chemical and physical molecular properties is employed to
define the association between structure and property. QSAR are wide spread in
medicinal chemistry since the advent of cheap and high speed computing
technology in the past 20 year.
The QSAR approach can be extended with the recognition that the ligand
occupies three dimensional space. The ability to determine or predict a
pharmacophore map by the use of molecular modeling technique and the
synthesis of rigid analogs then generates an hypothesis of bioactive
confirmation from which comparative molecular field analysis can used to
calculate the intermolecular interaction field that surround each molecule and
subsequently the relationship between the biologic activity and the calculated
fields is determined.
4.15 Glossary
 Lipophilicity: having an affinity for lipid
 Biophase: the period during which a effective concentration of a drug is
maintained the vicinity of this site of action
 Enantiomer: molecules that are mirror image of one another
 Inductive effect: it is an experimentally observed effect of the transmission
of charge through chain of atom in a molecule resulting in a permanent
dipole in a bond.
 Resonance: it is a way of describing delocalized of electrons within certain
molecule and poly atomic ions where the bonding cannot be expressed by a
single Lewis formula.
68
 Pharmacophore: a part of a molecular structure that responsible for a
particular biological or pharmacological interaction that it undergoes.
 Ligand: it is an ion or molecule that binds to a central metal atom to form a
coordination complex.
 Vander Waal radius: it is an atom of is the radius of a imaginary hard sphere
which can be used to model the atom for many purposes.
 H-bonding: it is bond that occurs between hydrogen and high
electronegative atom (N, O and F).
1. Define QSAR. Write about Hansch analysis.

2. Discuss in brief about physicochemical parameters used in QSAR.
3. Write a note on electronic parameters and steric parameters used in
QSAR.
4. Discuss how resonance effect and inductive effect affect drug design.
5. Write methods used in QSAR technique.

 Foye’s Principles of Medicinal Chemistry, David A. Williams, Thomas L.
Lemke (Fifth edition) 2005, B.I. Publication and Pvt. Ltd.
 S.S Kadam, K.R Mahadik and K.G Bothra Principles of Medicinal
Chemistry (13th edition) 2005, Nirali Prakashan.
 An Introduction to Drug Design- S.N. Pnadey and J.R. Dimmock (New
Age International Publisher) 2011.
 An Introduction to Medicinal Chemistry- Graham L. Patrick (Oxford
University Press) 2006.
69
Unit-5
Concepts of drug receptors
Structure of Unit:
5.1 Objectives
5.2 Introduction: Receptor
5.3 Forces involved in drug receptor interaction
5.4 Types of receptor
5.5 G-protein coupled receptors (GPCR)
5.6 Ligand gated ion channel receptor
5.7 Enzyme-linked receptors
5.8 Nuclear receptor
5.9 Summary
5.10 Glossary
5.1 Objectives
In this unit, we move from the general principles of drug action to the
molecules that are involved in recognizing chemical signals and translating
them into cellular responses. First, we consider the types of forces which are
involved in drug receptor interaction. Next, we describe the main families of
receptors and discuss the various forms of receptor-effectors linkage (signal
transduction mechanisms) through which receptors are coupled to the
regulation of cell function. The relationship between the molecular structure of
a receptor and its functional linkage to a particular type of effectors system is a
principal theme.
5.2 Introduction: Receptor
Pharmacodynamics is the study of drug effects. This includes physiological and
biochemical effects of drugs and their mechanism of action at organ system.
Majority of drugs produce their effects by interacting with a discrete target
biomolecule, which usually is a protein. Such mechanism confers selectivity of
action to the drug. Functional proteins that are targets of drug action can be
grouped into four major categories, as follows-
1. Ion channels
70
2. Enzymes
3. Carrier molecules (transporters)
4. Receptors
1. Ion channels
Proteins which act as ion selective channels participate in transmembrane
signaling and regulate intracellular ionic composition. This makes them a
common target of drug action. Drugs can affect ion channels either through
specific receptors (ligand gated ion channels, G-protein operated ion channels)
or by directly binding to the channel and affecting ion movement through it.
(Fig. 5.2(a);B)
2. Enzymes
Almost all biological reactions are carried out under catalytic influence of
enzymes. Enzymes are a very important target of drug action. Drugs can either
increase or decrease the rate of enzymatically mediated reactions. (Fig.
5.2(a);A)
3. Transporters
Several substrates are translocated across membranes by binding to specific
transporters (carriers) which either facilitate diffusion in the direction of the
concentration gradient or pump the metabolite/ion against the concentration
gradient using metabolic energy.
71
Fig. 5.2(a): Targets of drug action:(A) Enzyme; (B) Transmembrane ion
channel; (C) Membrane bound transporter; (D) Receptor
Many drugs produce their action by directly interacting with the solute carrier
(SLC) class of transporter proteins to inhibit the ongoing physiological
transport of the metabolite/ion. (Fig. 5.2(a);C)
4. Receptors
Receptors have become the central focus of investigation of drug effects and
their mechanisms of action (Pharmacodynamics). A fundamental concept of
pharmacology is that to initiate an effect in a cell, most drugs combine with
some molecular structure on the surface of or within the cell (Fig.5.2 (a);D).
This molecular structure is called a receptor. A drug receptor is a specialized
target macromolecule, present on the cell surface or intracellular, that binds a
drug and mediates its pharmacologic actions.
Drug + Receptor Drug-receptor complex Effect
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The following terms are used in describing drug-receptor interaction:
 Agonist- An agent which activates a receptor to produce an
effect similar to that of the physiological signal molecule. Figure
5.2 (b)
 Inverse agonist - An agent which activates a receptor to
produce an effect in the opposite direction to that of the agonist.
Fig. 5.2 (b): Illustrations of terms: Agonist; Antagonist; Inverse agonist;

Partial agonist
 Antagonist- An agent which prevents the action of an agonist
on a receptor or the subsequent response, but does not have any
effect of its own. Figure 5.2 (b)
 Partial agonist- An agent which activates a receptor to produce
sub maximal effect but antagonizes the action of a full agonist.
Figure 5.2 (b)
 Ligand- Any molecule which attaches selectively to particular
receptors or sites.
Although the term receptor is convenient, one should never lose sight of
the fact that receptors are in actuality molecular substances or
macromolecules in tissues that combine chemically with the drug. Since
73
most drugs have a considerable degree of selectivity in their actions, it
follows that the receptors with which they interact must be equally
unique. Thus, receptors will interact with only a limited number of
structurally related or complementary compounds.
5.3 Forces involved in drug receptor interaction
Biological receptors are capable of combining with drugs in a number of ways,
and the forces that attract the drug to its receptor must be sufficiently strong and
long-lasting to permit the initiation of the sequence of events that ends with the
biological response. Those forces are chemical bonds, and a number of types of
bonds participate in the formation of the initial drug–receptor complex.
Covalent bonds
The covalent bond is strongest bond, generally worth anywhere from 40 to 110
kcal/mol in stability. It is seldom formed by a drug receptor interaction, except
with enzymes and DNA.
Ionic interactions
For protein receptors at physiological pH basic groups such as the amino side
chains of arginine, lysine, and , to much lesser extent histidine are protonated
and, therefore provide a cationic environment acidic groups, such as
caroboxylic acid side chains of aspartic acid and glutamic acid, are
deprotonated to give anionic groups.
Drug and receptors group will be mutually attracted provides they have
opposite charges. This ionic interaction can be affective at distance further than
those required for other types of interactions and they can persist longer.
1. Ion-Dipole and Dipole-Dipole interactions
As a result of greater electro negativity of atoms such as oxygen, nitrogen,
sulfur and halogens relative to that carbon, C-X bonds in drug and receptors,
where X is an electronegative atom, will have an asymmetric distribution of
electrons; these produces an electronic dipoles.
2. Hydrogen Bonds
Hydrogen bonds are a type of dipole-dipole interaction formed between the
proton of a group X-H where X is an electronegative atom, and other
electronegative atoms Y containing a pair nonbonded electrons.
74
3. Charge-Transfer Complexes
When molecule that is a good electron donor comes into contact with a
molecule that is good electron acceptor, the donor may transfer some of its
charges to the acceptor. This forms a charge-transfer complex, which, in effect,
is a molecular dipole-dipole interaction.
4. Hydrophobic Interactions
In the presence of a non polar molecules or region of a molecule, the
surrounding water molecules orient themselves and, therefore are in a higher
energy state than when only other water molecules are around. When to non
polar groups, each surrounded by a ordered water molecules, approach each
other, these water molecules becomes disordered in an attempt to associate with
each other, this increase in entropy, therefore, results in a decrease in the free
energy that stabilizes the drug-receptor complex.
5. Vander Walls or London Dispersion Forces
Atoms in nonpolar molecules may have a temporary nonsymmetrical
distribution of electron density, which results in the generation of a temporary
dipole. As atoms from different molecules approach each other, the temporary
dipoles of one molecule induce opposite dipoles in the approaching molecule
consequently, intermolecular attractions, and known as Vander walls forces.
5.4 Types of receptor
Based on molecular structure and the nature of this linkage (the transduction
mechanism), we can distinguish four receptor types, or super families are
follows:
Type1: Ligand-gated ion channels
Type2: G-protein-coupled receptors
Type3: Kinase-linked receptors
Type4: Nuclear receptors
Table 5.4: Types of Receptor
Type 1 Type 2 Type 3 Type 4
Ligand-gated G-protein- Kinase-linked Nuclear
ion channels coupled receptors receptors
receptors
Location Membrane Membrane Membrane Intracellular
75
Effector Ion channel Channel or Enzyme Gene
enzyme transcription
Coupling Direct G-protein Direct Via DNA
Examples Nicotinic Muscarinic Insulin, growth Steroid,
acetylcholine acetylcholine factor, cytokine thyroid
receptor, receptor receptors hormone
gamma- (mAChR), receptors
aminobutyric adrenoceptors
acid type A
Structure Oligomeric Monomeric Single Monomeric
assembly of (occasionally transmembrane structure with
subunits dimeric) helix linking separate
surrounding structure extracellular receptor and
central pore comprising receptor DNA-
seven domain to binding
transmembrane intracellular domains
helices kinase domain
Type 1: Ligand-gated ion channels
The ligand-gated ion channels are also known as ionotropic receptors. These
are membrane proteins with a similar structure to other ion channels but
incorporating a ligand-binding (receptor) site, usually in the extracellular
domain.
Type 2: G-protein-coupled receptors
The G-protein-coupled receptors (GPCRs) are also known as metabotropic
receptors or seven-transmembrane-spanning (heptahelical) receptors. They are
membrane receptors that are coupled to intracellular effector systems via a G-
protein.
Type 3: Kinase-linked and related receptors
There is a large and heterogeneous group of membrane receptors responding to
protein mediators. They comprise an extracellular ligand-binding domain linked
to an intracellular domain by a single transmembrane helix. In many cases, the
intracellular domain is enzymic in nature (with protein kinase or guanylate
cyclase activity).
76
Type 4: Nuclear receptors
The nuclear receptors regulate gene transcription. The term nuclear receptor is
something of a misnomer since some are actually located in the cytosol and
migrate to the nuclear compartment when a ligand is present.
Fig.5. 4: Types of receptor-effector linkage
5.5 G-protein coupled receptors (GPCR)

These are a large family of cell membrane receptors which are linked to the
effector (enzyme/ channel/carrier protein) through one or more GTP-activated
proteins (G-proteins) for response effectuation. The molecule has 7 α-helical
membrane spanning hydrophobic amino acid (AA) segments which consists 3
extracellular and 3 intracellular loops. Fig. 5.5(a)
The agonist binding site is located somewhere between the helices on the
extracellular face, while another recognition site formed by cytosolic segments
binds the coupling G-protein. The G proteins float in the membrane with their
exposed domain lying in the cytosol, and are heterotrimeric in composition (α,
β and γ subunits). In the inactive state GDP is bound to their exposed domain;
activation through the receptor leads to displacement of GDP by GTP.
77
Fig. 5.5(a): Diagrammatic representation of G-protein coupled receptor
molecule
The active α- subunit carrying GTP dissociates from the other two subunits and
either activates or inhibits the effector. The βγ subunits have also been shown
to modulate certain effectors like receptor operated K+ channels,
adenylylcyclase (AC) and phospholipase C.
Number of G proteins distinguished by their α subunits have been described.
The important ones with their action on the effector are:
Gs : Adenylyl cyclase ↑, Ca2+ channel ↑
Gi : Adenylyl cyclase ↓, K+ channel ↑
Go : Ca2+ channel ↓
Gq : Phospholipase C ↑
G13 : Na+/H+ exchange ↑
There are three major effector pathways through which GPCRs function.
78
 Adenylyl cyclase (AC): cAMP pathway-
Activation of AC results in intracellular accumulation of second messenger
cAMP which functions mainly through cAMP-dependent protein kinase (PKA).
The PKA phosphorylates and alters the function of many enzymes, ion
channels, transporters and structural proteins to manifest as increased
contractility/impulse generation (heart), relaxation (smooth muscle),
glycogenolysis, lipolysis, inhibition of secretion/mediator release, modulation
of junctional transmission, hormone synthesis, etc. Fig. 5.5(b)
Fig. 5.5(b): The action-effect sequence of two G-protein coupled (β adrenergic

and muscarinic M2) receptor activation in myocardial cell
 Phospholipase C pathway: IP3-DAG pathway-
Activation of phospholipase C (PLC) hydrolyses the membrane phospholipid
phosphatidyl inositol 4, 5-bisphosphate (PIP2) to generate the second
messengers inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). The
IP3 mobilises Ca2+ from intracellular organellar depots and DAG enhances
protein kinase C (PKc) activation by Ca2+.Cytosolic Ca2+. PKc and other
effectors—mediates/modulates contraction, secretion/ transmitter release,
eicosanoid synthesis, neuronal excitability, intracellular movements, membrane
function, metabolism, cell proliferation, etc. Figure 5.5(c)
79
Figure 5.5(c): The important steps of phospholipase C(PLc) pathway of
response effectuation (in smooth muscle): histamine receptor (H1R);
phosphatidyl inositol 4, 5-bisphosphate (PIP2); inositol 1, 4, 5-trisphosphate
(IP3); diacylglycerol (DAG); calmodulin (CAM); myosin light chain kinase
(MLCK); calcium-calmodulin protein kinase (CCPK).
 Ion Channel pathway-
The activated G proteins can also open or close ionic channels specific for Ca2+,
K+ or Na+, without the intervention of any second messenger like cAMP or IP3,
and bring about hyperpolarization/depolarization/ changes in intracellular Ca2+.
5.6 Ligand gated ion channel receptor
These cell surface receptors, also called ligand gated ion channels, enclose ion
selective channels (for Na+, K+, Ca2+ or Cl¯) within their molecules. Agonist
binding opens the channel (Fig. 4.4) and causes
depolarization/hyperpolarization/ changes in cytosolic ionic composition,
depending on the ion that flows through.
80
5.7 Enzyme-linked receptors
This class of receptors has a subunit with enzymatic property or binds a JAK
(Janus-Kinase) enzyme on activation. The agonist binding site and the catalytic
site lie respectively on the outer and inner face of the plasma membrane. These
two domains are interconnected through a single transmembrane stretch of
peptide chain. There are two major subgroups of such receptors:
a) Those that have intrinsic enzymatic activity.
b) Those that lack intrinsic enzymatic activity, but bind a JAK-STAT kinase on
activation.
a) Intrinsic enzyme receptors:
The intracellular domain is either a protein kinase or guanylyl cyclase. On
binding the peptide hormone to the extracellular domains, the monomeric
receptors move laterally in the membrane and form diamers. Dimerization
activates tyrosine-protein kinase (t-Pr-K) activity of the intracellular domains so
that they phosphorylate tyrosine (t) residues on each other, as well as on several
SH2 domain substrate proteins (SH2-Pr). The phosphorylated substrate proteins
then perform downstream signaling function. Figure 5.7(a)
Fig. 5.7(a): Transduction mechanisms of kinase-linked receptors :( a) Intrinsic

enzyme receptors
81
b) JAK-STAT kinase binding receptor:
The intracellular domain of these receptors lacks intrinsic protein kinase
activity. Signal molecule binding to the extracellular domain induces receptor
dimerization which activates the intracellular domain to bind free moving JAK
(Janus Kinase) molecules. The activated JAK phosphorylate tyrosine residues
on the receptor which then binds another protein STAT (signal transducer and
activator of transcription). Tyrosine residues of STAT also get phosphorylated
by JAK. The phosphorylated STAT dimerize, dissociate from the receptor and
move to the nucleus to regulate transcription of target genes. Figure 5.7(b)
Fig. 5.7(b): Transduction mechanisms of kinase-linked receptors: (b) JAK-

STAT kinase binding receptor
5.8 Nuclear receptor

These are intracellular (cytoplasmic or nuclear) soluble proteins which respond
to lipid soluble chemical messengers that penetrate the cell. The receptor
protein (specific for each hormone/ regulator) is inherently capable of binding
to specific genes, and exposes the DNA binding regulatory segment located in
the middle of the molecule. Attachment of the receptor protein to the genes
facilitates their expression so that specific mRNA is synthesized on the
template of the gene. This mRNA moves to the ribosomes and directs synthesis
of specific proteins which regulate the activity of target cells.
The glucocorticoid (G) penetrates the cell membrane and binds to the
glucocorticoid receptor (GR) protein that normally resides in the cytoplasm.
The GR has a steroid binding domain; binding of the steroid to GR dissociates
82
the complexed proteins (HSP90, etc. Fig. 5.8. The steroid binding domain is
exposed, promoting dimerization of the occupied receptor. The steroid bound
receptor diamer translocates to the nucleus and interacts with specific DNA
sequences called ‘glucocorticoid responsive elements’ (GREs). The expression
of these genes is consequently altered resulting in promotion (or suppression) of
their transcription. The specific mRNA thus produced is directed to the
ribosome where the message is translated into a specific pattern of protein
synthesis, which in turn modifies cell function.
Fig. 5.8: Transduction mechanism of nuclear receptor : Glucocorticoid receptor
5.9 Summary
Receptor is the component of a cell or organism that interacts with a drug and
initiates the chain of events leading to the drug's observed effects. Receptors
mediate the actions of both pharmacologic agonists and antagonists. Some
drugs and many natural ligands, such as hormones and neurotransmitters,
regulate the function of receptor macromolecules as agonists; i.e., they activate
the receptor to signal as a direct result of binding to it. Some agonists activate a
single kind of receptor to produce all of their biologic functions, whereas others
selectively promote one receptor function more than another. Other drugs act as
pharmacologic antagonists; ie, they bind to receptors but do not activate
generation of a signal; consequently, they interfere with the ability of an agonist
to activate the receptor. Biological receptors are capable of combining with
drugs in a number of ways, and the forces that attract the drug to its receptor,
those forces are chemical bonds, and a number of types of bonds such as
83
hydrophobic interactions, charge-transfer complexes, hydrogen bonds, ion-
dipole and dipole-dipole interactions, ionic interactions, covalent bonds, vander
walls or london dispersion forces participate in the formation of the initial
drug–receptor complex.
5.10 Glossary
 Depolarisation- Rapid inflow of sodium ions and cell becomes
positive.
 Dimer- A combination of two identical molecules to form a single
compound.
 Hyperpolarisation- Rapid outflow of potassium ions and cell
becomes negative.
 Transcription- Synthesis of m-RNA molecule that is a
complimentary copy of a DNA gene.

1. What is Pharmacodynamics?
2. Explain mechanism of drug target action.
3. Define receptor. Discuss about GPCR.
4. Explain the transduction mechanism of nuclear receptor.
5. Discuss the molecular structure of GPCR.
6. Explain the transduction mechanism of ligand gated ion channel
receptor.
7. Discuss the chemistry of elementary treatment of drug receptor
interaction.
8. Enlist the forces that are involved in drug receptor interaction.
9. Explain the transduction mechanism of kinase linked receptor.
10. Discuss the drug-receptor transduction mechanism.
 Basic & Clinical Pharmacology (9th ed.)- Bertram G.Katzung (Mc Graw
Hill Publisher) 2004.
 The Pharmacological basis of Therapeutics (10th ed.)- Goodman & Gilman’s
(Mc Graw Hill Publisher) 2001.
84
 Principles of medicinal chemistry, volume II-Dr. S.S. Kadam, Dr. K.R.
Mahadik, Dr. K.G. Bothara (Nirali prakashan) 2007.
 Pharmacology (5th ed.)- H.P Rang and M.M Dale (Elsevier publisher) 2003.
 An introduction to medicinal chemistry (3rd ed.)- Graham L.Patrik 2006.
 Principles of medicinal chemistry(3rd ed.)- William O. Foye (Varghese
publisher) 1989.
 Textbook of Organic Medicinal and Pharmaceutical Chemistry (11th ed.)-
Wilson and Gisvold’s.
85
Unit - 6
Pharmacokinetic I
Structure of Unit:
6.1 Objectives
6.2 Introduction: Pharmacokinetics
6.3 Absorption
6.4 Transport across the membrane
6.5 Distribution
6.6 Metabolism
6.7 Elimination
6.8 Pharmacokinetics of Elimination
6.9 Summary
6.10 Glossary
6.1 Objectives
In this unit, we set out some general principles underlying the interaction of
drugs with living systems. We discuss drug translocation, absorption,
distribution, and chemical transformation by drug metabolism, and other
processes involved in drug elimination. The aim of drug therapy is to prevent,
cure, or control various disease states. To achieve this goal, adequate drug
doses must be delivered to the target tissues so that therapeutic, yet nontoxic
levels are obtained. The clinician must recognize that the speed of onset of drug
action, the intensity of the drug's effect, and the duration of the drug action are
controlled by four fundamental pathways of drug movement and modification
in the body. First, drug absorption from the site of administration permits entry
of the therapeutic agent (either directly or indirectly) into plasma (input).
Second, the drug may then reversibly leave the blood stream and distribute into
the interstitial and intracellular fluids (distribution). Third, the drug may be
metabolized by the liver, kidney, or other tissues. Finally, the drug and its
metabolites are eliminated from the body (output) in urine, bile, or feces.
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6.2 Introduction: Pharmacokinetics
Pharmacokinetics (Greek: Kinesis—movement) — What the body does to the
drug. Pharmacokinetics is the quantitative study of drug movement in, through
and out of the body. This refers to movement of the drug in and alteration of the
drug by the body; includes absorption, distribution,
binding/localization/storage, biotransformation (metabolism) and elimination of
the drug. (Fig. 6.1).
After entry of the drug into the systemic circulation either by intravascular
injection or by absorption from any extravascular site, drug is followed
different processes by which changes in its plasma concentration called
disposition processes.
Fig. 6.1: Representation of drug absorption, distribution, metabolism and

elimination: Drug disposition
Drug disposition is divided into four stages:
 Absorption from the site of administration
 Distribution within the body
 Metabolism
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 Excretion
6.3 Absorption
Absorption is the movement of the drug from its site of administration to the
blood stream. Rate and efficiency of absorption depend on the route of
administration. For intravenous delivery, absorption is complete, that is, the
total dose of drug reaches the systemic circulation. Drug delivery by other
routes may result in only partial absorption and thus lower bioavailability.
Routes of drug administration-
The route of administration is determined primarily by the properties of the
drug (such as water or lipid solubility, ionization, etc.) and by the therapeutic
objectives. There are two major routes of drug administration, enteral and
parenteral. (Figure 6.3)
A. Enteral
1. Oral:
Giving a drug by mouth is the most common route of administration,
but it is also the most variable, and requires the most complicated
pathway to the tissues. Some drugs are absorbed from the stomach;
however, the duodenum is often the major site of entry to the systemic
circulation because of its larger absorptive surface.
2. Sublingual:
Placement under the tongue allows the drug to diffuse into the capillary
network and therefore to enter the systemic circulation directly.
Administration of an agent by this route has the advantage that the drug
bypasses the intestine and liver and is not inactivated by metabolism.
3. Rectal:
Fifty percent of the drainage of the rectal region bypasses the portal
circulation; thus the biotransformation of drugs by the liver is
minimized. Both the sublingual and the rectal routes of administration
have the additional advantage that they prevent the destruction of the
drug by intestinal enzymes or by low pH in the stomach. The rectal
route is also useful if the drug induces vomiting when given orally or if
the patient is already vomiting.
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4. Parenteral:
Parenteral administration is used for drugs that are poorly absorbed
from the gastrointestinal (GI) tract, and for agents such as insulin that
are unstable in the GI tract. Parenteral administration is used for
treatment of unconscious patients and under circumstances that require
a rapid onset of action. Parenteral administration provides the most
control over the actual dose of drug delivered body.
Fig. 6.3: Commonly used routes of drug administration. (lV=intravenous;

lM=intramuscular; SC= subcutaneous)
The three major parenteral routes are intravascular (intravenous or intra-

arterial), intramuscular, and subcutaneous.
89
a) Intravascular: Intravenous (IV) injection is the most common
parenteral route. For drugs that are not absorbed orally, there is often no
other choice. With IV administration, the drug avoids the GI tract and,
therefore, first-pass metabolism by the liver. This route permits a rapid
effect and a maximal degree of control over the circulating levels of the
drug.
b) lntramuscular (IM): Drugs administered intramuscularly can be
aqueous solutions or specialized depot preparations-often a suspension
of drug in a nonaqueous vehicle, such as ethylene glycol or peanut oil.
Absorption of drugs in aqueous solution is fast, whereas that from depot
preparations is slow. As the vehicle diffuses out of the muscle, the drug
precipitates at the site of injection. The drug then dissolves slowly,
providing a sustained dose over an extended period of time.
c) Subcutaneous (SC): This route of administration, like that of IM
injection, requires absorption and is somewhat slower than the IV route.
SC injection minimizes the risks associated with intravascular injection.
B. Other
1. Inhalation:
Inhalation provides the rapid delivery of a drug across the large surface
area of the mucous membranes of the respiratory tract and pulmonary
epithelium, producing an effect almost as rapidly as by intravenous
injection. This route of administration is used for drugs that are gases
(for example, some anesthetics), or those that can be dispersed in an
aerosol. The route is particularly effective and convenient for patients
with respiratory complaints (for example, asthma or chronic obstructive
pulmonary disease) as drug are delivered directly to the site of action
and systemic side effects are minimized.
2. Intranasal:
Desmopressin is administered intranasally in the treatment of diabetes
insipidus; salmon calcitonin, a peptide hormone used in the treatment of
osteoporosis, is available as a nasal spray.
3. Intrathecal/lntraventricular:
It is sometimes necessary to introduce drugs directly into the
cerebrospinal fluid (CSF), such as methotrexate in acute lymphocytic
leukemia.
90
4. Topical:
Topical application is used when a local effect of the drug is desired.
For example, clotrimazole is applied as a cream directly to the skin in
the treatment of dermatophytosis, and atropine is instilled directly into
the eye to dilate the pupil and permit measurement of refractive errors.
5. Transdermal:
This route of administration achieves systemic effects by application of
drugs to the skin, usually via a transdermal patch. The rate of absorption
can vary markedly depending upon the physical characteristics of the
skin at the site of application. This route is most often used for the
sustained delivery of drugs, such as the antianginal drug, nitroglycerin.
Factor affecting drug absorption-
 Blood flow to the absorption site: Blood flow to the intestine is much
greater than the flow to the stomach; thus absorption from the intestine
is favored over that from the stomach.
 Total surface area available for absorption: Because the intestine has
a surface rich in microvilli, it has a surface area about 1,000 times that
of the stomach; thus absorption of the drug across the intestine is more
efficient.
 Contact time at the absorption surface: If a drug moves through the
GI tract very quickly, as in severe diarrhoea, it is not well absorbed.
Conversely, anything that delays the transport of the drug from the
stomach to the intestine delays the rate of absorption of the drug.
 Aqueous solubility: A drug given as watery solution is absorbed faster
than when the same is given in solid form or as oily solution.
 Concentration: Passive diffusion depends on concentration gradient;
drug given as concentrated solution is absorbed faster than from dilute
solution.
 Route of administration: Drug absorption is slower through enternal
route than parenteral route.
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6.4 Transport across the membrane
All pharmacokinetic processes involve transport of the drug across biological
membranes. Biological membrane this is a bilayer (about 100 Å thick) of
phospholipid and cholesterol molecules, the polar groups (glyceryl phosphate
attached to ethanolamine/choline or hydroxyl group of cholesterol) of these are
oriented at the two surfaces and the nonpolar hydrocarbon chains are embedded
in the matrix to form a continuous sheet. Extrinsic and intrinsic protein
molecules are adsorbed on the lipid bilayer Glycoproteins or glycolipids are
formed on the surface by attachment to polymeric sugars, aminosugars or sialic
acids. The specific lipid and protein composition of different membranes differs
according to the cell or the organelle type. The proteins are able to freely float
through the membrane: associate and organize or vice versa. Some of the
intrinsic ones, which extend through the full thickness of the membrane,
surround fine aqueous pores. Paracellular spaces or channels also exist between
certain epithelial/endothelial cells. Other adsorbed proteins have enzymatic,
carrier, receptor or signal transduction properties.
Drugs are transported across the membrane by:
1. Passive diffusion and filtration
2. Specialized transport
1. Passive diffusion-
The drug diffuses across the membrane in the direction of its concentration
gradient. The drug molecules moves from higher concentration to lower
concentration. This process does not require energy. More soluble drugs attains
higher concentration in the membrance and diffuse quickly. ex diazepam. (Fig.
6.4)
 Filtration-
Filtration is passage of drug through aquous pores in the membrane is through
paracellular spaces. This can be accelerated by hydrodynamic flow of the
solvents. Pore size is about 4A. Filtration is depends upon the molecular size
and weight of the drug. If the drug molecules are smaller than the pores, they
are filtered easily through the membrane. The intestinal mucosal cells and
RBCS have very small pores about 40A however capillaries have large
paracelular spaces. (Fig. 6.4)
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2. Specialized transport-
This can be carrier mediated or by pinocytosis. All the cell membrance express
a transmembrane protein serve as a carriers or transporters. Transports
combines with their substracts, undergo a conformational changes carrying the
substrate to the other side of the membrane where the substrate dissociate and
the transports returns back to its original state. Depends upon the requirement
of energy, carrier transport in two types-
 Facilitated diffusion
 Active transport
 Facilitated diffusion-
This is a type of carrier mediated transport. It does not require energy. The drug
attaches to a carriers in the membrane, which facilitates its diffusion across the
membrane. The molecules transport from lower concentration to higher
concentration. (Fig. 6.4) Eg: absorption of vit.B12 from gut, transport of amino
acids into the brain.
 Active diffusion-
The drug molecules move from a region of low concentration to high
concentration against the concentration gradient. It requires energy. (Fig. 6.4)
Eg. Transport of choline into cholinergic neurons.
 Pinocytosis-
It is the process of transport across the cell in particulate from by formation of
vesicles. (Fig. 6.4)
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Fig. 6.4: Transport of the drug across the membrane
6.5 Distribution
Distribution is the delivery of drug from the systemic circulation to tissues.
Once a drug has gained access to the blood stream, it gets distributed to other
tissues that initially had no drug, concentration gradient being in the direction
of plasma to tissues. Distribution is defined as the reversible transfer of drugs
between body fluid compartments. After drug absorption, a drug enters the
systemic circulation and is distributed in the body fluids. Distribution of a drug
depends on its-
 Lipid solubility
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 Ionization at physiological pH
 Extent of binding to plasma and tissue proteins
 Presence of tissue specific transporters
 Differences in regional blood flow
Apparent volume of distribution-
Is defined as the hypothetical volume of blood fluid into which a drug is
uniformly distributed at a concentration equal to that in plasma, assuming the
body to be a single compartment.
Redistribution-
Highly lipid soluble drug such as thiopentone , on i.v administration
immediately gets distributed to areas of high blood flow such as brain and
causes general anaesthesia. Immediately within a few minutes, it recrosses the
BBB and gets distributed into the blood and then to the less perfused tissues
such as muscle and adipose tissue.
Binding of drugs to plasma proteins
Most drugs found in the vascular compartment are bound reversibly with one or
more of the macromolecules in plasma. Although some drugs simply dissolve
in plasma water, most are associated with plasma components such as albumin,
globulins, transferrin, ceruloplasmin, glycoproteins, and α and β lipoproteins.
While many acidic drugs bind principally to albumin, basic drugs frequently
bind to other plasma proteins, such as lipoproteins and α1-acid glycoprotein
(α1-AGP), in addition to albumin. The extent of this binding will influence the
drug’s distribution and rate of elimination because only the unbound drug can
diffuse through the capillary wall, produce its systemic effects, be metabolized,
and be excreted.
Blood-brain barrier (BBB)-
In order to enter the brain, drugs must pass through the endothelial cells of the
capillaries of the central nervous system (CNS) or be actively transported.
Lipid-soluble drugs readily penetrate into the CNS, since they can dissolve in
the membrane of the endothelial cells. Ionized or polar drugs generally fail to
enter the CNS, since they are unable to pass through the endothelial cells of the
95
CNS, which have no slit junctions. These tightly juxtaposed cells form tight
junctions that constitute the so called blood-brain barrier.
Blood-Testis Barrier-
The existence of a barrier between the blood and testes is indicated by the
absence of staining in testicular tissue after the intravascular injection of dyes.
Morphological studies indicate that the barrier lies beyond the capillary
endothelial cells and is most likely to be found at the specialized Sertoli–Sertoli
cell junction. It appears that Pgp, the efflux transporter protein, also plays a role
in forming this blood-testis barrier. This protein probably plays a role in
preventing certain chemotherapeutic agents from reaching specific areas of the
testis and thus hinders treatment of the neoplasm.
Placental Barrier-
The blood vessels of the fetus and mother are separated by a number of tissue
layers that collectively constitute the placental barrier. Drugs that traverse this
barrier will reach the fetal circulation. The placental barrier, like the blood-
brain barrier, does not prevent transport of all drugs but is selective, and factors
that regulate passage of drugs through any membrane (e.g., pKa, lipid
solubility, protein binding) are applicable here.
In general, substances those are lipid soluble cross the placenta with relative
ease in accordance with their lipid–water partition coefficient and degree of
ionization. Highly polar or ionized drugs do not cross the placenta readily.
However, most drugs used in labor and delivery are not highly ionized and will
cross. They are generally weak bases with pKa values of about 8 and tend to be
more ionized in the fetal bloodstream, since the pH of fetal blood is around 7.3
as compared with the maternal blood pH of 7.44. Differences in maternal and
fetal blood pH can give rise to unequal concentrations of ionizable drugs in the
mother and the fetus.
Factors influencing drug distribution-
These include:
1 Capillary permeability,
2 Blood flow–tissue mass ratio (i.e., perfusion rate),
3 Extent of plasma protein and specific organ binding,
4 Regional differences in ph,
5 Transport mechanisms available, and
6 The permeability characteristics of specific tissue membranes.
96
6.6 Metabolism
Metabolism (Biotransformation) means chemical alteration of the drug in the
body. It is needed to render nonpolar (lipid-soluble) compounds polar (lipid
insoluble) so that they are not reabsorbed in the renal tubules and are excreted.
The primary site for drug metabolism is liver; others are—kidney, intestine,
lungs and plasma. Some agents are initially administered as inactive
compounds (pro-drugs) and must be metabolized to their active forms.
Reactions of drug metabolism
The kidney cannot efficiently eliminate lipophilic drugs that readily cross cell
membranes and are reabsorbed in the distal tubules. Therefore, lipid-soluble
agents must first be metabolized in the liver using two general sets of reactions,
called Phase I and Phase II reactions.
 Phase I/Nonsynthetic/ Functionalization reactions: a functional group
is generated or exposed—metabolite may be active or inactive.
 Phase II /Synthetic/Conjugation reactions: metabolite is mostly
inactive; except few drugs, e.g. glucuronide conjugate of morphine and
sulfate conjugate of minoxidil are active.
Phase I: Phase I reactions function to convert lipophilic molecules into more
polar molecules by introducing or unmasking a polar functional group, such as -
OH, or -NH2. Phase I metabolism may increase, decrease, or leave unaltered the
drug's pharmacologic activity.
Phase II: This phase consists of conjugation reactions. If the metabolite from
Phase I metabolism is sufficiently polar, it can be excreted by the kidneys.
However, many metabolites are too lipophilic to be retained in the kidney
tubules. A subsequent conjugation reaction with an endogenous substrate, such
as glucuronic acid, sulfuric acid, acetic acid or an amino acid results in polar,
usually more water-soluble compounds that are most often therapeutically
inactive. Glucuronidation is the most common and the most important
conjugation reaction. (Fig. 6.6)
97
Fig. 6.6: Metabolism of a drug by phase I and phase II reactions
6.7 Elimination
Removal of the drug and its metabolite from the body is known as drug
excretion. The main channel of excretion of drugs are the kidneys, others
include lungs, bile, feces, sweat, saliva, tears etc.
Drugs and their metabolites are excreted in:
 Urine- It is the most important channel of excretion for majority of
drugs.
 Faeces- Most of the drug present in faeces is derived from bile.
Macromolecules (MW > 300) are preferentially eliminated in the bile.
Liver transports into bile organic acids (especially drug glucuronides),
organic bases and steroids by nonspecific active transport mechanisms.
Some drugs are excreted directly in colon, e.g. anthracene purgatives,
heavy metals.
 Exhaled air- Gases and volatile liquids such as general anaesthetics,
paraldehyde, alcohol are eliminated by lungs. Lungs also serve to trap
and extrude any particulate matter injected i.v.
 Saliva and sweat-These are of minor importance for drug excretion.
However, Lithium, pot. Iodide, rifampin and heavy metals are excreted
through this way.
 Milk- Most drugs enter breast milk by passive diffusion, such as more
lipid soluble and less protein bound drugs. However, the excretion of
drug in milk is received by the suckling infant. Milk has a lower pH
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(7.0) than plasma, basic drugs are more concentrated in it. Although, the
total amount of drug reaching the infant through breast feeding is
generally small and majority of drugs can be given to lactating mothers
without ill effects on the infant.
Renal excretion-
The amount of drug or its metabolites ultimately present in urine is the sum
total of glomerular filteration, tubular reabsorption and tubular secretion. (Fig.
6.7)
Glomerular filtration- In the capillaries of glomerulus, larger pores are found
which are able to filter all non protein bound drugs. In renal failure or after the
age of 50 glomerular rate decreases progressively.
Tubular reabsorption- Lipid-soluble drugs filtered at the glomerulus back
diffuse in the tubules because 99% of glomerular filtrate is reabsorbed, but
nonlipidsoluble and highly ionized drugs are unable to do so.
Afferent Arteriole Efferent Arteriole
Fig. 6.7: Renal excretion of drugs

Tubular reabsorption depends on lipid solubility and ionization of the drug at
the existing urinary pH. If changes in urinary pH occur, it affects tubular
reabsorption of drugs in the following way:
99
 Weak acids ionize more and are less reabsorbed in alkaline urine.
 Weak bases ionize more and are less reabsorbed in acidic urine.
Tubular secretion- This is the active transfer of organic acids and bases.
Tubular transport mechanisms are not well developed at birth. Duration of
action in many drugs, example penicillin, aspirin cephalosporins etc. is longer
in neonates. These systems mature during infancy.
Clinical Implications of Renal Excretion
The rate of urinary drug excretion will depend on the drug’s volume of
distribution, its degree of protein binding, and the following renal factors:
1. Glomerular filtration rate
2. Tubular fluid pH
3. Extent of back-diffusion of the unionized form
4. Extent of active tubular secretion of the compound
5. Possibly, extent of active tubular reabsorption
6.8 Pharmacokinetics of Elimination

Drug elimination is the sum total of metabolic inactivation and excretion. The
pharmacokinetics of elimination of a drug gives an idea to devise rational
dosage regimens and to modify them according to individual needs.
Pharmacokinetic of elimination, such as :
1. Clearance (CL)
2. Plasma half life
3. Bioavailability (F)
1 Clearance [CL]-
The clearance of a drug is defined as the fraction of the apparent volume of the
distribution from which the drug is removed in unit time.
CL = Rate of elimination / plasma concentration of the drug
 First order kinetics-

The rate of elimination is directly proportional to the drug concentration, CL
remains constant; or a constant fraction of the drug present in the body is
eliminated in unit time.
100
 Zero order kinetics-
The rate of elimination remains constant irrespective of drug concentration,
CL decreases with increase in concentration; or a constant amount of the drug
is eliminated in unit time.
2. Plasma half life (t1/2)-
It is the time required for the plasma concentration of the drug to decrease by
50% of its original value.
Clinical importance of plasma half-life –
 Determine the duration of drug action
 Determine the frequency of drug administration
 Estimate the time required to reach the steady
3. Bioavailability (F)-
Bioavailability refers to the rate and extent of absorption of a drug from a
dosage form. It is a measure of the fraction (F) of administered dose of a drug
that reaches the systemic circulation in the unchanged form. Bioavailability of
drug injected i.v. is 100%, but is frequently lower after oral ingestion because—
 The drug may be incompletely absorbed.
 The absorbed drug may undergo first pass metabolism in the intestinal
wall/liver or be excreted in bile.
6.9 Summary
When a drug enters the body, the body begins immediately to work on the drug:
absorption, distribution, metabolism (biotransformation), and elimination.
These are the processes of pharmacokinetics. These processes modify specific
pharmacokinetic parameters. Absorption is the passage of the drug from its site
of administration into the blood; distribution is the delivery of the drug to the
tissues. Drug metabolism changes the chemical structure of a drug to produce a
drug metabolite, which is frequently but not universally less pharmacologically
active. Metabolism also renders the drug compound more water soluble and
therefore more easily excreted. The two basic parameters are clearance, the
measure of the ability of the body to eliminate the drug; and volume of
distribution, the measure of the apparent space in the body available to contain
the drug.
101
6.10 Glossary
 Antianginal- Preventing or relieving angina pectoris.
 Dermatophytes- They are fungi that can cause infections of the skin,
hair and nails.
 Depot preparations- A substance in a form that tends to keep in at the
site of injection so that absorption occurs over a long period.
 Extra vascular route- Outside a vessel.
 Portal circulation- The circulation of blood through liver.

1. What is pharmacokinetics?
2. Discuss the factors of absorption, distribution, metabolism and excretion.
3. Discuss the pharmacokinetic parameters of elimination.
4. Define drug disposition.
5. Enumerate the methods of route of drug administration.
6. Discuss the merits and demerits of route of drug administration.
7. Write a short note on parenteral route.
8. Discuss the processes which are involved in translocation of the drug.
9. Explain the metabolic reactions.
10. What are the phase II reactions? Give example.
Mahadik, Dr. K.G. Bothara(Nirali prakashan) 2007.
 Pharmacology (5th ed.)- H.P Rang and M.M Dale (Elsevier publisher) 2003.
 Essential of Medical Pharmacology (7th ed.)- KD Tripathi (JAYPEE
Publisher) 2013.
102
Unit - 7
Pharmacokinetic-II
Structure of Unit:
7.1 Objectives
7.2 Introduction
7.3 Pharmacokinetic
7.4 Absorption
7.5 Disposition
7.6 Distribution
7.7 Elimination and clearance
7.8 Plasma half life
7.9 Bioavailability
7.10 Pharmacokinetic in drug development process
7.11 Summary
7.12 Glossary
7.1 Objectives
 We study different parameters of pharmacokinetics by which drug has
maximum efficacy and minimum toxicity.
 Using these parameters calculate the dose of drug in individual patient
that is safe for patients.
 Pharmacokinetic is very useful in development of formulation by which
drug show maximum effectiveness.
 We describe the main pathways of drug elimination by the kidney and
biliary excretion.
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 We presents a simple approach to quantitative pharmacokinetics,
explaining how drug clearance determines the steady-state plasma
concentration
 How the characteristics of absorption and distribution and excretion,
determine the time course of drug concentration in the blood before and
after steady state and how these vary with different dosing regimens.
7.2 Introduction
The goal of therapeutics is to achieve a desired beneficial effect with minimum
adverse effects. For this purpose clinician must determine the dose that most
closely to achieve this goal. A rational approach of this objective combines the
principles of pharmacokinetic with pharmacodyanamic to clarify the dose effect
relationship. Pharmacodyanamics is related to concentration-effect part of the
interaction whereas the pharmacokinetic deals with dose-concentration part.
The pharmacokinetic process of absorption, distribution and elimination
determine how rapidly and for how long the drug will appear at target organ.
The pharmacodyanamic concept of maximum response and sensitivity
determine the magnitude of the effect at a particular concentration. The
relationship between dose, drug concentration and effects allows the clinician to
consider the various pathologic and physiologic condition of a particular patient
that makes him or her different from the average individual in responding to a
drug.
7.3 Pharmacokinetics
The standard dose of the drug is based on trials in healthy volunteers and
patient with average ability to absorb, distribute and eliminate the drug. This
dose will not be suitable for every patient. Dose of drug in individual patient
depends on physiologic (e.g. Maturation of organ functions in infants) and
pathologic conditions (e.g. Heart failure, renal failure). The two basic
parameters are clearance and volume of distribution. Pharmacokinetic is
defined as the kinetics of drug absorption, distribution, metabolism and
excretion and their relationship with the pharmacological, therapeutic and
toxicological response in human being.
104
Fig.7.1: The relationship between dose and effect can be separated into
pharmacokinetic (dose-concentration) and pharmacodynamic (concentration-
effect) components.
Pharmacokinetic means movement of drug. It means pharmacokinetic is the
study and characterization of the time course of drug absorption, distribution,
metabolism and excretion. It is a quantitative study of drug movement inside
and outside of the body. Pharmacokinetic consideration determines the route of
drug administration, dose, time of peak action, duration of action and frequency
of administration of drug. Pharmacokinetic is used in clinical setting to enhance
the safe and effective therapeutic management of individual patient.
There are some important pharmacokinetic parameters like absorption,
distribution, metabolism and excretion.
7.4 Absorption
Absorption is movement of drug from its site of administration into the
circulation, not only part of administered dose that gets absorbed, but also the
rate of absorption is important except when given intravenously, the drug has to
cross the biological membranes.
7.5 Disposition
Disposition means what happen with drug after absorption. In other terms it is a
process that tends to lower the plasma concentration of drug. In this parameter
distribution, metabolism and excretion processes are includes that reduce the
plasma concentration of drug. After absorption drug reached into blood stream,
drugs are simultaneously distributed throughout the body and eliminated.
105
7.6 Distribution
After administration of drug in the blood stream, it is ready to distribute to other
tissues. The transfer of drug from blood to extracellular fluids and tissue is
called distribution. Distribution of drugs depends upon its
 Solubility in lipids
 Differences in regional blood flow
 Binding to plasma and tissue proteins
 Ionization at physiological pH
The distribution of drug continuous till equilibrium occurs between unbound
drug in plasma and tissue fluids. A drug is circulated to various organ and tissue
from blood. When the process of distribution is complete, different organ and
tissues contain varying concentration of drug which can be varied according to
blood perfusion rate and volume of tissue. There is direct relationship between
the concentration of drug in plasma (C) and amount of drug in the body (X).
XαC
X= Vd x C
Vd is proportionality constant having the unit volume and popularly called as
apparent volume of distribution.
Vd is defined as the hypothetical volume of body fluid into which drug is
dissolved or distributed. Volume of distribution is calculated as follows:
The unit of measurement of volume of distribution is ml.

The transfer of drug from blood to extracellular fluids and tissue is called
distribution.
106
Fig.
7.2: Schematic representation of drug absorption, distribution and elimination
7.7 Drug elimination and clearance

Drug elimination:
It is a process in which transfer of pure drug or metabolite product of drug from
blood to urine or other excretory compartment. Drugs are removed from the
body by various elimination processes. Drug elimination refers to irreversible
removal of drug from the body by all route of elimination. Drug elimination is
usually divided into two major components: biotransformation and excretion.
Biotransformation or drug metabolism is the process by which the drug is the
drug is chemically converted in the body to a metabolite. Biotransformation is
usually an enzymatic process. The enzymes involved in the biotransformation
of drugs are located mainly in the liver.
Drug excretion is the removal of intact drug. Nonvolatile drugs are excreted
mainly by renal excretion. Volatile drug such as gaseous anaesthetics or drugs
with high volatility, are excreted via lungs into aspired air. Drug elimination is
described in terms of clearance from well stirred compartments containing
uniform drug distribution.
Clearance:
Clearance describes the process of drug elimination from the body or from a
single organ. Clearance may be defined as volume of drug in fluid cleared from
the body per unit time. The units of clearance are milliliters per minute
(ml/min) or liter per hour (L/hr). Drug elimination rate in terms of amount of
drug removed per unit time (mg/min).
Clearance is calculated as:
Cl= Rate of elimination / C
Where C is plasma concentration
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Clearance may also be defined as the rate of drug elimination divided by
plasma drug concentration.
ClT = Elimination rate / Plasma concentration

= dDE/ dt
Cp
Where DE is amount of drug eliminated and dDE/dt is the rate of elimination.

Drug clearance is a pharmacokinetic term for describing drug elimination from
the body. Drug clearance (body clearance, total body clearance or ClT)
considered the entire body as a single drug eliminating system from which
many unidentified elimination process may occur.
It is important to note the additive character of clearance. Elimination of drug
from the body may involve processes occurring in the kidney, the lung, the
liver, and other organs. Dividing the rate of elimination at each organ by the
concentration of drug presented to it yields the respective clearance at that
organ. Added together, these separate clearances equal total systemic clearance:
Renal Clearance: Renal clearance is defined as the volume of blood or plasma

that is cleared of drug per unit time through the kidney.
ClR = Excretion rate/ Plasma concentration

= dDU /dt
CP
Renal drug excretion: Renal excretion is major route of elimination for many
drugs. The process by which the drug is excreted via the kidney may include
 Glomerular filteration
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 Active tubular secreation
 Tubular reabsorption
Renal clearance is the ratio of “sum of sum rate of glomerular filteration and
active screation minus rate of reabsorption to plasma drug concentration”
Renal clearance =
The two major sites of drug elimination are the kidneys and the liver. Clearance
of unchanged drug in the urine represents renal clearance. Within the liver, drug
elimination occurs via biotransformation of parent drug to one or more
metabolites, or excretion of unchanged drug into the bile, or both. For most
drugs, clearance is constant over the concentration range encountered in clinical
settings, i.e., elimination is not saturable, and the rate of drug elimination is
directly proportional to concentration.
Rate of elimination = CL x C
This is usually referred to as first-order elimination. When clearance is first-
order, it can be estimated by calculating the area under the curve (AUC) of the
time-concentration profile after a dose. Clearance is calculated from the dose
divided by the AUC.
The different kinetic models are describes by clearance:
1. Capacity-Limited Elimination: For drugs that exhibit capacity-
limited elimination (eg, phenytoin, ethanol), clearance will vary
depending on the concentration of drug that is achieved. Capacity-
limited elimination is also known as saturable, dose- or concentration-
dependent, nonlinear, and Michaelis-Menten elimination.
Most drug elimination pathways will become saturated if the dose is
high enough. When blood flow to an organ does not limit elimination,
the relation between elimination rate and concentration (C) is expressed
mathematically as follow:
The maximum elimination capacity is Vmax, and Km is the drug

concentration at which the rate of elimination is 50% of Vmax. At
concentrations that are high relative to the Km, the elimination rate is
109
almost independent of concentration—a state of "pseudo-zero order"
elimination. If dosing rate exceeds elimination capacity, steady state
cannot be achieved: The concentration will keep on rising as long as
dosing continues. This pattern of capacity-limited elimination is
important for three drugs in common use: ethanol, phenytoin, and
aspirin. Clearance has no real meaning for drugs with capacity-limited
elimination, and AUC cannot be used to describe the elimination of such
drugs.
2. Flow-Dependent Elimination: In contrast to capacity-limited drug
elimination, some drugs are cleared very readily by the organ of
elimination, so that at any clinically realistic concentration of the drug,
most of the drug in the blood perfusing the organ is eliminated on the
first pass of the drug through it. The elimination of these drugs will thus
depend primarily on the rate of drug delivery to the organ of
elimination. Such drugs can be called "high-extraction" drugs since they
are almost completely extracted from the blood by the organ. Blood
flow to the organ is the main determinant of drug delivery, but plasma
protein binding and blood cell partitioning may also be important for
extensively bound drugs that are highly extracted.
There are several other route of drug excretion called non renal route of drug
excretion. The various such excretion processes are:
1. Biliary excretion: the ability of liver to excrete the drug in bile is
expressed by biliary clearance.
Biliary clearance =
2. Pulmonary excretion: Gaseous and volatile substances such as the general

anaesthetics are absorbed through the lungs by simple diffusion.
3. Salivary excretion: Excretion of drug through saliva is a passive diffusion
process. The bitter after taste in the mouth of patient on medication is an
indication of drug excretion in saliva. The process is responsible for side
effects such as black hairy tongue in patient receiving antibiotics.
4. Mammary excretion: Excretion of drug in milk is important since it can
entered into the breast feeding infant.
5. Skin/ dermal excretion: Drugs excreted through the skin via sweat.
Passive excretion of drugs and their metabolites through skin is responsible
110
to some extent for the urticaria and dermatitis and other hypersensitivity
reactions.
6. Gastrointestinal excretion: Excretion of drug through GIT usually occur
after parenteral administration when the concentration gradient favorable
for passive diffusion.
7. Genital excretion: reproductive tract and genital secretions may contain
the excreted drugs. Some drugs have been detected in semen.
7.8 Plasma half life
It is the time taken by the drug for its plasma concentration to be reduced to
half of its original value. At least distribution half life and elimination half life
can be calculated.
When the drug is given intravenously, which have one compartment
distribution and first order of elimination. A plot is drawn between plasma
concentration and time, which show two slopes:
 Due to distribution, initially declining an α- phase.
 Due to elimination, later less declining ß-phase
The elimination half life is called ‘half life’ of drugs.

Elimination t1/2 is:
T1/2=
111
Where ln 2 is natural logarithm of 2 or 0.693
K= elimination rate constant of the drug i.e., the fraction of total amount of
drug in the body which are removed in per unit time.
K = Cl/Vd
Now t1/2 = 0.693 x Vd / Cl
Repeated drug administration: if drug is repeated in ashort duration of time, it
accumulate in the body unless elimination balances input and a steady state
plasma concentration (Css) is attained. Css is expressed as:
CSS =
If the therapeutic plasma concentration of drug and clearance is known than the
dose rate can be obtained as:
Dose rate = Target CSS Χ Clearance
If a drug is taken orally only a fraction of dose reaches in systemic circulation
in the active form, in this case:
Dose rate =
Target level strategy: For those drugs whose effects are not easily quantifiable
and safety margin is small than target level strategy is best to achieve a certain
plasma concentration.
Drugs with small t1/2, means upto 2-3 hours, are administered at conventional
intervals. Generally 6-12 hours are required to achieve target levels.
Drugs whose t1/2, is longer a dose which is sufficient to attain the target
concentration after single administration. If repeated administration of dose
will be given than drug will accumulate and produce toxicity. If the dose is such
as to attain target level at steady state, the therapeutic effect will be delayed by
about 4 half lives. These drugs are generally taken by initial loading dose and
maintenance dose.
Loading Dose: Loading dose is a single or few rapidly repeated doses which
are given in the beginning to attain target concentration, it may be expressed.
Loading dose:=
112
Maintenance dose:
In most clinical situations, drugs are administered in such a way as to maintain
a steady state of drug in the body, ie, just enough drug is given in each dose to
replace the drug eliminated since the preceding dose. Thus, calculation of the
appropriate maintenance dose is a primary goal. Clearance is the most
important pharmacokinetic term to be considered in defining a rational steady
state drug dosage regimen. At steady state, the dosing rate ("rate in") must
equal the rate of elimination ("rate out").
Maintenance dose = Clearance x CSS
= Dosing rate x dosing interval
Thus, if the desired target concentration is known, the clearance in that patient
will determine the dosing rate. If the drug is given by a route that has a
bioavailability less than 100%, then the dosing rate will be predicted.
Note that the steady-state concentration achieved by continuous infusion or the
average concentration following intermittent dosing depends only on clearance.
The volume of distribution and the half-life need not be known in order to
determine the average plasma concentration expected from a given dosing rate
or to predict the dosing rate for a desired target concentration.
Fig.7. 3: Relationship between dose rate and average steady state plasma
concentration of drugs eliminated by first order and zero order kinetics
113
7.9 Bioavailability
Bioavailability is defined as the fraction of unchanged drug reaching the
systemic circulation after administration by any route. The area under the blood
concentration- time curve (area under the curve, AUC) is a common measure of
the extent of bioavailability for a drug given by a particular route. For an
intravenous dose of the drug, bioavailability is assumed to be equal to unity.
For a drug administered orally, bioavailability may be less than 100% because
 Incomplete extent of absorption
 First-pass elimination
Extent of Absorption: After oral administration, a drug may be incompletely
absorbed. This is mainly due to lack of absorption from the gut. Other drugs are
either too hydrophilic (eg, atenolol) or too lipophilic (eg, acyclovir) to be
absorbed easily, and their low bioavailability is also due to incomplete
absorption. If too hydrophilic, the drug cannot cross the lipid cell membrane, if
too lipophilic; the drug is not soluble enough to cross the water layer adjacent
to the cell. Drugs may not be absorbed because of a reverse transporter
associated with P-glycoprotein. This process actively pumps drug out of gut
wall cells back into the gut lumen. Inhibition of P-glycoprotein and gut wall
metabolism, eg., by grapefruit juice, may be associated with substantially
increased drug absorption.
First-Pass Elimination: After absorption of drug across the gut wall, the portal
blood delivers the drug to the liver prior to entry into the systemic circulation.
A drug can be metabolized in the gut wall (eg, by the CYP3A4 enzyme system)
or even in the portal blood, but most commonly it is the liver that is responsible
for metabolism before the drug reaches the systemic circulation. In addition, the
liver can excrete the drug into the bile. Any of these sites can contribute to this
reduction in bioavailability, and the overall process is known as first-pass
elimination.
Rate of absorption: The rate of absorption is determined by the site of
administration and the drug formulation. Both the rate of absorption and the
extent of input can influence the clinical effectiveness of a drug. The
mechanism of drug absorption is said to be zero-order when the rate is
independent of the amount of drug remaining in the gut. In contrast, when the
full dose is dissolved in gastrointestinal fluids, the rate of absorption is usually
proportional to the gastrointestinal concentration and is said to be first-order.
114
Oral formulation of a drug from different manufacturers or different batches
from the same manufacturer may have the same quantity (chemically
equivalent) of drug but may not yield same blood level (biologically
equivalent).
If the rate and extent of bioavailability of drug is not different under suitable
test conditions, two preparation of drug are considered bioequivalent.
As the figure given below, B is more slowly absorbed than A, B may not
produce therapeutic effect and C is absorbed to lesser extent that means has
lower bioavailability.
Fig.7. 4: Plasma concentration time curve showing bioavailability differences

between three cases of drug having same amount
7.10 Pharmacokinetic in drug development process

To use a drug for longer time, it is generally advantageous to modify a drug by
following manner:
 If frequency of administration of a drug is reduced, it may be used for a
longer period.
 It is better to use a contraceptive monthly or quarterly rather than to be
taken daily.
 A single monitoring dose is less likely to be forgotten than a 6 or 8
hourly regimen.
 Drug effect could be maintained overnight without disturbing sleep.
 Large fluctuations in plasma concentration are avoided.
115
The processes which are utilized for developing a drug and its action are given
as follows:
1. By prolonging absorption from site of administration:
a. Oral: Drug particles are coated with resins, plastic materials etc. which
disperse release of the active ingredients in the GIT. A semi permeable
membrane is used to control the release of drug from the tablet and capsule.
This technique may prolong the action by 4 to 6 hours and not beyond this
time because in that time drug particles reach in the colon.
b. Parenteral: The subcutaneous and intramuscular injection of drug in
insoluble form or as oily solution pallet implantation and biodegradable
implant may develop a drug action.
c. Transdermal drug delivery: The drug which is used as ointment, in
adhesive patchs, or strips applied on skin is becoming popular.
2. By increasing plasma protein binding: Development of drugs have been
made by increasing plasma protein binding which may be slowly released
in the free active form e.g. Sulphadoxine.
3. By retarding rate of metabolism: Some small chemical modifications
may affect the rate of metabolism without affecting the biological action,
such as addition of ethinyl group in estradiol makes it longer acting and
suitable for use as oral contraceptive.
4. By retarding renal excretion: The tubular secretion of drugb being an
active process which can be reduced by a competing substance, for
instance, probenecid prolongs time of action of penicillin and ampicillin.
7.11 Summary
The basic tenet of pharmacokinetic is that the magnitude of both the desired
response and toxicity are functions of drug concentration in blood. It is not only
the efficacy of a drug at the site of action that determine the intensity and
duration of its pharmacologic or therapeutic effects but also the amount of drug
and the rate at which the drug gets to the site of action. The vital process of the
body may delay the transport of drug molecules across membranes, convert
drug molecule into metabolites, and remove them from body as metabolites
and/or unchanged form. In this results, therapeutic failure as a result of drug
concentration being too low or unacceptable toxicity as a consequence of too
high drug concentration. Between these limits of concentration lies a region
associated with therapeutic success. The region may be regarded as a
therapeutic range or “therapeutic window”
116
7.12 Glossary
Area under the curve: It represents the total integrated area under the plasma
level time profile and expresses the total amount of drug that comes into the
systemic circulation after its administration.
Pharmacodyanamic: It is the study of drug effects
Heart failure: In ability of the heart to circulate blood effectively enough to
meet the body metabolic needs.
Renal failure: Raise in the serum creatinin level of 25% or more
Physiological pH: pH of the blood circulation
Blood perfusion: The blood goes into the particular organ by the artery.
Steady state concentration: The concentration of drug in plasma approaches a
constant value.
Urticaria: Multiple swollen raised areas on the skin that is intensely itchy
Dermatitis: An inflammatory rash marked by the itching and redness.
1. Define- (a) disposition and (b) distribution.
2. It is better to express Vd in liters/Kg body weight. Why?
3. What are various non renal route of drug excretion?
4. What is the reason bitter after taste of medicament in patient on drug
therapy?
5. What are the importances of pharmacokinetic in drug development
process?
6. Explain the extent of absorption and first pass elimination.
7. Write and explain the renal excretion.
8. Express the relationship between pharmacokinetic and pharmacodyanamic.
9. Why drugs show lower bioavailability?
 Foye’s Principles of Medicinal Chemistry, David A. Williams, Thomas L.
Lemke (Fifth edition) 2005, B.I. Publication and Pvt. Ltd.
 Biopharmaceutics and Pharmacokinetics A Treatise, D. M. Bramankar and
Sunil B. Jaiswal (First edition) 1995 Vallabh Prakashan
117
 Essential of Medical Pharmacology (Seventh edition)- KD Tripathi
(JAYPEE Publisher) 2013.
 Basic & Clinical Pharmacology (ninth edition)- Bertram G.Katzung (Mc
Graw Hill Publisher) 2004.
118
Unit - 8
Pharmacodynamics-I
Structure of Unit:
8.1 Objectives
8.2 Introduction: Pharmacodynamics
8.3 Enzymes
8.4 Mechanisms of enzyme catalysis
8.5 Elementary treatment of enzyme stimulation
8.6 Enzyme inhibition
8.7 Sulfonamides
8.8 Summary
8.9 Glossary
8.1 Objectives
The aim of this chapter is to present current approaches to
 Pharmacodynamics
 Mechanisms of drug action
 Enzyme
 Enzyme stimulation
 Enzyme inhibition
 Sulfonamides
Pharmacodynamics is the study of drug effects. It attempts to elucidate the
complete action-effect sequence and the dose-effect relationship. Modification
of the action of one drug by another drug is also an aspect of
pharmacodynamics.
Pharmacodynamics is the study that establishes and elucidates relationships
between concentrations of a drug at the receptor or target organ (effect site) and
the intensity of its pharmacological effect. Pharmacodynamic studies can
provide a means for identifying important pharmacological and toxicological
119
properties of a drug in animals and humans, including, e.g., efficacious target
concentrations, drug safety margin, potential risk factors, and the presence of
active metabolites. The effect site (site of action) of a drug can be a target
receptor/enzyme(s) or an organ(s) where the initial pharmacological responses
to the drug are produced.
Enzymes are special types of receptors. The receptors discussed in Chapter 3
are mostly membrane-bound proteins that interact with natural ligands and
agonists to form complexes that then elicit a biological response. Subsequent to
the response, the ligand is released intact. Enzymes, most of which are soluble
and found in the cytosol of cells, interact with substrates to form complexes,
but, unlike receptors, it is from these enzyme–substrate complexes that
enzymes catalyze reactions, thereby transforming the substrates into products
that are released. Therefore, the two characteristics of enzymes are their ability
to recognize a substrate and to catalyze a reaction with it.
8.3 Enzymes
Enzymes are natural proteins that catalyze chemical reactions; ribonucleic acids
(RNA) also can catalyze chemical reactions. The first enzyme to be recognized
as a protein was jack bean urease, which was crystallized in 1926 by Sumner
and was shown to catalyze the hydrolysis of urea to CO2 and NH3.
Almost all biological reactions are carried out under catalytic influence of
enzymes; hence, enzymes are a very important target of drug action. Drugs can
either increase or decrease the rate of enzymatically mediated reactions.
However, in physiological systems enzyme activities are often optimally set.
Thus, stimulation of enzymes by drugs, that are truly foreign substances, is
unusual. Enzyme stimulation is relevant to some natural metabolites only, e.g.
pyridoxine acts as a cofactor and increases decarboxylase activity. Several
enzymes are stimulated through receptors and second messengers, e.g.
adrenaline stimulates hepatic glycogen phosphorylase through β receptors and
cyclic AMP. Stimulation of an enzyme increases its affinity for the substrate so
that rate constant (kM) of the reaction is lowered. Apparent increase in enzyme
activity can also occur by enzyme induction, i.e. synthesis of more enzyme
protein. This cannot be called stimulation because the kM does not change.
How do Enzymes Work?
Following scheme shows a generalized scheme for an enzyme-catalyzed
reaction, where S is the starting reactant (substrate), E is the enzyme, TS is the
transition state, and P is the product. In general, enzymes function by lowering
120
transition state energies and energetic intermediates and by raising the ground
state energy (ground state destabilization). The transition state for an enzyme-
catalyzed reaction, just as in the case of a chemical reaction, is a high energy
state having a lifetime of about 10−14 s, the time for one bond vibration. There
is no spectroscopic method that can detect the transition state structure in an
enzyme.
Ks kcat
E+S E*S E*TS E*P E+P
An enzyme-catalyzed reaction always is initiated by the formation of an
enzyme–substrate (or E·S) complex, from which the catalysis takes place. The
concept of an E·S complex was originally proposed independently in 1902 by
Brown and Henri; this idea is an extension of the 1894 lock and key hypothesis
of Fischer in which it was proposed that an enzyme is the lock into which the
substrate (the key) fits. These curiosities led Koshland in 1958 to propose the
induced-fit hypothesis discussed in relationship to receptors in Chapter-3, when
a substrate begins to bind to an enzyme, interactions of various groups on the
substrate with particular enzyme functional groups are initiated, and these
mutual interactions induce a conformational change in the enzyme.
Enzyme catalysis is characterized by two features: specificity and rate
acceleration. The active site contains moieties that are responsible for both of
these properties of an enzyme, namely, amino acid residues and, in the case of
some enzymes, cofactors. A cofactor, also called a coenzyme, is an organic
molecule or a metal ion that binds to the active site, in some cases covalently
and in others non-covalently, and is essential for the catalytic action of those
enzymes that require cofactors.
8.4 Mechanisms of enzyme catalysis
Once the substrate binds to the active site of the enzyme via the interactions
noted in Chapter 3, there are a variety of mechanisms that the enzyme can
utilize to catalyze the conversion of the substrate to product. The most common
mechanisms are approximation, covalent catalysis, general acid–base catalysis,
electrostatic catalysis, desolvation, and strain or distortion. All of these act by
stabilizing the transition state energy or destabilizing the ground state (which is
generally not as important as transition state stabilization).
 Approximation is the rate enhancement by proximity, that is, the enzyme
serves as a template to bind a substrate so that it is close to reactive groups
121
of the enzyme (or to bind multiple substrates so that they are close to each
other) in the reaction center.
 Covalent catalysis involves covalent bond formation as a result of attack by
an enzyme nucleophile at an electrophilic site on the substrate.
 In any reaction where proton transfer occurs, general acid catalysis and/or
general base catalysis can be an important mechanism for specificity and
rate enhancement. There are two kinds of acid–base catalysis: general
catalysis and specific catalysis. If catalysis occurs by a hydronium (H3O+) or
hydroxide (HO−) ion and is determined only by the pH, not the buffer
concentration, it is referred to as specific acid or specific base catalysis,
respectively.
 An enzyme electrostatic catalyzes a reaction by stabilization of the
transition state and by destabilization of the ground state.
 The desolvation hypothesis posits that an enzyme active site, which is
largely or completely devoid of water, can mimic the reaction environment
found in the gas phase.
 Strain or distortion of the bound substrate is essential for catalysis, play an
important role in the reactivity of molecules. The much higher reactivity of
epoxides relative to other ethers demonstrates this phenomenon and is
another type of ground state destabilization.
A very important bacterial enzyme in medicinal chemistry is the peptidoglycan
transpeptidase, the enzyme that catalyzes the cross-linking of peptidoglycan
strands to make the bacterial cell wall.
122
Fig. 8.1: Hypothetical mechanism for peptidoglycan transpeptidase
8.5 Elementary treatment of enzyme stimulation
Many of the top 100 drugs sold worldwide for elementary treatment of enzyme
stimulation. In recent years, enzyme inhibitors not only have provided an
increasing number of potent therapeutic agents for the treatment of diseases, but
also have significantly advanced the understanding of enzymatic
transformations. The Elementary treatment of enzyme stimulation is current
approaches to socalled rational inhibitor design, which uses knowledge of
enzymic mechanisms and structures in the design process.
These enzymes constitute the various metabolic pathways that, in concert,
provide the requirements for the viability of the cell. A selective treatment of
enzyme stimulation may block either a single enzyme or a group of enzymes,
leading to the disruption of a metabolic pathway(s). This will result in either a
decrease in the concentration of enzymatic products or an increase in the
concentration of enzymatic substrates. The effectiveness of treatment of
enzyme stimulation as a therapeutic agent will depend on
123
1. The potency of the inhibitor,
2. Its specificity toward its target enzyme,
3. The choice of metabolic pathway targeted for disruption, and
4. The inhibitor or a derivative possessing appropriate pharmacokinetic
characteristics.
Clearly, the choice of target enzyme is also of prime importance for
chemotherapy, Good bioavailability of the drug is also crucial for the drug to
reach its site of action in the body in effective therapeutic concentrations. For
example, highly polar or charged compounds, such as phosphorylated
compounds, frequently cannot readily cross cell membranes and are therefore
generally less useful as drugs. Physical approaches to facilitate the transport of
this class of compounds into the cell include the use of liposomes or
nanoparticles. Chemical approaches may also be employed. These include the
use of prodrugs, in which functional groups on the inhibitor are modified in
such a manner that they are able to be taken up by the cell and, later,
metabolically converted to the active drug.
The human body, even though its defenses are constantly on guard, is still
susceptible to invasion by foreign pathogens. Since the development of the
sulfa drugs (sulfonamides), enzyme inhibitors have played a vital role in
controlling these infectious agents. Following tables provide a list of enzyme
inhibitors that have been used in the treatment of the various diseases caused by
these agents. All these compounds needed to satisfy the usual requirements for
specificity and low toxicity.
Table-8.1: Examples of Enzyme Inhibitors Used in the Treatment (elementary
treatment of enzyme) of Bacterial, Fungal, Viral, and Parasitic Diseases
S.
Clinical Use Enzyme Inhibited/ treated Inhibitor/Treatment
No.
Dihydropteroate
1. Antibacterial Sulphonamides
synthetase
Trimethoprim,
2. Antibacterial Dihydrofolate reductase
methotrexate
3. Antibacterial Alanine racemase D-Cycloserine
Penicillins,
4. Antibacterial Transpeptidase
cephalosporins
5. Antifungal Fungal sterol l4a- Clotrimazole,ketoconazol
124
demethylase e
Fungal squalene
6. Antifungal Terbinafine, naftifine
epoxidase
Thymidine kinase and
7. Antiviral Idoxuridine
thymidylate kinase
8. Antiviral DNA, RNA polymerases Cytosine arabinoside
9. Antiviral Viral DNA polymerase Acyclovir, vidarabine
Dideoxyinosine,
10 Antiviral HIV reverse transcriptase
zidovudine
11 Antiviral HIV protease Saquinavir
Influenza virus
12 Antiviral Zanamavir, oseltamivir
neuraminidase
13 Antiprotozoal Pyruvate dehydrogenase Organoarsenical agents
a-
14 Antiprotozoal Ornithine decarboxylase
Difluoromethylornithine
Table- 8.2: Examples of Enzyme Inhibitors/Trearment Used in the Cancer
Enzyme Inhibited/
S. No. Type of Cancer Inhibitor/Treatment
treated
Benign prostatic
1. Steroid 5a-reductase Finasteride
hyperplasia
Estrogen-mediated Arninoglutethimide,
2. Aromatase
breast cancer fadrozole
Leukemia,
Dihydrofolate
3. osteosarcoma, head, Methotrexate
reductase
neck, and breast cancer
4. Colorectal cancer Thymidylate synthase 5-Fluorouracil
Glutamine-PRPP 6-Mercaptopurine,
5. Leukemia
amidotransferase azathioprine
Small-cell lung cancer,
6. non- Hodgkin's Topoisomerase-II Etoposide
lymphoma
7. Hairy-cell leukemia Adenosine deaminase Pentostatin
125
Table-8.3: Examples of Enzyme Inhibitors/Treatment Used in Various Human
Disease States
S.
Clinical Use Enzyme Inhibited/ treated Inhibitor/Treatment
No.
1. Epilepsy GABA transaminase Vinyl GABA
2. Epilepsy Carbonic anhydrase Sulthiame
Succinic semialdehyde
3. Epilepsy Sodium valproate
dehydrogenase
Monoamine oxidase Tranylcypromine,
4. Antidepressant
(MAO) phenelzine
Angiotensin converting
5. Antihypertensive Captopril, enalaprilat
enzyme
Cardiac
6. Na+, K+-ATPase Cardiac glycosides
disorders
7. Gout Xanthine oxidase Allopurinol
8. Ulcer H+, K+- ATPase Omeprazole
Atorvastatin,
9. Hyperlipidemia HMG-CoA reductase
simvastatin
Prostaglandin synthase,
Anti- Aspirin, naproxen,
10 Cyclooxygenase (COX) I
inflammatory ibuprofen
and II
11 Arthritis Cyclooxygenase (COX) II Celecoxib
12 Glaucoma Acetylcholinesterase Neostigmine
Acetazolamide,
13 Glaucoma Carbonic anhydrase II
dichlorphenamide
8.6 Enzyme inhibition

Any compound that slows down or blocks enzyme catalysis is an enzyme
inhibitor. If the interaction with the target enzyme (specific enzyme for
inhibition) is irreversible (usually covalent), then the compound is a special
type of enzyme inhibitor referred to as an enzyme inactivator.
126
Enzyme inhibitors can be grouped into two general categories: reversible and
irreversible inhibitors. As the name implies, inhibition of enzyme activity by a
reversible inhibitor is reversible, suggesting that noncovalent interactions are
involved. An irreversible enzyme inhibitor, also called an enzyme inactivator, is
one that prevents the return of enzyme activity for an extended period,
suggesting the involvement of a covalent bond.
Reversible: E + I E - I complex
Irreversible: E + I E - I complex
Reversible Enzyme Inhibition

The inhibitors form a dynamic equilibrium system with the enzyme. The
inhibitory effects of reversible inhibitors are normally time dependent because
the removal of unbound inhibitor from the vicinity of its site of action by
natural processes will disturb this equilibrium to the left.
The most common enzyme inhibitor drugs are the reversible type, particularly
ones that compete with the substrate for active site binding. These are known as
competitive reversible inhibitors, typically compounds that have structures
similar to those of the substrates or products of the target enzymes and which
bind at the substrate binding sites, thereby blocking substrate binding.
As in the case of the interaction of a substrate with an enzyme, an inhibitor (I)
also can form a complex with an enzyme (E). The equilibrium constant Ki (koff
/kon) is a dissociation constant for breakdown of the E-I complex; therefore, as
discussed for the Kd of drug–receptor complexes, the smaller the Ki value for an
inhibitor I, the more potent the inhibitor.
kon
E + I E-I
koff
-S +S
E-S E-P E + P
Interaction of the inhibitor with the enzyme can occur at a site other than the
substrate-binding site (i.e., at an allosteric binding site) and still result in
127
inhibition of substrate turnover. When this occurs, often as a result of an
inhibitor-induced conformational change in the enzyme to give a form of the
enzyme that does not bind the substrate properly, then the inhibitor is a
noncompetitive reversible inhibitor.
Examples of Competitive Reversible Inhibitor Drugs
 Simple Competitive Inhibition: Epidermal growth factor receptor tyrosine
kinase as a target for cancer
 Stabilization of an Inactive Conformation: Imatinib, an Antileukemia Drug
 Alternative Substrate Inhibition: Sulfonamide Antibacterial Agents (Sulfa
Drugs)
Transition State Analogs and Multisubstrate Analogs: The enzyme achieves

this rate enhancement by changing its conformation so that the strongest
interactions occur between the substrate and enzyme active site at the transition
state of the reaction.
 Enalaprilat is a very potent slow, tightbinding inhibitor of angiotensin-
converting enzyme (ACE)
 Pentostatin: an antineoplastic agent is a potent inhibitor of the enzyme
adenosine deaminase (adenosine aminohydrolase).
 Isoniazid: The presently accepted mechanism of action of isoniazid
proposes the oxidation by the heme-containing peroxidase enzyme KatG to
form acyl radical.
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Slow, Tight-Binding Inhibitors: The equilibrium between enzyme and inhibitor
is reached slowly, and inhibition is time-dependent, reminiscent of the kinetics
for irreversible inhibition. Tight-binding inhibitors are those inhibitors for
which substantial inhibition occurs when the concentrations of inhibitor and
enzyme are comparable. Slow, tight-binding inhibitors have both properties,
can bind noncovalently or covalently. Example- Captopril, Hydrochlorothiazide
Dual-Acting Drugs: Dual-Acting Enzyme Inhibitors: When there are two

related enzymes whose inhibition would give an enhanced effect compared to
the sum of the effects of inhibiting either enzyme alone, it may be beneficial to
design a single inhibitor of both enzymes, a compound known as a dual-acting
enzyme inhibitor.
Irreversible Inhibition
A competitive irreversible enzyme inhibitor, also known as an active-site
directed irreversible inhibitor or an enzyme inactivator, is a compound whose
structure is similar to that of the substrate or product of the target enzyme and
which generally forms a covalent bond to an active site residue (a slow, tight-
binding inhibitor, however, often is a noncovalent inhibitor that can be
functionally irreversibly bound). Vigabatrin is a good example of this
phenomenon.
An affinity labeling agent is a reactive compound that has a structure similar to
that of the substrate for a target enzyme. Subsequent to reversible E·I complex
formation, it reacts with active site nucleophiles (usually amino acid side
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chains), generally by acylation or alkylation (SN2) mechanisms, thereby
forming a stable covalent bond to the enzyme.
KI kinact
E+I E•I E-I
Selected Affinity Labeling Agents:

Penicillins and Cephalosporins/Cephamycins: The penicillins, cephalosporins,
and cephamycins all have in common the β-lactam ring and are known
collectively as β-lactam antibiotics. They inactivate an enzyme that is essential
for bacterial growth, but which does not exist in animals, namely, the
peptidoglycan transpeptidase.
Aspirin and other NSAIDs inhibits prostaglandin-synthatase or cyclooxygenase

(COX), which in inhibition of prostaglandin (PG) biosynthesis.
Mechanism-Based Enzyme Inactivators:

A mechanism-based enzyme inactivator is an unreactive compound that bears a
structural similarity to the substrate for a specific enzyme. Once the inactivator
binds to the active site, the target enzyme, via its normal catalytic mechanism,
converts the compound into a product that inactivates the enzyme prior to
escape from the active site.
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k1 k2 k4
E+I E•I E • I' E - I"
k-1
k3
E + P
Examples of mechanism-based enzyme inactivators are vigabatrin
(anticonvulsant), eflornithine (antiprotozoal), tranylcypromine (antidepressant),
selegiline & rasagiline (antiparkinson), floxuridine & 5-fluorouracil
(antitumor), etc.
8.7 Sulfonamides
In the early 1930s, Gerhard Domagk, head of bacteriological and pathological
research at the Bayer Company in Germany, who was trying to find agents
against streptococcal infections, tested a variety of azo dyes. One of the dyes,
Prontosil, showed dramatically positive results, and successfully protected mice
against streptococcal infections. However, Bayer was unwilling to move rapidly
on getting Prontosil onto the drug market. As Albert tells it, when, in late 1935,
Domagk’s daughter cut her hand and was about to die of a streptococcal
infection, her father gave her Prontosil! Although she turned bright red from the
dye, her recovery was rapid, and the effectiveness of the drug became quite
credible. In 1939, Domagk was awarded the Nobel Prize in Medicine for this
achievement.
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Prontosil is a prodrug, a compound that requires metabolic activation to be
effective. Furthermore, they demonstrated that sulfanilamide was as effective as
Prontosil.
Fig. 8.2: Prodrug concept for sulfonamides
Mechanism of Action
Many bacteria synthesize their own folic acid (FA) of which para aminobenzoic
acid (PABA) is a constituent, and is taken up from the medium. Woods and
Fildes (1940) proposed the hypothesis regarding sulfonamide action.
Sulfonarnides, being structural analogues of PABA, inhibit bacterial folate
synthase -FA is not formed and a number of essential metabolic reactions
suffer. Sulfonamides competitively inhibit the union of PABA with pteridine
residue to form dihydropteroic acid which conjugates with glutamic acid to
produce dihydrofolic acid. Also, being chemically similar to PABA, the
sulfonamide may itself get incorporated to form an altered folate which is
metabolically injurious. Human cells also require FA, but they utilize
preformed FA supplied in diet and are unaffected by sulfonamides. Evidences
in favour of this mechanism of action of sulfonamides are:
(a) PABA, in small quantities, antagonizes the antibacterial action of
sulfonamides.
(b) Only those microbes which synthesize their own FA and cannot take it from
the medium are susceptible to sulfonamides. Pus and tissue extracts contain
purines and thymidine which decrease bacterial requirement for FA and
antagonize sulfonamide action. Pus is also rich in PABA.
132
Fig. 8.3: Mechanism of action of sulfonamides
Resistance to sulfonamides: Most bacteria are capable of developing

resistance to sulfonamides. Prominent among these are gonococci,
pneumococci, Staph. aureus, meningococci, E. coli, Shigella and some Strep.
pyogenes, Strep. viridans and anaerobes. The resistant mutants either:
 Produce increased amounts of PABA, or
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 Their folate synthase enzyme has low affinity for sulfonarnides, or
 Adopt an alternative pathway in folate metabolism.
Resistance developed in vivo is quite persistent. Sensitivity patterns have
changed depending on the extent of use. When an organism is resistant to one
sulfonamide, it is resistant to them all.
Structure-activity relationships (SAR):
The synthesis of a large number of sulfonamide analogues led to the following
conclusions.
 The p-amino group is essential for activity and must be unsubstituted (i.e. R
= H). The only exception is when R = acyl (i.e. amides). The amides
themselves are inactive but can be metabolized in the body to regenerate the
active compound. Thus amides can be used as sulfonamide prodrugs.
 The aromatic ring and the sulfonamide functional group are both required.
 The aromatic ring must be para-substituted only.
 The sulfonamide nitrogen must be secondary.
 R" is the only possible site that can be varied in sulfonamides.
 Changing the nature of the group R" has also helped to reduce the toxicity
of some sulfonamides. The primary amino group of sulfonamides is
acetylated in the body and the resulting amides have reduced solubility
which can lead to toxic effects. For example, the metabolite formed from
sulfathiazole (an early sulfonamide) is poorly soluble and can prove fatal if
it blocks the kidney tubuls.
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 Sulfadiazine was also found to be more active than sulfathiazole and soon
replaced it in therapy.
Fig. 8.4: SAR of Sulphonamides
Classification
Sulphonamides i.e., the systemic antibacterial drugs may be classified broadly
on the basis of their site of action as described in the sections that follows:
1. Sulphonamides for General Infections: These sulphonamides are invariably
employed against the streptococcal, meningococcal, gonococcal,
staphylococcal and pneumococcal infections. Examples: sulfanilamide,
sulfapyridine, sulfathiazole, sulfadiazine, sulfamerazine, sulfadimidine,
sufalene, sulfamethizole etc.
2. Sulphonamides for Urinary Infections: A number of sulphonamides have
been used extensively for the prevention and cure of urinarytract infections
over the past few decades. They are used sometiems as a prophylactic before
and after manipulations on the urinary tract. A few such sulphanilamide
analogues belonging to this category shall be dealt with here. Examples:
sulfacetamide, sulfafurazole, sulfisoxazole acetyl, sulfacitine, etc.
3. Sulphonamides for Intestinal Infections: A plethora of insoluble
sulphonamide analogues, for instance phthalylsulfathiazole and
succinylsulfathiazole, are not readily absorbed from the gastrointestinal tract.
However, the release of active sulphonamide in high concentration, obtained
due to hydrolysis in large intestine, enables their application for intestinal
infections and also for pre-operative preparation of the bowel for surgery.
135
Examples: sulfaguanidine, phthalylsulfathiazole, succinylsulfathiazole,
phthalylsulfacetamide, salazosulfapyridine, etc.
4. Sulphonamides for Local Infection: There are some sulphonamides which
are used exclusively for certain local applications. Examples: Sulfacetamide
sodium, Mafenide, etc.
5. Sulphonamide Related Compounds: There are some sulphonamides which
essentially differ from the basic sulphonamide nucleus, but do possess anti-
bacterial properties. Examples: Nitrosulfathiazole, dapsone, silver
sulfadiazine, etc.
Uses of Sulfonamides:
Systemic use of sulfonamides alone (not combined with trimethoprim or
pyrimethamine) is rare now though they can be employed for suppressive
therapy of chronic urinary tract infection, for streptococcal pharyngitis and gum
infection; such uses are outmoded. Combined with trimethoprim (as
cotrimoxazole) sulfamethoxazole is used for many bacterial infections, P.
jiroveci and nocardiasis. Along with pyrimethamine, certain sulfonamides are
used for malaria and toxoplasmosis. Ocular sulfacetamide sod. (10-30%) is a
cheap alternative in trachoma/ inclusion conjunctivitis, though additional
systemic azithromycin or tetracycline therapy is required for eradication of the
disease. Topical silver sulfadiazine or mafenide are used for preventing
infection on burn surfaces.
ADME of Sulfonamides:
Absorption: Normally given orally or applied topically; some soluble salts
given parenterally, readily absorbed from GIT, achieving peak blood levels in
30 min, except for those remain in intestine.
Distribution: Highly plasma protein bound; will displace other bound drugs
and bilirubin. Sulfonamides given in late term can induce neonatal jaundice
distributed in total body water, readily enter CNS, synovial and ocular fluid,
fetal circulation and milk.
Metabolism: Primarily by acetylation at free amino group; some oxygenation
of aromatic ring and/or side chain. Acetylated metabolites inactive
Elimination: Majority eliminated unchanged concentrated in urine; useful in
urinary tract infections; older sulfonamides actually formed crystals in tubules
and ureter.
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8. 8 Summary
Pharmacodynamics deals with the relationship between drug concentrations at
the effect site or concentrations (usually unbound concentrations) in plasma in
equilibrium with effect site concentrations, and the magnitude of the observed
pharmacological effect of the drug. Almost all biological reactions are carried
out under catalytic influence of enzymes; hence, enzymes are a very important
target of drug action. Since the development of the sulfa drugs (sulfonamides),
enzyme inhibitors have played a vital role in controlling these infectious agents.
Sulfonamides, also known as sulfa drugs, have a history that dates back to
almost 70-80 years. A sulfonyl group plays a very important role as a key
constituent of number of biologically active molecules.
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8. 9 Glossary
 Pharmacodynamics is the study of drug effects.
 Enzymes are natural proteins that catalyze biochemical reactions, works as
receptor.
 Coenzyme is an organic molecule or a metal ion that binds to the active site,
in some cases covalently or non-covalently.
 Any compound that slows down or blocks enzyme catalysis is an enzyme
inhibitor.
 Sulfonamide (Sulfa drugs) grouping is derived from a sulfonic acid group by
replacing its hydroxyl group with an amino group.
8. 10 Review questions / Comprehensive Questions
1. Define pharmacodynamics. What is the role of pharmacodynamics in drug
design?
2. What are enzymes? Discuss the mode of enzyme action.
3. What do you understand about elementary treatment of enzyme stimulation?
4. Describe different types of enzyme inhibition with suitable examples.
5. What is the role of enzyme inhibition in drug discovery & design?
6. Define sulfonamides. Classify them with examples.
7. Describe mechanism of action of sulfonamides with suitable
scheme/reaction.
8. Discuss the SAR and uses of sulfonamides.
 Povl Krogsgaard-Larsen, Kristian Stromgaard & Ulf Madsen; “Textbook of
Drug Design and Discovery” 4th edition 2010; CRC Press, Taylor & Francis
Group.
 Donald J. Abraham; “Burger’s Medicinal Chemistry and Drug Discovery”
 K.D. Tripathi; “Essentials of Medical Pharmacology” 6th edition 2008;
Jaypee Brothers Medical Publishers (P) Ltd New Delhi.
138
 John H. Block John M. Beale Jr.; “Wilson & Gisvold's Textbook of Organic
Williams & Wilkins
 Donald Cairns; “Essentials of Pharmaceutical Chemistry”, 3rd edition 2008;
 Alfonso R. Gennaro; “Remington: The Science and Practice of Pharmacy”
20th edition 2001; Lippincott Williams & Wilkins
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Unit-9
Pharmacodynamics – II
Structure of Unit:
9.1 Objectives
9.3 Membrane active drugs
9.4 Xenobiotics
9.5 Biotransformation (Metabolism)
9.6 Metabolism sites and enzymes
9.7 Biotransformation reactions
9.8 Significance of drug metabolism
9.9 Summary
9.10 Glossary
9.1 Objectives
 Meaning of xenobiotics
 Membrane disrupters
 Concept of biotransformation
 Metabolizing enzymes
 Types of biotransformation reactions
 Role of biotransformation in new drug development
Pharmacodynamics-
It is the study of drug effect on the body. This includes physiological and
biochemical effects of drugs and their mechanism of action at organ system.
Drugs (except those gene based) do not impart new functions to any system,
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organ or cell, they only alter the pace of ongoing activity. The basic types of
drug action can be categorized as:-
Stimulation- It refers to the drugs which stimulate activity of specialized
organs.
Depression- It means drugs which suppress activity of specialized organs.
Irritation- This is a noxious effect and particularly applied to less specialized
cells.
Replacement- It means use of natural metabolites or hormones in deficiency
states.
Cytotoxic Action- It refers to selective cytotoxic action for parasites or cancer
cell, without affecting the host cells.
Mechanism of drug action
Majority of drugs act by interacting with a discrete target. The target sites at
which drugs act may vary with different types of drugs.
Common sites for drug action are-
 Cell Membranes and Walls
 Enzymes
 Receptors
 Nucleic Acids
9.3 Membrane active drugs
Both types of cells either eukaryotic or prokaryotic consists a membrane called
cytoplasmic membrane or plasma membrane. It acts as a barrier and separates
the internal contents (Intracellular fluid) of cell from external medium
(extracellular fluid).
The cell wall, a rigid external covering protect the fragile membranes of
microorganism. The cell wall and plasma member are together known as the
cell envelope.
Transport of drug ions and biomolecules across the membranes occur by –
 Passive diffusion and filtration
 Specialized transport
Many drugs exert their pharmacological effect by affecting the membrane
transport processes.
Example – (A) Local anesthetics
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(B) Cardiotonic drugs (Digitals Glycosides)
Local anesthetics are the drugs which reversibly block impulse conduction
upon topically or local application and cause loss of sensory perception,
especially of pain in a restricted area of the body. Local anesthetics are sodium
channel blockers. They act by blocking the voltage sensitive sodium channel
and reducing the influx of ions, thereby prevent conduction of action potential.
Examples- Procaine Lidocaine
Digitalis selectively binds to extracellular face of the membrane associated Na+
K+ ATPase of myocardial fibers and inhibits this enzyme. Inhibition of this
cation pump results in progressive accumulation of Na+ intracellularly. This
indirectly results in intracellular Ca+2 accumulations. Thus digitalis increases
force of cardiac contraction.
Many drugs act either disrupting the structure of membranes and walls or
inhibit the synthesis of cell membrane or blocking ion channels. These drugs
produce their action by one of the following way-
 Inhibit enzymes which are assisting in production of compounds
necessary for maintaining the integrity of membrane.
 Inhibit processes of cell wall formation; so that incomplete cell wall
formed through which loss of vital cellular material and finally death of
cell occur.
 Make cell membrane porous by forming channels through it which leads
loss of vital cellular material and subsequent death of cell.
Membrane disrupters are –
(I) Antifungal agents
 Azoles
 Allylamines
 Phenols
(II) Antimicrobials-
 Ionophoric Antibiotics
 Cell wall Synthesis Inhibitors
Antifungal agents
Fungal infections usually involve the skin and mucous membranes of the body.
The fungal microorganisms are believed to damage the cell membrane, leading
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to a loss of essential cellular components. Antifungal agents counter this attack
by both fungi static and fungicidal action.
Azoles
Imidazoles- Clotrimazole Econazole Miconazole
Triazoles- Fluconazole Itraconazole Voriconazole
These agents inhibit the fungal cytochrome P450 enzyme 'lanosterol l4-
demethylase' and thus impair the biosynthesis of ergosterol for the cytoplasmic
membrane leading to a cascade of membrane abnormalities in the fungus.
Azoles exhibit fungi static activity at low concentration and fungicidal activity
at higher concentrations.
Allylamines
They act by inhibiting squalene epoxidase non-competitively, the enzyme for
the squalene epoxidation stage in the biosynthesis of ergosterol in the fungi.
This leads to an increase in squalene concentration in the membrane with
subsequent loss of membrane integrity, which allows loss of cell contents to
occur. Examples- Terbinafine
Phenols
There are numerous phenolic antifungal agents. The mechanism by which the
membrane destruction occurs is not well known. They are believed to acts by
disrupting bacterial membranes and denaturing bacterial proteins and the death
of the cell.
Antimicrobials-
Antibacterial antibiotics normally act by either making the plasma membrane of
bacteria more permeable to essential ions and other small molecules by
Ionophoric action or by inhibiting cell wall synthesis. Those compounds that
act on the plasma membrane also have the ability to penetrate the cell wall
structure. In both cases, the net result is a loss in the integrity of the bacterial
cell envelope, which leads to irreversible cell damage and death. Antimicrobials
agents’ are-
 Ionophoric Antibiotics
 Cell wall Synthesis Inhibitors
Ionophoric Antibiotics
Ionophores are substances that can penetrate a membrane and increase its
permeability to ions. They transport ions in both directions across a membrane.
Consequently, they will only reduce the concentration of a specific ion until its
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concentration is the same on both sides of a membrane. This reduction in the
concentration of essential cell components of a microorganism is often
sufficient to lead to the destruction of the organism.
Ionophores are classified as-
1. Channel Ionophores
2. Carrier Ionophores
Channel Ionophores form channels across the membrane through which ions
can diffuse down a concentration gradient. Example- gramicidin
Carrier Ionophores pick up an ion on one side of the membrane, transport it
across, and release it into the fluid on the other side of the membrane. Example-
Valinomycin
Cell wall synthesis inhibitors
All β-lactam antibiotics interfere with the synthesis of bacterial cell wall. The
bacteria synthesize UDP-N-acetylmuramic acid pentapeptide and UDP-N-
acetyl glucosamine. The peptidoglycan residues are linked together forming
long strands and UDP is split off. The final step is cleavage of the terminal D-
alanine of the peptide chains by transpeptidases; the energy so released is
utilized for establishment of cross linkages between pepide chains of the
neighbouring strands. This cross linking provides stability and rigidity to the
cell wall. The β-lactam antibiotics inhibit the transpeptidases so that cross
linking does not take place.
Example-Penicillins Cephalosporins Cycloserine, Vancomycin Bacitracin.
Many bacteria are resistant to antibiotics especially to b-lactam antibiotics.
Bacteria that have developed a resistance to β-lactam antibiotics are treated
using either incorporating a β-lactamase inhibitor, such as clavulanic acid or
sulbactam, or a lactamase resistant drug, such as vancomycin.
9.4 Xenobiotics
Xenobiotics (substances foreign to the body)
Humans are exposed daily to a wide verity of foreign compounds through
exposure to environmental contaminants as well as in diets. All chemical
substances that are not nutrients for body called xenobiotics or exogenous
compounds. Drugs are also considered xenobiotics and are extensively
metabolized in humans.
Xenobiotics are Categories as followings -
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 Drugs
 Food constituents
 Food additives
 Chemicals of abuse (ethanol, coffee, tobacco etc)
 Agrochemicals (fertilizers, insecticides, herbicide etc)
 Industrial chemicals (solvents, dyes, monomers, polymers)
 Pollutants
In general these are lipophilic chemicals that in the absence of metabolism
would not be efficiently eliminated, and thus would accumulate in the body,
resulting in toxicity. The ability of humans to metabolize and clear drug is a
natural process that involves the same enzymatic pathways and transport
systems that are utilized for normal metabolism of dietary constituents. With
few exceptions, all xenobiotics are subjected to one or multiple pathways that
constitute the phase I and Phase II metabolic systems, which modify
xenobiotics enzymatically in body. The chemical modification of xenobiotics is
called biotransformation or metabolism.
9.5 Biotransformation (Metabolism)

The terms biotransformation and metabolism are often used synonymously;
particularly when applied to drugs. Biotransformation or Metabolism of a drug
is complex and important process whereby living organism’s effect chemical
change to a molecule. The product of such a chemical change is called a
metabolite.
The general principle of drug metabolism is to change the non polar (lipid
soluble) compounds in to polar (hydrophilic), water soluble derivatives via
several chemical reactions, and promoting their excretion in to urine by
kidneys. The term detoxification means inactivation of drug molecule and
excretion of its less toxic metabolites. The term is discarded as the chemical
reactions in the body can same times yield metabolites of greater toxicity or
activity than original molecule. Metabolism is a wider term which refers for
the chemical alteration that occur within the body and its processes alters drugs
in two ways-
1-Conversion of lipophilic compounds in to hydrophilic-
Metabolic reactions convert a drug molecule progressively more water soluble
and so favors its elimination in the urine.
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2-Alteration in Biological Activity-
Inactivation –
Inactivation means conversion of pharmacologically active substance to an
inactive substance or less active.
Examples – Paracetamol Lidocaine
Active metabolites–
Metabolic reactions convert pharmacologically active drug to one or more
active metabolites.
Examples – Codeine Morphine Diazeparn
Activation of Inactive drug –
Metabolic reactions convert inactive to an active substance i.e. Prodrug.
Examples – Dopamine Aspirin
9.6 Sites and enzymes of metabolism

Sites of biotransformation –
Liver is the most important site, for metabolism of almost all drugs due to
presence of large variety of enzymes in it. Other site involved in metabolism is
kidney, plasma, intestine, skin, lungs, and spleen.
Enzymes of metabolism –
The drug metabolizing enzymes are following-
 Microsomal Enzymes
 Non-microsomal Enzymes
Microsomal Enzymes – These are present in endoplasmic reticulum, liver,

intestinal mucosa, kidney and lungs. These enzymes catalyze a majority
metabolic reaction such as oxidation, reduction, hydrolysis, and glucuronidation.
Example – Monooxygenases Cytochorome P 450
Non-microsomal Enzymes –
These are present in the cytoplasm and mitochondria of hepatic cells and also in
other tissues. These enzymes catalyse few oxidations, reduction a number of
hydrolytic reactions and conjugation reactions other than glucuronidation.
Examples – Esterases Amidases
9.7 Biotransformation Reactions
The metabolism of xenobiotics involves two sequential steps-
1. Phase I reactions
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2. Phase II reactions
Phase I reactions
These reactions usually convert the parent drug to a more polar metabolite by
introducing or unmasking a functional group (-OH, -NH2, -SH). The polar
group created serves then as an anchor point for the second metabolic step.
Phase-II reactions
These reactions consists of conjugation of reactive groups, present either in the
parent molecule or after Phase-I transformation. If phase I metabolites are
sufficiently polar, they may be readily excreted. However, many phase I
products are not eliminated rapidly and undergo a subsequent reaction in which
an endogenous substrate such as glucuronic acid, sulfuric acid, acetic acid, or
an amino acid combines with the newly incorporated functional group to form a
highly polar conjugate.
Fig.9.1: Mechanism of drug action
PHASE-I REACTIONS (NONSYNTHETIC REACTIONS)

(I) OXIDATION REACTIONS
Oxidation is the most common metabolic reaction which involves addition of
O2 or removal of hydrogen from the drug.
Microsomal oxidation:
The smooth endoplasmic reticulum of cells in many organs, specially the liver,
contains membrane-associated enzymes which are responsible for dug
oxidation. The primary components of this enzyme system are cytochrome P-
450 reductase and cytochrome 450. This enzyme system has been termed a
mixed function oxygenase.
147
Examples- Phenytoin Pentobarbital
Non-microsomal oxidation:
Soluble enzymes in mitochondria of cells can metabolize few compounds.
Examples
 Xanthine oxidase converts hypxanthine to xanthine and xanthine to uric
acid.
 Tyrosine hydroxylase hydroxylates tyrosine to dopa.
Various oxidation reactions are:
1-Hydroxylation
RCH2CH3→ RCH2CH2OH
Aromatic hydroxylation
Examples- Phenobarbital Phenylbutazone Amphetamine
Aliphatic hydroxylation
Examples- Chlorpropamide Ibuprofen Digitoxin
2-Oxygenation at N or S atoms
 Oxygenation at N atom
RNH2 RNHOH
Examples-Aniline
 Oxygenation at S atom
Examples- chlorpromazine
3-Oxidative dealkylation
 N- Dealkylation
Examples- Morphine
 O-Dealkylation
Examples- Codeine
 S-Dealkylation
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Examples- 6-Methylthiopurine
4-Oxidative deamination
Examples- Amphetamine
(II) REDUCTION REACTIONS

This reaction is the converse of oxidation and occurs in both the microsomal and
nonmicrosomal metabolizing system. It is less common than oxidation.
Examples:
Microsomal reduction- Chloramphenicol
Nonmicrosomal reduction- Chloral hydrate
1-Aldehydes Reduction
RCHO → RCH2OH
Examples- Chloral hydrate
2-Azo Reduction
R1N = NR2 → R1NH2 + R2NH2
Examples- Azo gantrisin
3-Nitro Reduction
O2NR → H2NR
Examples- Chloramphenicol
(III) HYDROLYSIS REACTIONS
This is cleavage of drug molecule by taking up a molecule of water.
Hydrolysis
Nonmicrosomal hydrolases:
 Procainamide (Amidases)
 Proinsulin (Peptidases)
Microsomal hydrolases:
 Cyclization
 Decyclization
1-Ester Hydrolysis
R1COOR2 → R1COOH + HOR2
Examples- Procaine aspirin
149
2-Amide Hydrolysis
R1CONHR2 → R1COOH + H2NR2
Examples- lidocaine Indomethacin
3-Cyclization
This is formation of ring structure from a straight chain compound.
Example- Proguanil
4-Decyclization
This is opening up of ring structure of the cyclic drug molecule,. This is
generally a minor pathway.
Examples- Phenytoin
PHASE II REACTIONS (SYNTHETIC REACTIONS / CONJUGATE
REACTIONS)
In these reactions a drug or its metabolite is couple (conjugated) enzymatically
with an endogenous substance usually a carbohydrate or an amino acid or a
derivative of these, resulting almost invariably in inactivation of the parent drug.
Nearly all conjugates are inert and water soluble and pass in urine or bile.
These involve conjugation of the drug or its phase I metabolite with an
endogenous substrate to form a polar highly ionized organic acid, which is
easily excreted in urine or bile
1-GLUCURONIDE CONJUGATION
Glucuronidation is a major pathway of xenobiotic biotransformation.
Glucuronidation requires the cofactor uridine diphosphate-glucuronic acid (UDP
glucuronic acid), and the reaction is catalyzed by UDP glucuronosyltransferases
(UGTs). The site of glucuronidation is generally an electron-rich nucleophilic
heteroatom (O, N, or S). Therefore, substrates for glucuronidation contain such
functional groups as aliphatic alcohols and phenols (which form O-glucuronide
ethers), carboxylic acids (which form O-glucuronide esters), primary and
secondary aromatic and aliphatic amines (which form N-glucuronides), and free
β -glucuronidase.
150
Cofactor- Uridine-5’- diphospho-D-glucronic acid (UDP-GA)
Example- Chloramphenicol
The arrow indicates the site of glucuronidation.

2-ACETYLATION
Compounds having amino or hydrazine residues are conjugated with the help of
acetyl coenzyme-A.
Cofactors- Acetyl coenzyme-A

Example-Isoniazid
The arrow indicates the site of Acetylation.

3-METHYLATION
Methylation differs from most other phase II reactions because it generally
decreases the water solubility of xenobiotics and masks functional groups that
might otherwise be conjugated by other phase II enzymes.
The amines and phenols can be methylated; methionine and cysteine acting as
methyl donors. Example – Adrenaline Histamine Nicotinic Acid Methyldopa
151
Cofactors- S-Adenosylmethionine (SAM)
4-SULFATE CONJUGATION
Sulfate conjugation generally produces a highly water soluble sulfuric acid ester.
The reaction is catalyzed by sulfotransferases (SULTs) enzymes. The phenolic
compounds and steroids are sulfated by sulfate conjugation. Sulfate conjugation
involves the transfer of sulfonate not sulfate (i.e. SO3- not SO4-) from PAPS to
the xenobiotic.
Cofactors- 3-phosphoadenosine- 5-phosphosulfate (PAPS)
5- GLYCINE CONJUGATION
In glycine conjugation salicylates and other drugs having carboxylic acid group
are conjugated with glycine.
6- GLUTATHIONE CONJUGATION
Glutathione conjugation is carried out by glutathione s-transferase forming a
mercapturate is normally a minor pathway. However, it serves to inactivate
highly reactive quinone or epoxide intermediates formed during metabolism of
certain drugs, e.g. paracetamol. When large amount of such intermediates are
formed (in poisoning or after enzyme induction), glutathione supply falls short-
toxic adducts are formed with tissue constituents - tissue damage.
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Glutathione
Fig. 9.2: Drug metabolism pathways
9.8 Significance of Drug Metabolism

The metabolic changed-drugs have been of considerable interest and of great
practical value in the search for new and improved medicines.
Significance of drug development related to metabolism are-
 The Azo dye, prontosil which is inactive in vitro, is converted in the
body to the active sulphanilamide by metabolic reduction process.
 The metabolic acetylation of the sulphonamides served in the
development of compunds which are acetylated to a lesser extent and
acetylated derivatives are more soluble, hence reduce kidney damage to
crystallization in the renal tubules.
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 Analgesic properties of phenacetin depends on its conversion by O-
dealkylation to produce an active metabolite, acetaminophen i.e., p-
hydroxyacetanilide.
 The antidepressant properties of imipramine and amitriptyline, both
tertiary amines are to be mediated by their secondary amine metabolites,
called desipramine and notriptyline.
 Cholroguanide shows its antimalarial activity when it is converted into 1-
(chlotpheny)-2,4-diamino-6-dimethy1-dihydro-1,3,5 triazine by the
human body.
 Arsine-oxide is a therapeutically useful compound resulted from arseno
compound-As =As-, when it undergoes oxidation reaction, Arsine-oxide
is although more toxic but a superior therapeutic compound developed
by drug metabolism process.
 The introduction of mandelic acid as a genito-urinary antiseptic drug
showed the observation that it gets excreted unchanged and in the acidic
pH of urine, it has significant bactericidal properties. Thus the
metabolism of a drug may have a profound effect on its pharmacological
activity. It plays an important and rapidly exploring role in the
development of new drugs.
9.9 Summary
Majority of drugs exert their pharmacological effect either by affecting the
membrane transport processes or disrupting the structure of membranes and
walls or inhibit the synthesis of cell membrane or blocking ion channels.
During the process of biotransformation, the molecular structure of a drug is
changed from one that is absorbed to one that can be readily eliminated from
the body. The liver has enzymes that facilitate chemical reactions such as
oxidation, reduction, and hydrolysis of drugs (phase I). It has other enzymes
that attach substances to the drug, producing reactions called conjugations
(phase II).
The knowledge of the metabolic fate of a drug is highly important, since the
metabolism can generate toxic species, activate the drug or lead to the loss of
pharmacological activity. The liver is the principal, but not the only, site of
drug biotransformation. The biotransformation reactions are very important in
the development for new medicines.
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9.10 Glossary
 Antibiotics- These are substances produced by microorganisms, which
selectively suppress the growth of or kill other microorganisms at very low
concentrations.
 Antifungal- Agents counter fungal infection attack by both fungi static and
fungicidal action.
 Biotransformation- It refers to chemical alteration of drug
molecule.
 Conjugate Reactions- Drug or its metabolite is couple enzymatically with
an endogenous substance
 Cytochrome P 450- Heme-containing protein, P-it is pink, 450- absorption
spectrum has a maximum at 450 nm.
 Cytoplasmic membrane- It is a barrier between internal and external
medium of cell.
 Detoxification- It means inactivation of drug molecule.
 Drugs- Chemicals alter the pace of ongoing activity of body in diseases
state.
 Local Anesthetics- Local anesthetics are the drugs which reversibly block
impulse conduction in a restricted area of the body.
 Xenobiotics- All chemical substances those are foreign to the body.
1. What is biotransformation?
2. Explain biotransformation reactions.
3. Define xenobiotics and discuss about metabolizing enzymes.
4. Discuss role of metabolism in new drug development process.
5. Discuss the mechanism of action of membrane active agents.
6. Write note on-
A. Antifungal agents
B. Cell wall Synthesis Inhibitors
7. Explain the effect of biotransformation on the biological activity.
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9.12 References And Suggested Readings
 Basic & Clinical Pharmacology (9th ed.)- Bertram G. Katzung (Mc Graw
 Essential of Medical Pharmacology (7thed.)- KD Tripathi (JAYPEE
Publisher) 2013.
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Unit-10
Antineoplastic agents
Structure of Unit:
10.1 Objectives
10.2 Introduction: Cancer
10.3 Characteristic of tumors
10.4 Types of tumors
10.5 Carcinogenic agents
10.6 Pathogenesis
10.7 Cancer Chemotherapy
10.8 Special problems
10.9 Action of Antineoplastic agents
10.10 Role of Alkylating agents in treatment of cancer
10.11 Role of antimetabolites in treatment of cancer
10.12 Carcinolytic antibiotics
10.13 Mitotic inhibitor
10.14 Summary
10.15 Glossary
10.1 Objectives
In this chapter we deal with cancer and anticancer therapy, emphasising first the
pathogenesis of cancer before proceeding to describe the drugs used
therapeutically. Finally we consider the extent to which new knowledge of
cancer biology is leading to new treatments.
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10.2 Introduction: Cancer
The medical term for ‘tumor’ or ‘cancer’ is neoplasm, which is defined as
growth or mass of abnormal tissue formed due to excess and uncoordinated cell
proliferation. Cancer is a disease in which there is uncontrolled multiplication
and spread within the body of abnormal forms of the body's own cells. It is one
of the major causes of death in the developed nations-at least one in five of the
population of Europe and North America can expect to die of cancer.
The anticancer drugs either kill cancer cells or modify their growth. Most
anticancer drugs are antiproliferative-most damage DNA and thereby initiate
apoptosis. They also affect rapidly dividing normal cells and are thus likely to
depress bone marrow, impair healing, depress growth, cause sterility and hair
loss, and be teratogenic. Most cause nausea and vomiting.
10.3 Characteristic of tumors
Cancer cells manifest, to varying degrees, four characteristics that distinguish
them from normal cells:
 Abnormal uncontrolled cell divison
 Dedifferentiated and loss of function
 Ability to spread to other parts of the body
 Metastasis
10.4 Types of tumors
A. Malignant tumor- these are cancerous tumor which are fast grouing and
invade other body parts. They cannot be removed by surgery. These tumors
may lead to death.
B. Non malignant tumor or benign tumor- These are non-cancerous
tumor which are slow growing and do not invade other parts of the body.
They are removed by normal surgery and does not lead to death. According
to the embryologic origin the name for cancers is divided into two general
categories-
 Sarcoma- Sarcoma is a cancer which aries from the abnormal growth of
mesodermal tissue.
 Carcinoma- Carcinoma is a cancer which arises from ecto or endodermal
cells is called a carcinoma.
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10.5 Carcinogenic agents
These agents causes cancer or tumor, as follows-
1. Chemical agents-
 Initiators- These agents are initiate the growth of tumors. eg:polygenic
aromatic hydrocarbons, azodyes, aromatic amines, alkylating agents.
 Promoters- These agents are initiate the growth of already present
tumor, but itself does not initiate tumor growth. eg:phenolic
compounds,artificial swetners(saccharin and cyclamate) and
phenobarbitol.
2. Physical agents-
 Radiation
 Mechanical injury for tissues
 Ionizing and U.V. radiation
3. Hormonal agents-
 Oestrogen hormone
 Anabolic ateroids
4. Biological agents-
 Stones in gall bladder and urinary tract
 Viral infections
10.6 Pathogenesis
The basis for tumor formation is change in gentic factors which leads to non
lethal genetic damage of cells. There are two types of regulatory genes in the
body which protects during development of cancer,these two genes are the
primary targets-
 Growth promoting proto onchogene
 Growth suppressor genes or entionchogens.
10.7 Cancer Chemotherapy
Cancer is a disease characterized by a shift in the control mechanisms that
govern cell survival, proliferation, and differentiation. Cells that have
undergone neoplastic transformation usually express cell surface antigens that
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may be of normal fetal type, may display other signs of apparent immaturity,
and may exhibit qualitative or quantitative chromosomal abnormalities,
including various translocations and the appearance of amplified gene
sequences. Such cells proliferate excessively and form local tumors that can
compress or invade adjacent normal structures. A small subpopulation of cells
within the tumor can be described as tumor stem cells. They retain the ability to
undergo repeated cycles of proliferation as well as to migrate to distant sites in
the body to colonize various organs in the process called metastasis.
Cancer chemotherapy means anticancer agents or antineoplastic agents. Cancer
chemotherapy is aimed either to kill cancer cells or modify their growth.
Anticancer drugs generally attack the metabolic sites that are essential in cell
replication. The drugs used in chemotherapy of cancer destroys an constant
fraction of malignant cells (Fig. 10.7).
Cancer chemotherapeutic agents-
(1)Drugs acting directly on cells (Cytotoxic drugs)
(A) ALKYLATING AGENTS
 Mechlorethamine
(a) Nitrogen mustards (Mustine HCl)
 Cyclophosphamide,
 Chlorambucil,
 Melphalan
(b) Ethylenimine
 Thio-TEPA
(c) Alkyl sulfonate
 Busulfan
(d) Nitrosoureas
 Carmustine (BCNU),
 Lomustine (CCNU)
(e) Triazine
 Dacarbazine (DTIC)
(B) ANTIMETABOLITES
(a) Folate antagonist
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 Methotrexate (Mtx)
(b) Purine antagonist
 6-Mercaptopurine (6-MP)
 6-Thioguanine (6-TG)
 Azathioprine
 Fludarabine
(c) Pyrimidine antagonist
 5-Fluorouracil (5-FU)
 Cytarabine (cytosine arabinoside)
(C) VINCA ALKALOIDS

 Vincristine (Oncovin)
 Vinblastine
(D) TAXANES
 Paclitaxel
 Docetaxel
(E) EPIPODOPHYLLO TOXIN

 Etoposide
(F) CAMPTOTHECIN ANALOGUES

 Topotecan, Irinotecan
(G) ANTIBIOTICS
 Actinomycin
 Doxorubicin
 Daunorubicin
 Mitoxantrone
 Bleomycins,
 Mitomycin C
(H) MISCELLANEOUS
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 Hydroxyurea
 Procarbazine
 L-Asparaginase
 Cisplatin
(II) Drugs altering hormonal milieu
(A) GLUCOCORTICOIDS
 Prednisolone and others
(B) ESTROGENS
 Fosfestrol
 Ethinylestradiol
(C) SELECTIVE ESTROGEN RECEPTOR MODULATORS
 Tamoxifen
(D) SELECTIVE ESTROGEN RECEPTOR DOWN REGULATORS
 Fulvestrant
(E) AROMATASE INHIBITORS
 Anastrozole
 Exemestane
(F) ANTIANDROGEN
 Flutamide
 Bicalutamide
(G) 5-ALPHA REDUCTASE INHIBITOR
 Finasteride
 Dutasteride
(H) GNRH ANALOGUES
 Nafarelin
 Triptorelin
(I) PROGESTINS
 Hydroxyprogesterone acetate
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Fig.10.1: Summary of the mechanisms and sites of action of some
chemotherapeutic agents useful in neoplastic disease. PALA = N-
phosphonoacetyl-L-aspartate; TMP = thymidine monophosphate.
10.8 Special problems
Majority of the cytotoxic drugs have more profound effect on rapidly
multiplying cells,because the most important target of action are the nucleic
acids and their precursors; rapid nucleic acid synthesis occurs during cell
division. Many cancers (especially large solid tumours) have a lower growth
fraction (lower percentage of cells are in division) than normal bone marrow,
epithelial linings, reticuloendothelial (RE) system and gonads. These tissues are
particularly affected in a dose-dependent manner by majorityof drugs; though,
there are differences in susceptibility to individual members.
1. Bone marrow: Depression of bone marrow results in granulocytopenia,
agranulocytosis, thrombocytopenia, aplastic anaemia. This is the most
serious toxicity; often limits the dose that can be employed. Infections and
bleeding are the usual complications.
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2. Lymphoreticular tissue: Lymphocytopenia and inhibition of lymphocyte
function results in suppression of cell mediated as well as humoral
immunity.
3. Oral cavity: The oral mucosa is particularly susceptible to cytotoxic drugs
because of high epithelial cell turnover. Many chemotherapeutic drugs
produce stomatitis as an early manifestation of toxicity. The gums and oral
mucosa are regularly subjected to minor trauma, and breaches are common
during chewing. Oral microflora is large and can be the source of infection.
Neutropenia and depression of immunity caused by the drug indirectly
4. Increase the chances of oral infections. Thrombocytopenia may cause
bleeding gums. Xerostomia due to the drug may cause rapid progression of
dental caries.
5. GIT: Diarrhoea, shedding of mucosa, haemorrhages occur due to decrease
in the rate of renewal of the mucous lining. Drugs that frequently cause
mucositis are—bleomycin,actinomycin D, daunorubicin, doxorubicin,
fluorouracil and methotrexate. Nausea and vomiting are prominent with
many cytotoxic drugs. This is due to direct stimulation of CTZ by the drug
as well as generation of emetic impulses/mediators from the upper g.i.t.
6. Skin Alopecia occurs due to damage to the cells in hair follicles. Dermatitis
is another complication.
7. Gonads: Inhibition of gonadal cells causes oligozoospermia and impotence
in males; inhibition of ovulation and amenorrhoea are common in females.
Damage to the germinal cells may result in mutagenesis.
8. Foetus: Practically all cytotoxic drugs given to pregnant women profoundly
damage the developing foetus → abortion, foetal death, teratogenesis.
9. Carcinogenicity: Secondary cancers, especially leukaemias, lymphomas
and histocytic tumours appear with greater frequency many years after the
use of cytotoxic drugs. This may be due to depression of cell mediated and
humoral blocking factors against neoplasia.
10. Hyperuricaemia: This is secondary to massive cell destruction (uric acid is
a product of purine metabolism). Gout and urate stones in the urinary tract
may develop. Allopurinol is protective by decreasing uric acid synthesis. In
addition to these general toxicities, individual drugs may produce specific
adverse effects, e.g. neuropathy by vincristine, cardiomyopathy by
doxorubicin, cystitis and alopecia by cyclophosphamide.
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10.9 Action of Antineoplastic agents
Anticancer drugs act in many ways-
a) They can react with the nuclei iof cells as well as with the cell membrances
and other cell organelles.
b) Antitumor drugs can act at all phases of the cell cycle (fig-10.9) by
inhibiting cellular process : such as by inhibiting the growth of the cell
components such as DNA,RNA and protein.
c) They act by distrupting DNA dependent enzymes such as DNA or RNA
polymerase, which are essential for replication and transcription of the
cellular DNA.
Fig. 10.9: The Cell Cycle and the relationship of antitumor drug action to the
cycle G1 is the gap period between mitosis and the beginning of DNA
synthesis. Resting cells (cells that are not preparing for cell division) are said to
be in a subphase of G1, G0. S is the period of DNA synthesis, G2 the premitotic
interval, and M the period of mitosis.
10.10 Role of Alkylating agents in treatment of cancer
These are called as polyfunctional alkyleting agents and characterized by
containing at least one and usually two or more reactive allyl groups in the
molecule which perform omportant cellular functions. Alkylating agents act
upo DNA,RNA and certain enzymes. These compounds produce highly
165
reactive carbonium ion intermediates which transfer alkyl groups to cellular
macromolecules by forming covalent bonds (Fig. 10.10). Alkylating agents can
damage bone marrow and cautiously used in the treatment of cancers of
lymphoid tissues. The alkylating agents are thought to react with the 7 position
of guanine in each of the double strands of DNA causing cross-linking. This
interferes in the separation of the strands and prevent mitosis. Alkylating agents
have cytotoxic and radiomimetic action.
Fig. 10.10: Mechanism of action of Alkylating agents

Mechlorethamine-
It is the nitrogel mustard drug and also known as mustine hydrochloride.The
principal use of mechlorethamine is in combination chemotherapy of hodgkin’s
disease and the non-hodgkin’s lymphomas. It has veterinary use,including
treatment of lymphosarcoma and mast cell sarcoma in dogs and leukesis in
chickens.
Structure-
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Cyclophosphamide-
Cyclophosphamide consist of a nitrogen and phospharamide moiety in its
structure. It is used to treat lymphosarcomas and hodgkin’s disease as well as
breast,ovarian and lung cancer.
Structure-
Chlorambucil-
It has properties similar to that of mechlorethamine . chlorambucil is the drug
of choice in chronic lymphatic lukaemia. It is also used in hodgkin’s disease
and some solid tumors. It has some immunosuppressive property.
Structure-
CHLORAMBUCIL
Melphalan-
It is an phenylalanmine nitrogen mustard. It is very effective in multiple
mycloma,breast cancer and advanced ovarian cancer.
Structure-
MELPHALAN
Thiotepa-
It is an ethyleneimine compound. It is used for superficial bladder tumours.
Busulphan-
It is an alkyl sulphonate.
Structure-
CH3SO2OCH2CH2CH2CH2OSO2CH3
Busulphan
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It is highly effective on granulocyte and is used in chronic myclocytic bukemia.
Nitrosoureas-
Nitrosoureas (carmustine and lomustine) are highly lipid soluable alkylating
agents. Nitrosoureas have cumulative depressive effect on bone narrow. They
have clinical activity against. The lymphomas, malignant melanoma and
Hodgkin’s disease.
10.11 Role of antimetabolites in treatment of cancer
Antimetabolites are structurally related to normal components of DNA or of
coengymes involved in the nuclic acid aynthesis. Antimetabolites inhibits a
metabolic pathway which is essential for survival or reproduction of cancer
cells through inhibition of folate, purine, pyrimidine and pyrimidine nucleoside
which are also required for DNA synthesis. Antimetabolites can kill the cancer
cells without damaging the host cells.
Methotrexate-
It is an analogue of folic acid. It is an antimetabolite of tolic acid.
Structure-
Methotrexate
In the cell, folic acid is first of all reduced to dihydrofolic acid and then to
tetrahydrofolic acid. Methotrexate is able to inhibit the enzyme dihydrofolate
reductase and does not allow the formation of tetrahydrofolate which has been
essential for synthesis of purine and pyrimidine and then inhibits the DNA
,RNA and protein synthesis.
Methotrexate used in choriocarcinoma, the acute leukemias,,osteosarcoma and
head, neck and breast cancer.
6-mercaptopurine(6-mp) –
It is an analogue of purine , which is essential component of DNA called
adenine. The drug is converted in the cells to ribonucleotide of 6-mp, which
then suppresses the denovo biosynthesis of purines and DNA.
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Structure-
6-mercaptopurine
It is effective in choriocarcinoma leukemias and chronic myelocytic leukemia.
5-Flurouracil-
It is a pyrimidine analogue.
Structure-
5-Flurouracil
5-Fluorouracil converted into
5-dump(deoxyuridine monophosphate)
and interfere with DNA synthesis and functions by inhibiting thymidylate

synthetase enzyme
The drug is mainly used in solid tumors of breast, colon, urinary bladder, liver
etc. it is also effective in treating superficial basal cell carcinomas by topical
application.
10.12 Carcinolytic antibiotics
These are products obtained from microorganisms and have antitumour
activity. They intercalate between DNA strands and interfere with its template
function.
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Dactinomycin-
It is very potent antineoplastic antibiotic obtained from the species of
streptomyces. The drug interfere with the movement of RNA polymerase along
the gene and thus preventing transcription. It may also cause strand breaks and
stabilize DNA-topoisomerase-2 complex.
It is effective in combination with methotrexate against gestational
choriocarcinomr.
Bleomycin-
Bleomycin are a group of metal-chelating geycopeptide antibiotics obtained
from streptomyces verticillus. They have antitumour activity. These antibiotics
degrade performed DNA, causing chain fragmentation and release of free
bases.
Bleomycin is mainly used in the treatment of testicular tumors. it is also highly
effective in squamous cell carcinoma of skin, oral cavity, head ,neck,
genitourinarytract, esophagus and hodgkin’s lymphoma.
Mithramycin-
It is an antibiotic, produced by streptomyces argillaceous. It is binds to DNA
and is more inhibitory to RNA.
It is useful in hypercalcemia, and paget’s disease of bone.
Anthramycin-
it is derived from streptomycetes. The drug binds in the narrow groove of DNA
with the guanine by a covalent binding and the drug inhibits nucleic acid
synthesis.
It is used as a antitumor agent.
Mitomycins-
It is obtained from streptomyces caespitosus. It cross links DNA and may also
degrade DNA by generating free radicals. It is highly toxic drug used in
resistant cancers of stomach, cervix, colan, rectum, and bladder etc.
10.13 Mitotic inhibitor
Mitotic inhibitors such as ‘vincristine’ and vinblatine, are the main vinca
alkaloids used in cancer chemotherapy. They bind to microtubular protein-
‘tubulin’ which prevents its polymerization, causes disruption of mitotic spindle
and interfese with cytoskeletal function interfese with cytoskeletal function in
mitosis and metaphase arrest occurs, vincristine is mainly used in treatment of
childhood acute leukaemia. It is also used in lymposarcoma, Hodgkin,s disease
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and carcinoma lung. Vinblastine is used in combination Hodgkin,s disease and
testicular carcinoma.
Structure-
Vincristine Vinblastine
Vinblastine-
Vinblastine is an alkaloid obtained from vinca rosea. Its mode of action
involves depolymerization of microtubules, which are important part of mitotic
spindle. The drug useful in Hodgkin,s disease and other lymphomas.
Vincristine-
Vincristine is an alkaloid derived from vinca rosea, causes arrest of mitotic
cycle(spindle poison) .
Vinblastine and vincristine
Binds to β tubulin (drug tubulin complex)
Disruption of mitotic spindle
Chromosome fail to move apart during mitosis
Metaphase arrest
Cell division is inhibited

Use: This drug useful in acute lukaemia in children.
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10.14 Summary
Cancer is a disease characterized by a shift in the control mechanisms that
govern cell survival, proliferation, and differentiation. The terms cancer,
malignant neoplasm and malignant tumour are synonymous; they are
distinguished from benign tumours by the properties of dedifferentiation,
invasiveness and the ability to metastasis. There are three main approaches to
treating established cancer- surgical excision, irradiation and chemotherapy-and
the role of each of these depends on the type of tumour and the stage of its
development. Chemotherapy can be used on its own or as an adjunct to other
forms of therapy. Cancer Chemotherapeutic agents are: alkylating agents and
related compounds, which act by forming covalent bonds with DNA and thus
impeding DNA replication; antimetabolites, which block or subvert one or
more of the metabolic pathways involved in DNA synthesis; cytotoxic
antibiotics, i.e. substances of microbial origin that prevent mammalian cell
division; plant derivatives (vinca alkaloids, taxanes, camptothecins): most of
these specifically affect microtubule function and hence the formation of the
mitotic spindle; Hormones-of which the most important are steroids, namely
glucocorticoids, estrogens and androgens-and drugs that suppress hormone
secretion or antagonise hormone action.
10.15 Glossary
 The term cancer refers to a malignant neoplasm (new growth).
 A small subpopulation of cells within the tumor can be described as
tumor stem cells.
 Metastases are secondary tumours formed by cells that have been
released from the initial or primary tumour and have reached other sites
through blood vessels or lymphatics, or as a result of being shed into
body cavities.
 Alkylating agents have alkyl groups that can form covalent bonds with
cell substituents; a carbonium ion is the reactive intermediate.
 Antimetabolites block or subvert pathways in DNA synthesis.
 Carcinolyting agents inhibits DNA and RNA synthesis.
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1. What is antineoplastic agents?
2. Explain and classify the antineoplastic agents.
3. Define cancer. And discuss about carcinogenic agent
4. Discuss the role of alkylating agents.
5. Discuss the role of antimetabolites.
6. Discuss the mitotic inhibitors and carcinolytic agents.
7. Discuss the mechanism of action of cancer chemotherapeutic agents.
8. What is neoplasm?
Publisher) 2013.
 Pharmacology(4th ed.)- Lippincott’s (Wolters Kluwer Publisher) 2002.
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Unit - 11
Synthesis Antineoplastic agents
Structure of Unit:
11.1 Objectives
11.2 Introduction: Antineoplastic agents
11.3 Classification of antineoplastic agents
11.4 Synthesis approach of antineoplastic agents: mechlorethamine,
cyclophosphamide, melphalan, mustards, uracil, 6-mercaptopurine
11.5 General toxicity of cytotoxic drugs
11.6 Recent development in cancer chemotherapy
11.7 Summary
11.8 Glossary
11.1 Objectives
 Cancer
 Types of cancer treatment
 Cancer Chemotherapy (Background)
 Cancer Chemotherapy
 Antineoplastic Agents
 Mechanism of action
 Synthesis of anticancer drugs
 Recent development in cancer treatment
11.2 Introduction: Antineoplastic agents
Cancer remains one of the major causes of death in the world and it has been
estimated that there will be 15 million new cases and 10 million deaths in 2020.
Cancer is a disease present in people and animals in which the structure and
normal function of body tissues are disrupted. Cancer is a term used for
diseases in which abnormal cells divide without control and are able to invade
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other tissues. Cancer cells can spread to other parts of the body through the
blood and lymph systems, this process is called metastasis.
Categorized based on the functions/locations of the cells from which they
originate:
 Carcinoma - skin or in tissues that line or cover internal organs. E.g.,
Epithelial cells. 80-90% reported cancer cases are carcinomas.
 Sarcoma - bone, cartilage, fat, muscle, blood vessels, or other connective
or supportive tissue.
 Leukemia - White blood cells and their precursor cells such as the bone
marrow cells, causes large numbers of abnormal blood cells to be
produced and enter the blood.
 Lymphoma - cells of the immune system that affects lymphatic system.
 Myeloma - B-cells that produce antibodies- spreads through lymphatic
system.
 Central nervous system cancers - cancers that begin in the tissues of the
brain and spinal cord.
 A neoplasm, or tumour is an abnormal mass of tissue, the growth of
which exceeds and is uncoordinated with that of the normal tissue and
continues in the same manner after cessation of the stimuli which have
initiated it.
 A malignant tumour grows rapidly and continuously, and even when it
has impoverished its host and source of nutrition, it still retains the
potentiality for further proliferation. Besides, malignant tumours invade
and destroy neighbouring tissues and possess no effective capsule, a
malignant tumour readilty ulcerate and tend sooner or later to
disseminate and form metastases.
The causation of neoplasms are many, for instance : the genetic factors e.g.,
retinoblastoma is determined by a Mendelian dominant factor and so are the
multiple benign tumours ; the chemical carcinogens e.g., arsenic, soot, coal tar,
petroleum lubricating oil ; the polycyclic hydrocarbon carcinogens e.g., 1, 2, 5,
6-dibenzanthracene, 3, 4-benzpyrene.
The important characteristics differentiating cancer cells from normal cells are:
1. Limitless replicative potential: Cells begin to divide uncontrollably
because the mechanisms that control growth are disrupted.
2. Self-sufficiency in growth signals;
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3. Nonresponsiveness to normal growth-inhibitory signals;
4. Escape from senescence and apoptotic death;
5. Ability to invade normal tissues and metastasize to distant sites; and
6. Support angiogenesis within the growing tumor.
There has been a tremendous growth in different aspects of cancer research,
cancer chemotherapy vis-a-vis a better understanding of the intricacies of the
‘tumour biology’ that has ultimately led to not only the legitimate evolution but
also the explicite elucidation of the probable mechanisms of action for the
antineoplastic agents. In fact, the various strategies involved to augment the
speedy as well as meaningful progress in the develoment of antineoplastic
agents may be accomplished as follows:
 Fundamental basis for the more rational approach in the design of newer
drugs,
 Large collaborative investigations, concerted integrated research based
on recent developments and advances in the clinical techniques, and
 Combination of such privileged advantages with improved preliminary
screening methodologies.
As on data nearly ten different types of ‘neoplasms’ may be ‘cured’* with the
aid of chemotherapy in patients quite satisfactorily, namely: leukemia in
children, Hodgakin’s disease, Burkitt’s lymphoma, Ewing’s sarcoma,
choriocarcinoma in women, lymphosarcoma, mycosis fungoides,
rhabdomyosarcoma, testicular carcinoma, and retinoblastoma in children.
Treatment of cancer includes surgical intervention, radiation, immunotherapy,
and chemotherapy using neoplastic drugs. Chemotherapy is currently used in
addition to surgical intervention in order to remove possible metastatic cells
that still remain. Moreover, some types of tumors are currently treated first with
chemotherapeutic agents. All characteristics targeted by recent therapies. In
addition, the modulation of resistance with new drugs to potentate existing
chemotherapeutic agents and/or the chemoprevention of primary tumors
provide exciting new targets for cancer therapeutics. Salient-Features of
Antineoplastic Drugs are as follows:
 Block the biosynthesis or transcription of nucleic acids to check cell-
division through direct interference with mitotic spindles,
 Both mitosis phases and cells that are engaged in DNA-synthesis are
found to be highly susceptible to these antineoplastic agents, and
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 In the resting state the not-so-fast growing tumours invariably possess
good number of cells.
11.3 Classification of Antineoplastic agents
1. Alkylating Agents:
Alkylating agents are chemically reactive compounds that combine most
readily with nucleophilic centres a fully saturated carbon atom of the alkylating
group becoming attached to the nucleophile.
(i) Mustards: Nitrogen mustards were selected for the clinical application for
the treatment of neoplasms because they presented fewer problems in handling,
besides their respective hydrochlorides and other salts are generally stable
solids having low vapour pressure and high solubility in water. A few important
nitrogen mustards used as antineoplastic agents are discussed below, for
instance: Mechlorethamine hydrochloride, Mephalan, Cyclophosphamide,
Ifosamide and Chlorambucil.
(ii) Methanesulphonates: The most important alkylating agent in this group is

Busulfan.
(iii) Ethylenimines: Ethylenimines are highly reactive alkylating reagents.

They alkylate DNA at position N7 of guanine, analogous to mechlorethamine.
Ethyenimines exhibit cytostatic action and suppress development of
proliferating, as well as malignant tissues. They disrupt the metabolism of
nucleic acids and block mitotic cell division. They are used for breast and
ovarian cancer, nonoperable tumors, and other reoccurrences and metastases.
Example- triethylenphosphortriamide or thiotepa, benzotef, dipin, thiodipin,
fosphemide, etc.
177
(vi) Nitrosoureas: It is believed that in the body, nitrosoureas break down to β-
chloroethanol and alkylisocyanate. The resulting β-chloroethanol is a highly
reactive alkylating agent, and the alkylisocyanates are carbamoylating agents
for proteins, which also exhibit certain cytotoxic activity. Example-
Carmustine, Lomustine, Streptozocin, Cisplatin, Carboplatin, etc.
2. Antimetabolites:
Antimetabolites are structural analogs of ordinary cellular metabolites such as
folic acid, pyrimidines and pyrines, which after being introduced in the body,
begin to imitate the structure of ordinary metabolites. They compete with
metabolites to block important reactions leading to formation of DNA/RNA. In
general, following are the various classes of antimetabolites usually employed
in the treatment, namely:
(i) Antifolic acid compounds: Folic acid antagonists, in particular
methotrexate, act by competitively binding with the enzyme dehydrofolate
reductase in place of folic acid.
(ii) Analogues of Purines: These compounds inhibit synthesis of purine

nucleotides, which are made up of purine bases and phosphorylated ribose.
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Purine, mercaptopurine and thioguanine turned out to be the most effective in
chemotherapy for cancer, both compounds must be transformed into
nucleotides by adding a phosphoribosyl fragment.
(iii) Analogues of Pyrimidines: It is possible that the most important

mechanism of action of fluorinated pyrimidines is the inhibition of thymidylate
synthetase synthesis, thus affecting the process of DNA production. Example-
fluorouracil, fluoxuridine, Cytarabine, etc.
(iv) Amino acid antagonists: The amino acid antagonists broadly act as
glutamine antagonists in the synthesis of formylglycinamidine ribotide from
glutamine and formylglycinamide ribotide.
Example- Azaserine.
3. Antibiotics:
A number of antibiotics possess pronounced cytostatic properties, and they are
extremely effective in treating certain tumors. Included in this group are
dactinomycin, anthracyclins (daunorubicin and doxorubicin), bleomycin, etc.
179
4. Plant products:
Vinblastine and vincristine are alkaloids isolated from plants of the periwinkle
family (Vinca rosea). These compounds cause cells to stop at metaphase and
inhibit assembly of microtubules, and likewise, failure of mitotic spindle
formations. They inhibit synthesis of nucleic acids and proteins. Vinblastine
and vincristine differ only in the substituent on the nitrogen atom of the indol
fragment of the molecule, and are used in combination with other
chemotherapeutic agents. They are mainly used for leukoses, myelomas,
sarcomas, cancer of various organs, and for lymphomas.
Etoposide and teniposide are synthetic derivatives of the extract of the
American mandragora plant (May Apple). The mechanism of their action has
not been completely explained; however, they act on the enzyme topoisomerase
II, which disturbs the twisting of DNA. In addition, they inhibit DNA and RNA
180
synthesis, as well as transport of nucleotides to cells. Cytotoxic action on
normal cells is observed only in very high doses. These drugs exhibit
significant activity in lymphomas, leukemia, Kaposi’s sarcomas, and in
testicular cancer.
5. Hormones:
Hormonal drugs are successfully used for complex treatment of malignant
tumors. Tumors can be both hormone-dependent, as well as hormone-sensitive.
Hormone-dependent tumors regress in the absence of hormonal activity. In
particular, the antiestrogen drug tamoxifen prevents stimulation of cancerous
breast tumor cells by estrogens. This also applies to aminoglutethimide, an
inhibitor of corticosteroid synthesis by the adrenal glands. Hormonal drugs that
inhibit growth of certain human tumors are steroids, including androgens,
estrogens, progestins, and corticosteroids, although only glucocorticoids are
used. Moreover, neither cortisol nor cortisone is used to treat malignant tumors,
but instead prednisone, prednisolone, methylprednisolone, and dexametasone
are used.
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11.4 Synthesis approach of antineoplastic agents
5. Non-hormonal drugs:
In addition to hormonal drugs, five other nonsteroids that have a direct
relationship to this section are also used in cancer chemotherapy. They are
aminoglutethimide, flutamide, mitotan, tamoxifen, and leuprolide.
Synthesis of mechlorethamine:
Mechlorethamine, bis-(2-chloroethyl)methylamine, is made by reacting
methylamine with ethylene oxide, forming bis-(2-hydroxyethyl)methylamine,
which upon reaction with thionyl chloride turns into the desired
mechlorethamine.
Fig.11.1: Synthesis of mechlorethamine
182
Mechlorethamine is widely used intravenously in combination with other drugs
to treat Hodgkin’s disease, lymphosarcoma, leukemia, and bronchogenic
carcinoma.
Synthesis of cyclophosphamide: Cyclophosphamide, 2-[bis-(2-chloroethyl)
amino]tetrahydro-2H-1,3,2- oxazaphosphorin-2-oxide, is made by reacting
bis(2-chloroethyl)amine with phosphorous oxychloride, giving N,N-bis-(2-
chloroethyl)dichlorophosphoramide, which upon subsequent reaction with 3-
aminopropanol is transformed into Cyclophosphamide.
Fig. 11.2: Synthesis of cyclophosphamide

The distinctive chemical structure of this drug gives it selective antineoplastic
activity. Present in the blood, it is practically inactive, although upon
penetrating cancerous cells and reacting with a relatively large number of
phosphamidases, it cleaves, essentially releasing a cytostatic substance, bis-(2-
chloroethyl)amine. This means that the alkylating action of this drug is
specifically directed toward cancerous cells.
It is used for chronic lymphatic leukemia, Hodgkin’s disease, Burkitt’s
lymphoma, multiple myeloma, and cancer of the breast, neck, ovaries, etc.
Synthesis of melphalan:
Melphalan, L-3-[p-[bis-(2-chloroethyl)amino]phenyl]alanine, is a structural
analog of chlorambucil in which the butyric acid fragment is replaced with an
aminoacid fragment, alanine. This drug is synthesized from L-phenylalanine,
the nitration of which with nitric acid gives 4-nitro-L-phenylalanine. Reacting
this with an ethanol in the presence of hydrogen chloride gives the
hydrochloride of 4-nitro-L-phenylalanine ethyl ester, the amino group of which
is protected by changing it to phthalamide by a reaction with succinic anhydride
to give intermediate. The nitro group in this molecule is reduced to an amino
group using palladium on calcium carbonate as a catalyst. The resulting
aromatic amine is then reacted with ethylene oxide, which forms a bis-(2-
hydroxyethyl)-amino derivative. The hydroxy groups in this molecule are
replaced with chlorine atoms upon reaction with thionyl chloride, after which
treatment with hydrochloric acid removes the phthalamide protection, giving
melphalan.
183
Fig. 11.3: Synthesis of melphalan
Melaphalan is used intravenously and orally to treat multiple myeloma and
cancers of the breast, neck, and ovaries. A synonym of this drug is alkeran. The
racemic form of this drug, D,L-3-[p-[bis-(2-chloroethyl)amino]phenyl]alanine,
is also widely used under the name sarcolysine or racemelfalan.
Synthesis of Fluorouracil:
Fluorouracil, 4-fluorouracil, is made by condensing the ethyl ester of
fluoroacetic acid with ethylformate in the presence of potassium ethoxide,
forming hydroxy-methylenfluoroacetic ester, which cyclizes by reacting it with
S-methylisothiourea to 2-methylthio-4-hydroxy-5-fluoropyrimidine, which is
subsequently hydrolyzed by hydrochloric acid to fluorouracil. An alternative
method of synthesizing 5-fluorouracid is direct fluorination of uracil with
fluorine or trifluoromethyl hypofluoride.
Fig. 11.4: Synthesis of Fluorouracil
184
Fluorouracil acts by inhibiting synthesis of pyrimidine, and thus the formation
of DNA. Fluorouracil is used to treat carcinomas of the head, neck, colon,
rectum, breast, stomach, bladder, pancreas, and for actinic and solar creatitis.
Synthesis of mercaptopurine:
Mercaptopurine, 6-purinthiol, is made from uric acid, which is synthesized
from barbituric acid. Barbituric acid is easily made by condensing urea with
malonic ester and then nitrosylating it with nitrous acid. The nitroso derivative
is reduced by hydrogen (obtained in situ by reacting tin with hydrochloric acid)
to an amine (uramil), and then reacted with isocyanic acid, which forms
pseudouric acid. This undergoes cyclization to uric acid when heated in the
presence of hydrochloric acid. Upon reacting phosphorous pentachloride with
uric acid, 2,6,8-trichloropurine is formed. The three chlorine atoms in
trichloropurine differ significantly in terms of reactivity for nucleophilic
substitution. The chlorine atom at C6 is much more active than the chlorine
atom at C2, and this is more active than the chlorine atom at C8, which allows
subsequent manipulation by them. Interaction of 2,6,8-trichloropurine with
sodium hydroxide allows to replace the chlorine atom at C6, forming the
dichloro-derivative, which is then reduced by hydriodic acid to hypoxanthine.
Upon reaction with phosphorous pentasulfide, hypoxanthine is transformed into
mercaptopurine.
Fig. 11.5: Synthesis of mercaptopurine
185
In the body, mercaptopurine is converted into an active form of the drug,
nucleotide 6-thioinosin-5-phosphate. Nucleotide 6-thioinosin-5-phosphate
inhibits the first step in the synthesis of inosin-5-phosphate by negative
feedback, preventing its transformation to adenosine or guanine nucleotides,
which are necessary for synthesizing DNA. Thus, mercaptopurine inhibits
synthesis and interconversion of purine nucleotides, which leads to a halt in
DNA synthesis in proliferating cells during the cell cycle.
Mercaptopurine is used for treatment of lymphobastomas, myeloblastoma
leucosis, and to treat neuroleukemia.
11.5 General toxicity of cytotoxic drugs
An understanding of toxicities, adverse effects, and special dosing
considerations of existing anticancer compounds is important to the design of
effective drug combinations and to the interpretation of the toxicological profile
of new chemical entities. Most cytotoxic anticancer agents are dosed to
maximum tolerated levels to achieve maximum cell kill.
Majority of the cytotoxic drugs have more profound effect on rapidly
multiplying cells, because the most important target of action are the nucleic
acids and their precursors; rapid nucleic acid synthesis occurs during cell
division. Many cancers (especially large solid tumours) have a lower growth
fraction (lower percentage of cells are in division) than normal bone marrow,
epithelial linings, reticuloendothelial (RE) system and gonads. These tissues are
particularly affected in a dose-dependent manner by majority of drugs; though,
there are differences in susceptibility to individual members.
1. Bone marrow: Depression of bone marrow results in granulocytopenia,
agranulocytosis, thrombocytopenia, aplastic anaemia. This is the most
serious toxicity; often limits the dose that can be employed. Infections and
bleeding are the usual complications.
2. Lymphoreticular tissue: Lymphocytopenia and inhibition of lymphocyte
function results in suppression of cell mediated as well as humoral
immunity.
3. Because of action (1) and (2) + damage to epithelial surfaces, the host
defence mechanisms (specific as well as nonspecific) are broken down
susceptibility to all infections is increased. Of particular importance are the
opportunistic infections due to low pathogenicity organisms Infections by
fungi (Candida and others causing deep mycosis), viruses (Herpes zoster,
186
cytomegalo virus), Pneumocystis jiroveci (a fungus) and Toxoplasma are
seen primarily in patients treated with anticancer drugs.
4. Oral cavity: The oral mucosa is particularly susceptible to cytotoxic drugs
because of high epithelial cell turnover. Many chemotherapeutic drugs
produce stomatitis as an early manifestation of toxicity. The gums and oral
mucosa are regularly subjected to minor trauma, and breaches are common
during chewing. Oral microflora is large and can be the source of infection.
Neutropenia and depression of immunity caused by the drug indirectly
increase the chances of oral infections. Thrombocytopenia may cause
bleeding gums. Xerostomia due to the drug may cause rapid progression of
dental caries.
5. GIT: Diarrhoea, shedding of mucosa, haemorrhages occur due to decrease
in the rate of renewal of the mucous lining. Drugs that frequently cause
mucositis are-bleomycin, actinomycin D, daunorubicin, doxorubicin,
fluorouracil and methotrexate. Nausea and vomiting are prominent with
many cytotoxic drugs. This is due to direct stimulation of CTZ by the drug
as well as generation of emetic impulses/mediators from the upper g.i.t. and
other areas.
6. Skin: Alopecia occurs due to damage to the cells in hair follicles.
Dermatitis is another complication.
7. Gonads: Inhibition of gonadal cells causes oligozoospermia and impotence
in males; inhibition of ovulation and amenorrhoea are common in females.
Damage to the germinal cells may result in mutagenesis.
8. Foetus: Practically all cytotoxic drugs given to pregnant women profoundly
damage the developing foetus may results abortion, foetal death,
teratogenesis.
9. Carcinogenicity: Secondary cancers, especially leukaemias, lymphomas
and histocytic tumours appear with greater frequency many years after the
use of cytotoxic drugs. This may be due to depression of cell mediated and
humoral blocking factors against neoplasia.
10. Hyperuricaemia: This is secondary to massive cell destruction (uric acid is
a product of purine metabolism). Gout and urate stones in the urinary tract
may develop. Allopurinol is protective by decreasing uric acid synthesis. In
addition to these general toxicities, individual drugs may produce specific
adverse effects, e.g. neuropathy by vincristine, cardiomyopathy by
doxorubicin, cystitis and alopecia by cyclophosphamide.
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11.6 Recent development in cancer chemotherapy
In 2013, WHO launched the Global Action Plan for the Prevention and Control
of Noncommunicable Diseases 2013-2030 that aims to reduce by 25%
premature mortality from cancer, cardiovascular diseases, diabetes and chronic
respiratory diseases.
There are many new approaches to cancer therapy, some at the very early
research stage and others at later phases of development. These approaches
range from novel drugs, biological agents and drug delivery systems, to gene
targeting, gene therapy and, more recently, the possibility of targeting cancer
stem cells.
New types of cancer treatment
 Hormonal Treatments: These drugs are designed to prevent cancer cell
growth by preventing the cells from receiving signals necessary for their
continued growth and division. E.g., Breast cancer – tamoxifen after surgery
and radiation
 Specific Inhibitors: Drugs targeting specific proteins and processes that are
limited primarily to cancer cells or that are much more prevalent in cancer
cells.
 Antibodies: The antibodies used in the treatment of cancer have been
manufactured for use as drugs. E.g., Herceptin, avastin
 Biological Response Modifiers: The use of naturally occuring, normal
proteins to stimulate the body's own defenses against cancer. E.g.,
Abciximab, rituxmab
 Vaccines: Stimulate the body's defenses against cancer. Vaccines usually
contain proteins found on or produced by cancer cells. By administering
these proteins, the treatment aims to increase the response of the body
against the cancer cells.
11.7 Summary
The main goal of anti-neoplastic drug is to eliminate the cancer cells without
affecting normal tissues. Early diagnosis is the key. Combination therapy and
adjuvant chemotherapy are effective for small tumor burden. Because
chemotherapeutic agents target not only tumor cells, but also affect normal
dividing cells including bone marrow, hematopoietic, and GI epithelium.
188
Treatment of cancer includes surgical intervention, radiation, immunotherapy,
and chemotherapy using neoplastic drugs.
11. 8 Glossary
 Chemotherapy means the use of any drug (such as aspirin or penicillin) to
treat any disease, but to most people chemotherapy refers to drugs used for
cancer treatment. It’s often shortened to “chemo.”
 Two other medical terms used to describe cancer chemotherapy are
Antineoplastic (meaning anti-cancer) therapy and cytotoxic (cell-killing)
therapy.
 Alkylating agent: a reactive chemical that forms a covalent bond with
chemical moieties on the biological target (usually a protein). For instance,
b-haloalkylamines generate an aziridinium ion in aqueous base that inserts
into –SH, –CHOH, or other chemical structures in peptides. Once inserted,
the effects of the alkylating agent are irreversible.
 Gene the sequence of DNA that codes for a complete protein.
 Antimetabolites: Interfere with the formation of key biomolecules including
nucleotides, the building blocks of DNA.
1. What is a neoplasm? What are the causations of neoplasm ?
2. How would you classify the ‘antineoplastic agents’ ? Give the structure,
chemical name and uses of one important member from each category.
3. How would you classify ‘Antimetabolities’ ?
4. Give the structure, chemical name and uses of the following: Methotrexate,
Meracaptopurine, Fluorouracil, Azaserine.
5. Discuss the synthesis of Meracaptopurine, Fluorouracil.
6. Classify the ‘plant products’ employed in the treatment of malignant
disease. Give structure, name and uses of one potent drug from each
category.
7. Give a comprehensive account of ‘hormones’ that are potent as
antineoplastic agents. Support your answer with suitable examples.
8. Give a brief account of Pharmacokinetics, pharmacodynamic and mode of
action of antineoplastic agents.
189
 R.S. Vardanyan and V.J. Hruby; “Synthesis of Essential Drugs”, edition
2006; Elsevier Science Ltd.
 Y. Lu, R.I. Mahato, “Pharmaceutical Perspectives of Cancer
Therapeutics”, edition 2009; Springer Science & Business Media.
Drug Design and Drug Action” 3rd edition 2014; Academic Press,
Elsevier.
 Donald J. Abraham; “Burger’s Medicinal Chemistry and Drug
Discovery” 6th Edition 1988; A John Wiley and Sons, Inc. Publication
 Gareth Thomas; “Fundamentals of Medicinal Chemistry” edition 2003;
John Wiley & Sons Ltd, England
 John H. Block John M. Beale Jr.; “Wilson & Gisvold's Textbook of
Organic Medicinal and Pharmaceutical Chemistry” 11th edition 2004;
Lippincott Williams & Wilkins
 Graham L. Patrick; “An Introduction to Medicinal Chemistry” edition
1995; Oxford University Press, Oxford
 Donald Cairns; “Essentials of Pharmaceutical Chemistry”, 3rd edition
2008; Pharmaceutical Press, An imprint of RPS Publishing.
 Michael J Gleeson, Ray C Clarke; “Scott-Brown's, Head and Neck
Surgery”, 7th edition 2008, Volume 1; CRC Press, Taylor & Francis
Group.
 Thurston David E; “Chemistry and Pharmacology of anticancer drugs”,
edition 2007; CRC Press, Taylor & Francis Group.
 Manuel Hidalgo, S. Gail Eckhardt, Elizabeth Garrett-Mayer, Neil J.
Clendeninn; “Principles of Anticancer Drug Development”, edition
2011; Springer Science & Business Media.
190
Unit - 12
Cardiovascular Drugs
Structure of Unit:
12.1 Objectives
12.2 Introduction: Cardiovascular system
12.3 Cardiovascular Diseases
12.3.1 Disorders of Heart
12.3.2 Disorders of blood vessels
12.3.3 Disorders of blood pressure
12.4 Drugs inhibitors of peripheral sympathetic Function
12.5 Central intervention of Cardiovascular Output
12.6 Directly Acting Arteriolar Dilators
12.7 Clotting Prevention and Lysis
12.8 Summary
12.9 Glossary
12.1 Objectives
 Cardiovascular system (Heart)
 Cardiac output
 Blood Pressure
 Various types of cardiovascular diseases
 Class of drugs inhibit peripheral sympathetic function
 Centrally acting sympatholytics
 Directly acting vasodilators
 Prevention of blood coagulation
 Lysis of blood clot
191
12.2 Introduction: Cardiovascular system
The Cardiovascular system consists of heart, blood and blood vessels. It is a
transport system which through blood transports respiratory gases, nutrients and
excretory products to various parts of the body.
HEART –
Heart is surrounded by outer covering called pericardium. It contains two layers
known as visceral pericardium and parietal pericardium.
Middle layer- Myocardium
Inner layer– Endocardium
Chambers of Heart-
 Atrium – 2 (Right and left)
 Ventricle – 2 (Right and left)
Functions-
It acts as a pump and maintains a constant circulation of blood throughout the
body.
Fig. 12.1: Frontal section of the heart in anterior view, showing internal
structures
CARDIAC OUTPUT –
It is defined as the quantity of blood pumped by heart in one minute. Cardiac
output depends on –
1- Venous return – Amount of blood returned to the heart through veins.
192
2- Force of heart contraction
3- Peripheral resistance offered by blood vessels.
BLOOD PRESSURE –
The hydrostatic pressure exerted by blood on the walls of a blood vessel. Blood
pressure generates due to contraction of ventricles.
 Systolic blood pressure– It is maximum pressure recorded during
ventricular systole.
 Diastolic blood pressure– It maximum pressure recorded during
ventricular diastole.
Factors affecting blood pressure -
1. Blood volume
2. Cardiac output
3. Peripheral resistance
4. Elasticity of blood vessels
5. Diameter of lumen of blood vessels
12.3 Cardiovascular Diseases
Cardiovascular diseases can be classified as followings-
 Disorders of Heart
 Disorders of blood vessels
 Disorders of blood pressure
12.3.1 Disorders of Heart
1-Heart Failure
2-Ischemic heart disease
 Myocardial Infarction
 Angina Pectoris
3-Cardiac arrhythmias
4-Congenital heart disease
5-Infective heart disease (Endocarditis)
1-HEART FAILURE
It is defined as impairment of cardiac output (function) so that heart is unable to
maintain adequate circulation of blood to meet body’s metabolic need.
193
Cardiac output depends upon –
 Preload
 Afterload
 Strength of myocardial muscle.
Types of heart failure –
1-Systolic and diastolic heart failure
2-Acute and chronic heart failure
3-Left sided and right sided heart failure
4-Forward and backward heart failure
5-High output and low output heart failure
Etiology-
1-Intrinsic pump Failure
2-Increased work load
3-Impaired Filling of heart
2-ISCHEMIC HEART DISEASE
Ischemic heart disease (Coronary arterial disease) is defined as the cardiac
disability due to imbalance between demand and supply of oxygenated blood.
It is a syndrome consisting of-
 Myocardial Infarction
 Angina pectoris
 Chronic heart disease with heart failure
 Sudden cardiac death
MYOCARDIAL INFARCTION-
It is defined as ischemic necrosis of the myocardium due to sudden occlusion of
branch of coronary artery. An acute thrombus at the site of atherosclerotic
obstruction is common cause. The term heart attack used alternatively.
ANGINA PECTORIS –
It is a pain syndrome due to an imbalance between o2 supply and oxygen
demand in a portion of myocardium.
Types of angina pectoris –
Stable Angina (Classical)
It occurs during exercise due to increased demand of oxygen.
Prinzenetals angina (Variant) –
It occurs at rest due to spasm of coronary arteries.
194
Unstable Angina –
Repeated progressive episodes of angina occur, at rest or increased frequency
and duration of anginal attack. In most cases, it is common due to rupture of
atheromatous plaque and platelet aggregation in coronary artery, leading to
progressive thrombosis.
O2 Supply decreases
 Coronary atherosclerosis
 Coronary vasospasm
 Coronary thrombosis
O2 Supply increases
 Increases heart rate
 Ventricular contractility
 Ventricular hypertrophy
 Ventricular wall tension
ARRHYTHMIAS
Arrhythmias are irregularities in cardiac rhythm.
Arrhythmias arises due to-
a. Delayed after depolarization- It is caused by an inward current
associated with abnormally raised intracellular Ca+2, which trigger
ectopic beats.
b. Re-entry – It is occur due partial conduction block. Re–entry facilitated
when parts of the myocardium are depolarized, conduction then
depending on slow Ca+2current.
c. Ectopic pacemaker activity - In arrhythmias, pacemaker activity can
arise in other part of heart than SA node & conducting tissue. It is
encouraged by sympathetic activity.
d. Heart block – It is result from damage to the atrioventricular node or
ventricular conducting system.
Clinically arrhythmias divided as –
On the basis of site of origin
 Supra ventricular
 Ventricular
195
On the basis of heart rate
Tachycardia– It means increased heart rate, due to either increased
automaticity, after depolarization or re-entry of an impulse.
Bradycardia– It means decreased heart rate, due to reduced automaticity or
abnormal slowing/blockade of impulse conduction.
CONGENITAL HEART DISEASE-
These are present since birth and accounts for 0.5% of newborn children. It is
attributed to multifactorial inheritance involving genetic and environmental
factors like rubella drugs alcohol etc.
INFECTIVE ENDOCARDITIS
It is defined as invasion of heart valve or endocardium by bacteria.
Types-
 Acute endocarditis
 Chronic endocarditis
12.3.2.1 Disorders of blood vessels-

ATHEROSCLEROSIS-
It means hardening of arteries. It is slowly progressive vascular disease,
characterized by deposition of fibro fatty plaque in the inner layer of medium or
large sized muscular arteries. It is composed of blood, calcium deposits,
cholesterol esters, smooth muscle cells and covering of Fibrous plaques. Its
growth causes a reduction in blood flow and weakening of affected areas of
vessel wall.
EMBOLUS –
It is a clot moving in circulation and become impacted in small vessels.
THROMBUS –
It is a clot obstructing a blood vessel at the point where it is actually formed.
12.3.4 Disorders of blood pressure

A-HYPERTENSION –
It is a very common disorder, affecting worldwide population. It increases the
risk for various other cardiovascular diseases. Hypertension is defined as
abnormally higher blood pressure in arteries.
Category Blood pressure (mmHg)

196
Systolic Diastolic
Normal <120 <80
Pre hypertension 120-139 80-89
Hypertension (Mild) 140-159 90-99
Moderate 160-179 100-109
Severe 180-209 110-119
Emergency 210< 120<
Types –
Primary/Essential hypertension- 90% to 95% of all cases of hypertension is
primary hypertension, which is a persistently elevated blood pressure that
cannot be attributed identifiable cause.
Secondary hypertension– The remaining 5-10% of cases is secondary
hypertension, which has an identifiable underlying cause. Several disorders
cause secondary hypertension.
1-Obstruction of renal blood Flow – Damage of renel tissue may cause the
kidneys to release excessive amounts of renin in to the blood. The resulting
high level of angiotensin II causes vasoconstriction, thus increasing systemic
vascular resistance.
2-Hypersecretion of aldosterone– It stimulates excessive re absorption of salts
and water by kidneys, which increases the volume of body fluids.
3-Hypersecretion of epinephrine and nor epinephrine – These increase heart
rate, contractility and systemic vascular resistance.
B-HYPOTENSION –
It is a defined as the lowering of blood pressure. It is occur as a complication of
other diseases- shock, Myocardial infarction etc. Hypotension leads to
inadequate blood supply to brain. It may produce brief unconsciousness
(Fainting). If this is prolonged death may occur.
12.4 Drugs inhibitors of peripheral sympathetic Function

Drugs inhibitors of peripheral sympathetic Function
1 Ganglionic blocking drugs
2 Adrenergic neuronal blockers
3 Adrenergic receptor blockers
 α- Adrenoceptor blockers
197
 β- Adrenoceptor blockers
 α + β- Adrenoceptor blockers
1-GANGLIONIC BLOCKING DRUGS
These agents act at nicotinic receptors (NN type) of autonomic ganglia and
block both parasympathetic and sympathetic ganglia and produce complex
effects.
Classification –
A. Competitive blockers
1-Quaternary ammonium compounds
 Hexamethonium
 Pentolinium
2-Amines (secondary/tertiary)
 Mecamylamine
 Pempidine
3-Monosulfonium compound
 Trimethaphan
B. Persistent depolarizing blockers
 Nicotine (large dose)
 Anticholinesterases (large dose)
Uses – They were used for hypertension and peptic ulcer but now totally
replaced due to intolerable side effects. There is at present no clinical relevance
of Ganglionic blockers. Trimethaphan occasionally used to produce controlled
hypotension and in hypertensive emergency due to aortic dissection.
2-ADRENERGIC NEURONAL BLOCKERS
Reserpine –
It is an alkaloid extracted from root of Rauwolfia serpentina. Reserpine enters
adrenergic neuron, binds to the intra neuronal vesicles which store monoamines
(NA, 5-HT, DA) and inhibits the vesicular catecholamine uptake and storage.
The monoamines are leak in to cytoplasm and destroyed MAO enzyme.
Uses –
Antihypertensive effect is due to depletion of biogenic amines.
Mild antipsychotic effect is due to DA depletion.
198
Guanethidine-
It is a polar guanidine compound which is taken up into the adrenergic nerve
endings by active amine transport, and has three important facets of action:
a. Displaces NA from storage granules.
b. Inhibits nerve impulse coupled release of NA.
c. Engages and blocks NA uptake mechanism at the axonal membrane.
Uses –
It has gone out of use now due to marked side effects.
3-ADRENERGIC RECEPTOR BLOCKERS
 α- ADRENOCEPTOR BLOCKERS
These agents block receptors, thus inhibiting receptors mediated responses of
sympathetic stimulation and adrenergic agonists.
Classification –
(I) Nonselective (α 1and α 2 blockers)-
(A)Reversible-
 Phentolamine
 Tolazoline
(B)Irreresible-
 Phenoxybenzamine
(II) Selective α -receptors blockers –
(A) α 1-Blockers –
 Prazocin
 Terazcin
 Doxazocin
(B) α 2-Blockers -
 Yohimbine
Phentolamine –
It is an imidazoline derivative. It competitively blocks the effect of
noradrenaline at adrenergic receptors.
Tolazaline –
It is similar to phentolamine and is rarely used.
199
Phenoxybenzamine –
It cyclizes spontaneously in the body produce a highly reactive intermediate
ethyleniminium which covalently binds to α-receptors and cause irreversible
blockade. It also inhibits the reuptake of NA into adrenergic nerve endings.
Prazocin –
It is potent and highly selective α1-adrenergic blocker. Prazocin block
sympathetically mediated vasoconstriction and produce fall in BP. It also
inhibits phophodiesterase which degrades cyclic AMP. Rise in smooth muscle
cyclic AMP could contribute to its vasodilator action.
Terazocin –
It is chemically and pharmacologically similar to prazocin but due to longer
duration of action, only daily single dose required.
Doxazocin –
It is longer acting congener of prazocin with similar pharmacological activity.
Yohimbine –
Yohimbine is an alkaloid. It is competitively blocks α 2-receptors. It is rarely
used clinically.
Uses of α -blockers –
 Pheochromocytoma
 Hypertension
 Benign prostatic hypertrophy
 Secondary shock
 Peripheral vascular disease
 Congestive heart failure
 Male sexual dysfunction
β- ADRENOCEPTOR BLOCKERS
These drugs blocks adrenergic responses or sympathetic stimulation mediated
by β- receptors.
Classification –
Nonselective –
 Propranolol
 Sotalol
200
 Timolol
 Pindolol
β 1- Selective (Cardio selective)-
 Atenolol
 Metoprolol
 Bisoprolol
 Esmolol
 Celiprolol
 Nebivolol
Actions of β – blockers –
Propranolol is the prototype drug.
Cardiovascular system-
HEART-
 Decrease heart rate
 Decrease myocardial contractility Force
 Decrease cardiac output
 Decrease automaticity of ectopic foci
 Decrease cardiac work so that reduce O2 demand of myocardium.
BLOOD VESSELS – Continuous administration leads to a decrease peripheral
vascular resistance in hypertensive patients, reduce blood pressure.
Pindolol –
It has intrinsic sympathomimetic activity (Partial agonistic activity), Stimulate
β - receptors partially in the absence of catecholamine’s. It also has membrane
stabilizing activity (local anaesthetic activity).
Esmolol –
Selective β - blocker and has short duration of action. It has no membrane
stabilizing effect. It is poorly lipid soluble.
Atenolol –
 No membrane stabilizing effect
 Longer duration of action
 More potent
201
 Poorly Lipid soluble
Therapeutic uses of β- blockers –
 Hypertension
 Angina pectoris and Myocardial Infarction
 Cardiac arrhythmias
 Congestive heart Failure
 Pheochromocytoma
 Hypertrophic obstructive cardiomyopathy
α + β -ADRENOCEPTOR BLOCKERS
These agents are capable of blocking both α and β receptors.
Lobetalol –
 Competitive blocker at β 1 β 2 and α 1 adrenergic receptors.
 Partial agonistic activity at β 2 receptors
 times more potent in blocking β than α
 Moderately potent hypotensive and is especially useful in
pheochromocytoma and essential hypertension
Carvidilol–
 It also block β 1 β 2 and α 1 -adrenergic receptors
 No intrinsic sympathomimetic activity
 Antioxidant, membrane stabilizing and vasodilator activity
 Used as cardio protective in CHF.
12.5 Central intervention of Cardiovascular Output
These are centrally acting sympatholytics which blocks adrenergic responses.

CLONIDINE –
It is an imidazoline derivative.
Mechanism of action –
202
Uses - Clonidine occasionally used with a diuretic in combination for
hypertension due to frequent side effect.
METHYLDOPA –
It is the α -methyl analogue of dopa, the precursor of DA and NA. The α -
methyl - NA formed in the brain from methyldopa acts on central α 2 receptors
to decrease efferent sympathetic activity.
Mechanism of action –
203
Uses – Methyldopa used to treat hypertension during pregnancy.
12.6 Directly Acting Arteriolar Dilators

These drugs directly produce vasodilatory effect.
Minoxidil
Diazoxide
Hydralazine
Sodium nitroprusside
MINOXIDIL-
It is a powerful arteriolar dilator
Minoxidil is a prodrug converted to an active metabolite by sulfate conjugation.
Mechanism of action-
Uses -
1-It is used in combination with B-blockers or diuretics.
2-Topically used to male pattern boldness.
DIAZOXIDE
 It is K+ Channel opener arteriolar dilator
 Mechanism of action similar to minoxidil
Uses - Hypertensive emergencies.
SODIUM NITROPRUSSIDE-
It is a powerful arteriolar and venodilator.
204
HYDRALAZINE-
It is a directly acting arteriolar vasodilator with little action on venous
capacitance vessels, reduces total peripheral resistance. It causes greater
reduction of diastolic than systolic BP.
Uses-
It is not used alone. Large doses are not recommended for long periods.
It is used in moderate-to-severe hypertension not controlled by the first line
drugs.
Usually, low doses are added to the diuretic and -blocker already being
administered.
205
12.7 Clotting Prevention and Lysis
Haemostasis and blood coagulation involve complex interactions between the
injured vessel wall, platelets and coagulation factors.
ANTICOAGULANTS
These are drugs used to reduce the coagulability of blood. They may be:
 Heparin
 Heparinoids
 Danaparoid
 Lepirudin
 Bishydroxycoumarin (dicumarol)
 Warfarin sodium
 Acenocoumarol (Nicoumalone)
 Ethylbiscoumacetate
 Phenindione
Uses-
 Deep vein thrombosis and pulmonary embolism
 Myocardial infarction (MI)
 Atrial fibrillation (AF)
FIBRINOLYTICS (Thrombolytics)
These are drugs used to lyse thrombi/clot to recanalize occluded blood vessels
(mainly coronary artery). They are work by activating the natural fibrinolytic
system.
The clinically important fibrinolytics are:
 Streptokinase
 Urokinase
 Alteplase (rt-PA)
 Reteplase
 Tenecteplase
Uses-
 Acute myocardial infarction
206
 Deep vein thrombosis
 Pulmonary embolism
 Peripheral arterial occlusion
ANTIPLATELET DRUGS (Antithrombotic drugs)
These are drugs which interfere with platelet function and are useful in the
prophylaxis of thromboembolic disorders.
The clinically important antiplatelet drugs are:
 Aspirin
 Clopidogrel
 Dipyridamole
 Abciximab
 Ticlopidine
12.8 Summary
The Cardiovascular system is a transport system which consists of heart, blood
and blood vessels. Various cardiovascular diseases disturb hearts normal
function. These disorders may be related to cardiac output, blood vessels and
blood pressure. These consist of different type of factors and causes. Many
types of drugs are used to correct conditions in which heart not work properly
such as- peripheral and central sympathetic function inhibitors, directly acting
arteriolar dilator and agents that prevent clotting and produce lysis of blood
clots.
12.11 Glossary
 Afterload: - Systemic peripheral resistance or pulmonary circulation
resistance.
 Aldosterone: - The most biologically active mineralocorticoid hormone
secreted by adrenal cortex.
 Atrial Fibrillation (AF): - AF is an irregular and often rapid heart rate
that commonly causes poor blood flow to the body.
 Benign Prostatic Hypertrophy: - BPH also called benign enlargement of
the prostate. It involves hyperplasia of prosthetic cells resulting in the
formation of large nodules in the transition zone of the prostate.
207
 Cardiac Rhythm: - The predominant electrical activity of the heart.
 Haemostasis: - Arrest of blood loss
 Pheochromocytoma: - It is a tumour or adrenal medulla which release
excessive adrenaline and noradrenaline. This increase concentration of
catecholamines can cause intermittent or persistant hypertension.
 Preload - Volume and pressure of blood in ventricles before systolic
contraction of heart.
 Thrombosis: - Thrombosis is the formation of a blood clot inside a blood
vessel obstructing the flow of blood.
 Vasospasm: - It is refers to a condition in which a blood vessels spasm
leads to vasoconstriction.

1. What is hypertension? Describe its types.
2. Explain the mechanism of action of followings-
A. Minoxidil
B. Diazoxide
C. Hydralazine
D. Sodium nitroprusside
3. Write short note on-
A. - adrenoceptor blockers
B. - adrenoceptor blockers
C. + - adrenoceptor blockers
4. Enlist cardiac disorders Explain cardiac arrhythmias.
5. What is ischemic heart disease? Explain myocardial infarction and angina
pectoris.

Publisher) 2013.
208
 The Pharmacological basis of Therapeutics (10th ed.)- Goodman &
Gilman’s (Mc Graw Hill Publisher) 2001.
 Foye’s Principles of Medicinal Chemistry, David A. Williams, Thomas
L. Lemke (Fifth edition) 2005, B.I. Publication and Pvt. Ltd.
 Introduction to medicinal chemistry: how drugs act and why by Alex
Gringauz.
209
Unit - 13
Synthesis of Cardiovascular Drugs
Structure of Unit:
13.1 Objectives
13.2 Introduction
13.3 Synthesis of Amyl Nitrate
13.4 Synthesis of Diltiazem
13.5 Synthesis of Verapamil
13.6 Synthesis of Methyldopa
13.7 Synthesis of Atenolol
13.8 Synthesis of Sorbitrate
13.9 Synthesis of Quinidine
13.10 Synthesis of Oxyprenolol
13.11 Summary
13.12 Glossary
13.1 Objectives
 In this chapter we discuss the drugs which are used for different type of
cardiac disorder.
 Here we study about the method of synthesis of different cardio vascular
drugs.
13.2 Introduction: Cardiovascular Drugs
Cardiovascular drugs are the group, which have major action on the heart or
blood vessels, or those used primarily for cardiovascular disorders, so that they
check the total output of the heart as well as the distribution of blood to certain
parts of the circulatory system. Amyl nitrate, sorbitrate, diltiazem, quinidine,
verapamil, methyldopa, atenolol and oxyprenolol are some important
cardiovascular drugs, which can be synthesized in the following manner:
210
13.3 Synthesis of Amyl nitrate:-
Amyl nitrate have been found effective in both relieving and preventing the
painful angina attacks. Although it is short acting antianginal agent, when
oxygen is insufficient to meet the myocardial work load, which can occur due
to vasospasm of the coronary vessels. The amyl nitrate induces the vasodilation
of the coronary vessels.
The most prominent action of this drug is exerted on vascular smooth muscle.
Nitrate dilates veins more than arteries which cause peripheral pooling of
blood, this reduces the preload on heart and diastolic size and pressure therefore
decrease cardiac work load.
Alkyl nitrates are employed as reagents in organic synthesis. Amyl nitrate is
used as an additive in diesel fuel, where it acts as an 'ignition improver' by
accelerating the ignition of fuel
Structure: - Amyl nitrate is the chemical compound with the formula CH3
(CH2)4ONO2. This molecule consists of the 5-carbon amyl group attached to a
nitrate functional group. It is the ester of amyl alcohol and nitric acid.
Synthesis:-
C5H11OH + NaNO3 + H2SO4

Amyl alcohol Sod. nitrate Amyl Nitrate
The amyl nitrate can be prepared by esterification of simple amyl alcohol with
nitric acid or sodium nitrate in conc. Sulphuric acid. In the synthesis of amyl
nitrate, the amyl alcohol is react with sodium nitrate in presence of sulphuric
acid and the reaction give amyl nitrate, sodium thiosulphate and water molecule
as final product.
This drug can be hydrolysed easily; therefore moisture should be avoided on
storage.
13.4 Synthesis of Diltiazem:-
Diltiazem is in a group of drugs called calcium channel blockers. It works by
relaxing the muscles of your heart and blood vessels. Diltiazem is used to treat
hypertension (high blood pressure), angina (chest pain), and certain heart
rhythm disorders.
Diltiazem is a calcium channel blocker for the treatment of myocardial
insufficiency and angina pain, Ca++ (calcium ion) is inhibited to influx into
211
myocardial cells. Since 1960, calcium ions are known to play a critical role in
many physiological functions. Physiologic calcium is found in a variety of
location such as intracellular and extracellular, both.
Diltiazem interfere the movement of Ca++ ions into the cell.
Structure:-
Do not use diltiazem if you have certain heart conditions such as "sick sinus
syndrome" or "AV block" (unless you have a pacemaker), low blood pressure,
or if you have recently had a heart attack.
Diltiazem may impair your thinking or reactions. Be careful if you drive or do
anything that requires you to be alert. Do not stop taking this medication
without first talking to your doctor. If you stop taking diltiazem suddenly, your
condition may become worse.
Diltiazem may be only part of a complete program of treatment that also
includes diet, exercise, and other medications. Follow your diet, medication,
and exercise routines very closely.
If you are being treated for high blood pressure, keep using diltiazem even if
you feel well. High blood pressure often has no symptoms.
Synthesis: - Diltiazem can be prepared in the following way:
212
Before taking this medicine:-
Should not use this medication if allergic to diltiazem or if have:
 certain heart conditions, especially "sick sinus syndrome" or "AV block"
(unless you have a pacemaker);
 low blood pressure; or
 If recently had a heart attack.
Uses- Diltiazem is used to prevent chest pain (angina). It may help to increase
your ability to exercise and decrease how often you may get angina attacks.
Diltiazem is called a calcium channel blocker. It works by relaxing blood
vessels in the body and heart and lowers the heart rate. Blood can flow more
easily and your heart works less hard to pump blood.
213
Diltiazem may also be used to control your heart rate if you have a
fast/irregular heartbeat (such as atrial fibrillation).
13.5 Synthesis of Verapamil:-
Verapamil is a calcium channel blocker. It works by relaxing the muscles of
your heart and blood vessels.
It is a calcium channel blocker which is used in the treatment of angina.
Verapamil is also effective and widely used for the treatment of
superaventricular arrhythmias chemically; it is a derivative of papaverine and
was originally conceived as vasodilator for angina.
After oral administration, verapamil is well absorbed and is metabolized to a
great extent in liver (first –pass effect) so that only about 20% of an oral dose is
bioavailable. This first pass effect disappears in prolonged use.
One of the major metabolite of verapamil is norverapamil. The therapeutic
effects of verapamil after oral administration are observed with 2 hours.
Structure:-
Verapamil is a phenylalkylamine derivative, consisting a chiral i.e., one

asymmetric centre. Its L-isomer is more potent as a calcium channel blocker
than the other enantiomer.
Synthesis: - verapamil can be prepared as follows:
214
Verapamil is used to treat hypertension (high blood pressure), angina (chest
pain), and certain heart rhythm disorders
Before taking this medicine:-
Should not use verapamil if allergic to it, or if have a serious heart condition
such as:
 "Sick sinus syndrome" or "AV block" (unless you have a pacemaker);
 Severe heart failure;
 Slow heartbeats that have caused you to faint; or
 Certain heart rhythm disorders of the atrium (the upper chambers of the
heart that allow blood to flow into the heart).
13.6 Synthesis of Methyldopa: -
It is the alpha-methyl analogue of dopa, which is a precursor of dopamine. It
has been one of the oldest and most widely used antihypertensive agents. It is
alpha methyl derivative of dopa (3, 4-dihydroxy phenyl alanine). The chemical
name of methyl dopa is (-)-3,-(3, 4-dihydroxyphenyl)-2-methyl-L-alanine
sesqui hydrate.
It is supposed that methyldopa shows its hypotensive effect within the central
nervous system by its conversion to a metabolite called alpha-methyl nor-
adrenaline which acts as a potent O2 –adrenergic agonist, this may result in a
decrease in sympathetic out flow from the CNS. Methyldopa is used in the
treatment of moderate to severe hypertension. It may be administered as tablets.
Methyldopa is an alpha-2 receptor agonist. It reduces elevated blood pressure
by relaxing and dilating (widening) blood vessels. Blood flows more freely and
at a lower pressure through dilated blood vessels.
Structure:-
215
When the blood transfers from arteries to the tissue capillaries and veins, it
results in excessive stimulation of sympathetic nervous system (CNS). This
may cause arteriole contraction and increased peripheral resistance to the flow
of blood. As a result, blood pressure increases. Methyldopa is used for
contracting this condition i.e., reducing blood pressure and its accompanying
symptoms.
Treating high blood pressure, it may be used with other high blood pressure
medicines.
Do not use methyldopa if:
 Allergic to any ingredient in methyldopa
 Have liver disease, severe kidney problems, a liver reaction caused by
past use of methyldopa, or a history of anemia caused by immune
system
 Receiving enteral feedings
 Taking a monoamine oxidase inhibitor (MAOI) (eg. phenelzine)
Before using methyldopa:
Some medical conditions may interact with methyldopa. Tell your doctor or
pharmacist if you have any medical conditions, especially if any of the
following apply to you:
 If pregnant, planning to become pregnant, or are breast-feeding
 If taking any prescription or nonprescription medicine, herbal
preparation, or dietary supplement
 If have allergies to medicines, foods, or other substances
 If have hemolytic anemia or other blood problems, liver problems,
kidney problems, or tumors on your adrenal glands
Synthesis: - Methyldopa can be prepared as given below:
216
13.7 Synthesis of Atenolol:-
Atenolol is anti arrhythmic agent and known as beta-adrenoreceptor blocking

agent. Its half life is 6 to 9 hours. Since atenolol is hydrophilic in nature,
therefore, very little quantity of this drug penetrates into the brain.
Structure:-
217
Synthesis:-
Uses- its principle effect has been to reduce cardiac activity by decreasing or
preventing beta-adrenoreceptor stimulation. This drug also finds use in the
treatment of angina pectoris for reducing the oxygen consumption and for
increasing the exercise tolerance of heart. Atenolol is also useful in the
treatment of hypertension.
13.8 Synthesis of Sorbitrate
This drug is also known as isosorbide dinitrate. Sorbitrate is used for both
treatment and prevention of painful angina attacks. It is a long acting
antianginal agent. This drug can be administered sub lingually i.e., transdermal
and buccal administration routes. The action of sorbitratre may last for 4 to 6
hours. Sorbitrate is metabolized primarily in the liver by glutathione-nitrate
reductase. This enzyme catalizes the denitration of the parent drug to yield two
metabolites, 2- and 5- isosorbide mononitrate.
Sorbitrate is chemically 1,4:3,6-dianhydro-D-glucitol-2,5-dinitrate. It may get
exploded when it gets subjected to percussion or excessive heat. Diluted
sorbitrate has been a dry mixture of isosorbide dinitrate with lactose or some
other suitable inert excipient. This allows for safe handling of this drug. This
drug is also useful as adjunctive therapy in congestive heart failure.
Structure:-
218
 Isosorbide dinitrate is in a group of drugs called nitrates.
 Isosorbide dinitrate dilates (widens) blood vessels, making it easier for
blood to flow through them and easier for the heart to pump.
 Isosorbide dinitrate is used to treat or prevent attacks of chest pain
(angina).
 Only the sublingual tablet should be used to treat an angina attack that
has already begun.
 Isosorbide dinitrate regular and extended-release tablets are used to
prevent angina attacks but will not treat an angina attack.
 Do not use isosorbide dinitrate if taking sildenafil (Viagra). Serious, life-
threatening side effects can occur if take isosorbide dinitrate while you
are using sildenafil.
Synthesis:- Sorbitrate can be prepared as follows-
13.9 Synthesis of Quinidine:-

Quinidine is an alkaloid, found in cinchona bark (cinchona officinalis L) and is
a close relative of quinine. In fact, quinidine and quinine are diastereomers of
one another.
219
Structurally quinidine and quinine are similar, and quinidine is dextro-isomer of
quinine. Despite this similarity, quinidine and quinine differ markedly in their
effects on cardiac muscle. Frey (1918) found quinidine superior to quinine for
this purpose.
Quinidine consists of quinoline ring and the bicyclic quinuclidine ring system
with a hydroxyl methylene bridge connecting these two components.
Examination of quinidine shows 2 basis nitrogen atoms. The character of
quinidine is basic; hence it is always used in more water soluble salt forms.
These salts are gluconate, polygalacturonate, and quinidine sulphate.
The use of intravenous quinidine is rare, however, in special situations it may
be administered intravenously as the gluconate salt.
Quinidine is metabolized mainly in liver. Its renal excretion is also significant.
Quinidine has some alpha-adrenergic blocking property. At higher dose it
directly dilates blood vessels which cause fall in BP.
Structure:-
Uses- quinidine is effective in a large number of atrial and ventricular

arrhythmias, but is not a preferred drug for treatment of acute arrhythmias. It is
mainly used to maintain sinus rhythm.
Synthesis:-
220
13.10 Synthesis of Oxyprenolol:-
Oxyprenolol is a beta-adrenergic blocking drug. The branch of the autonomic
nervous system in which norepinephrine is the neurotransmitter between the
nerve ending and the effector muscle is known as the adrenergic nervous
system.
The adrenergic nervous system plays an important role in regulating many
physiological functions, including blood pressure, heart rate and force,
bronchial tone and gastrointestinal motility.
Oxyprenolol acts as competitive inhibitors of the effects of catecholamine at
beta-receptor sites. The principal effect of this drug has been to reduce cardiac
activity by decreasing or preventing beta-adrenoceptor stimulation and find use
in the treatment of cardiac arrhythmias. Oxyprenolol is also useful in angina
pectoris for reducing the oxygen consumption and for increasing the exercise
tolerance of the heart.
Structure: -
221
Oxyprenolol consist of O-allyl oxyphenoxy moiety. Officially it is found as
hydrochloride salt.
13.11 Summary
In this unit we have discussed the synthesis of cardiovascular drugs. During the
study of this unit we synthesise the different cardiovascular agent which are
used for the treatment of cardiac disorders like cardiac arrhythmia, angina
pectoris, hypertension etc. Methyldopa exhibits variable absorption from the
gastrointestinal tract. It is metabolized in the liver and intestines and is excreted
in urine. Isosorbide dinitrate regular and extended-release tablets are used to
prevent angina attacks but will not treat an angina attack. Avoid drinking
alcohol, It can increase some of the side effects of isosorbide dinitrate. Atenolol
is used to treat angina (chest pain) and hypertension (high blood pressure). It is
also used to treat or prevent heart attack.
13.12 Glossary
 Antianginal Agent:- these are the drugs used in the treatment of angina
pectoris (angina is a type of chest pain caused by reduced blood flow to
the heart muscle).
 Asymmetric Centre:- An atom having a spatial arrangement of ligands
which is not superimposable on its mirror image.
 Cardiac Arrhythmias:- An arrhythmia is an irregular heartbeat- the
hear may beat too fast (tachycardia), too slowly (bradycardia), too early
(premature contraction) or too regularly (fibrillation). Arrhythmias are
heat-rhythm problems, they occur when the electrical impulses to the
heart that coordinate heartbeats are not working properly, making the
heartbeat too fast/slow or inconsistently
 Diastereomers:- these are stereoisomers that are not mirror images of
one another and are non-superimposable on one another
 Enantiomer:- these are chiral molecules that are mirror images of one
another.
 Esterification: - the process of combining an organic acid (RCOOH)
with an alcohol (ROH) to form an ester (RCOOR) and water.
 Haemolytic Anemia :- this is a form of anemia due to hemolysis, the
abnormal breakdown of red blood cells (RBCs), either in the blood
222
vessels (intravascular hemolysis) or elsewhere in the human body
(extravascular)
 Sick Sinus Syndrome: - this is also known as sinus node disease or
sinus node dysfunction- is the name for a group of heart rhythm
problems (arrhythmias) in which the sinus node- the heart’s natural
pacemaker- doesn’t work properly.
 Sinus Rhythm: - it is normal beating of the heart, as measured by an
electrocardiogram (ECG).
 Supraventricular Arrhythmias: - this is supraventricular tachycardia
which means that from time to time your heartbeats very fast for a
reason other than exercise, high fever, or stress. For most people who
have SVT, the heart still works normally to pump blood through the
body.
13.13 Review questions /comprehensive questions:-
1. Write the preparation and use of amyl nitrate.
2. How methyldopa synthesises?
3. Give the synthesis of isosorbide dinitrate with its structure and uses.
4. How sorbitrate is synthesised from glucose?
5. Give the synthesis of quinidine from cinchotoxine with its uses.
6. Give any one synthesis of antiarryhthmic agent.
7. Write short note on oxyprenolol hydrochloride.
 Textbook of Organic Medicinal and Pharmaceutical Chemistry (11th

ed.)- Wilson and Gisvold’s.
 Introduction to medicinal chemistry, Alex Gringauz-1996
 A Book of Medicinal Chemistry; (second edition) D. Srirm and P.
Yogeswari, published by pearson education.
 A Book of medicinal chemistry volume I; (first edition 2008-2009) Dr.
Anees Ahmad Siddiqui, Seemi Siddiqui, Dr. R. Rajesh, published by
birla publication pvt. Ltd.
 A Text book of medicinal chemistry; (third edition 2003) P. Parimoo,
published by CBS publication.
223
 A Text book of medicinal chemistry (synthesis and Biochemical
Approach) Vol. I; (third edition 2004, reprint 2006) Surendrs N.
Pandeya, published by S. G. Publisher.
 Principle of medicinal chemistry-vol. II; (eighteenth edition, september
2007, reprint edition- March 2008, August 2008,) Dr. S. S. Kadam, Dr.
K. R. Mahadik, Dr. K. G. Bothara, published by- Nirali prakashan.
 Medicinal Chemistry; (revised third edition-2005, reprint-2008)
Ashutosh Kar, published by New age international (P) Ltd.
 Essential of medical Pharmacology; (seventh edition-2013) K. D.
Tripathi, Published by- JAYPEE brothers medical publishers (P) Ltd.
224
Unit-14
Local Anti-infective Drugs
Structure of Unit:
14.1 Objectives
14.2 Introduction: Local Anti-Infective Drugs
14.3 Antifungal Drugs
14.4 Antiviral Drugs
14.5 Antimalarial Drug
14.6 Antiamoebic Drugs
14.7 Antigiardiasis Drugs
14.8 Antitrichomoniasis Drugs
14.9 Antileishmaniasis Drugs
14.10 Antihelminthics Drugs
14.11 Antileprotic Drugs
14.12 Summary
14.13 Glossary
14.1 Objectives
This chapter deals with drugs used to treat infections caused by bacteria,
fungus, protozoan, virus and helminthes etc We give first some necessary
information about bacteria, fungus, protozoan, virus and helminthes etc. after
then we describe the various types of drugs and their general mode of action.
14.2 Introduction: Local Anti-infective Drugs
The anti-infective drugs act against the infections by bacteria, fungus,
protozoan, virus and helminthes etc. drugs of this class differ from all others in
that they are designed to inhibit/kill the infecting organism and to have no or
minimal effect on the recipient or host. Local anti-infective drugs can be
classified in many ways:
 Antifungal Drugs- Antifungal drugs are used for deep systemic and
superficial fungal infections.
 Antiviral Drugs- Antiviral Drugs act against the infection causes due to
viruses.
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 Antimalarial drug- These are drugs used for prophylaxis, treatment and
prevention of relapses of malaria.
 Antiamoebic drugs- These are drugs useful in infection caused by the
protozoa Entamoeba histolytica.
 Antigiardiasis drugs- These are drugs act against giardiasis, caused by
Giardia lamblia
 Antitrichomoniasis drugs- These are drugs effective against
Trichomonas vaginalis is another flagellate protozoon which causes
vulvovaginitis.
 Antileishmaniasis drugs- These are drugs act against Visceral
leishmaniasis (kala-azar) caused by Leishmania donovani.
 Antihelminthics drugs- Anthelmintics are drugs that either kill
(vermicide)
or expel (vermifuge) infesting helminths.
 Antileprotic Drugs- These are drugs act against leprosy, caused
by Mycobacterium leprae.
14.3 Antifungal Drugs
Antifungal drugs are used for deep systemic and superficial fungal infections.
Infections caused by fungi are called mycoses and they can be divided into
superficial infections (affecting skin, nails, scalp or mucous membranes) and
systemic infections (affecting deeper tissues and organs). Systemic mycoses
fungal disease is systemic candidiasis caused by a yeast like organism. Other
more infections are cryptococcal meningitis or endocarditis, pulmonary
aspergillosis and rhinocerebral mucormycosis.
Classification of Antifungal Drugs-
1. Antibiotics
A. Polyenes
 Amphotericin B (AMB)
 Nystatin
B. Heterocyclic benzofuran
 Griseofulvin
2. Antimetabolite
 Flucytosine (5-FC)
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3. Azoles
A. Imidazoles (topical)
 Clotrimazole
 Miconazole
 Ketoconazole (systemic)
B. Triazoles (systemic)
 Fluconazole
4. Allylamine
 Terbinafine
5. Other topical agents
 Tolnaftate
 Quiniodochlor
 Sod. Thiosulfate
General mode of action of Antifungal agents-
Polyene antibiotics:
Amphotericin B:
Amphotericin B is naturally obtained polyene macrolide antibiotic from
streptomyces nodous. Though, it is potentially toxic, it is the drug of choice for
the treatment of the systemic mycoses.
Mechanism of Action:
Amphotericin bind to the ergosterol present in the cell membranes and
interferes with permeability and with transport function. This from of the cell,
resulting in cell death. Amphotericin has a selective action, binding to the
membranes of fungi and some protozoan, less ability mammalian cells and not
at all to bacteria. Figure14.3 (a)
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It is used topically for oral, vaginal and cutaneous candidiasis and ostomycosis.
It is most effective for various types’ systemic mycoses. Amphotericin B is
most effective drug for resistant cases of kala azar and mucocutaneous
leishmaniasis.
Fig.14.3: General mode of action of Antifungal agents

Griseofulvin :
Griseofulvin is a narrow-spectrum antifungal agent isolated from cultures of
penicillium griseofulvum. It is the first chemical compound to cure efficiently
infections due to the superficial dermatophytes (ringworm), when administered
orally.
Griseofulvin interferes with the mitosis by interacting with microtubules. It also
has a weak anti-inflammatory effect. It acts mainly on the growing fungal cells.
It accumulates in the infected, newely synthesized, keratin-containing tissues,
making them unsuitable for the growth of the fungi. Therapy must be continued
until normal tissue replaces infected tissues. Figure14.3 (a)
Griseofulvin is used orally for ringworm infections. It is ineffective topically.
Majority of the tinea infections are treated with Griseofulvin.
228
Flucytosine:
Flucytosine is a synthetic fluorinated pyrimidine that is given orally and is
effective against systemic infections due to yeast.
Flucytosine
Flucytosine is taken up by fungal cells and is converted into antimetabolite 5-
fluorouracil in them but not in human cells. 5-fluorouracil inhibits thymidylate
synthetase and thus DNA synthesis. Figure14.3 (b)
Flucytosine is useful in cryptococcal meningitis and systemic candidiasis
including urinary tract infections.
Figure14.3 (b): Mechanism of action of 5-Flucytosine

Azoles :
Azoles are group of synthetic fungistatic agents with a board spectrum of
activity and the most extensively used antifungal drugs. The important drugs of
this group are fluconazole, itaconazole, ketoconazole, miconazole, clotrimazole
and econazole.
Mechanism of Action :
The mechanism of all azoles (imidazoles and triazoles) is the same. They
inhibit the fungal cytochrome P450 3A (CYP3A) enzyme, lanosine 14α-
demethylase which is responsible for the conversion of lanosterol to ergosterol
which is main sterol in the fungal cell membrane. This inhibition disrupts
229
membrane function and increases permeability. The net effect s an inhibition of
replication azoles also inhibit the transformation of candidal yeast cells into
hyphae the invasive and pathogenic form of the parasite.
Ketoconazole :
Ketoconazole was the first azole, which is orally effective broad spectrum
antifungal drug, useful is both dermatophytosis and deep mycosis.
Ketoconazole
In addition to its antifungal activity, it also inhibit gonadal and adrenal steroid
synthesis in humans. Thus, it suppresses testosterone and cortisol synthesis.
Terbinafine :
Terbinafine is administered both orally and topically and is effective against
dematophytes and candida.
It acts by selectively inhibiting the enzyme squalene epoxidase, which is

involved in the synthesis of ergosteral from squalene in the fungal cell wall.
The accumulation of squalene within the cell is toxic to the organism. It acts as
a fungicidal agent.
It is used topically for tinea and pityriasis infections. Onchomycosis is also
treated. It is also used to treat the fungal infections of the nails.
230
14.4 Antiviral Drugs
Antiviral drugs act against the infection causes due to virus. Viruses are
obligate intracellular parasites consisting essentially of nucleic acid (either
RNA or DNA) enclosed in a protein coat or capsid. The nuclein acid and coat
together is termed as nucleocapsid. Some viruses my also contain antigenic
viral glycoproteins as well as host phospholipids acquired when the virus
nucleocapsid buds through the nuclear or plasma membrane of the host cell.
Viruses do not have metabolic machinery of their own. They not only take
nutrition from the host cell but also direct its metabolic machinery to synthesize
new viral particles. Most viruses survive outside the host cell only for a short
time. After penetration into the target cell, viral replication occurs in following
steps:
 Uncoating of viral nucleic acid strands
 Early, regulatory protein synthesis
 Replication of viral RNA or DNA)
 Late structural protein synthesis
 Coating and maturation of viral particles and
 Release of viral particles from the cell
Antiviral agents can target any one of the above steps. To be effective therapy
is to be started in the incubation period(prophylactic).
Classification of Antiviral Drugs-
1. ANTI-HERPES VIRUS-
 Idoxuridine
 Acyclovir
 Valacyclovir
2. ANTI-RETROVIRUS-
(a) Nucleoside reverse transcriptase inhibitors (NRTIs):
 Zidovudine (AZT)
 Didanosine
(b) Nonnucleoside reverse transcriptase inhibitors(NNRTIs):
 Nevirapine
 Efavirenz
(c) Protease inhibitors:
231
 Ritonavir
 Indinavir
 Nelfinavir
3. ANTI-INFLUENZA VIRUS-
 Amantadine
 Rimantadine*
4. NONSELECTIVE ANTIVIRAL DRUGS-
 Ribavirin
 Adefovir dipivoxil
 Interferon α
General mode of action of Antiviral agents-
Fig.14.4 (a): General mode of action of Antiviral agents

1. Anti-Herpes Virus Agents:
Herpes viruses are associated with diseases such as cold sores, viral
encephalitis and genital infections. Genital infections are a hazard to the
newborn during parturition. The drugs that are effective against these viruses
act mainly during the acute phase of viral infections. These drugs act mainly by
inhibiting viral DNA polymerase or inhibition of attachment to the host cell.
Figure14.4(b)
232
Fig.14.4(b): General mode of action of Anti-Herpes Virus agents
Acyclovir-
Acyclovir (9-[(2-hydroxy-ethoxy) methyl]-9H-guanine) is an acyclic guanine
nucleoside analog with a high specificity for Herpes simplex and Varicella
zoster viruses.
Acyclovir is converted to its active metabolite via three phosphorylation steps.
First, viral thymidine kinase converts acyclovir to acyclovir monophosphate.
Next, host cell enzymes convert the monophosphate to the diphosphate and
then to the active compound, acyclovir triphosphate, the active metabolite that
inhibits DNA synthesis and viral replication. Figure14.4(b)
233
Oral acyclovir is useful in the treatment of HSV-1 and HSV-2 infections, such
as genital herpes, herpes encephalitis, herpes keratitis, herpes labialis, and
neonatal herpes.
2. Anti-retrovirus drugs-
These are drugs active against human immunodeficiency virus (HIV) which is a
retrovirus.
Nucleoside reverse transcriptase inhibitors (NRTIs)-
Zidovudine-
It is a thymidine analogue (azidothymidine, AZT), the prototype NRTI.
After phosphorylation in the host cell—zidovudine triphosphate selectively
inhibits viral reverse transcriptase (RNA-dependent DNA polymerase) in
preference to cellular DNA polymerase. Figure14.4(c)
234
Zidovudine is used in HIV infected patients only in combination with at least 2
other anti retrovirus drugs.
Didanosine (ddI)-
It is a purine nucleoside analogue which after intracellular conversion to
didanosine triphosphate competes with ATP for incorporation in viral DNA,
inhibits HIV reverse transcriptase and terminates proviral DNA. Figure14.4(c)
Non nucleoside RT inhibitor

Fig.14.4(c): General mode of action of Anti-Retro Virus agents
Non-nucleoside reverse transcriptase inhibitors (NNRTIs)-
Nevirapine (NVP) and Efavirenz (EFV) –
These are nucleoside unrelated compounds which directly inhibit HIV reverse
transcriptase Figure14.4(c) without the need for intracellular phosphorylation.
235
Retroviral protease inhibitors (PIs)-
An aspartic protease enzyme encoded by HIV is involved in the production of
structural proteins and enzymes (including reverse transcriptase) of the virus.
The large viral polyprotein is broken into various functional components by this
enzyme. This protease acts at a late step in HIV replication, i.e. maturation of
the new virus particles when the RNA genome acquires the core proteins and
enzymes. They bind to the protease molecule, interfere with its cleaving
function. Figure14.4(c)
3. Anti influenza virus agents-
Amantadine and Rimantadine-
Amantadine (Symmetrel) is a synthetic tricyclic amine, and rimantadine
(Flumadine) is its α-methyl derivative. Both drugs inhibit the replication of the
three antigenic subtypes of influenza A (H1N1, H2N2 and H3N2) and have
negligible activity against influenza B.
Inhibition of the viral M2 protein, an integral membrane protein that acts as a
H+ channel. Blockade of the M2 protein prevents the acid-mediated
dissociation of the ribonucleoprotein complex that occurs early in replication.
In certain strains, the pH changes that result from M2 inhibition alter the
conformation of hemagglutinin, hence inhibit viral assembly. Figure14.4(d)
Fig.14.4 (d): General mode of action of Anti influenza Virus agents
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14.5 Antimalarial drug
There are the drugs used for prophylaxis, treatment and preventing of relapses
of malaria. Malaria caused by 4 species of the protozoal parasite plasmodium,
is endemic in most parts of india and other tropical countries. Malaria is a
mosquito-borne acute infectious disease caused by four species of the protozoal
parasite plasmodium. The symptoms of malaria include fever, shivering, pain in
the joints, headache, repeated vomiting, generalized convulsions and coma.
Classification of Antimalarial drugs-
1. 4-AMINOQUINOLINES-
 Chloroquine
 Amodiaquine
2. QUINOLINE-
 Mefloquine
3. CINCHONA ALKALOID-
 Quinine
 Quinidine
4. BIGUANIDES-
 Proguanil
5. DIAMINOPYRIMIDINES-
 Pyrimethamine
6. 8-AMINOQUINOLINE-
 Primaquine
 Bulaquine
7. SULFONAMIDES-
 Sulfadoxine and sulfone
 Dapsone
8. TETRACYCLINES-
 Tetracycline
 Doxycycline
9. SESQUITERPINE –
 Artesunate
 Artemether
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10. AMINO ALCOHOLS-
 Halofantrine
 Lumefantrine
11. MANNICH BASE-
 Pyronaridine
12. NAPHTHOQUINONE-
 Atovaquone
General mode of action of Antimalarial agents-
Antimalarial drugs attack the parasites at its various stages of life cycle in the
human host. Antimalarials which act on erythrocytic schizogony are calle
erythrocytic schizontocides, those which act on preerythrocytic and also
exoerythrocytic stages in liver are called tissue schizontocides, whereas those
which kill gametocytes in blood are called gametocides. Figure14.5
Fig.14.5: Life cycle of malaria parasites and locations where specific drugs
are effective
Chloroquine :
Chloroquine is a potent blood schizonticidal agent effective against the
erythrocytic forms of all four parasites but has no action against sporozoites,
hypnozoites or gametocytes.
238
Mechanism of action :
The mechanism of action of chloroquine is complex. Chloroquine which is
unionized at netural PH diffuses freely into the parasite lysosome. At the acidic
PH of the lysosome, it is converted to a protonated, membrance impermeable
form and is trapped inside the parasite. At high concentrations, it inhibits the
synthesis of protein RNA and DNA synthesis. Chloroquine acts mainly on
haem disposal by preventing digestion of haemoglobin by the parasite and thus
reducing the supply of amino acid necessary for survival of parasite. It also
inhibits the enzyme haem polymerase that polymerises toxic free haem to
haemozoin, rendering it harmless. Figure14.5
Chloroquine is the drug of choice for clinical cure and suppression of all types
of malaria. It is also used in giardiasis, rheumatoid arthritis and to control acute
manifestations of lepra reaction.
Quinine :
Quinine is an alkaloid obtained from cinchona bark.
It is the oldest of all agents used in the treatment of malaria and is still used for
cerebral malaria and chloroquine-resistant P.falciparum malaria. Quinine is a
blood schizonticidal agent and is effective against erythrocytic forms of all the
four species of falciparum but has no effect on exoerythrocytic forms or
gametocytes.
239
14.6 Antiamoebic drugs
Amoebiasis (amoebic dysentery) is an infectious disease caused by protozoa,
entamoeba histolytica, which is produced by the ingestion of cysts of this
organism. The ingested cysts develop into trophozoites and adhere to the
colonial epithelial cells in the intestine. These trophozites then lyses the host
cell and invades the submucosa. This produces the amoebic ulcers and cause
acute dysentery or chronic intestinal amoebiasis. The parasite may also pass
into blood stream and invades the liver causing liver abscesses. Other organs
like lung, spleen, kidney and brain are rarely involved in extraintestinal
amoebiasis. Some individuals act as carriers of parasite, without developing any
disease, but the cysts that are present in their faces affect others. The cysts can
survive outside the body for atleast a week in a moist and cool environment.
Amoebiasis can be acute or chronic with patients showing various degrees of
illness and symptoms such as mild diarrhoea to fulminating diarrhoea. The use
of drugs in treating amoebiasis is aimed not only in ill patients but also on
carriers. Different drugs are available for treating acute, chronic and extra-
intestinal infections and also in the carrier state.
1. TISSUE AMOEBICIDES
(a) For both intestinal and extraintestinal amoebiasis
 Nitroimidazoles: Metronidazole
 Alkaloids: Emetine
(b) For extraintestinal amoebiasis
 Chloroquine
2. LUMINAL AMOEBICIDES
(a) Amide
 Diloxanide furoate
 Nitazoxanide
(b) 8-Hydroxyquinolines
 Quiniodochlor
(c) Antibiotics
 Tetracyclines
General mode of action of Antiamoebic drugs -
The mode of action of these drugs is that they are selectively toxic to anaerobic
microorganisms. After entering into the cell by diffusion the drug gets reduced
by some redox proteins which operate only in anaerobic microbes and exerts
240
cytotoxicity by damaging DNA and other critical biomolecules. DNA helix
destabilization and strand breakage has been occurred in susceptible organisms.
Metronidazole-
Metronidazole is the drug of choice in the treatment of different forms of
amoebiasis. It kills the trophozites of E.histolytica but has no effect on the
cysts.
It is often used in combined with diloxanide furoate for the treatment of

amoebiasis.
Mechanism of action:
Metronidazole is selectively toxic to anaerobic organisms and amoebae. Some
anaerobic protozoan parasites possess ferrodoxin like, low-redox potential,
electron transport proteins that participate in metabolic electron removal
reactions. The nito group of metronidazole accepts electrons, forming reduced
cytotoxic compounds that bind to proteins and DNA causing cell death.
It is used in treatment of amoebiasis, giardiasis, trichomonas vaginitis and
pseudomembranous enterocolitis. It is also used in treatment of many anaerobic
bacterial infections and in peptic ulcers.
Diloxanide Furoate-
Diloxanide furoate (Furamide) is an amebicide that is effective against
trophozoites in the intestinal tract.
14.7 Antigiardiasis drugs
Giardia lamblia is a flagellate protozoon which mostly lives as a commensal in
the intestine. It is transmitted from man too man by faecal contamination of
food and water. It sometimes invades the mucosa and causes diarrhoea. Many
drugs which are useful in amoebiasis are also used in the treatment of
giardiasis.
The drugs are-
1. Metronidazole
2. Mepacrine
3. Quinodocholor
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4. Furazolidone
14.8 Antitrichomoniasis drugs :
Trichomonas vaginalis is another flagellate protozoon which causes
vulvovaginits. The main trichomonas organism that causes disease in human is
T.vaginalis. Virulent strains of the organism can cause inflammation of the
vagina in females and sometimes of the urethra in males.
The drugs are-
1. DRUGS USED ORALLY-
 Metronidazole
2. DRUGS USED INTRAVAGINALLY-
 Diiodo hydroquin, Quiniodochlor, Clotrimazole
14.9 Antileishmaniasis drugs
Visceral leishmaniasis (kalazar) caused by leishmania donovani occurs in
tropical and subtropical region of the world. Leishmaniasis is transmitted by the
bite of the female sand fly phlebotomus. In this fly the parasite present in the
flagellate extracellular (promastigote) form, while in human it is found
extracellularly with in macrophages in the nonflagellate (amastigote) form.
Mucocutaneous and dermal leishmaniasis are caused respectively by L.
Brazilliensis and L. Tropica.
In visceral type (liver and speen), the Parasite is present in blood stream and
causes very serious problems, such as hepatomegaly, anaemia and intermittent
fever. In mucocutaneous form, large ulcers are produced in mucous
membrances. In cutaneous form, simple skin infections that may heal
spontaneously are observed.
Drugs used in the treatment of leishmaniasis are-
1. ANTIMONIALS-
 Sodium stibo gluconate
2. DIAMIDINE-
 Pentamidine
3. OTHERS-
 Amphotericine B
 Ketoconazole
 Miltefosine
242
General mode of action of Antileishmaniasis drugs-
Antimonials: Sodium stibogluconate-
Sodium stibogluconate is the drug of choice for kala-azar (visceral
leishmaniasis). The drug inhibited SH-dependent enzymes and may cause
oxidative damage of the parasite by producing free radicals. It has been shown
to block glycolytic and fatty acid oxidation pathway.
Miltefosine:
Miltefosine is effective in treatment of both cutaneous and visceral
leishmaniasis. It probably acts by interfering with cell signaling pathways.
Diamidine: Pentamidine-
It interacts with kinetoplast DNA and inhibits topoisomerase II or interferes
with aerobic glycolysis.
Pentamidine is used in antimony-resistant leishmaniasis.
14.10 Antihelminthics drugs
Helminthic infections are the major health problem in topical countries and
many people are suffering from worm infestations. Helminths (worms) can
cause various gastrointestinal and general symptoms. They also cause blood
loss, nutritional deficiencies, urticaria allergic manifestations and even
intestinal obstruction. Humans are the primary hosts for many helminth
infections. Most of the worms reproduce sexually in human host, producing
eggs and larvae which pass out of the body and infect secondary or intermediate
host. Helminthic infections are rarely fatal, but are major cause for ill health.
The drugs which are useful against helminth are-
1. Mebendazole
2. Albendazole
3. Thiabendazole
4. Ivermectin
5. Pyrantel
6. Metronidazole
7. Praziquantel
General mode of action of Anthelminthic drugs-
Anthelminthic drugs aim the metabolic targets of the parasite that are either
absent or have different characteristics than those of the host. The drug must be
243
able to penetrate the cuticle of the worm or gain access to its alimentary tract.
These drugs act by causing paralysis of the worm or by damaging its cuticle
which leads to partial digestion or rejection by immune system. They also
interfere with the metabolism of the worms, as the metabolic requirements vary
greatly between different species. The anthelminthic drug that kills the worm is
called vermicidal and that affects the worm causing its expulsion is known as
vermifuge.
Benzimidazoles :
Benzimidazoles are broad-spectrum anthelminthic drugs and include
mebendazole, thiabendazole and albendazole.
These drugs mainly bind to free β-tubulin and inhibits its polymerisation, thus
interfering eith microtubule-dependent glucose uptake by the worm. These have
a selective inhibition on microtubular function of helminths than in mammalian
tissue.
Mebendazole :
Mebenazole is effective in the treatment of ascariasis, enterobiasis, trichuriasis
and in hook worm infestation. It also has some action against S.stercoralis. it
acts very slowly and the affected parasites are expelled with faces. It also
affects the ova of trichuris and Hook worm and is also effective against larvae
of trichinella spiralis and Echinococcus granulosus(Hydatid worm).
Praziquantel:
Praziquantel is a broad-spectrum anthelminthic and is the drug of choice for
treatment of schistosomiasis and for cestode infections like cysticercosis. It acts
mainly by increasing the permeability of the cell membrance of the paralysis
and death of the worm. It also modifies the parasite rendering it susceptible to
the immune response of the host. The drug is not only active against adult
schistosomes but also their immature forms that cause infections in humans by
penetrating the skin.
Pyrantel:
Pyrantel is a derivative of tetrahydropyrimidine and is effective against round
worms, pin worms and hook worms. It is less active against strongyloides and
has no action against Trichuris and other worms. Pyrantel acts by depolarizing
the neuromuscular junction in the helminths, causing spasm and paralysis. It
also possess some anticholinesterase activity. The paralyzed worms are
expelled from the hosts intestinal tract.
244
14.11 Antileprotic Drugs
These drugs act against Mycobacterium leprae, causing leprosy disease.
Drugs are-
1. SULFONE-
 Dapsone (DDS)
2. PHENAZINE DERIVATIVE-
 Clofazimine
3. ANTITUBERCULAR DRUGS-
 Rifampin, Ethionamide
4. OTHER ANTIBIOTICS-
 Ofloxacin
 Minocycline
 Clarithromycin
Dapsone (DDS)-
It is diamino diphenyl sulfone (DDS).
Mechanism of Action-
The sulfones are structural analogues of PABA and are competitive inhibitors
of folic acid synthesis. Folic acid functions as a coenzyme in the transfer of
one-carbon units required for the synthesis of thymidine, purines, and some
amino acids and consist of three components: a pteridine moiety, PABA, and
glutamate. The sulfonamides, as structural analogues, competitively block
PABA incorporation; sulfonamides inhibit the enzyme dihydropteroate
synthase, which is necessary for PABA to be incorporated into dihydropteroic
acid, an intermediate compound in the formation of folinic acid. Since the
sulfonamides reversibly block the synthesis of folic acid, they are bacteriostatic
drugs.
Sulfones are bacteriostatic and are used only in the treatment of leprosy.
245
14.12 Summary
There are different drugs that are used in the treatment of infection. Some drugs
are act on the site of infection locally. Drugs follow different path of
mechanism by which infection may be cure. Pharmacotherapy of local infective
disease such as antiviral, antifungal, antimalarial, antileprotic, antigiardiasis,
antileishmaniasis, antiamoebic and antiprotozoans etc. may be cure by drugs
used alone or in combination. Anti-infective drugs may act by penetration into
the cell of infective agent and distrupt their cell and cell wall components and
inhibit their genetic material and their metabolic function.
14.13 Glossary
 Anti-infective- Any agent that is used to combat infection.
 Antiinflammatory- An agent that counteracts inflammation.
 Anaemia- A reduction in the mass of circulating red blood cells.
 Bacteriostatic- Inhibiting bacterial growth.
 Diarrhoea- The passage of fluid or unformed stools.
 Fungistatic- Inhibiting fungi growth.
 Urinary tract infection- Infection of the kidneys, ureters, or bladder by
microorganisms.
 Vaginitis- Inflammation of the vagina.
1. What are the local anti-infective agents?
2. Enlist the local anti-infective agents.
3. Discuss the general mode of action of local anti-infective agents.
4. Explain the mechanism of action and uses of NNRTIs.
5. Classify the antiviral drugs.
6. Discuss the mechanism of action and uses of azoles.
7. Discuss the general mode of action of anti protozoal drugs.
8. Write the mechanism of action and uses of quinine.
9. Enlist the drugs which are used in the treatment of giardiasis and
trichnosomiasis.
10. What are the antihelminthics? Discuss their general mode of action.
246
1. Basic & Clinical Pharmacology (9th Ed.)- Bertram G.Katzung (Mc Graw
2. The Pharmacological basis of Therapeutics (10th Ed.)- Goodman &
3. Pharmacology (5th Ed.)- H.P Rang and M.M Dale (Elsevier publisher) 2003.
4. An introduction to medicinal chemistry (3rd Ed.)- Graham L.Patrik 2006.
Principles of medicinal chemistry (3rd ed.)- William O. Foye (Varghese
publisher) 1989.
5. Essential of Medical Pharmacology (7th ed.)- KD Tripathi (JAYPEE
Publisher) 2013.
247
Unit-15
Synthesis of Local
Anti-Infective Drugs
Structure of Unit:
15.1 Objectives
15.2 Introduction
15.3 Sulphonamides
15.4 Ciprofloxacin
15.5 Econazole
15.6 Fluconazole
15.7 Griseofulvin
15.8 Chloroquin
15.9 Primaquin
15.10 Summary
15.11 Glossary
15.1 Objective
 In this unit we will discuss about the drugs which are used for local
infections and also their method of synthesis and uses.
 Here we study that how sulphonamides are prepared.
 Here we also explain the use and adverse effect of these drugs.
15.2 Introduction
Anti-infective is an agent that is capable of acting against infection, either by
inhibiting the spread of an infectious agent or by killing the infectious agent
outright. Drugs of this class differ from all others in that they are designed to
inhibit/kill the infecting organism and to have no or minimal effect on the
recipient or host. These drugs are used for superficial fungal infections. Fungal
infection is due to fungi, which are plant-like, non photosynthetic eukaryotes
248
growing either in colonies of single cell (yeasts) or in filamentous multicellular
aggregates (molds). Drugs which are used for local infections are
sulphonamides, chloroquin, primaquin, econazole, fluconazol etc.
15.3 Sulphonamide
The sulphonamides are synthetic bacteriostatic antibiotics with a wide spectrum
against most gram-positive and many gram-negative organisms. The
sulphonamides and sulphone antibacterial as well as the 2,4-diaminopyrimidine
antifolates continue to be successful chemotherapeutic agents.
Synthesis:-
General methods of preparation:-
Method-I
Acetanilide on treatment with chlorosulphonic acid gives sulphonyl chloride

derivative, which on reaction with appropriate primary amine gives
sulphonamide derivative. Saponification gives the final target compound.
Method-II
 Synthesis of local anti-infective sulphonamides with their

structure
A. Structure of sulphacetamide:-
249
Synthesis of sulphacetamide:-
It is prepared by the selective and partial hydrolysis of the N1, N4-diacetyl

derivatives of sulphanilamide which is obtained by acetylation of
sulphanilamide.
It possesses general characteristic of a sulphonamide and was formerly used in
the treatment of bacterial infections of the urinary tract.
B. Structure of sulphacetamide sodium:-
Synthesis of sulphacetamide sodium:-
It may be prepared by heating together sulphacetamide and sodium hydroxide

in equimolar concentration.
It is chiefly employed by local application in injuries or infections of the eyes at
various strengths ranging from 10% to 30%, also used in the treatment of acute
conjunctivitis.
250
C. Structure of Mafenide:-
N-benzylacetamide is prepared by the acetylation of benzylamine, which on

treatment with chlorosulfonic acid at 15-20°c yield p-benzylamide sulphonyl
chloride. This on amination gives the corresponding sulphonamide derivative,
which upon hydrolysis with sodium hydroxide and subsequent neutralization
with acetic acid yields mafenide.
It is used in the treatment and cure of gas gangarene.
Synthesis of Mafenide:-
251
Synthesis of Mafenide acetate:-
D. Structure of silver sulfadiazine:-
Benzenesulfonamide, 4-amino-N-2-pyrimidinyl, mono silver (1+) salt

It is an effective topical antimicrobial agent especially against “pseudomonas
species”. it find its extensive use in burn therapy because it attacks the
pseudomonas radically which is perhaps considered to be the ultimate cause of
failures in the treatment of burn case.
15.4 Ciprofloxacin:- (ciproxin)
It is a bactericidal drug. Its mode of action depends upon blocking bacterial
DNA replication by binding itself to an enzyme called DNA gyrase.
Structure of ciprofloxacin:-
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Synthesis:-
Ciprofloxacin is a broad spectrum antibiotic that is active against both gram-

positive and gram-negative bacteria. The major adverse effect seen with the use
of ciprofloxacin is gastro-intestinal irritation, common with many other such
antibiotics.
It is effective for the treatment of urinary tract infection and prostatitis and for
acute diarrheal disease caused by E.coli shigela, salmonella and campylobacter.
15.5 Econazole
It is deschloro derivative of miconazole. Its actions are like miconazole. It is
available as a water insoluble cream (1%) to be applied twice a day.
Structure of Econazole:-
253
Synthesis of Econazole
Econazole is synthesised from 2,4-dichlorophenacyl. It reacts with hydrogen

bromide and give 2,4-dichlorophenacyl bromide, which is reacted with
imidazole to make 1-(2,4-dichlorobenzoylmethyl)-imidazole. Reducing the
carbonyl group in this molecule with sodium bromohydride gives 1-(2,4-
dichlorophenyl)-3-(1-imidazolyl)-ethanol and the hydroxyl group is alkylated
by 4-chlorobenzylchloride using base such as sodium hydride to make
econazole.
15.6 Fluconazole
Fluconazole is a widely used bis-triazole antifungal agent. Fluconazole is
generally considered to be a fungistatic agent. It is principally active against
candida speices and crytococcus species. fluconazole has useful activity against
coccidioides immitis and is often used to suppress the meningitis produced by
that fungus.
Structure of Fluconazole:-
IUPAC- 2-(2,4- diflurophenyl)-1,3-

bis(1H-1,2,4-triazol-1-yl) propane-2-ol
Synthesis:-
Method-I
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It is prepared from 2,4-diflurophenacyl chloride. Displacement of chlorine by
triazole affords intermediate condensation of carbonyl group with the yield
from trimethylsulphonium iodide, leads to an addition product.
Method-II
The anion formed on the carbonyl oxygen then internally displaces dimethyl
sulphide to give on oxiran or (epoxide). Reaction of this with triazole leads to
epoxide ring opening with consequent incorporation of the second triazole, and
affords fluconazole.
The drug is indicated for the treatment of systemic candida infection and the
treatment of cryptococcal meningitis.
The adverse effect profile of fluconazole has remained very favourable. Nausea
and vomiting occur. Allergic rash, eosinophillia and thrombocytopenia have
been encountered in patients with AIDS.
15.7 Griseofulvin:- (fulvicin)
It is obtained from the mould “penicillium griseofulvum”. Griseofulvin is a
fungistatic drug that cause disruption of the mitotic spindle by interacting with
polymerised microtubules.
255
It is a white, tasteless powder and slightly soluble in water. It is naturally
occurring spirane. The drug is principally fungistatic, effective against the
dermatophytes- Trichophyon, Microsporum and Epidermophyton.
Structure:-
IUPAC 7-chloro- 2,4,6-trimethoxy
6methylspiro[benzofuran-2(3H),1 (2)cyclohexen]-3,4-dione
Synthesis:-
15.8 Chloroquin:- (Resochin)

It is white crystalline powder with bitter taste, slowly decolourise on exposure
to light.
Structure:-
IUPAC Name- 7-chloro-4-[4-(diethyl amino)-1-methylbutylamino] quinoline.

Synthesis:-
256
Chloroquin is made by reacting 4,7-dichloroquinoline with 4-dimethylamino-1-
methylbutylamine at 180°c.
The drug completely cures faciparum malaria. the major metabolite,
monodesethyl chloroquine has also antimalarial activity.
15.9 Primaquin
It is an antimalarial drug which is specifically kills the primary exoerythrocytic
stages 0f p. vivax, p. falciparum, p. Malariae and p. Ovale, and the secondary
exoerythrocytic form of all except p. falciparum, which has no secondary
forms.
Structure of Primaquin:-
IUPAC Name-8-[(4-amino-1-methylbutyl)amino]-6-methoxy quinoline

Synthesis :-
The synthesis of primaquin may be accomplished by either of the two following
methods:-
Method I- From 2-chloropentylamine:-
It may also be prepared by the condensation of 2-chloro-pentylamine with 8-
amino-6-methoxy quinoline to obtain primaquin base which on treatment with
bimolar quantity of phosphoric acid yield primaquin.
257
Method-II Elderfield’s from 1,4-dibromopentane:-
2-bromo-5-phthalimido pentane is prepared by the interaction of 1,4-
dibromopentane with potassium phthalimide, which on reaction with 8-amino-
6-methoxy quinoline yields the condensed product. Further treatment with
hydrazine eliminates the phthalimido residue and yields the primaquin base
which on reaction with a double molar quantity of phosphoric acid forms the
official compound.
258
Method- III
15.10 Summary
The antimicrobial activity of sulphonamides extends to many microbial species
having a folic acid pathway which consist of many gram positive and gram
negative cocci and bacilli, fungi, mycobacteria, some large viruses, and
protozoa.
The use of sulphonamides includes the treatment of acute and chronic gram-
positive and gram negative bacterial infections, consisting of leprosy, malaria,
trachoma, toxoplasmosis and cocci diosis
Fluconazole can be administered orally as well as intravenously in severe
infections. It is longer acting, safer and more efficacious drug. Econazole has
broad spectrum antifungal activity.
Chloroquin is the drug of all types of malaria except that caused by P.
falciparum, because P. falciparum has acquired significant resistance against
chloroquin.
15.11 Glossary
 Gangrene: - is a potentially life-threatening condition that arises when a
considerable mass of body tissue dies (necrosis). This may occur after
an injury or infection, or in people suffering from any chronic health
problem affecting blood circulation.
 Eosinophillia: - is a condition in which the eosinophil count in the
peripheral blood exceeds 4.5×108/L.
 Meningitis: - is an acute inflammation of the protective membranes
covering the brain and spinal cord, known collectively as the meninges.
259
The inflammation may be caused by infection with viruses, bacteria, or
other microorganisms, and less commonly by certain drugs.
 Mitotic Spindle: - The collectively term for all the spindle fibers that
form during mitosis. It is a spindle-shaped structure that develops
outside the nucleus during mitosis.
 Prostatitis: - is inflammation of the prostate gland. Prostatitis is
classified into acute, chronic, asymptomatic inflammatory prostatitis,
and chronic pelvic pain syndrome.
 Saponification: - Saponification is a process that produces soap, usually
from fats and lye.
 Urticaria: - commonly referred to as hives, is a kind of skin rash
notable for pale red, raised, itchy bumps. Hives may cause a burning or
stinging sensation. They are frequently caused by allergic reactions.
15.12 Review questions/comprehensive question-

1. What are local anti-infective agents with examples? Give synthesis of any
one local anti infective agent.
2. Give the different methods for the synthesis of primaquin as local anti-
infective agent.
3. Give the synthesis of chloroquin with its structure.
4. What are sulphonamides? Which type of sulphonamides are used as local
anti infective agent.
5. Give the synthesis of Mafenide.
6. Give the synthesis of any one local anti infective agent belongs to
sulphonamide category.
7. Give the structure and synthesis of chloroquin.
8. Give the synthesis of following-
 Sulphacetamide sodium.
 Econazole.
 Flconazole
 Chloroquin.
260
 A Book of medicinal chemistry volume II; (first edition 2008-2009) Dr.
Approach) Vol. II; (third edition 2004, reprint 2006) Surendrs N.
 Principle of medicinal chemistry-vol. I; (eighteenth edition, september
261
Unit-16
Psychoactive Drugs
Structure of Unit:
16.1 Objectives
16.2 Introduction: Psychoactive Drugs
16.3 Neurotransmitters
16.4 Neurochemical Transmission
16.5 CNS depressants
16.6 General Anesthetics
16.7 Sedative – Hypnotics
16.8 Anti-anxiety drugs
16.9 Neurochemistry of mental diseases
16.10 Summary
16.11 Glossary
16.1 Objectives
 Meaning of Psychoactive Drugs
 Different types of Neurotransmitters
 General Mechanism of Neurochemical Transmission
 CNS depressants
 Different types of General Anesthetics
 Mechanism of action of Sedative – Hypnotics
 Mechanism of action of Anti-anxiety drugs
 Biochemical theories of affective disorders
16.2 Introduction: Psychoactive Drugs
Psychoactive or Psychotropic drugs are the agents which affectmental processes
and are used to treat mental disorders.
Psychoactive drugs may be classified on the basis of primary use as following-
1-Antipsychotics (Neuroleptics/Ataractic/Major Tranquillizer)
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2-Antidepressants (Thymoleptics)
3-Antianxiety drugs (Anxiolytics/Minor Tranquillizer)
4-Antimanic (Mood Stabilizer)
16.3 Neurotransmitters (Mediators)
These are chemical messengers through with nerve transmit their message
across synapse and neuroeffector junction. Neurotransmitters are synthesized
by nerve cells, actively transported along the axons and stored in the synaptic
vesicles. They are released by exocytosis in response to the action potential and
diffuse across the synaptic cleft. Classically, neurotransmitters fall into two
major categories:
Excitatory- Ion channels are opened to permit net influx of positively charged
ions, leading to depolarization with a reduction in the electrical resistance of the
membrane; and
Inhibitory- Selective ion movements lead to hyper polarization, also with
decreased membrane resistance.
Classification-
1-Excitatory Neurotransmitter –
Glutamate Aspartate
2-Inhibitory Neurotransmitter –
GABA Glycine Dopamine
3-Excitatory and Inhibitory Neurotransmitter –

Acetylcholine Serotonin Noradrenaline
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16.4 Neurochemical Transmission
Neurohumoral transmission implies that nerves transmit their message across
synapses and neuroeffector junctions by the release of chemical messengers.
Fig.16.1: Diagrammatic representation of steps in excitatory and inhibitory

Neurochemical transmission.
Excitatory postsynaptic potential (EPSP)
When an excitatory transmitter binds with specific receptor on post junctional
membrane, the membrane permeability to Na+ or Ca+2increases, influx of
cations causes depolarization followed by K+ efflux.
Inhibitory postsynaptic potential (IPSP)
When an inhibitory transmitter binds with specific receptor on post junctional
membrane, the membrane permeability to K+ or Cl- increases, K+ moves out and
Cl- in moves and hyper polarization occur.
Basic steps in Neurochemical transmission-
Figure16-2: Diagrammatic representation steps of Neurochemical

transmission.
264
Neurochemical transmission steps are as followings-
 Uptake of precursors
 Synthesis of transmitter
 Uptake/Transport of transmitter into vesicles
 Degradation of surplus transmitter
 Depolarization by propagated action potential
 Influx of Ca2+ in response to depolarization
 Release of transmitter by exocytosis
 Diffusion to postsynaptic membrane
 Interaction with postsynaptic receptors
 Inactivation of transmitter
 Reuptake of transmitter or degradation products by nerve terminals
 Uptake of transmitter by non-neuronal cells; and interaction with
presynaptic receptors
The transporters (11 and 12) can release transmitter under certain conditions by
working in reverse.
Some neurotransmitters bind to their receptors and act quickly to open or close
ion channels in the membrane. Others act more slowly via second-messenger
systems to influence chemical reactions inside cells. The result of either process
can be excitation or inhibition of postsynaptic neurons. Many neurotransmitters
are also hormones released into the bloodstream by endocrine cells in organs
throughout the body.
Acetylcholine-
It is released by many PNS neurons and by some CNS neurons. ACh is an
excitatory neurotransmitter at some synapses, such as the neuromuscular
junction, where the binding of ACh to inotropicreceptors opens cation channels.
It is also an inhibitory neurotransmitter at other synapses, where it binds to
metabotropic receptors coupled to G proteins that open K+ channels. The
enzyme acetyl cholinesterase inactivates ACh by splitting it into acetate and
choline.
265
Glutamate (glutamic acid)
Excitatory synaptic transmission is mediated by glutamate, which is present in
very high concentrations in excitatory synaptic vesicles. Glutamate is released
into the synaptic cleft by Ca+2-dependent exocytosis. The released glutamate
acts on postsynaptic glutamate receptors and is cleared by glutamate
transporters present on surrounding glia. In glia, glutamate is converted to
glutamine by glutamine synthetase, released from the glia, taken up by the
nerve terminal, and converted back to glutamate by the enzyme glutaminase.
Gamma amino butyric acid (GABA) and glycine are important inhibitory
neurotransmitters. At many synapses, the binding of GABA to inotropic
receptors opens Cl-channels. GABA is found only in the CNS, where it is the
most common inhibitory neurotransmitter. One-third of all brain synapses use
GABA.
Like GABA, the binding of glycine to inotropic receptors opens Cl channels.
About half of the inhibitory synapses in the spinal cord use the amino acid
glycine; the rest use GABA.
Norepinephrine (NE)–
A smaller number of neurons in the brain use epinephrine as a neurotransmitter.
Norepinephrine also serves as hormones. Cells of the adrenal medulla, the inner
portion of the adrenal gland, release them into the blood.
Dopamine (DA)-
Brain neurons containing this neurotransmitter are active during emotional
responses, addictive behaviors and pleasurable experiences. In addition,
dopamine-releasing neurons help regulate skeletal muscle tone and some
aspects of movement due to contraction of skeletal muscles. The muscular
stiffness that occurs in Parkinson disease is due to degeneration of neurons that
release dopamine.
Nor epinephrine and dopamine are classified chemically as catecholamines.
Inactivation of catecholamine occurs via reuptake into synaptic end bulbs. Then
they are either recycled back into the synaptic vesicles or destroyed by the
enzymes. The two enzymes that break down catechol amines are catechol-O-
methyltransferase (COMT) and monoamine oxidase (MAO).
Serotonin-
It is also known as 5-hydroxytryptamine (5-HT), concentrated in the neurons in
a part of the brain called the raphe nucleus. It is thought to be involved in
266
sensory perception, temperature regulation, control of mood, appetite, and the
induction of sleep.
16.5 CNS depressants
These are drugs which produce central nervous system depressant effect.
Manifestations of CNS depression are-
 Drowsiness
 Sedation
 Hypnosis
 Disorientation
 Confusion
 Unconsciousness
 Coma
 Death
CNS depressants-
 General Anesthetics
 Sedative – Hypnotics
 Anti-anxiety drugs
16.6 General Anesthetics

Drugs produce reversible loss of all sensations and state of unconsciousness.
The physiologic state induced by general anesthetics typically includes
analgesia, amnesia, loss of consciousness, inhibition of sensory and autonomic
reflexes, and skeletal muscle relaxation. An ideal anesthetic drug would induce
loss of consciousness smoothly and rapidly, while allowing for prompt recovery
of cognitive function after its administration is discontinued. The anesthetic
technique will vary according to the proposed type of diagnostic, therapeutic, or
surgical intervention.
Stages of Anesthesia-
 Stage of analgesia
 Stage of excitement
 Stage of surgical anesthesia
 Stage of medullary depression
267
CLASSIFICATION-
(I) INHALATIONAL
(A) GAS
 Nitrous oxide
 Ether
(B) VOLATILE LIQUIDS
 Halothane
 Enflurane
 Isoflurane
 Desflurane
 Sevoflurane
(II) INTRAVENOUS
(A) INDUCING AGENTS
 Thiopentone sod.
 Methohexitone sod.
 Propofol
 Etomidate
(B) SLOWER ACTING DRUGS
(1)Benzodiazepines
 Diazepam
 Lorazepam
 Midazolam
(2) Dissociative anaesthesia
 Ketamine
(3) Opioid analgesia
 Fentanyl
Mechanism of Action –
The main site of action of anesthetics is reticular formation, which normally
maintains a state of consciousness. Most anesthetics depress reticular formation
by enhancing the activity of inhibitory transmitters and blocking the activity of
excitatory transmitters.
Ligand gated ion channels are the major targets of anesthetic action. The
GABA-A receptor gated Cl- channel is the most important of these. Many
268
inhalational anesthetics, barbiturates, benzodiazepines and propofol potentiate
the action of inhibitory transmitter GABA to open Cl- channels. These interact
with its own specific binding site on the GABA-A receptor Cl- channel
complex, but none binds to the GABA binding site as such; though some
inhaled anesthetics and barbiturates (but notbenzodiazepines) can directly
activate channels.
Action of inhibitory transmitter which activates Cl- channels in the spinal cord
and medulla is augmented by barbiturates, propofol and many inhalational
anesthetics. This action may block responsiveness to painful stimuli resulting in
immobility of the anesthetic state. N2O and ketamine do not affect GABA or
glycine gated Cl- channels. They selectively inhibit the excitatory NMDA type
of glutamate receptor. This receptor gates mainly Ca+2 selective cation
channels in the neurons, inhibition of which appears to be the primary
mechanism of anesthetic action of ketamine as well as N2O. The volatile
anesthetics have little action on this receptor.
INHALATIONAL ANAESTHETICS
Inhalational Gas
Nitrous oxide-
It is a colourless, odourless, noninflammable gas.

Nitrous oxide is a good analgesic
Onset of action is quick andsmooth
Recovery is rapid
Potency is low
Generally used as a carrier and adjuvant to other anesthetics
Volatile liquids
Ether-
(C2H5 - O - C2H5)
It is a highly volatile produces irritating vapours which are inflammable and
explosive. Ether is a potent anesthetic, produces good analgesia. Now it is not
used in developed countries due to unpleasant and inflammable properties.
Halothane
269
It is nonirritant, noninflammable and potent anesthetic.For induction 2-4% and
for maintenance 0.5-1% is delivered by the use of a special vaporizer. It is
currently one of the most popular anesthetic suitable for children as well as
adults.
Enflurane-
This is the substitute of halothane with rapid acting property. It is replaced by
isoflurane due to its tendency to provoke seizures.
Isoflurane-
Isoflurane is an isomer of Enflurane. It has similar properties, but more potent,

more volatile and less soluble in blood. It produces relatively rapid induction
and recovery and is administered through a special vaporizer, used for
maintenance.
Desflurane-
It is a newer congener of isoflurane. Thermostatically heated special vaporizer

is used to deliver desflurane in the carrier gas (N2O + O2) mixture. It is a
alternative to isoflurane for routine surgery as well, especially prolonged
operations.
INTRAVENOUS ANAESTHETICS
INDUCING AGENTS
These are drugs which on i.v. injection produce loss of consciousness, are
generally used for induction because of rapidity of onset of action. They also
use to reduce the amount of maintenance anesthetic.
Thiopentone sodium-
It must be prepared freshly before injection.

Thiopentone is a commonly used inducing
270
agent. It can be employed as the sole anesthetic for short operations that are not
painful.
Methohexitone sodium- It is more potent and has a rapid action than
thiopentone.
Propofol- It is an oily liquid employed as a 1% emulsion. Pain during injection
can be minimized by combining with Lidocaine
Etomidate-
It is has a rapid onset and short duration of action. It
is a poor analgesic and has not found much favour.
SLOWER ACTING DRUGS

Benzodiazepines (BZDs) –
BZDs are frequently used for inducing maintaining and anesthesia. BZDs are
poor analgesics, an opioid or N2O is usually added if the procedure `is painful.
The action of BZDs can be reversed by flumazenil. They are useful for
endoscopies, cardiac catheterization, fracture setting etc. they include
diazepam, lorazepam etc.
Ketamine-
It is pharmacologically related to the hallucinogen phencyclidine. The primary
site of action is in the cortex and sub cortical areas. Ketamine has been used for
short operations. It is good for repeated use; particularly suitable for burn
dressing.
271
Fentanyl-
This is related to pethidine, short acting potent opioid analgesic given at the
beginning of painful surgical procedures. It is frequently used to supplement
anesthetics in balanced anesthesia.
16.7 Sedative – Hypnotics

Sedative – Drugs that reduce excitement and relax the individual (person)
without producing sleep.
Hypnotics – Drugs that produce or maintains sleep, similar to normal sleep.
A drug in small dose may induce sedation while same drug in large dose may
act as hypnotic.
CLASSIFICATION
1. Barbiturates
A. Long acting
 Phenobarbitone
B. Short acting
 Butobarbitone
 Pentobarbitone
C. Ultra-shortacting
 Thiopentone
 Methohexitone
2. Benzodiazepines
A. Hypnotic
 Diazepam
 Flurazepam
 Nitrazepam
 Alprazolam
 Temazepam
 Triazolam
B. Antianxiety
 Diazepam
 Chlordiazepoxide
272
 Oxazepam
 Lorazepam
 Alprazolam
C. Anticonvulsant
 Diazepam
 Lorazepam
 Clonazepam
 Clobazam
3. Newer nonbenzodiazepine hypnotics
 Zopiclone
 Zolpidem
 Zaleplon
Fig. 16.3: Schematic depiction of GABAA-benzodiazepine receptor-chloride

channel complex
273
Benzodiazepines
Therapeutic uses-
Benzodiazepines decrease time required to fall asleep. The total sleep time is
increased. Now Benzodiazepines are preferred drugs for treatment of short-term
insomnia. Long term use of Benzodiazepines not recommended but suitable for
occasionally use by air travelers, shift workers.
Barbiturates-
274
Therapeutic uses- Barbiturates cause marked alteration in sleep latency and
duration. At present Barbiturates not used for the treatment of insomnia.
Non- benzodiazepines-
16.8Antianxiety drugs
Anxiety – It is an emotional state associated with uneasiness, discomfort and
fear about same defined or undefined threat.
Antianxiety drugs-
These are drugs, mostly mild CNS depressants, which produce a restful state of
mind without interfering with normal mental or physical functions and control
the symptoms of anxiety. The drugs differ markedly closely resemble to
sedative-hypnotics.
CLASSIFICATION
1. Benzodiazepines
 Diazepam
 Oxazepa
 Lorazepam
 Alprazolam
2. Azapirones
 Buspirone
 Gepirone
275
 Ispapirone
3. Sedative antihistaminic
 Hydroxyzine
4. β-blocker
 Propranolol
Benzodiazepines-
Benzodiazepines act on limbic system and facilitate inhibitory effect of
GABA.These drugs are useful in short-term treatment of anxiety.
Azapirones-
It is a new class of antianxiety drugs. It does not interact with BZD
receptor.The mechanism of anxiolytic action is not clearly known, but may be
dependent on its selective partial agonistic action on 5-HT1A receptors. By
stimulating presynaptic 5-HT1A autoreceptors, it reduces the activity of dorsal
raphe serotonergic neurones. These mainly used in the treatment of generalized
anxiety states. Its effect may take time to develop. So it is not effective in acute
cases.
Sedative antihistaminic-
H1 antihistaminic Hydroxyzine have selective anxiolytic action. It may be used
in reactiveanxiety or that associated with marked autonomicsymptoms.
β- blocker-
Propranolol and other nonselective β-blockers are mainly used to reduce the
symptoms of anxiety which are occur due to sympathetic over activity,
potentiate anxiety symptoms. They may be used for performance/situational
anxiety or as adjuvant to BZDs.
16.9 Neurochemistry of Mental Diseases
The term "psychosis" denotes a variety of mental disorders. The pathogenesis
of these conditions is unknown. In 1880s some experiments had suggested a
possibility of chemical factors affecting the pathology of psychoses. Research
over the past decades has resulted in interesting theories involving amines and
their receptors. It should be pointed out, that these concepts are still theories,
not established explanations of the disease state. The basic concept is that
neurotransmitter imbalances within the brain are the main causes of psychiatric
disorders.
276
Biochemical theories of affective disorders-
The Amine Hypothesis
In the early 1950s after the introduction of reserpine, it became apparent that
the drug could induce depression. Studies revealed that the principle
mechanism of action of reserpine was to inhibit the neuronal storage of amine
neurotransmitters such as serotonin and nor epinephrine. Reserpine induced
depression and depleted stores of amine neurotransmitters; therefore, it was
reasoned, depression must be associated with decreased functional amine-
depended synaptic transmission. This idea provided the basis for what became
known as the amine hypothesis of depression. Drugs that increased amine
function in appropriate synaptic areas would relieve depression.
Both depression and mania are associated with changes in brain monoamines.
The monoamine hypothesis proposes that, in depression, there is deficiency of
the neurotransmitters nor adrenaline and serotonin in the brain which can be
altered by antidepressants. Drugs that depression can modify affect amine
storage, release or uptake. Thus the concentration of amines in nerve endings or
at postsynaptic receptors is enhanced. In support of the monoamine hypothesis
are the findings that amphetamines, which release presynaptic nor adrenaline
and dopamine from stores and prevent their reuptake, have a weak
antidepressant effect. The importance of serotonin is illustrated by the finding
that depressed patients may exhibit down-regulation of some postsynaptic
serotonin receptors.
Specific serotonin reuptake inhibitors, act predominantly by preventing
serotonin reuptake and have more limited effects on noradrenaline reuptake.
Tricyclic antidepressant in general inhibits nor adrenaline reuptake, but effects
on serotonin reuptake vary widely; desipramine and protriptyline have minimal
potential for raising serotonin concentrations. MAOIs increase the availability
of nor adrenaline and serotonin by preventing their destruction by the
monoamine oxidase type, a enzyme in the presynaptic terminal.
The amine hypothesis has provided the major experimental models for the
discovery of new antidepressant drugs. As a result, all currently available
antidepressants, excepts bupropion, are classified as having their primary
actions on the metabolism reuptake, or selective receptor antagonism of
serotonin, nor epinephrine, or both.
277
Schizophrenia
In schizophrenia, there appears to be over activity of dopamine systems in areas
of the brain associated with complex mental and emotional functions. This is
the dopamine hypothesis of schizophrenia.
Dopamine systems in the brain
Fig.16.4: Dopamine pathway in brain

More recently, it has been suggested that schizophrenia may be a
developmental disorder of the prefrontal cortex where there is actually a
deficiency of dopamine, which leaves dopamine activity in the mesolimbic
pathway unbalanced.
There is some evidence for the involvement of serotonin (5HT) and possibly
other transmitters interacting with dopamine pathways. Most anti-psychotic
drugs seem to work by blocking dopamine receptors in the brain, although
some of the new atypical anti-psychotics also block serotonin receptors.
Dopamine receptors
There are two main types of dopamine receptor: the D1 type, which includes
D1 and D5, and is excitatory; and the D2 type, which includes D2, D3 and D4,
and is inhibitory. The significance of different types of dopamine receptors is
still unclear, but drugs that are effective in schizophrenia appear to have an
affinity for D2 type receptors.
The Dopamine Hypothesis of Schizophrenia:
Based on the efficacy of antipsychotic drugs, efforts continue to link the
disorder with abnormalities of amine neurotransmitter function, especially that
of dopamine. The dopamine hypothesis for schizophrenia is the most fully
developed of several hypotheses and is the basis for much of the rationale for
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drug therapy. Several evidences suggests that excessive dopaminergic activity
plays a role in the disorder:
 Many antipsychotic drugs strongly block postsynaptic D2 receptors in
the central nervous system, especially in the mesolimbic-frontal system.
 Drugs that increase dopaminergic activity, such as levodopa (a
precursor), amphetamines (releasers of dopamine), and apomorphine (a
direct dopamine receptor agonist), either aggravate schizophrenia or
produce psychosis in some patients.
 Dopamine receptor density has been found postmortem to be increased
in the brains of schizophrenics who have not been treated with
antipsychotic drugs.
 Positron emission tomography (PET) has shown increased dopamine
receptor density in both treated and untreated schizophrenics when
compared with such scans of non schizophrenic persons.
 Successful treatment of schizophrenic patients has been reported to
change the amount of homovanillic acid (HVA), a metabolite of
dopamine, in the cerebrospinal fluid, plasma, and urine.
The dopamine hypothesis is far from complete, however. If an abnormality of
dopamine physiology were completely responsible for the pathogenesis of
schizophrenia, antipsychotic drugs would do a much better job of treating
patients—but they are only partially effective for most and ineffective for some
patients. The cloning and characterization of multiple dopamine receptor types
may permit more direct testing of the dopamine hypothesis if drugs can be
developed that act more selectively on each receptor type. The traditional
antipsychotics bind D2 50 times more avidly than D1 or D3 receptors. Until
recently, the main thrust in drug development was to find agents that were more
potent and more selective in blocking D2 receptors. The fact that several of the
atypical antipsychotic drugs have much less effect on D2 receptors and yet are
effective in schizophrenia has redirected attention to the role of other dopamine
receptors and to no dopamine receptors, especially serotonin receptor subtypes
that may mediate synergistic effects or protect against the extra pyramidal
consequences of D2 antagonism.
Current brain imaging and biochemical studies in patients do not support a
single biologic abnormality as common to most depressions. Rather, prevailing
hypotheses emphasize an underlying role for several brain circuits that have a
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propensity to become dysfunctional, in individuals with a range of genetic
predispositions. It is likely that several pathophysiologic processes will
ultimately be identified to account for the presentation of mental disorders. As a
result of these considerations, the direction of research has changed to a greater
focus on compounds that may act on several transmitter-receptor systems. The
great hope is to produce drugs with greater efficacy and fewer adverse effects,
especially extra pyramidal toxicity.
16.10 Summary
Drugs acting in the central nervous system are the most widely used group of
pharmacologic agents. The mechanisms by which various drugs act in the CNS
have not always been clearly understood. In the last three decades, however,
dramatic advances have been made in the methodology of CNS pharmacology.
Neurotransmitters mediate signal from one neuron to another.
Neurotransmitters are either excitatory or inhibitory. Pharmacological agents
which are use in the treatment of mental disorders called Psychoactive Drugs.
The physiologic state induced by general anesthetics typically includes
analgesia, amnesia, loss of consciousness, inhibition of sensory and autonomic
reflexes, and skeletal muscle relaxation. General anesthetics are usually
administered by intravenous injection or by inhalation. Both the inhaled and the
intravenous anesthetics can depress spontaneous and evoked activity of neurons
in many regions of the brain. The sedative-hypnotic class cause sedation or to
encourage sleep. Anxiety is an emotional state, unpleasant in nature, associated
with uneasiness. The anxiolytic and sedative-hypnotics drugs are closely
resemble. There are some biochemical hypotheses which explain the role of
neurotransmitters in mental disorders pathogenesis.Neurotransmitter functions
provide potential targets for pharmacologic therapy.
16.11 Glossary
 Ataractic: Drugs producing state of mental calm and tranquility.
 Coma: A state of unconsciousness from which one cannot be aroused.
 Confusion: Not being aware of or oriented to time, place or self
 Disorientation: Inability to estimate direction or location, or to be
cognizant of time or of persons.
 Drowsiness: The of almost falling asleep
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 Neuroleptics: Drug producing symptoms similar to central nervous
system (CNS) depressant diseases.
 Thymoleptics: Synonym of antidepressant drugs.
 Tranquilizers: Drugs reducing mental tension without affecting normal
function.
1. Define and classify Psychoactive Drugs.
2. Classify neurotransmitters and write briefly about Neurochemical
transmission.
3. Define and classify CNS depressant drugs.
4. Explain the mechanism of action of followings-
A. General Anesthetics
B. Sedative – Hypnotics
C. Anti-anxiety drugs
5. Write in detail about biochemical theories of affective disorders.
6. Write short note on-
A. Inhalational anesthetics
B. Dopamine Hypothesis of Schizophrenia

 Basic & Clinical Pharmacology (9thed.)- Bertram G.Katzung (McGraw
Mahadik, Dr. K.G. Bothara (Niraliprakashan) 2007.
 Pharmacology (5thed.)- H.P Rang and M.M Dale (Elsevier publisher)
2003.
 Essential of Medical Pharmacology (7thed.)- KD Tripathi (JAYPEE
Publisher) 2013.
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Unit-17
Antipsychotic Drugs
Structure of Unit:
17.1 Objectives
17.2 Introduction: Psychosis
17.3 Schizophrenia
17.4 Neruoleptic- Antipsychotic drugs
17.5 Distinctive features of neuropleptics
17.6 Depression
17.7 Antidepressant drugs
17.8 Buturophenones– Serendipity and drug development
17.9 Stereo chemical aspects of psychotropic drugs
17.10 Summary
17.11 Glossary
17.1 Objectives
 Meaning of Psychosis
 Symptoms of Schizophrenia
 Neruoleptic Drug Classes and Mechanism of Action
 Characteristics of different Neruoleptic Drugs
 Meaning and Types of Depression
 Treatment of Depression
 Serendipity and Drug Development
 Stereochemistry of Psychotropic Drugs
17.2 Introduction:
The term psychosis refers to a variety of mental disorders characterized by one
or more of the following symptoms: diminished and distorted capacity to
process information and draw logical conclusions, hallucinations, delusions,
incoherence or marked loosening of associations, catatonic or disorganized
behavior, and aggression or violence.
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 Cognitive disorders (Acute and chronic organic brain syndromes)
 Functional disorders
i. Schizophrenia (split mind)
ii. Paranoid states
17.3 Schizophrenia – (split mind)

It is a chronic disorder, typically arising in early adulthood and progressing
throughout the rest of the life.
The symptoms of schizophrenia are followings-
Positive symptoms– Not normally found in healthy individuals.
 Hallucinations
 Delusions
 Thought disorder
Negative symptoms– Normally present in healthy individuals.
 Impoverishment of thought
 Blunted Emotion
 Attention deficit
 Lack of motivation or initiative
17.4 Neruoleptic- Antipsychotic Drugs

The neruoleptic drugs (antipsychotic drugs or major tranquilizers) are used in
the treatment of all type of psychosis, especially schizophrenia but are also
effective in some other psychotic states, such as manic states with psychotic
symptoms such as grandiosity or paranoia and hallucinations, and delirium.
CLASSIFICATION –
1-Phenothiazines
a. Aliphatic side chain
 Chlorpromazine
 Triflupromazine
b. Piperidine side chain
 Thioridazine
c. Piperazine side chain
 Trifluoperazine
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 Fluphenazine
2-Butyrophenones –
 Haloperidol
 Trifluperidol
3-Thioxanthenes-
 Flupenthixol
4-Other heterocyclic’s-
 Pimozide
 Loxapine
5-Atypical antipsychotics
 Clozapine
 Risperidone
 Olanzapine
 Quetiapine
 Aripiprazole
 Ziprasidone
Mechanism of action
The antipsychotic actions of neruoleptic drugs appear to reflect a blockade at
dopamine and/or serotonin receptors. All of the older and most of the newer
neruoleptic drugs block dopamine receptors in the brain and the periphery. The
neruoleptic drugs bind to these receptors to varying degrees. Most of the newer
atypical agents appear to exert part of their unique action through inhibition of
serotonin receptors (5-HT), particularly 5-HT2A receptors.
17.5 Distinctive Features of Neuropleptics
Antipsychotic drugs differ in potency and in their propensity to produce
different effects.
1-Phenothiazines
(A) Aliphatic side chain
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Chlorpromazine (Prototype drug)
R= Cl
R1 = (CH2)3N (CH3)2
In schizophrenia patients CPZ
 Reduces agitation and aggressiveness
 Reduces spontaneous movements
 Suppresses hallucinations and delusions
 Corrects disturb thought and behavior
 Relives anxiety
TriFlupromazine
R= CF3
R1 = (CH2)3N (CH3)2
 More potent than CPZ
 Used mainly as antiemetic
(B) Piperidine side chain

Thioridazine
R = SCH3
R1 =
 Low potency
 Central anticholinergic action
 Risk of eye damage limits long-term use
(C) Piperazine side chain

R R1
Trifluoperazine CF3
Fluphenazine CF3
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These are high potency piperazine side chain phenothiazines. They have
minimum autonomic actions. Extra pyramidal side effects are marked.
2-Butyrophenones –
Haloperidol
 Widely used Potent antipsychotic drug

 Does not cause weight gain
 Used for acute schizophrenia, acute mania, senile psychoses.
TriFluperidol
 Pharmacologically similar to haloperidol

 Slightly more potent
3-Thioxanthenes-
Flupenthixol
 It is less sedating than CPZ
 Indicated in schizophrenia and other psychoses
 Infrequently used now
4-Other heterocyclic’s-
Pimozide
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 Long duration of action
 Preferred for maintenance therapy
Loxapine
 Antipsychotic activity like CPZ

 Quick and short lasting actions
5-Atypical Antipsychotics
 These have weak D2 blocking activity
 Potent 5-HT2 antagonistic activity
 Improve the impaired cognitive function in psychotics.
 Minimal extra pyramidal side effects
Clozapine
 Mainly block 5-HT2 receptors

 Weak D2 blocking activity
 Suppresses both positive and negative symptoms of schizophrenia
 Used as a reserve drug in resistant schizophrenia
Olanzapine
Resembles clozapine in blocking multiple monoaminergic, muscarinic and
H1receptors. Beneficial in both positive and negative symptoms of
schizophrenia. Approved for use in mania
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Risperidone
Block multiple monoaminergic, muscarinic and H1receptors, This blockade may

contribute to efficacy as well as side effects. Used for the treatment of
schizophrenia and short term treatment of mania associated with bipolar
disorder.
Quetiapine
 Short-acting atypical antipsychotic

 Blocks 5-HT1A, 5-HT2, D2, α1, α2 and H1 receptors in the brain
 D2 blocking activity is low
 Quetiapine has not been found to benefit negative symptoms of
schizophrenia
 Used in mania/bipolar disorder
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Aripiprazole
 Quite long-acting
 Partial agonist at D2and 5-HT1A receptor
 Antagonist at 5-HT2 receptor
 Indicated in schizophrenia as well as mania and bipolar illness
Ziprasidone
 It is the newer atypical antipsychotic with combined D2+ 5-HT 2A/ + H1

+ α1 blocking activity.
 In comparative trials, its efficacy in schizophrenia has been rated
equivalent to haloperidol
 It is also indicated in mania
17.6 Depression
It is an affective disorder refers to a pathological change in mood state.
Depression is characterized by sad mood, loss of interest and pleasure
worthlessness, guilt, physical and mental slowing, self destructive thoughts etc.
Depression is a heterogeneous disorder that has been characterized in a variety
of ways. A simplified classification based on presumed origin is as follows:
1- Brief reactive or secondary depression (most common), occurring in response
to real stimuli such as grief, illness, etc.
2- Melancholic and recurrent depression, a genetically determined biochemical
disorder manifested by an inability to experience ordinary pleasure or to cope
with ordinary life events; and
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3-Depression associated with bipolar affective (manic-depressive) disorder.
17.5 Antidepressant Drugs
These drugs enhance mood in depressive state and increased output of behavior.
CLASSIFICATION
I. Reversible inhibitors of MAO-A (RIMAs)
Phenelzine Tranylcypromine
II. Tricyclic antidepressants (TCAs)

A. NA + 5-HT reuptake inhibitors
DRUG R1 R2 R3
Imipramine C H N(CH2)3N(CH3)2
Amitriptyline C H C=CH(CH2)2N(CH3)2
Clomipramine C Cl N—(CH2)3 N(CH3)2
Doxepin O H C=CH (CH2)2N (CH3)2
B. Predominantly NA reuptake inhibitors
Desipramine Nortriptyline Amoxapine
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III. Selective serotonin reuptake inhibitors (SSRIs)
Fluoxetine Fluvoxamine
Paroxetine Sertraline
Citalopram Escitalopram
IV. Atypical antidepressants
Trazodone Mirtazapine
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Duloxetine Bupropion
I. Reversible inhibitors of MAO-A (RIMAs)

MAO is a mitochondrial enzyme regulates the metabolic degradation of
catecholamine’s, 5-HT, and other endogenous amines in the CNS and peripheral
tissues. Hepatic MAO has a crucial defensive role in inactivating circulating
monoamines and compounds. Two isoenzyme forms of MAO have been
identified, MAO-A and MAO-B.
Dopamine is degraded equally by both isoenzymes. Inhibition of this enzyme
system by MAO inhibitors causes a reduction in metabolism and a subsequent
increase in the concentrations of biogenic amines. Selective MAO-A inhibitors
are more effective in treating major depression than type MAO-B inhibitors.
II. Tricyclic Antidepressants (TCAs)
Mechanism of action
The TCAs and related drugs inhibit active reuptake of biogenic amines into their
respective neurons and thus potentiate them. Reuptake inhibition results in
increased concentration of the amines in the synaptic cleft in the CNS and
periphery.
III. Selective Serotonin Reuptake Inhibitors (SSRIs)
These drugs inhibit serotonin transporter (SERT) and block reuptake of 5-HT
into the neuron. This blockade increase the availability of 5-HT at receptors in
the CNS and enhance serotoninergic activity.
IV. Atypical antidepressants
Trazodone –
 Block 5-HT reuptake and 5-HT2 antagonist
 Block α1-adrenergic receptors
Mirtazapine
 Blocks α2-autoreceptors on noradrenergic neurons and heteroreceptors on 5-
HT neuron increases NA and 5-HT release
Duloxetine
 SNRI - ‘Serotonin and nor adrenaline Reuptake Inhibitor’
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 It inhibits uptake of these amines into the neuron
Bupropion
 Inhibits reuptake of DA and NA into the neuron
17.8 Buturophenones– Serendipity And Drug Development
Serendipity (i.e. chance)
Frequently lead compounds are found as a result of serendipity. Serendipitous
observation means that an agent developed for another purpose has a desirable
but unexpected clinical effect.
Psycho pharmacological drugs discover by serendipity
 Amphetamine
 Buspirone
 Carbamazejine
 Chlorpramine
 Clozapine
 Fluoxetine
 Haloperidol
 Imipramine
 Iproniazid
 Reserpine
 Valproic acid
Buturophenones– Serendipity and Drug Development
The potent neuropleptics Buturophenones are classic examples of
serendipitously discovered lead compound. Paul Jansen undertook a systemic
study of the 4-phenylpiperidine molecule, particularly to evaluate the limit of
N-substitution of normepridine.
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R = CH3
Replacement of methyl of meperidine with p-aminophenylethyl moiety

(anileridine) and a phenylaminopropyl group (piminodine) afforded active
analgesics property.
Piminodine R = CH2CH2CH2NHC6H5
Anileridine R = CH2CH2 pC6H4NH2
First molecular modification produced a normepridine propiophenone analog

which is 100 times more potent than morphine.
Lengthening the chain by one CH2 produced a butyrophenone which show

analgesic potency more than morphine but also surprisingly produce CPZ-like
activity in animal models at low level.
Replacement of
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the 4-carboethoxy group with OH led to disappearance of analgesic activity
while show neruoleptic activity comparable to CPZ.
The next step was to determine the proper positions (Para) for halogen
substituent in both aromatic rings to increase the effectiveness of above
compound. First halogen substitution was on ketonic phenyl ring p-F atom.
Halogen substitution on both rings- Haloperidol
Further modification of the 4-piperidine position resulted in

spirotriazolodecanes carrying a keto function where the 4-OH was on earlier
compounds. Here potencies exceed CPZs by several thousand times.
Structure Activity Relationship (SAR)
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1. When Ar is an aromatic ring system, antipsychotic activity is seen,
substitution of fluoro at Para position increases the activity.
2. When X = carbonyl (c=o), optimum antipsychotic activity is occur.
3. When n=3, optimum activity is seen, change in length of chain (longer
or shorter) decreases the activity.
4. Aliphatic amino nitrogen when incorporated into cyclic form maximum
activity is seen.
5. Ar1 is an aromatic and required. It should be directly attached to forth
position or occasionally separated from it by one interventing atom.
6. The group Y can vary and help in activity.
17.9 Stereo chemical aspects of psychotropic Drugs
Antipsychotic drugs have various neuro pharmacological properties as a result

of their structural diversity. The chemical structure of antipsychotic drugs plays
an essential role in their receptor-binding affinities in the brain and their
therapeutic profiles and metabolic side effects in schizophrenia treatment.
In the determination of type of psychotropic activity obtained stereo chemical
and other geometric factors are significantly important. The tricyclic 6-6-6
system of the phenothiazines shows that in planar ring systems optimal
neruoleptic activity occurs.
R = R1 = H
However, compounds with total rigid planarity, as in a 6-5-6 system are

invariably inactive.
Examples-
Carbazole derivatives
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Fluorene derivatives
It might be postulated that neruoleptic receptors are planar but have rather strict
size requirements for binding.
Ring systems with relatively few deviations from planarity, by angling of the
atoms in the middle ring, begin to show some thymoleptic effects while still
maintaining neruoleptic activity.
Examples-
Drug R1 R2 R3
Amitriptyline C H C=CH (CH2)2N (CH3)2
Doxepin O H C=CH (CH2)2N (CH3)2
More pronounced twisting of the ring system usually results in exclusive

antidepressant action. A non planar angled thymoleptic receptor concept might
be involved.
Examples-
Imipramine
R1 = C
R2 = H
R3 = N—(CH2)3N (CH3)2
Acridine derivatives
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Compound I displays good antipsychotic activity.
Compound II, however, shows antidepressant activity similar to that of
imipramine. The two additional methyl groups at position 9 result in a twisting
of the three-ring system to a sufficient degree that the requirements of the
postulated non planar angled antidepressant receptor site are accommodated.
Two situations arise in compound II that may explain the clinical observations.
First, it can be assumed that the planar acridine ring simply cannot
accommodate two bulky methyl groups at the 9 position and maintain flatness.
Thus a twisting must occur that results in loss of co planarity of the three rings.
Second, it can be argued that the bulk of the methyl groups prevent a good fit to
the planar neruoleptic receptors.
The framework of the tricyclic system at a fundamental level, seen as angled or
flexed, to varying degrees.
Fig.17.1: Steric parameters of tricyclic psychotropic drugs
298
Flexure represents the degree of non planarity between the A1 and A2 rings.
Annulation is the angle at which these two rings attached to middle ring.
Torsion is the degree to which the molecule is twisted out of symmetry.
When the angle of flexure is small the system is relatively flat and clinically
neruoleptic. Further twisting out of the plane results in thymoleptic properties.
Angles of annulation and torsion do not appear to have that much bearing on
therapeutic effects.
The insufficient neuro-chemical knowledge is the main problem in
development of safer and especially more effective compounds. Research is
active in areas such as α-2 adrenoceptors, several HT receptors, GABA
receptors, lithium mimetic, certain anticonvulsant calcium antagonists,
neuropeptides (e.g., endorphins, GH), and even corticosteroids.
17.10 Summary
The term "psychosis" denotes a variety of mental disorders. Schizophrenia is a
particular kind of psychosis characterized mainly by a clear sensorium but a
marked thinking disturbance. Major depression is one of the most common
psychiatric disorders. The symptoms of depression are often subtle and
unrecognized both by patients and by physicians.
The antipsychotic and antidepressant drugs affect cortical, limbic,
hypothalamic, and brainstem mechanisms that are of fundamental importance
in the regulation of arousal, consciousness, affect, and autonomic functions.
Physiological and pharmacological modifications of these brain regions may
have important behavioral consequences and useful clinical effects regardless
of the underlying cause of any mental disorder.
17.11Glossary
 Bipolar disorder : Bipolar disorder (manic depression) is a mental
illness that brings severe high or low moods and changes in sleep,
energy, thinking, behavior.
 Catatonic : It is characterized by marked lack of movement, activity, or
expression.
 Cognition : It is the mental act or process by which knowledge is
acquired, including perception, intuition, and reasoning.
 Delusions : It is the act of deluding or state of being deluded.
299
 Extra pyramidal : Extra pyramidal side effects are drug induced
moment disorders such as tremor, akathisia, Parkinsonism etc.
 Partial agonist : Partial agonists are drugs that have only partial
efficacy at the receptor.
1. Classify antipsychotic drugs. Explain mechanism of action, effects and

uses of chlorpromazine.
2. Write briefly on-
a. Haloperidol
b. Clozapine
c. Risperidone
d. Olanzapine
3. Classify antidepressants. Explain the mechanism of action of each class
with example.
4. Write briefly on-
a. Reversible inhibitors of MAO-A (RIMAs)
b. Tricyclic antidepressants (TCAs)
5. Explain role of serendipity in finding of lead compounds with special
emphasis on development of Buturophenones,
6. Explain that the chemical structure of antipsychotic drugs plays an
essential role in their receptor-binding affinities and type of
psychotropic activity obtained.
Publisher) 2013.
 The Pharmacological basis of Therapeutics (10th ed.)- Goodman &
 Introduction to medicinal chemistry: how drugs act and why by Alex
Gringauz.
300
Unit-18
Synthesis Of Antipsychotic Drugs
Structure of Unit:
18.1 Objectives
18.2 Introduction
18.3 Diazepam
18.4 Oxazepam
18.5 Clonazepam
18.6 Alprazolam
18.7 Barbiturates
18.8 Summary
18.9 Glossary
18.1 Objective
 In this chapter we discuss the drugs which are used for different type of
Psychotic disorder.
 Here we study about the method of synthesis of different Antipsychotic
drugs.
 Here we also explain the use and adverse effect of these drugs.
18.2 Introduction
These drugs are used for the treatment of major psychosis. They are also called
as “major tranquilizers”. Since they reduce agitation and disturbed behavior
seen in schizophrenia. These drugs have the pharmacological property of
antagonizing the action of dopamine and this is responsible for most of their
effects on the nervous system.
Most of these agents have also antiemetic, sympatholytic and α-adrenergic
blocking actions.
The most important type of psychosis are –
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 Schizophrenic
 Affective disorders (eg. depression, mania)
 Organic psychoses.
Classification:-
[A] Typical neuroleptics :– Phenothiazines (eg. Chlorpromazine)
Butyrophenones (eg. Haloperidol)
Thioxathenes (eg. Fluperthioxol)
[B] Atypical neuroleptics :- Benzamides (eg. Sulpiride)

Diphenylbutyl piperazines (eg. Pimozide)
Dibenzyldiazepines (eg. Clozapine)
18.3 Diazepam
Diazepam is a benzodiazepine (ben-zoe-dye-AZE-eh-peens). It affects
chemicals in the brain that may become unbalanced and cause anxiety.
Diazepam is used to treat anxiety disorders, alcohol withdrawal symptoms, or
muscle spasms. Diazepam is sometimes used with other medications to treat
seizures.
Do not drink alcohol while taking diazepam. This medication can increase the
effects of alcohol.
Before taking this medicine :-
Should not use this medication if allergic to diazepam or similar drugs (Ativan,
Klonopin, Restoril, Xanax, and others), or if have:
 Myasthenia Gravis (A Muscle Weakness Disorder);
 Severe Liver Disease;
 Narrow-Angle Glaucoma;
 A Severe Breathing Problem; Or
 Sleep Apnea (Breathing Stops during Sleep).
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Structure of Diazepam
IUPAC Name :- (7-chlon-1, 3-dihydro-1-methyl-5-phenyl-2H-1,4-

benzodiazepine-2-one)
Do not give this medication to a child younger than 6 months old.
The sedative effects of diazepam may last longer in older adults. Accidental
falls are common in elderly patients who take benzodiazepines. Use caution to
avoid falling or accidental injury while you are taking this medicine.
Synthesis of Diazepam:-
One of the more straightforward approaches to this compound involves first the
acetylation of aminobenzophenone with chloroacetyl chloride to give the
chloromethyl amide. Heating this compound with ammonia or its latent
equivalent, hexamethylene tetramine (HMTA), can be envisaged to involve the
initial displacement of chlorine to give a glycineamide. Cyclization by imine
formation then affords diazepam. Support for this sequence comes from the
observation that a modest yield of diazepam can be obtained on heating with
glycine ethyl ester in pyridine.
The second way consists of the direct cyclocondensation of 2-amino-5-

chlorobenzophenone with glycine ethyl ester hydrochloride. The amide
nitrogen atom of the obtained 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-
benzodiazepin-2-one, is methylated by dimethylsulfate, which leads to the
formation of diazepam.
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The first method differs from the second in that the methylation of nitrogen is
accomplished before the cyclocondensation reaction.
To do this, the initial 2-amino-5-chlorobenzophenone is first tosylated by p-
toluenesulfonylchloride and the obtained tosylate transformed into the N-
sodium salt, which is then alkylated by dimethylsulfate. The resulting 2-N-
tosyl-N-methyl-5-chlorobenzophenone is hydrolyzed in an acidic medium,
giving 2-methylamino-5-chlorobenzophenone, which undergoes
cyclocondensation by reaction with ethyl ester of glycine hydrochloride,
forming the desired diazepam.
Another method of synthesis is- from m-chloraniline:-
2-amino-5-chlorobenzophenone is reacted with glycine ethyl ester in presence

of pyridine to give the cyclized nordiazepam, which is methylated with
dimethyl Sulffate.
Use: - It is used for the control of anxiety and tension states, the relief of
muscle spasm.
Properties: - off white to yellow crystalline powder melting point 131-135.
Sparingly soluble in water, freely soluble in chloroform and alcohol.
18.4: Oxazepam
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It is one of the metabolites of diazepam and used in the relief of
psychoneuroses. It has reduced toxicity as compared to diazepam because the
3-OH group is easily eliminated as the glucuronide which is in active
pharmacologically.
This benzodiazepine is slowly absorbed on oral administration. Also
penetration in brain is slow. It has a short duration of action. So it is also used
mainly in short lasting anxiety states.
Structure of Oxazepam
IUPAC Name-7-chloro-1, 3-dihydro-3- hydroxy-5- pheyl-1, 4-

benzodiazepin-2-one.
Synthesis of Oxazepam
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Side effects-
The side effects of oxazepam are similar to those of other benzodiazepines, and
may include dizziness, drowsiness, headache, memory impairment, paradoxical
excitement, and anterograde amnesia, but does not affect transient global
amnesia. Side effects due to rapid decrease in dose or abrupt withdrawal from
oxazepam may include abdominal and muscle cramps, convulsions, depression,
inability to fall asleep or stay asleep, sweating, tremors, or vomiting.
18.5: Clonazepam (clonopin):-
Clonazepam is in a group of drugs called benzodiazepines (ben-zoe-dye-AZE-
eh-peens). It affects chemicals in the brain that may become unbalanced and
cause anxiety.
Clonazepam is used to treat seizure disorders or panic disorder.
Structure of Clonazepam:-
IUPAC Name:- 5-(2-chlorophenyl)-7-nitro-2,3-dihydro-1,4-benzodiazepin-2-

one
Should not use this medication:-
 If have severe liver disease or narrow-angle glaucoma, or
 If allergic to clonazepam or other benzodiazepines, such as alprazolam
(Xanax), chlordiazepoxide (Librium), clorazepate (Tranxene),
lorazepam (Ativan), or oxazepam (Serax).
The sedative effects of clonazepam may last longer in older adults. Accidental
falls are common in elderly patients who take benzodiazepines. Use caution to
avoid falling or accidental injury while taking clonazepam.
It is a yellow colored crystalline powder, insoluble in water acid soluble in
alcohol. It is useful either alone or in combination with other anti-convulsant
drugs for the treatment of petitmal epilepsy, not responsive to a valporate or
ethosuximide.
Do not drink alcohol while taking clonazepam. This medication can increase
the effects of alcohol.
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Synthesis of Clonazepam:-
In the synthesis of clonazepam first p-nitroaniline is react with o-chlorobenzoyl

chloride in the presence of zinc chloride which give 2-amino-5-nitro-2-chloro-
benzophenone, this again react, with 1,2-dibromomethanone and give 2-
bromoacetamido-5-nitro-2-chlorobenzophenone. At last in the presence of
ammonia, methanol and pyridine it give the main compound i.e. Clonazepam
Adverse effects:- Include drowsiness, “glassy eyed” appearance, confusion,
chest congestion, hair loss, anorexia, and anemia
18.6 Alprazolam (Xanax)
Alprazolam belongs to a group of drugs called benzodiazepines (ben-zoe-dye-
AZE-eh-peens). It works by slowing down the movement of chemicals in the
brain that may become unbalanced. This results in a reduction in nervous
tension (anxiety).
Alprazolam is used to treat anxiety disorders, panic disorders, and anxiety
caused by depression.
Structure of Alprazolam:-
IUPAC Name- 8-chloro-1-methyl-6-pheyl-4H-5-triazolo(4,3-a)

benzodiazepine
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Do not drink alcohol while taking alprazolam. This medication can increase the
effects of alcohol. Alprazolam may be habit-forming and should be used only
by the person for whom it is prescribed.
It is a recently introduced antianxiety drug. In addition to anxiolytic effect, it
has a mood elevating action. Also it produces less drowsiness.
The drug is highly potent as anoxiolytic on a milligram basis. Oxidative
metabolism of the methyl group to the methyl alcohol followed by conjugation
is rapid and the duration of action is short.
Should not take alprazolam:
 If pregnant, because it could harm the unborn baby.
 If have Narrow-angle glaucoma;
 If also taking itraconazole (Sporanox) or ketoconazole (Nizoral); or
 If allergic to alprazolam or to other benzodiazepines, such as
chlordiazepoxide (Librium), clorazepate (Tranxene), diazepam
(Valium), lorazepam (Ativan), or oxazepam (Serax).
Synthesis
Alprazolam is a chemical analogue of triazolam that differs by the absence of a
chlorine atom in the o-position of the 6-phenyl ring. The same scheme that was
used to make triazolam can be used to make alprazolam, with the exception that
it begins with 2-amino-5-chlorobenzophenone.
Another way of making alprazolam has been suggested, which comes from 2,6-
dichloro-4-phenylquinoline, the reaction of which with hydrazine gives 6-
chloro-2-hydrazino-4-phenylquinoline. Boiling this with triethyl orthoacetate in
xylene leads to the heterocyclization into a triazole derivative. The resulting
product undergoes oxidative cleavage using sodium periodate and ruthenium
dioxide in an acetone–water system to give 2-[4-(3’-methyl-1,2,4-triazolo)]-5-
chlorobenzophenone. Oxymethylation of the last using formaldehyde and
subsequent substitution of the resulting hydroxyl group by phosphorus
tribromide, gives 2-[ 4- (3’-methyl - 5’ – bromomethyl - 1, 2, 4 – triazolo ) ] –
5 - chlorobenzophenone.
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Substitution of the bromine atom with an amino group using ammonia and the
spontaneous, intramolecular heterocyclization following that reaction gives
alprazolam.
Method I
Method II
18.7 Barbiturates
Barbiturates are derivatives of barbituric acid (malonyl urea) which is obtained
by the condensation of urea and malonic acid.
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Barbituric acid itself does not possess hypnotic activity. But hypnotic activity is
produced if the hydrogen atoms at position 5-are replaced by alkyl or aryl
groups.
General structure of barbiturates-
Use of barbiturates
 At low doses barbiturates are indicated for the relief of anxiety and
tension.
 At high doses they are used for the management of insomnia
(sleeplessness)
 Long duration acting barbiturates are also used as anti-convulsant
agents.
Classification
[A] Long Acting :- Phenobarbitone
(6 or more hrs) Mephobarbitone
Metharbital
[B] Intermediate duration:- Butabarbital

(3-6 hrs) Amobarbital
Aprobarbital
Hexobarbital
[C] Short Acting :- Buto barbitone
(les than 3 hrs) Secobarbitone
Pento barbitone
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General method of preparation of 5,5-dialkyl barbiturates :-
This method is applicable for the synthesis of all barbiturates except
Phenobarbital and hexobarbital.
If R R1 R2
Phenobarbital C2H5 C6H5 H

Butabarbital C2H5 CH3CH2CH(CH3)- H
Pentobarbital C2H5 CH3CH2CH2CH(CH3)- H
Synthesis of Phenobarbital (5-ethyl-5-phenyl barbituric acid):-
Benzyl chloride on reaction with potassium cyanide affords benzyl cyanide.

Ethanolysis of benzyl cyanide in the presence of acid gives phenyl acetic acid
ethyl ester. The methylen group of which undergoes acylation using the diethyl
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oxalate, giving diethyl ester of phenyloxobutandionic acid, which upon heating
easily loses carbon oxide and turns into phenylmalonic ester.
Alkylation of the obtained product using ethyl bromide in the presence of
sodium ethoxide leads to the formation of α–phenyl–α–ethyl malonic ester, the
condensation of which with urea gives Phenobarbital.
18.8 Summary
Atypical antipsychotic agents are used to treat the symptoms schizophrenia and
bipolar disorder. Clonazepam may cause harm to an unborn baby, and may
cause breathing or feeding problems in a newborn. But having seizures during
pregnancy could harm both mother and baby. Do not start or stop taking
clonazepam during pregnancy without medical advice. Oxazepam is
contraindicated in myasthenia gravis, chronic obstructive pulmonary disease,
and limited pulmonary reserve, as well as severe hepatic disease.
18.9: Glossary
 Agitation:- It is defined as the state of feeling irritated or restless (A

state of anxiety or nervous excitement).
 Anemia:- It is usually defined as a decrease in the amount of red blood
cells (RBCs) or the amount of hemoglobin in the blood. It can also be
defined as a lowered ability of the blood to carry oxygen
 Anterograde Amnesia:- Anterograde Amnesia is a loss of the ability to
create new memories after the event that caused the amnesia, leading to
a partial or complete inability to recall the recent past, while long-term
memories from before the event remain intact
 Anti-Convulsants :- It is also known as antiepileptic drugs or as
antiseizure drugs. These are a diverse group of pharmacological agents
used in the treatment of epileptic seizures.
 Myasthenia Gravis:- It is characterized by weakness and rapid fatigue
of any of the muscles under voluntary control. Myasthenia gravis is
caused by a breakdown in the normal communication between nerves
and muscles.
 Narrow-Angle Glaucoma:- This is the second most common form of
glaucoma. Patients often have acute attacks of eye pain due to sudden
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increase in eye pressure. Between attacks the eye pressure is normal. An
attack of this type of glaucoma is an emergency. Untreated, it may cause
blindness in a day or two.
 Paradoxical :- A paradoxical reaction is an adverse reaction to a
substance, almost always to a drug, that is exactly the opposite of the
intended effect. A paradoxical reaction to any substance can be
frightening and uncomfortable.
 Psychoneurosis:- Psychoneurosis is the emotional maladaptation due to
unresolved unconscious conflicts. This leads to disturbances in thought,
feelings, attitudes, and behavior.
 Schizophrenia:- It is a mental disorder that generally appears in late
adolescence or early adulthood- however, it can emerge at any time in
life. It is one of many brain diseases that may include delusions, loss of
personality (flat affect), confusion, agitation, social withdrawal,
psychosis, and bizarre behavior.
 Transient Global Amnesia:- It is a sudden, temporary episode of
memory loss that cannot be attributed to a common neurological
condition, such as epilepsy or stroke.

1. Give the general method of synthesis of barbiturates.
2. What is the method for synthesis of Diazepam?
3. Give the synthesis of any two-
a. Alprazolam
b. Clonazepam
c. Oxazepam
4. Give the synthesis of phenobarbitone.
5. Give the chemical synthesis of diazepam from chloroaniline.
6. Discuss about the chemistry of diazepam and its synthesis.

313
 A Book of medicinal chemistry volume I; (first edition 2008-2009) Dr.
Approach) Vol. I; (third edition 2004, reprint 2006) Surendrs N.
 Principle of medicinal chemistry-vol. II; (eighteenth edition, september
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Unit-19
Antibiotics
Structure of Unit:
19.1 Objective
19.2 Introduction
19.3 What is antibiotic?
19.4 Classification of antibiotics
19.6 Bacterial cell wall biosynthesis
19.7 Cell wall biosynthesis inhibitors
19.8 Penicillin
19.9 Cephalosporins
19.10 Antibiotic inhibiting protein synthesis
19.11 Summary
19.12 Glossary
19.13 Review Questions
19.14 References
19.1 Objectives
 Antibiotics inhibit the growth and survival of microorganism without
serious toxicity to the host.
 Antibiotics and antimicrobial agents to keep infectious disease under
control.
 To study about different cell wall biosynthesis inhibitor that cures the
infection.
 Antibiotics that inhibit protein synthesis by which housekeeping protein
not synthesize and indirectly kill the bacteria such as tetracycline,
aminoglycoside etc.
19.2 Introduction
Paul Ehrlich introduced the term chemotherapy in 1907 in referring to
antiparasitic therapy. Now refers more broadly to the use of any chemical
compound that selectively acts on microbes or cancer. Ehrlich had previously
developed selective chemical stains for the microscopic examination of
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Mycobacterium tuberculosis and other microorganisms, using the coal-tar
derivative dyes. The search for safe, effective chemotherapeutic drugs is
hindered by humans share with all living organisms. Success requires
exploitation of metabolic or structural differences between normal human cells
and disease-producing cells. Humans were not the first to exploit the selective
toxicity of chemicals. Many fungi and bacteria make toxic substances that kill
or suppress the growth of competing microorganisms or facilitate infection of a
host. Plants make a vast array of toxins for their self-defence. Exploitation of
the selective toxicity of chemicals is an ancient and widely employed
technique.
History of chemotherapy may be divided into 3 phases:-
(a) The period of empirical use of ‘mouldy curd’ by Chinese on boils,
chaulmoogra oil by Hindus in leprosy, chenopodium by Aztecs for intestinal
worms, mercury by Paracelsus for syphilis, cinchona bark for fevers.
(b) Ehrlich’s phase of dyes and organometallic compounds (1890-1935): with
the discovery of microbes and they are the cause of many diseases. Ideas of
Ehrlich that if certain dyes could selectively stain microbes, they could also be
selectively toxic to these organisms and tried methylene blue, trypan red etc.
Ehrlich eventually discovered the arsenical compound- atoxyl for sleeping
sickness (Trypanosoma brucei, the tsetse fly–borne parasite that causes African
trypanosomiasis), arsphenamine in 1906 and neoarsphenamine in 1909 for
syphilis.
(c) The modern era of chemotherapy was demonstrating the therapeutic effect
of Prontosil, a sulphonamide dye in pyogenic infection. It was soon realised
that the active moiety was paraamino benzene sulphonamide, and the dye part
was not essential. Fleming 1929 found that a diffusible substance was
elaborated by Penicillium mould which could destroy Staphylococcus on the
culture plate. The well known observation of a clear zone inhibition of (lysis) of
bacterial colonies surrounding a colony of contaminating air borne.
19.3 What is Antibiotic ?
Antibiotics are microbial metabolites or synthetic analogs which suppress the
growth and survival of microorganism at low concentration without serious
toxicity to the host. This definition excludes other natural substances which also
inhibit microorganisms but are produced by higher forms eg. Antibodies or
even those produced by microbes but are needed in higher concentration eg.
Lactic acid, Ethanol. Antibiotics are among the most frequently prescribed
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medications today although microbial resistance due to misuse threatens their
continued efficacy. In many cases the clinical utility of natural antibiotics has
been enhanced through medicinal chemical manipulation of the original
structure leading to broader antimicrobial spectrum, greater potency, lesser
toxicity, more convenient administration etc. Examples of such semi synthetic
antibiotics are amoxicillin and doxycycline.
19.4 Classification of antibiotics
Antimicrobial drugs can be classified according to their chemical structure and
their mechanism of actions.
(A) On the basis of Chemical structure
1. Sulphonamide and related drugs: Sulfadiazine, sulfamethoxazole and
others
2. Diaminopyrimidines: Trimethoprim, pyrimethamine
3. Quinolones: Nalidixic acid, Norfloxacin, Ciprofloxacin
4. β- lactam antibiotics: Penicillins, Cephalosporins, Monobactams,
Carbapenems
5. Tetracyclines: Oxytetracycline, Doxycycline, etc.
6. Nitrobenzene derivative: Chloramphenicol
7. Aminoglycosides: Streptomycin, Gentamicin, Amikacin, Neomycin, etc.
8. Macrolide antibiotics: Erythromycin, Clarithromycin, Azithromycin,
etc.
(B) On the basis of mechanism of action
1. Inhibit cell wall synthesis: Penicillins, Cephalosporins, Cycloserine,
Vancomycin Bacitracin.
2. Cause leakage from cell membranes: Poly-peptides-Polymyxins, Colistin,
Bacitracin Polyenes-Amphotericin B, Nystatin, Hamycin.
3. Inhibit protein synthesis: Tetracycline, Chloramphenicol, Aminoglycosides,
Erythromycin, Clindamycin, Linezolid.
19.5 Bacterial cell wall biosynthesis
The bacterial cell wall differs in structure and functions compared to outer layer
of mammalian cells. This makes easy to provide a number of potentially
attractive target for selective chemotherapy of bacterial infection. The bacterial
cell wall is chemically distinct from mammalian cell walls construction. The
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initial units of cell wall constructed within the cell and final assembly takes
place outside the inner membrane.
According Gram staining bacteria are differentiate in two types: Gram (+)
bacteria and Gram (-) bacteria. The difference in two bacteria is composition of
bacterial cell wall.
Gram (+) Bacteria:
The cell wall of Gram (+) bacteria is simpler than Gram (-) bacteria. On the
outside of the cell is a characteristic carbohydrates and proteins that together
make up antigenic determinants that differ from species to species. The next
barrier that the wall presents is peptidoglycan layer. This is a spongy, gel-
forming layer consisting of a series of alternating sugars (N-acetyl glucosamine
[NAG] and N-acetylmuramic acid [NAM]) linked in a long chain. To the free
lactic acid carboxyl moieties of N-acetylmuramic acid units is attached with a
series of amino acids of which L-alanin-D-glutamine-L-lysine-D-alanin through
peptide linkage. D-stereochemistry of the glutamate and the terminal alanin is
important feature in protecting the peptidoglycan from hydrolysis by host
peptidase.
The terminal D-alanyl unit is bonded to the lysyl unit of an adjacent tetrapetide
strand through a pentaglycyl unit. The last step in the biosynthesis is a
transamidation wherein the terminal amino moieties on the last glycine of the A
strand displaces the terminal D-ala unit on the nearby B strand. This step is
catalysed by a cell wall transamidase (one of the penicillin binding protein,
PBP) which form a covalent bond during the synthesis phase with a particular
serine hydroxyl on the enzyme. Completion of the catalytic cycle by cross
linking through displacement of the enzyme and substitution by a glycine
residue regenerates the enzyme and produces a thickened three dimensional cell
wall.
Gram (-) Bacteria:
The cell wall of gram –ve bacteria is more complex and more lipoidal. These
cells usually contain an additional, outer membrane. The outer layer contains
complex lipopolysaccharides that encode antigenic responses. This exterior
layer also contains a number of enzymes and proteins.
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Fig. 19.1: Biosynthesis of bacterial cell wall
19.6 Cell wall biosynthesis inhibitors
β- Lactam antibiotics
The name lactam means cyclic amides and the term lactone means cyclic esters.
According to nomenclature, second carbon in an aliphatic carboxylic acid was
designated as alpha, the third beta. β- Lactam is a cyclic amide with four atoms
in its ring. The contemporary name for this system is azetidinone. It is note that
beta lactam ring proved to be the main component of pharmacophore so the
term possesses medicinal as well as chemical significnce. The beta lactam
antibiotics are penicillin and cephalosporin. The penicillin subclass of β-
Lactam antibiotics is characterised by presence of a substituted 5-membered
thiazolidine ring fused to the β- Lactam ring. This fusion and the chirality of the
β- Lactam ring results in the molecule representing possessing a “V” shape.
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19.7 Penicillin
Penicillin had been discovered in 1929 and is a member of β- Lactam
antibiotics The original fermentation-derived penicillins were produced by
uncontrolled fermentation of the fungus Penicillium chrysogenum. Penicillin
can be considered as the amido derivatives of the 6-aminopenicillanic acid.
In the basic skeleton, a thiazolidine ring (A) is fused with β- Lactam ring (B)
which is a four membered cyclic amide. Classification of penicillin is given in
Table 19.1
Table 19.1: Classification of penicillin antibiotic

S.No. Name Nature of substituent, R
1 Penicillinase susceptible penicillins:
i. Penicillin G
ii. Penicillin V
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2. Penicillinase resistant penicillins:
i. Methicillin
3. Amino penicillins:
i. Ampicillin (R1= H)
ii. Amoxicillin (R1= OH)
4. Carboxypenicillins:
i. Carbenicillin (R1= H)
ii. Ticracillin
5. Uriedopenicillins:
Azlocillin
Molecular mode of action of the β- Lactam antibiotics is a selective and
irreversible inhibition of the enzyme processing the developing peptidoglycan
layer. Just before the cross-linking occurs, the peptide unit from the lactate
carboxyl of a muramic acid unit terminate in a D-ala-D-ala unit. This is cleaved
between these two amino acids by hydrolysis catalysed by a cell wall
transamidase. This is one of the penicillin binding proteins that normally
present in bacterial inner membrane and perform construction, repair and
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housekeeping functions maintaining cell integrity and playing a vital role in cell
growth and division.
Uses:
1. Streptococcal infections like pharyngitis, otitis media, scarlet fever,
rheumatic fever respond to ordinary doses of PnG given for 7-10 days.
For subacute bacterial endocarditis (SABE) caused by Streptococci
viridans or faecalis treated with high doses (10-20 MU i.v. daily).
2. Pneumococcal infections
3. Meningococcal infections are still mostly responsive. Meningitis and
other infections may be treated with intravenous injection of high
doses.
4. Gonorrhoea PnG has become unreliable for treatment of gonorrhoea due
to spread of resistant strain.
5. Syphilis Trypanosoma pallidum has not shown any resistance and PnG
is the drug of choice. Early and latent syphilis is treated either with daily
injection of 1.2 MU of procaine penicillin.
19.8 Cephalosporins
Penicillin which has outstanding biological antibiotics properties that it entered
clinical uses with comparatively little change. Cephalosporin was produced by
Cephalosporium arcemonium. One of the constituents had the useful property
of activity against penicillin resistant cultures due to its stability to β-
lactamases. The nature of side chain produced 7-aminocephalosporanic acid (7-
ACA) which analogous to 6-aminopenicilllanic acid. Many of the compounds
produced in this way. They differ from one another in antimicrobial spectrum,
β- lactamase stability, absorption from GI tract, metabolism, stability and side
effect. The cephalosporins have their β- lactam ring attached to a 6-membered
dihydrothiazine ring.
In the cephalosporin antibiotic two rings are fused. Ring A is dihydrothaizine
ring and ring B is β-lactam ring. By addition of different side chain at position 7
of β-lactam ring and position 3 of dihydrothiazine ring, a large number of
semisynthetic compound have been produced. Basic structure of cephalosporin
is given below. Classification of cephalosporin is given in Table 19.1
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Table 19.1: Classification of cephalosporins
First Generation Second Generation Third Generation
 Cefazolin  Cefaclor  Cefoperazone
 Cephalexin  Cefanocid  Cefotaxime
 Cephaprin  Cefoxitin  Ceftriaxome
 Cephalothin  Cefuroxine axetil  Cefixime
Structures of some cephalosporins:
Mechanism of action: The cephalosporins are believed to act in manner

similar to penicillins by binding to penicillin binding proteins followed by cell
lysis. Cephalosporins are bactericidal.
Uses:
Cephalosporin is used in upper respiratory tract, skin and related soft tissue,
urinary tract infection, bones and joints, as well as septicemias and
intraabominal and bile tract infection caused by susceptible Gram (+) organism.
Carbepenem: Carbepenam are synthetic beta lactam antibiotics that differ
from the penicillins in that the sulfur atom of the thiazolidine ring has been
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externalized and replaced by a carbon atom. Imepenem is the only drug is
available.
Monobectam: The monobactams, of which aztreonam is the only commercially

available example, are unique because the β-lactam ring is not fused to another
ring. Monobactams also disrupt cell wall synthesis. The drug's narrow
antimicrobial β-Lactam ring spectrum precludes its use alone in empiric
therapy. Aztreonam is resistant to the action of β-lactamases.
19.9 Antibiotics inhibiting protein synthesis

Some antibiotic show their lethal effect on bacteria by inhibiting ribosomally
mediated protein synthesis. Eukaryotic organism made their essential proteins
on ribosomal organelles and the sequence of biochemical steps in both biologic
classes is closely analogous to prokaryotic organisms. Eukaryotic organisms
have 80S ribosome while prokaryotic organisms have 70S ribosome. The
binding sites for the important antibiotics lie on the proteins or the ribosomal
DNA of the bacterial 70S ribosome. Interference with the bacterial protein
biosynthesis prevents repair, cellular growth, and reproduction and in clinical
achievable doses is bactericidal or bacteriostatic. Some of the protein synthesis
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inhibitors are synthetic compounds and other were first isolated from the
fermented culture filtrate of various organisms as antibiotic.
Aminoglycosides:
The aminoglycoside class of antibiotics contains a pharmacophoric 1,3-
diaminoinositol moiety. The chemistry, spectrum, potency, toxicity and
pharmacokinetics of these agents are a function of the specific identity of
diaminoinositol unit.
Several aminoglycoside antibiotics are discovered such as Streptomycin,
amikacin, gentamycin, neomycin and tobramycin etc. the structures of
aminoglycoside antibiotic are given below.
Mechanism of action: All members of this family are believed to inhibit

bacterial protein synthesis by the mechanism determined for streptomycin.
Susceptible organisms have an oxygen dependent systems that transport the
antibiotic across the cell membrane. Antibiotics than binds to the separated 30S
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ribosomal subunit and interfering with assembly of the functional ribosomal
apparatus or causing the 30S subunit of the complete ribosome to misread the
genetic code.
Uses:
In most other situations, e.g. urinary tract infection, peritonitis, septicaemias,
etc. where streptomycin was used earlier, gentamicin or one of the newer
aminoglycosides is now preferred due to low potency and widespread
resistance to streptomycin.
Macrolides:
The macrolides are a group of antibiotics with a macrocyclic lactone structure.
The clinical important members of this class have two or more characteristic
sugars attached to the 14-membered ring. The 14 membered ring macrolides are
biosynthesized from propionic acid units so that every second carbon of
erythromycin bears a methyl group with one exception is oxygen bearing.
Erythromycin was the first of these to find clinical application both as the drug
of first choice and as an alternative to penicillin in individuals who are allergic
to β-lactam antibiotics. The new members of this family, clarithromycin (a
methylated form of erythromycin) and azithromycin (having a larger lactone
ring) have some features in common with and others that improve on,
erythromycin. Recently, dirithromycin, a macrolide similar to erythromycin in
antibacterial spectrum, but with the advantage of one-daily dosage, has been
approved.
Mechanism of action: the macrolide inhibiting bacteria by interfering with

programmed ribosomal protein biosynthesis by inhibiting translocation of
aminoacyl t-RNA following binding to the 50S subtype.
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Uses: macrolide are used for treatment of upper and lower respiratory tract and
soft tissue infection, caused by gram (+) microorganism like Streptococcus
pyogens and Streptococcus pneumonia.
Chloramphenicol
Chloramphenicol was obtained from streptomyces venezuelae. It has nitro
benzene substitution which is responsible for its antibacterial activity. It is
soluble in alcohol but poorly soluble in water. Chloramphenicol succinate,
which is used for parenteral administration, is highly water-soluble. It is
hydrolyzed in vivo with liberation of free chloramphenicol.
Chloramphenicol is broad spectrum antibiotic that is active against gram-
positive and gram-negative bacteria, rickettsiae, micoplasma and Chlamydia. It
is inactive against pseudomonas, many proteus viruses and fungi. It is highly
active agaist salmonella including S. typhi. It is less active against gram positive
cocci, spirochetes and certain anterobacteriaceae. It is inactive on antamoeba
and plasmodia.
Mode of action:- Chloramphenicol inhibits bacterial protein synthesis by

interfering with ‘transfer’ of the elongating peptide chain to the newly attached
aminoacyl-tRNA at the ribosome mRNA complex. It attaches to the 50s
ribosome and hence hinders the access of aminoacyl-tRNA to the acceptor side
for amino acid incorporation. Most probably, by acting as a peptide analogue, it
prevents formation of peptide bonds.
Use- it is a drug of choice for typhoid fever. It is also used in intraocular
infections, H. influenza meningitis, anaerobic infections, external ear infections
and urinary tract infection. It may be considered for treatment of serious
rickettsial infections, such as typhus or Rocky Mountain spotted fever, in
children for whom tetracyclines are contraindicated. Chloramphenicol is
occasionally used topically in the treatment of eye infections because of its
wide antibacterial spectrum and its penetration of ocular tissues and the
aqueous humor.
Tetracycline:
All are obtained from soil actinomycetes. The first to be introduced was
chlortetracycline in 1948 under the name aureomycin (because of the golden
yellow colour of S. aureofaciens colonies producing it). It contrasted markedly
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from penicillin and streptomycin (the other two antibiotics available at that
time) in being active orally and in affecting a wide range of microorganisms-
hence called 'broadspectrum antibiotic'. Tetracycline antibiotic is characterized
by highly functionalized partially reduced naphthacene ring system from which
both the family name and numbering system is derived. The structures of
tetracycline antibiotic are given below.
R1 R2 R3 R4
Tetracycline H OH CH3 H
Chlortetracycline H OH CH3 Cl
oxytetracycline OH OH CH3 H
Demeclocycline H OH H Cl
All tetracyclines are solid, bitter taste and weak water soluble antibiotics. Their
aqueous solutions are unstable. Tetracycline are divided in three classes
Class 1 Class 2 Class 3

Tetracycline Demeclocycline Doxycycline
Chlortetracycline Methacycline Minocycline
Oxytetracycline
Tetracyclines enter microorganisms in part by passive diffusion and in part by
an energy-dependent process of active transport. Susceptible cells concentrate
the drug intracellularly. Tetracyclines bind reversibly to the 30S subunit of the
bacterial ribosome, blocking the binding of aminoacyl-tRNA to the acceptor
site on the mRNA-ribosome complex. This prevents addition of amino acids to
the growing peptide.
Uses:
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Tetracycline possesses very wide bacteriostatic antibacterial activity. They are
popular and low dose oral and topical therapy for acne. They are also used in
urinary tract infection, upper respiratory tract infection, ophthalmic infections,
sexually transmitted diseases, rickettsial infection, prophylaxis for malaria and
prevention of traveler’s diarrhea.
19.10 Summary
Antimicrobial agents are the greatest contribution of the 20th century to
therapeutics. Antibiotics are produced by microorganisms and selectively
suppress the growth or kill other microorganisms at very low concentration.
Antimicrobial drugs produce action in many ways such as- inhibition of cell
wall synthesis, inhibition of protein synthesis etc. Antibiotics which consists β-
lactum ring in their chemical structure are called β-lactum antibiotics. The two
major groups are penicillin’s and cephalosporins. Cell wall is the outer covering
of microorganisms which provide protection and stability to microorganisms.
All β-lactum antibiotics interfere with the synthesis of bacterial cell wall. Broad
spectrum antibiotics tetracycline, chlormphenical and macrolides erythromycin
act by inhibiting bacterial protein synthesis.
19.11 Glossary
 Pyogenic infection: infection that result in pus production
 Inhibition zone: zone where no bacterial colony is present
 Pharmacophore: component in the structure that is responsible to
activity
 Genetic code: set of rules by which information encoded within genetic
material (DNA)
 Rocky mountain spotted fever: an infection disease caused by
bacteriaum Rickettsia and transmitted by wood tick.
1. Define antibiotics. Classify β-Lactum antibiotics.
2. Write a detail note on cell wall biosynthesis.
3. Write mechanism of action and clinical uses of β-Lactum antibiotics.
4. Write note on-
a. Streptomycin
b. Tetracycline
329
c. Chloramphenicol
d. Erythromycin
5. Write note on-
a. Penicillin G
b. Methicillin
c. Cloxacillin
d. Amphicillin
 Principles of medicinal chemistry, volume II- Dr. S.S. Kadam, Dr. K.R.
Mahadik, Dr. K.G. Bothara(Niraliprakashan) 2007.
 Pharmacology (5thed.)- H.P Rang and M.M Dale (Elsevier publisher)
2003.
 Basic & Clinical Pharmacology (ninth edition)- Bertram G.Katzung (Mc
Graw Hill Publisher) 2004.
330
Unit - 20
Synthesis of Antibiotics
Structure of Unit:
20.1 Objectives
20.2 Introduction
20.3 Ampicillin
20.4 Amoxicillin
20.5 Chloramphenicol
20.6 Cephalosporin
20.7 Tetracyclins
20.8 Penicillin G
20.9 Streptomycin
20.10 Summary
20.11 Glossary
20.1 Objective:
 In this unit we will discuss about the drugs which are used for bacterial
infections and also their method of synthesis and uses.
 Here we will study about the drugs which show their action against
Gram-positive bacteria and Gram-negative bacteria or both.
20.2 Introduction
The term antibiotic has been derived from the word antibiosis which according
to biology concept means survival of fittest i.e. process in which one organism
may destroy another to preserve itself it is define as chemical substance
produced by living cells which is capable in small concentration inhibiting the
life processes or even destroy the micro-organism. Penicillin was the first
antibiotic introduced as a successful antimicrobial drug.
Historically the most common classification has been based on chemical
structure and proposed mechanism of action, as follows:-
331
 Agents that inhibit the synthesis of bacterial cell walls, these include the
penicillin and cephalosporin, which are structurally similar, and
dissimilar agents such as cycloserine, Vancomycin bacitracin, and the
imidazole antifungal agents.
 Agents that act directly on the cell membrane of the micro-organisms
affecting permeability and leading to leakage of intracellular
compounds. These include polymyxin, polyene antifungal agents,
nystatin and anphotericin B, which bind to cell wall sterols.
 Agents that affect the function of 30S and 50S ribosomal subunits to
cause reversible inhibition of protein synthesis; these include
tetracyclines, erythromycins, chloramphenicol and clindamycin.
 Agents that bind to the 30S ribosomal subunit and alter protein
synthesis, which eventually leads to cell death; these include amino
glycosides.
 Agents that affect nucleic acid metabolism such as rifamycins, which
inhibit DNA-dependent RNA polymerase.
20.3 Ampicillin:- (Omnipen)
It is broad spectrum penicillin, because it also acts against Gram- negative
bacteria. It is susceptible to inactivation by enzyme, β-lactamase. Ampicillin
can be prepared microbiologically by incubation of microbes (pseudomonas
speicies) with 6-aminopenicillanic acid and α-phenylglycine via enzyme
acylation of 6-APA (amino penicillanic acid).
Ampicillin has an amino group in its side chain. Ampicillin is not degraded by
gastric acid. Its oral absorption is incomplete. Food interferes with absorption
of ampicillin.
Structure of Ampicillin:-
IUPAC- (2S,5R,6R)-6-([(2R)-2-amino-2-phenylacetyl]amino)-3,3-dimethyl-7-
oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid
Synthesis of Ampicillin:-
332
Method-I
Method-II
It is prepared with the acylation of 6-aminopenicillanic acid (6-APA) with acid
chloride from D-2-azidophenylacetic acid followed by a catalytic reduction.
Anpylrous ampicillin is a white odorless, crystalline powder, slightly soluble in

water. The sodium salt has a bitter taste with hygroscopic properties. Ampicillin
333
is the drug of choice for gonococcal urethritis and upper respiratory tract
infections.
Use:- Ampicillin is used for most acute infections of urinary tract. Respiratory
tract infection including bronchitis, Otitis media, sinusitis etc. are generally
treated with ampicillin. It is also a first line drug for meningitis and gonorrhea.
Averse effect:- Diarrhoea is frequent adverse effect after oral administration of
ampicillin. It produce a high incidence of rashes, particularly, in AIDS,
lymphatic leukemia and EB virus infections. Sometimes rashes may be of toxic
nature.
20.4 Amoxicillin (Amoxil)
It is a moderate beta-lactam antibiotic used to treat baeterial infections caused

by susceptible micro organisms. It is usually the drug of choice with the class
because it is better absorbed following oral administration, than other beta-
lactam antibiotics.
Amoxicillin is susceptible to degradation by beta-lactamase producing bacteria,
and so may be given with clavulanic acid to decrease its susceptibility. It is
commonly available by proprietary names such as “Augmentin”.
Structure of Amoxicillin:-
IUPAC Name- [6-D (-)-α-amino-p-hydroxyphenylacetamido penicillanic acid]

Synthesis of Amoxicillin:-
334
It is fine, white crystalline powder that is sparingly soluble in water. Its
antibacterial spectrum is nearly identical to that of ampicillin.
20.5 Chloramphenicol (Chloromycetin, Mychel)
Chloramphenicol is a broad spectrum antibiotic. It is elaborated by streptomyes

venizulae. It is now prepared synthetically. Chloramphenicol is a nitrobenzene
derivative.
Chloramphenicol is bacteriostatice. It acts by inhibiting bacterial protein
synthesis.
Structure of Chloramphenicol:-
IUPAC Name:- 2,2–Dichloro-N-[2-hydroxy-1-(hydroxylmethyl)-2-(4-

nitrophenyl)ethyl]-acetamide.
335
Synthesis:-
Properties and Use: - It occurs as a fine yellowish white, needle like crystals.
It is slightly soluble in water and has a bitter taste.
Chloramphenicol is an important drug for the treatment of typhoid fever caused
by salmonella typhi, also give excellent result in haemophilus influenzae
meningitis, Neisseria meningitis.
20.6 Cephalosporin
The cephalosporins are beta- lactum antibiotics isolated from cephalosporium

Species and are prepared semi synthetically. These come under the class of 7-
336
amino cephalosporinic acid (7-ACA) derivatives and are much more acid stable
than the corresponding 6-APA compounds.
The cephalosporin have a mechanism of action similar to that of penicillin’s,
mainly they inhibit the cross – linking of the peptidoglycane units in bacterial
cell wall by inhibiting transpeptidase enzyme.
The cephalosporin nucleus, 7-amino cephalosporonic acid (7-ACA) was
derived from cephalosporin C. Modification of the 7-ACA side chain resulted
in the development of the useful antibiotic agents.
Basic Structure of Cephalosporin
If-
R1 R2
Cephalexin C6H5-CH(NH2)- CH3
Cefadroxil HO-C6H4-CH(NH2)- CH3
Synthesis of 7-amino cephalosporinic acid (7-ACA) from cephalosporin C:-

Cephalosporin C is isolated on an industrial scale by fermentation using
“Cephalosporium acremonium”
337
The key reaction based on a method for removing glutamate residue in
cephalosporinic C, involves conversion of the primary amine in the molecule to
a diazo function by reaction with nitrosyl chloride and formic acid. The diazo
function can be displaced by oxygen from the enol form of the amide at the 7
position to form iminolactone. Hydrolysis of imine leads to 7-ACA.
Examples of cephalosporin derivatives:- cephalexin, cefadroxil, cefuroxime,
ceftizoxime, cefazolin etc.
Synthesis of cephalexin:- (Keflex)
Method- I
In first method 7-aminodesacetoxy cephalospranic acid react with D-phenyl

glycine methyl ester and give the final product i.e. Cephalexin
Method- II
338
It is rapidly and completely absorbed from the GI tract and thus has become
popular. It is acid stable used as the monohydrate, primarily for the treatment of
respiratory, urinary, skin and soft tissue infections.
20.7 Tetracyclins
These are broad spectrum antibiotics. They are effective against gram positive
organisms, actinomyces, rickettsiae and Chlamydia organisms.
Chlortetracycline is obtained from “streptomyces aureofaciens”
Basic Structure:-
Synthesis:-
 The phenolic group was benzylated to the ether (2). This was converted
to the methyl carbinol (3) with methyl magnesium iodide.
339
 The acetate rearranged during the later process, following hydrolysis of
the acetate ester, the tris alcohol was oxidised with chronic acid in
acetone to yield the enolised Beta-diketone (4).
 Hydrogenation yielded the tetracycline BCD-model compound (5).
 The beta ketone was condensed with ethyl nitroacetate then dehydrated
to yield the nitro ester (6) reduced to the amino ester (7) with zinc dust
in acetic acid and converted to the phthalimidoester (8) by reacting with
carbethoxy phthalimide.
 Methylation with methyl iodide/silver oxide followed by saponification
and recrystallization of intermediate phthalimide (9) from hot acid (10).
 Treatment of (10) with phosphorus pentachloride formamide followed

by C2H5OMgCH(CO2C2H5)CONH2 gave the N-phthaloylgalylo
malonate (11), which was cyclised by dicylanion in dimethyl sulfoxide
to the hydronaphthalene (12), in turn hydrolysed with hydrogen bromide
in acetic acid and methylated with methyl iodide in THF to ± (-12-
deoxy-5a,6-anhydrotetracyclin) (12).
340
20.8 Penicillin G
Penicillin is a generic term which refers to a class of compounds of the

molecular formula CH11N2O4SR, produced by various strains of “penicillium
notatum”, “penicillium chrysogenum” and some other fermented moulds.
Penicillin G or benzyl penicillin is the most important commercial penicillin. It
is a narrow spectrum antibiotic and its activity is limited primarily to gram –
positive bacteria and few others
Structure of Penicillin G:-
IUPAC Name:- (2S,5R,6R)-3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-

thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid
Synthesis:-
341
Penicillin G is obtained in small quantities by condensing D-penicillamine (I)
with 2-benzyl-4-methoxy methylene oxazolone (II), in pyridine at 70°C. The
benzyl penicillin was isolated as the crystalline triethyl amine salt. The starting
material II was prepared by methylphenaceturate in the following way-
20.9 Streptomycin
It is a member of aminoglycoside antibiotics, obtained naturally and

semisynthetically, having polybasic amino groups linked glcosidically to two or
more amino sugars (streptidine, 2-deoxy streptamine, garosamine) residues.
Streptomycin was first discovered in 1944 by Wakesman et. at. from
streptomyces giseus. Unlike penicillin (Which was a chance discovery)
streptomycin was a product of deliberate search for drugs effective against
Gram-negative bacteria. Neomycin was next drug (1949) to be isolated, but
could not be used systemically.
All amino glycosides are produced from soil actinomycetes and have many
common properties.
342
Streptomycin assumed great importance because this antibiotic is active against
tubercle bacilli, but now practically restricted to treatment of tuberculosis.
The mode of action of this antibiotic is in 2 steps:

 Transport of the streptomycin through the bacterial cell wall and
cytoplasmic membrane.
 Binding to ribosomes resulting in inhibition of protein synthesis.
Adverse effects:- By streptomycin, rashes, eosinophilia, fever, exofoliative

dermatitis, amphylaxis, scotoma, parethesias, pain at injection site, auditory
disturbances are found as adverse effects.
Uses:- It is used in tuberculosis, urinary tract infections, peritonitis,
septicaemia, subacute endocarditis, tularemia and plague.
Structure:-
Synthesis:-
Synthesis of N-methyl glucosamine: It is prepared from L-arabinose.
343
20.10 Summary
Antibiotics or antibacterials are a type of antimicrobial used specifically against

bacteria; antibiotics are used to treat various infections. and are often used in
medical treatment of bacterial infections. They may either kill or inhibit the
growth of bacteria.
With advances in medicinal chemistry, most modern antibacterials are semi
synthetic modifications of various natural compounds. These include, for
example, the beta-lactam antibiotics, which include the penicillins (produced by
fungi in the genus Penicillium), the cephalosporins, and the carbapenems.
Compounds that are still isolated from living organisms are the
aminoglycosides, whereas other antibacterials—for example, the sulfonamides,
the quinolones, and the oxazolidinones—are produced solely by chemical
synthesis.
Side-effects range from mild to very serious depending on the antibiotics used,
the microbial organisms targeted, and the individual patient.
20.11 Glossary
 Amphylaxis:- This is a serious allergic reaction that is rapid in onset
and may cause death. It typically causes a number of symptoms
including an itchy rash, throat swelling, and low blood pressure.
Common causes include insect bites and stings, foods, and medications.
 Antifungal Agents:- is a pharmaceutical fungicide used to treat and
prevent mycoses such as athlete's foot, ringworm, candidiasis (thrush),
serious systemic infections such as cryptococcal meningitis, and others.
 Hygroscopic:- Describing the ability or tendency of a material to take
up moisture readily from the surrounding air or other moist materials.
 Gonococcal Urethritis:- In men, purulent discharge usually indicates a
urethritis of gonococcal nature, while clear discharge indicates urethritis
of non-gonococcal nature.
 Scotoma:- This is a defect of vision in a defined area of the visual field
in one or both eyes.
 Septicaemia:- Septicemia is also known as bacteremia or blood
poisoning. Septicemia occurs when a bacterial infection enters the
bloodstream. Untreated septicemia can quickly progress to sepsis, which
344
is a serious complication of an infection characterized by inflammation
throughout the body. This inflammation can cause blood clots and block
oxygen from reaching vital organs, resulting in organ failure and death
in some cases.
 Tularemia:- This is a serious infectious disease caused by the
bacterium Francisella tularensis. The bacteria can penetrate into the
body through damaged skin and mucous membranes, or through
inhalation. Humans are most often infected by tick bite or through
handling an infected animal.
1. What are antibiotics? Discuss in detail with the synthesis of any one
antibiotic drug.
2. Give the synthesis of any two-
 Ampicillin
 Amoxicillin
 Cephalosporin.
3. Give the basic structure and basic method for the synthesis of
antibiotics.
4. Give the synthesis of Penicillin G.
5. Give the Synthesis of tetracycline.
6. How 7-amino cephalosporinic acid (7-ACA) Synthesize from
cephalosporin C?
7. Discuss about streptomycin. Give structure and synthesis of N-methyl
glucosamine.
20.13 eferences and suggested readings

345
 A Book of medicinal chemistry volume II; (first edition 2008-2009) Dr.
Approach) Vol. II; (third edition 2004, reprint 2006) Surendrs N.
 Principle of medicinal chemistry-vol. I; (eighteenth edition, september
Tripathi, Published by- JAYPEE br
346

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Vardhman Mahaveer Open University, Kota

Drugs and Pharmaceuticals

Drugs and Pharmaceuticals

Academic and Administrative Management

Chemistry Applied Chemistry

Fig.1.1: Relation Cycle of Applied Chemistry

Fig.1.2: The general steps in the design of a new drug

(C) Discovery of Drugs through Metabolism Studies

Fig.1.3: Mechanism of action of Sildenafil (Viagra)

Lead Modification (Lead Optimization)

Figure 1.7: Prodrugs transformed by spontaneous reactions

Fig.1.8: Design of prodrugs with improved bioavailability

(ii) Macromolecular Prodrugs: Conjugation of small drug molecules to high

When a substituent is present on the aromatic ring, this equilibrium is affected.

Benzoic acids containing electron-withdrawing substituents will have larger KX

Diastereoisomers also can be found in cyclic compounds. For example, the

b) Divalent atoms and groups

c) Trivalent atoms and groups

II. Non-classical bioisosteres

Another example is the use of double bond to position essential functional

2.9 Spatial arrangement

(2) Cinnamic acids:

 Foyes Principle of Medicinal Chemistry (6th ed.)- Thomas L Lemke and DA

Fig. 3.1: Generalized schematic illustration of processes and mechanisms

3.3 Drug–Receptor Complex

Formation of the drug–receptor complex involves an elaborate equilibrium.

The bonds formed between a drug and receptors are following:

Subsequently, it has been realized that occupation of the receptor is essential

Depending on the agonist, DR could generate a stronger or weaker S, probably

3. 8 Other theories & models of drug–receptor interactions

Fig. 3.5: Two-state model of receptor activation. D is the drug, R is the

3.12 References and Suggested readings

4.5 Physicochemical parameters

Fig. 4.2: Parabolic relationship between biologic activity (log 1/C)

Inductive effect of phenol is predominates at meta position.

n = index of refraction at the sodium line

Log 1/C = K1 (log P)2 + K2 log P + K3 σ + K4 ES + K5

1. Define QSAR. Write about Hansch analysis.

4.17 References and Suggested readings

Fig. 5.2 (b): Illustrations of terms: Agonist; Antagonist; Inverse agonist;

Fig.5. 4: Types of receptor-effector linkage

5.5 G-protein coupled receptors (GPCR)

Fig. 5.5(b): The action-effect sequence of two G-protein coupled (β adrenergic

Fig. 5.7(a): Transduction mechanisms of kinase-linked receptors :( a) Intrinsic

Fig. 5.7(b): Transduction mechanisms of kinase-linked receptors: (b) JAK-

5.8 Nuclear receptor

Fig. 5.8: Transduction mechanism of nuclear receptor : Glucocorticoid receptor

5.11 Review questions / Comprehensive Questions

Fig. 6.1: Representation of drug absorption, distribution, metabolism and

Fig. 6.3: Commonly used routes of drug administration. (lV=intravenous;

The three major parenteral routes are intravascular (intravenous or intra-

Afferent Arteriole Efferent Arteriole

Fig. 6.7: Renal excretion of drugs

6.8 Pharmacokinetics of Elimination

 First order kinetics-

6.11 Review questions / Comprehensive Questions

The unit of measurement of volume of distribution is ml.

7.7 Drug elimination and clearance