PRINCIPLE OF PHARMACOLOGY

Pharmacology By:
for PC I DEJENE HAILU
 INTRODUCTION TO PHARMACOLOGY
What is Pharmacology?

 Derived from Greek “pharmakon [drug], logos [Science ].

 Pharmacology is the science of drugs dealing with

pharmacokinetics and pharmacodynamics of drugs.

 Pharmacology studies the effects of drugs and

how they exert their effects.

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 In a broad sense, it deals with interaction of exogenously

administered chemical molecules (drugs) with living systems.

 It encompasses all aspects of knowledge about drugs, but

most importantly those that are relevant to effective and safe

use for medicinal purposes.

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 GENERAL DEFINITIONS

 Pharmacology:- is the study of the interaction of chemicals

with living systems.

• Chemical properties

• Biochemical and physiological effects

• Absorption, distribution, metabolism and excretion of

drugs
 History of pharmacology
5

 Primitives :undoubtedly recognized the beneficial or

toxic effects of many plant and animal products
1. Herbal Remedies
2. Arrow Poisons [d-tubocurarine]
3. Mood altering plants [Opium ,nicotine, hashish]
Hippocrates:- father of medicine
Paracelsus (1493 – 1541)
 Grandfather of pharmacology (introduce chemicals
for treatment of disease).

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 History of pharmacology…
6

1550:- Egyptian created Ebers medical

papyrus.
 Castroil oil:- laxative
hair growth
 Opium:- pain

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 History of pharmacology…
7

Modern pharmacology

 Oswald Schmiedeberg (1838 – 1921)

 regarded as the ‘father of pharmacology’, together with his

many disciples like J Langley, T Frazer, P Ehrlich, AJ Clark,
JJ Abel propounded some of the fundamental concepts in
pharmacology.

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 History of pharmacology…
8

 John Jacob Abel( 1857 -1938)

 isolation of epinephrine from adrenal gland (1897–1898)

 isolation of histamine from pituitary extract (1919), and

 preparation of pure crystalline insulin (1926).

 Paul Ehlrich ( 1854 -1915)

 Father of chemotherapy :- find cure for syphilis in 1909

 Nobel prize winner

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 History of pharmacology…
9

 Alexander Fleming (1818 – 1955)

Discovered penicillin

 Ramnath Chopra ( 1882 – 1973)

Father of Indian Pharmacology

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 Definitions
10

 Pharmacokinetics: Deals with absorption, distribution,

biotransformation/metabolism/ and excretion of drugs.
 Pharmacodynamics: study of biochemical and physiological
effects of drugs and their mechanisms of action.
 Pharmacotherapeutics: use of drugs in prevention &
treatment of disease.
 Toxicology: Branch of pharmacology which deals with the
undesirable effects of chemicals on living systems.

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 11

 Drug: any substance that brings about a change in

biologic function through its chemical action.

 Xenobiotics (Gr. xenos - stranger):- chemicals that are

not synthesized by the body, but introduced into it from

outside.

 Medical pharmacology:- is the study of drugs used for

the diagnosis, prevention, and treatment of disease.

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 What are drugs?
12
 A drug is any chemical or biological substance, synthetic or

non-synthetic, that when taken into the organism's body, will

in some way alter the functions of that organism.

 Drugs chemicals that are intended for treatment, diagnosis,

prevention and control of diseases

 Drugs are usually distinguished from endogenous

biochemicals by being introduced from outside the organism.

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 Drug

 The WHO (1966) has given a more comprehensive

definition

 “Drug is any substance or product that is used or is

intended to be used to modify or explore physiological

systems or pathological states for the benefit of the
recipient.”

 The term ‘drugs’ is being also used to mean

addictive/abused/illicit substances.
 DRUG NOMENCLATURE
 Many names are given to drugs often confusing.

 It is therefore necessary to know drug nomenclature.

The following is the drug name system
1)Chemical/Molecular/Scientific name: It depicts the
chemical/molecular structure of the drug
 e.g. Paracetamol

N-acetyl-p-amino-phenol

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2) Generic/ Approved Name:

 It is the official medical name of the drug.

 Removes confusion of giving several names to the same

drug regardless of who manufactures them.

 e.g: paracetamol (Britain English) or Acetaminophen

(American English)

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3. Trade/Brand Name:

 These are names given to the drug by the manufacturing and

marketing company.

 In most cases one drug could have so many trade/brand names

 e.g paracetamol has many trade names. Like : Pacimol,

Tylenol, Paramol, Panadol, Capol etc.

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 Sources of Drugs
17

 Plants
 Microorganisms
 Animals
 Chemical synthesis
 Biotechnology
 Semi-synthetic: heroin, oxacilin,
Currently majority of the drugs used in therapeutics are
from synthetic source

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1-Plant sources
 Various parts of plants are used
Leaves: belladonna for atropine , digitalis for digoxin,
tobacco for nicotine
Flower: poppy for morphine, vinca rosea for
vinicristine and vinblastine,
Bark: cinchona for quinine and quinidine
Roots: Ipecacuaha for emetine
Stem: chondredrom tometosom for tubocurarine
Seeds: nux vomica from 18strychinine
 19

2-Animal sources
Insulin from pancreas of different animals e.g. cattle or pig,

Thyroid extract, heparin, anti-toxin sera

 HCG from urine of pregnant woman
 Cod liver for vitamin A and D
 Blood of animals for vaccine
 Hormones of different glands
3-Mineral sources: e.g. Magnessium sulphate and
iodine, magnesium trisilicate
4-Microreganism: Fungi and bacteria isolated from soil
are important sources of antibiotics e.g. Pencillin,
streptomycin,
5-Synthetic drugs: Many drugs are produced in the
laboratory
e.g. sulphonamide, barbiturate, aspirin, zidovudine
Currently majority of the drugs used in therapeutics are from
synthetic source
6-Biotechnology: Human insulin and growth hormone
have successfully been produced
20 by genetic engineering
 Major divisions of pharmacology
21

 The two major subdivisions of pharmacology consists of:

 PHARMACOKINETICS
 FATE of drug in the body
 Action of body on the drug
 ADME( Absorption, distribution metabolism and excretion)
 Quantitative study of the relation among drug dose with
respect to time
 PHARMACODYNAMICS
 ACTION of drugs on the body
 Drug receptor interaction and the consequence
 Non-receptor interaction and consequences
 Response – concentration relationship of a drug
 Subdivisions of pharmacology
22

Pharmacology also have other sub-division, based on different

criteria, for example:
 The organ system of primary concern: Neuropharmacolgy,
Cardiovascular pharmacology, Renal pharmacology …

 Techniques used: biochemical pharmacology, molecular

pharmacology, behavioral pharmacology…

 Purpose or application to which the knowledge is used: Clinical

pharmacology, Pharmacogenomics, Toxicology, Agricultural
pharmacology…
 General Concepts
23
Drug Dose
Administration

Absorption/distribution
Pharmacokinetics metabolism/excretion

Drug/Receptor
Pharmacodynamics Interaction/effect

Pharmacotherapeutics Drug use

 Development and evaluation of new drugs

 Drug development comprises

1. Preclinical development
2. Clinical development
1. Preclinical development: synthesis of new chemical entity
is done on the basis of:
 Random synthesis
 Structure activity relationship
 Biochemical & pharmacological insight
 Chance finding
• Used to explore drug’s safety & efficacy
• Drugs tested on animals or in vitro
• Pharmacodynamic, pharmacokinetic and toxicity will
be studied
2. Clinical development
a. Pharmaceutical study: formulation study
b. Pharmacological study: chronic toxicology study in animal
c. Clinical trial: safety and efficacy of a compound is studied in
human
I. Phase I: conducted on healthy volunteer (20-50);
-designed to test tolerable dose and duration of
action.
II. Phase II: 100-500 patients, to determine dose
level and to establish that treatment offers some
benefits
III. Phase III: standard treatment is done; involves
randomized controlled trial (up to 2000 patients)
IV. Phase IV: post marketing surveillance
 Report about safety & efficacy

 Renewal or cancellation of the product

depends on comment of review
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Pharmacokinetics

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 Pharmacokinetics

 Greek: Kinesis—movement

 What the body does to the drug.

 Deals with the dose-concentration part.

 This refers to movement of the drug in and alteration of the drug

by the body; includes absorption, distribution,

binding/localization/storage, biotransformation and excretion of the

drug.
PHARMACOKINETICS
29

PHARMACOKINETIC IMPORTANCE

To know the dose

To know the suitable route of

administration

To know the dosage

interval
To know the
duration of
therapy
 Pharmacokinetics
or Fate of drugs in the human body
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 Absorption
31

Absorption
Passage of a drug from its site of administration into
blood stream.
 is the transportation of the drug across the biological
membranes
There are different mechanisms for a drug to be
transported across a biological membrane:
 Passive (simple) diffusion
 Active transport
 Pinocytosis
 Facilitated diffusion
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 Principles of drug transfer
Membrane Structure 32
All membranes are phospholipids bilayers with embedded
proteins. Drug has to pass through this membrane

Phospholipid Bilayer
Label the:
Hydrophilic heads
Hydrophobic tails
33
 SIMPLE (PASSIVE) DIFFUSION
34

• The major role for the transportation of the drugs across

the cell membrane is simple (passive) diffusion.
• The substances move across a membrane according to a
concentration gradient.
• The concentration gradient is the factor that determines
the route and rate of the diffusion.
 No energy is required.
 There is no special transport (carrier) protein.
 No saturation.

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 ACTIVE TRANSPORT
35
 The transportation of the drug molecules across the cell
membrane against a concentration or an electrochemical
gradient.
 It requires energy (ATP) and a special transporter (carrier)
protein.
 There is «transport maximum» for the substances (the rate
of active transport depends on the drug concentration in
the enviroment).
e.g. levodopa and Methyl DOPA are actively absorbed from the
gut by the aromatic amino acid transporter.

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 FACILITATED DIFFUSION
36

 Occurs by the carrier proteins.

 Net flux of drug molecules is from the high concentration

to low concentration.

 No energy is required.

 Saturable.

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 Pinocytosis
37
 It is the process of transport across the cell in particulate
form by formation of vesicles.
 This is applicable to proteins and other big molecules, and
contributes little to transport of most drugs.
 The drugs which have MW over 900 can be transported by
pinocytosis.
 It requires energy.
 The drug molecule holds on the cell membrane and then
surrounded with plasma membrane and inserted into the
cell within small vesicles.

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 FACTORS THAT AFFECT THE ABSORPTION OF THE
DRUGS
38
A)DRUG-RELATED FACTORS
 Molecular size
 Lipid solubility
 Degree of ionization
 Dosage form
 Chemical nature (Salt/organic forms, crystal forms,
solvate form etc.)
 Particle size
 Complex formation
 Concentration of the drug
B) SITE OF APPLICATION RELATED FACTORS
 Blood flow (at site of application)
 Area of absorption
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 SITE of APPLICATION RELATED FACTORS
39

 Blood flow (at site of application):

 If the blood flow is high at the site of application, it
causes an increase in absorption rate.
 Area of absorption:
 If the surface area that allows the absorption of the
drug molecules is wide, then absorption rate from that
surface becomes high.

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 Route Of Administration
40

Affects drug absorption, because each route has its own

peculiarities.
Oral Route
 Drug molecules are mostly absorbed from duodenum,
jejunum and upper ileum.
 Disintegration and dissolution are the two main processes
for the oral administered drugs before the absorption
process.
 The absorption rate and absorption ratio of the orally
administered drugs are closely related with the above two
parameters.
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 Oral application.
41

 Unionized lipid soluble drugs (e.g. ethanol) are readily absorbed

from GIT.

 Acid drugs (aspirin, barbiturates, etc.) are predominantly unionized

in the acid gastric juice and are absorbed from the stomach.

 Acid drugs absorption from the stomach is slower, because the

mucosa is thick, covered with mucus and the surface is small.

 Basic drugs (e.g. atropine, morphine, etc.) are largely ioni-zed and

are absorbed only from the duodenum.

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Advantage
1. Safe

2. Convenient

3. Economical

Disadvantage
 Limited absorption for some drugs

 Slow onset of action

 Destruction of drugs by digestive enzymes or extremely low
gastric PH
 Irregularities in absorption or propulsion in the presence of
food or other drugs.
 Not suitable for unconscious and vomiting patient
 Irritatants and unpalatable drugs cannot be given
 Rapid first pass for some drugs Eg nitroglycerin.
 Drugs that absorbed from the stomach and intestine must
first pass through the portal vein in to the liver before it
reaches the systemic circulation.
 Some of the drugs will be inactivated by the liver before

reaching the systemic circulation

 If the metabolic capacity of the liver is great for the agent,

bioavailability will decreased.

 This effect is called “first pass effect”

 2. Sublingual Administration

 Absorption from oral mucosa has special significance for

some drugs despite the fact that the surface area available is
small.

 Venous return from the mouth is to superior vena cava, which

protects the drug from rapid first pass metabolism.

 For example nitroglycerin is effective when retained

sublingually because its non ionic and has higher lipid
solubility.
Advantage
 Rapid onset of action
 No destruction by gastric acid and digestive enzymes
 Excess drug can be expelled
Disadvantage
 Not suitable for administration of large volume
 Not suitable for drugs with low lipid/water partition
coefficient.
 3. Rectal administration

 Drugs are inserted in to the rectal lumen, when oral route is

impractical

 Certain irritant or unpleasant drugs can be given

 Drugs absorbed from external haemorrhoidal vein

(systemic circulation) about 50% by pass liver but not those
which absorbed from the internal haemorrhoidal vein
(portal circulation), subjected to first pass.
Advantage
 Can be used in the presence of vomit, in unconscious and non
cooperative patient
 Used for some drugs which are inactivated by gastric juice or
digestive enzymes
 First pass effect can be 50% avoided
Disadvantage
 Inconvenience of administration
 Slow and uncertain absorption of drugs
 Many drugs can cause irritation of rectal mucose
 4. Parental Route
A) Intravenous (IV)

– Only aqueous preparation can be injected in to one of the

superficial veins.

– The drug ca be injected as a bolus or slow infusion over

hours.

– The drug is injected directly to the blood leading in to

rapid onset.

– The dose is small, bioavailability is 100%.

Advantage

 Suitable for emergency

 Very irritant drugs can be given because blood vessels are

insensitive to pain and the drug is rapidly diluted in blood.

 Suitable for unconscious patient

 Suitable for giving large amount of solutions either by slow IV

bolus injection or by infusion over period of time.

 Gives relatively steady state drug concentration.

 Proper adjustment of the dose due to absence of the stage of

absorption and luck of the first pass effect as incase of the oral
route.
Disadvantage
• Necessity of strict aseptic measures

• Velocity reaction due to rapid injection

• Self medication is not suitable

 Increased risk of adverse effect

 Expensive

 Not suitable for oily solutions and insoluble substances.

 Phlebitis and thrombo-phlebitis can occur in injection site

 Extravasations of drugs may lead in to sloughing and tissue

necrosis
B) Intramuscular (IM)

• Drugs are injected in one of the large skeletal muscle such as;

 Gluteus maximus

 Deltoid

 Rectus

 Femoris

 Triceps

• Skeletal muscles are less richly supplied with sensory nerves

and more vascular.

 Mild to moderate irritant drugs can be injected in to skeletal muscle.
 Drugs in the form of solutions or suspensions in oil or water

can be injected

 Depot preparations can be due reach blood also be injected

 Absorption from the IM route is rapid than from SC route due

reach blood supply.

Advantage
 Suitable for moderate volume, oily vehicles, suspensions and
some irritant drugs.
 Uniform absorption
 Suitable for depot preparations
Disadvantage
 Necessity of strict aseptic measures, introduction of an
organism leads in to abscess formation.
 Not suitable for severe irritant drugs
 Not suitable for injection of drugs that form hematoma eg:
heparin
C) Subcutaneous (SC)

• Drugs are usually injected in the posteriolateral surface of the

arm or anterior surface of the thigh.

• The drug is deposited in the loose SC tissue which is

richly supplied by nerves (irritant drugs can’t be injected) but
less vascular (absorption is slow).

• This route should be avoided in shock (there is

vasoconstriction of SC blood vessels i.e. less absorption)
 Depot preparations, oily preparations or aqueous suspensions

can be injected for prolonged action.

 It is not suitable for large volumes of drug solutions or

suspensions

 Absorption from SC site is slower than the IM site but are

faster than oral

D) Other parental routes

Intradermal- the drug is injected b/n dermis and epidermis

• Useful for sensitivity test and penicillin allergy test

Intraperitoneal- not preferred because of production of

infection. E.g; rabies vaccines

Intrathecal- injection given via subarachnoid space. E.g;

spinal anesthetic for minor surgery
Inthracardiac- indicated during emergency.

 Emergency cardiac arrest.

Intraarticular- given to treat local conditions

 Eg. Hydrocortisone acetate in a rheumatoid arthritis

Jet injection- known as hypo spray. The drug is introduced

with the help of syringe through micro fine orifice by means
of a high velocity jet
 5. Inhalational Route

• Administration of drugs with the inspired air either through

the nose or through the mouth,
• Absorption takes in alveolar membranes
• Gases, volatile liquids and aerosol preparations can be given
by inhalations.
Rapid absorption
 Thinness of alveolar membrane
 Large surface area of alveolar membrane
 Alveolar membrane rich in blood supply and the
circulation is rapid.
Advantage
 Desired local site of action
 Rapid onset of action
 Avoid first pass biotransformation
Disadvantage
 Poor ability to regulate the dose (Dose variation). Can be avoided
by use of metered dose inhaler
 Irritation of respiratory tract
 Cumbersome method of administration
 6. Topical Application

A) Mucous membranes

• Drugs are applied to mucous membranes of the conjunctiva,

nasophyarynx, orophyarynx, vagina, colon, urethra and urinary

bladder primarily for their local effects.

B) Eye

• Topically applied ophthalmic drugs are used for their local

effects
C) Transdermal drug delivery
• Given in the form of adhesive patches which delivered the

contained drug at constant rate in to systemic circulation.

 Not all drugs readily penetrate the intact skin

 Absorption through epidermis is dependent on:

 Surface area

 Lipid solubility of the drug

 The epidermis, however, is permeable to many solutes

 Inflammation and other conditions that increase coetaneous

blood flow also enhance absorption.

• Absorption through skin can be enhanced by:

 Suspending drug in an oily vehicle

 Rubbing the resulting preparation in to the skin
 Hydrating the skin (occlusive dressing)
D) Controlled release topical patches
 Nicotine for tobacco smoking withdrawal
 Scopolamine for motion sickness nitroglycerine is vasodilator and angina
pectoris is fat deposit in the coronary artery

 Nitroglycerine for angina pectoris

 Bioavailability

 Refers to the rate and extent of absorption of a drug

 Bioavailability: fraction of administered drug (F) that

reaches the systemic circulation in unchanged form.

 The area under the blood concentration time-curve is a

common measure of the extent of bioavailability.

 BA = AUC Oral X100%
AUC Injected IV

A
Cp
C B

AUC= shows extent of absorption or amount of the drug inter to

the blood
Cp= therapeutic concentration
 DISTRIBUTION
68
Factors Affecting the Distribution of Drugs:
 Lipid solubility (diffusion rate)

 Ionization at physiological pH (dependent on pK)

 The Affinity of the drug to the tissue Proteins

 Blood Flow (Perfusion Rate)

 Binding to Plasma Proteins

 Disease like CHF, uremia, cirrhosis.

N.B Movement of a drug proceeds until an equilibration is

established between unbound drug in plasma and tissue fluids.

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 Factors Affecting the Distribution of Drugs

69

4. Plasma Proteins:
 The most important protein that binds the drugs in blood is
albumin for most of the drugs.
 Especially, the acidic drugs (salicylates, vitamin C,
sulfonamides, barbiturates, penicillin, tetracyclines,
warfarin, probencid etc.) are bound to albumin.
 Basic drugs (streptomycin, chloramphenicol, digitoxin,
coumarin etc.) are bound to alpha-1 and alpha-2 acid
glycoproteins, globulins, and alpha and beta lipoproteins.

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 Properties of plasma protein-drug binding

70
 Only the free (unbound) fraction of the drug circulating in

plasma can pass across the capillary membrane .

 Bound fraction serves as “drug storage”.

[DRUG]=1 mM [DRUG]=1 mM

[DRUG+PROTEIN]=9 mM

[TOTAL DRUG]=10 mM [TOTAL DRUG]=1 mM

INTERCELLULAR FLUID
PLASMA
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 The clinical significant implications of PPB
are:

a) Highly PPB drugs are largely restricted to the vascular compartment and
tend to have lower Vd.

b) The PPB fraction is not available for action.

c) There is an equilibration between the PPB fraction of the drug and the
free molecules of the drug.

d) The drugs with high physicochemical affinity for plasma proteins (e.g.
aspirin, sulfonamides, chloramphenicol) can replace the other drugs (e.g.
acenocoumarol, warfarin) or endogenous compounds (bilirubin) with lower
affinity.
 Conti--

e) High degree of protein binding makes the drug long-acting,

because bound fraction is not available for metabolism, unless it
is actively excreted by the liver or kidney tubules.

f) Generally expressed plasma concentrations of the drug refer

to bound as well as free drug.

g) In hypoalbuminemia, binding may be reduced and high

concentration of free drug may be attained (e.g. phenytoin).
 FACTORS AFFECTING DISTRIBUTION

73

5. Storage (Concentration-Sequestration) of the

Drugs in Tissues
◦ Stored drug molecules in tissues serve as drug
reservoir.
◦ The duration of the drug effect may get longer.
◦ May cause a late start in the therapeutic effect or a
decrease in the amount of the drug effect.

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 Tissue storage
74
 Heart and skeletal muscles – digoxin (to muscle proteins)
 Liver – chloroquine, tetracyclines, digoxin
 Kidney – digoxin, chloroquine
 Thyroid gland – iodine
 Brain – chlorpromazine, isoniazid, acetazolamide
 Retina – chloroquine (to nucleoproteins)
 Iris – ephedrine, atropine (to melanin)
 Bones and teeth – tetracyclines, heavy metals (to
mucopolysaccharide of connective tissue)
 Adipose tissues – thiopental, ether, minocycline, DDT

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 DISTRIBUTION
metronidazole ---- can pass with out inflammation
gentamycin---- cant even with inflammation
pencilin and cephalosporin----- pass at the time of inflammation (meningitis)
75

 Passage of the drugs to CNS:

 A BBB exists (except some areas in the brain) which limits the
passage of substances.

 Non-ionized, highly lipophilic, small molecules can pass into the

CNS and show their effects.

 Inflammation of the meninges of the brain increases

permeability of the BBB.

 Some antibiotics like penicillin can pass through the inflamed

BBB while it can’t pass through the healthy one.

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 Placental barrier
76
 Placental membranes are lipid and allow free passage of
lipophilic drug, while restricting hydrophilic drugs.
 The placental P-gp also serves to limit foetal exposure to
maternally administered drugs.
 However restricted amounts of nonlipid soluble drugs,
when present in high concentration or for long periods in
maternal circulation, gain access to the foetus.
 Thus, it is an incomplete barrier and many drugs, taken by
the mother, can affect the foetus or the newborn.
 Penicillins, azithromycin, and erythromycin do not affect
the foetus and can be used during the pregnancy.
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 Placental barrier
77
 Passage of the drugs to fetus:
◦ Placenta doesn’t form a limiting barrier for the drugs to
pass to fetus.
◦ The factors that play role in simple passive diffusion,
effect the passage of drug molecules to the fetus.
 Placental blood flow
 Molecular size
 Drug solubility in lipids
 Fetal pH (ion trapping): fetal plasma pH: 7.0 to 7.2;
pH of maternal plasma: 7.4, so according to the ion
trapping rules, weak basic drugs tend to accumulate
in fetal plasma compared to maternal plasma.
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 Volume of Distribution (Vd)
• Presuming that the body has single homogenous compartment
with volume V in to which drugs get immediately and uniformly
distributed.

Vd = Amount of drug in the body

C
• An apparent volume --- “the volume that would accommodate
all the drug in the body, if the concentration through out is the
same as plasma”
• E.g, if 25mg of a drug is administered and the plasma
concentration is 1mg/L. find Vd ?
• Vd = 25mg
1mg/L

 Vd = 25L
• Lipid insoluble drugs couldn’t inter cells ------ Vd approximates
extracellular fluid volume.
• Drugs extensively bound to plasma proteins have low Vd.
• Drugs sequestered in other tissues may have Vd much more
than total body water or even body mass.
BIOTRANSFORMATION
 BIOTRANSFORMATION

81

The process of alterations in the drug structure by the

enzymes in the body is called “biotransformation (drug
metabolism)” and the products form after these reactions
are called “drug metabolites”.
Some drugs which don’t have any activity in vitro, may
gain activity after their biotransformation in the body.
These types of drugs are called “pro-drug” or “inactive
precursor”.
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 cont’d…
82

Drug examples that gain activity after

biotransformation (pro-drugs):
Pro-drug effective
metabolite
Enalapril enalaprilat
Lovastatin lovastatin acid
L-Dopa dopamine
levodopa is transformed to dopamine because dopamine can not cross BBB … it is administered for people
with Parkinson disease

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 Biotransformation
83
 Drug examples that is transformed to more active compounds
after biotransformation:

DRUG MORE ACTIVE

METABOLITE
Imipramine Desmethylimipramine
Codeine Morphine
Nitroglycerin Nitric oxide

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 Biotransformation
84
 Drug examples that is transformed to less active
compounds
DRUG after biotransformation:
LESS ACTIVE
METABOLITE
Aspirin Salicylic acid
Meperidine Normeperidine
Lidocaine De-ethyl lidocaine
(dealkylated)

 Drug examples that is transformed to inactive metabolites

afterDRUG
biotransformation INACTIVE
METABOLITE
Most of the drugs Conjugated compounds
Ester drugs Hydrolytic products
Barbiturates Oxidation products
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 Biotransformation

85
 The metabolites that are formed after biotransformation are
generally more polar, more easily ionized compounds compared to
the main (original) drug.
 So, these metabolites can be excreted from the body easily.
Organs in which biotransformation occurs:
 Liver** (the most important organ, the number and
variability of the biotransformation enzymes are the highest)
 Lungs

 Kidney (tubular epithelium, sulphate conjugation)

 Gastrointestinal system (duodenal mucosa)

 Placenta

 Adrenal glands

 Skin

 CNS and Blood

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 ENZYMATIC REACTIONS
86

The enzymatic reactions which the drugs are exposed to:

1. Oxidation
2. Reduction PHASE I
3. Hydrolysis
4. Conjugation PHASE II

DRUG X (inactive or less active**, same activity, higher activity) Y (generally inactive)

PHASE I PHASE II

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 CONJUGATION REACTIONS
87

1. Glucuronidation

2. Methylation
1. N- methylation

2. O-methylation

3. N-acetylation

4. Sulfate conjugation (sulfation)

5. Glutathione conjugation

6. Conjugation with amino acids

7. Conjugation with ribose or ribose phosphates

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 Glucuronidation
88

 These involve conjugation of the drug or its phase I meta-

bolite with an endogenous substrate to form a polar highly
ionized organic acid, which is easily excreted in urine or
bile.
 Conjugation reactions have high energy requirements.
 Glucuronic acid is a highly hydrophilic compound, so it
decreases the lipid solubility of the drug after conjugation.
 Glucuronosyl transferases catalyze the reaction.
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 Characteristics of phase II products:
89

1) Product = conjugate

2) Usually are pharmacologically inactive.

3) Polar

4) More readily excreted in urine.

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Factors That Affect The Biotransformation of Drugs
90
1. Induction or inhibition of microsomal enzymes

2. Genetic differences

3. Age
the most important isoenzyme for drug metabolism is
CYP4503a4
4. Gender
induction --- increase drug metabolism decreasing drug

5. Liver diseases
effectiveness
increasing the dose would reverse the effect
inhibition --- inhibit drug interaction with the body
decreasing the dose would reverse the effect
6. Environmental factors

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 Induction or inhibition of microsomal enzymes
91
 Various drugs or environmental factors lead to increases in the

activity of these enzymes by increasing the synthesis of

microsomal enzymes.

 The importance of the enzyme induction is the increasing

metabolism rate of the drugs and the reduction in their activities.

 On the other hand, some drugs stimulate the enzymes that inhibit

themselves (biochemical tolerance).

 Unlike the enzyme induction, some drugs can inhibit the

microsomal enzymes.

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 INDUCERS
ENZYME DRUG or SUBSTANCE
92 THAT INDUCES THE ENZYME

Cigarette smoke, grilled meat (barbecue), aromatic

CYP1A2
polycyclic hydrocarbons, phenytoin

CYP2C9 Barbiturates, phenytoin, carbamazepine, rifampin

CYP2C19 NOT INDUCIBLE

CYP2D6 NOT INDUCIBLE

Barbiturates, phenytoin, rifampin, carbamazepine,

CYP3A4
glucocorticoids, griseofulvin, 2/29/2024
 Use of inducers result in

93
1. Increase the metabolism of the inducer.
2. Tolerance : Decreases the inducer’s pharmacological action.
3. Increase the metabolism of co-administrated drugs (drug
interaction)
E.g. Barbiturates and warfarin thrombosis.
Phenytoin and oral contraceptive ( the woman gets pregnant )
4. Increase tissue toxicity by metabolite.
E.g. Paracetamol , phenacetin .
5. As therapy.
E.g. Phenobarbitone (given to babies with physiological
jaundice to induce liver microsomal enzymes) and
hyperbilirubinemia.
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 INHIBITORS
94
ENZYME DRUG or SUBSTANCE THAT INHIBITS THE
ENZYME

CYP1A2 Cimetidine, ethinyl estradiol, ciprofloxacin

Amiodarone, isoniazid, co-trimoxazole, cimetidine,
CYP2C9
ketoconazole
CYP2C1
Fluoxetine, omeprazole
9
Amiodarone, cimetidine, fluoxetine, paroxetine,
CYP2D6
haloperidol, diphenhydramine
Ketoconazole, erythromycin, , isoniazid, Ca
CYP3A4
channel blockers, red wine, grapefruit juice
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 Use of inhibitors result in:

95

 Impede the metabolism and excretion of the inhibitor and

Co-administered drugs, thus increasing t1/2.

 Prolong the action of the inhibitor and co- administrated

drugs increased pharmacological activity

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 Liver Diseases
96

 Especially, the metabolism of drugs with a “high hepatic

clearance” decreases in liver diseases.

 This leads to accumulation of drugs in the body which are

metabolized in liver, and eventually causes an increase in

the effect and adverse effects as well.

 On the other hand, transformation of pro-drugs into their

active forms occurs less in liver diseases.

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 ENVIRONMENTAL FACTORS

97
 Especially pollutants can affect the microsomal enzymes.

 Induction of microsomal enzymes can occur with;

 DDT and some insecticides

 Benzopyrenes and other polycyclic aromatic hydrocarbons
(products of burned coal and petroleum products)
 Polycyclic hydrocarbons in the cigarette smoke can induce some enzymes like
CYP1A2 and CYP1A1 (For this reason, the metabolism rate of
chlorpromazine, theophylline and imipramine is significantly high in heavy
smokers).
 Diet (Cabbage and cauliflower can induce CYP1A1 and CYP1A2)
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 ENVIRONMENTAL FACTORS
98

 Inhibition of microsomal enzymes can occur with;

 Carbon monoxide inhibits the microsomal enzymes.

 Grapefruit juice (some flavonoids in grapefruit juice can inhibit

CYP3A4)

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 99

EXCRETION

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 4. Excretion

• Transportation of unaltered or altered drug out of the body.

Drugs and their metabolite excreted in:

A) Urine: the most important channel for excretion of most

drugs

B) Faces: apart from the un absorbable fraction, most of the

drugs present in faces is derived from bile

C) Exhaled air: gasses and volatiles are eliminated by lung

irrespective of their lipid solubility
D) Saliva and sweat: this are of minor importance for excretion

 As saliva swallowed the drug meets the same fate as orally

swallowed.

E) Milk: the excretion of drug in milk is not important for the

mother, but the suckling infant inadvertently receives the drug.

 Drugs inter breast milk by passive diffusion

 Milk has a lower PH (7.0) than plasma, basic drugs are

some what more concentrated in plasma.
 Renal excretion

 Excretion of water soluble drugs and metabolites three process:

Glomerular filtration

Passive tubular reabsorption

Active tubular secretion

 Renal function is not constant

 In neonates, renal function is low but mature rapidly

 During adulthood, there is a slow decline in renal function

RENAL EXCRETION
103

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 A) Glomerular Filtration

 Glomerular filtration capillaries have pores larger than all

non protein bound drug (whether lipid soluble or

insoluble) presented to glomeruls is filtered.

 Thus GF of a drugs depends on its;

1. Plasma protein binding

2. Renal blood flow.

only free unbound drugs/metabolites filtered by glom
Lipid solubility and pH do not influence the passage of drugs into the glomerular
filtrate.
 B) Tubular Reabsorption

 This depend on lipid solubility and ionization of the drug at

the urinary PH.
 Lipid soluble drugs filtered at glomeruls back diffuse in the
tubules, because 99% of glomerular filtrate is reabsorbed.
 Non lipid soluble and ionized drugs unable to do so.

 Thus the rate of excretion for such drugs eg,

aminoglycosides, tubocurarine, parallels with glomerular
filtration rate.
Weak Acids:
When a drug is in a lipid-soluble form during its passage through the renal tubule, a significant fraction can be reabsorbed by
passive diffusion across membranes and back into the blood.
The protonated form of a weak acid is the neutral, more lipid-soluble form.
In alkaline urine, a greater fraction of the weak acid drug becomes charged (ionized), which prevents reabsorption. Charged
forms are less lipid-soluble and cannot easily cross membranes.
Therefore, weak acids are excreted faster in alkaline urine because they remain in their charged form, making them less likely to
be reabsorbed

Reabsorption depends on PH
 Weak bases ionize more and less reabsorbed in acidic urine.

 Weak acids ionize more and less reabsorbed in alkaline

urine

 Excretion of drugs can be hastened by alkalinization and

acidification of the urine.

 C) Tubular Secretion

• Active transfer of organic acids and bases by two separate non

specific mechanisms which operates in the proximal tubules.

I. Organic acid transport - for penicillin, probenecid,

uric acid, salisylate, sulfinprazone, nitrofurantoin,
methotrixate, drug glucuronide

II. Organic base transport – for thiazides, quinine,

procaineamide, choline, cimetidine, amiloride, etc.
• Inherent both transport process are bidirectional.

Drug interactions:

 Probenicid decrease excretion of nitrofurantoin, penicillin and

methotrixate

 Sulfinprazone inhibit excretion of tolbutamide

 Quinidine decrease renal and biliary clearance of digoxin.

 Kinetics of Elimination

• The knowledge of kinetics of elimination of a drug provides the

basis for, as well as serves to devise rational dosage regimens

and to modify them according to individuals needs.

There fundamental pharmacokinetic parameters

1. Bioavailability (F)

2. Volume of distribution (Vd)

3. Clearance (CL)
• Drug elimination is the sum total of metabolic inactivation
and excretion
Clearance (CL)- the clearance of the drug is the theoretical
volume of plasma from which the drug is completely removed
in a unit time.
• CL = Rate of elimination/Cp
• Where Cp is plasma concentration
• First order kinetics - CL= Dose/AUC
• For majority of drugs the process involved in elimination are

not saturated over the clinically obtained concentrations, they

follow:

First order kinetics

• The rate of elimination is directly proportional to drug

concentration, CL - remain constant

 first order kinetics
Cp

 CL = Rate of elimination/Cp
 Rate of elimination = Vmax (C)
Km + C
Eg; calculate the total clearance rate of a drug with elimination rate

of 500μg/min and plasma concentration of 10μg/ml.

CL = rate of elimination/Cp

CL =500μg/min/10μg/ml = 50ml/min

Interpretation: 50ml of plasma volume is cleared in a minute by

liver, kidneys, or any other organs

• Saturated elimination mechanisms are handled by:

Zero order kinetics:

 The rate of elimination remain constant

 CL decrease with increase in Cp. Eg; ethanol
 Kinetics change from first order to zero order at higher doses
(therapeutic range). Eg; phenytoin, tolbutamide, theophylline,
warfarin
 Increase in AUC leads decrease in CL for zero order kinetics
AUC= Cp
 Zero order kinetics

Cp

time
 Km = the concentration at which velocity would be ½ Vmax

 Vmax = maximum rate of elimination

 CL = Rate of elimination

Cp (AUC)
 Plasma half-Life (t 1/2)

• t1/2 of a drug is the time it takes for one half of the original
amount of a drug in the body to be removed.

• t1/2 = 0.7 x Vd/CL ln2= 0.7

• t1/2 is a derived parameter from two variables Vd and CL

both of which may change independently
• 100mg----50mg----25mg----12.5mg----6.75mg---

t 1/2 t 1/2 t 1/2 t 1/2

 t ½ is not an exact index of drug elimination

 1 t ½ = 50% of the drug is eliminated

 2t ½ = 75% of the drug is eliminated

 3t ½ = 87.5% of the drug is eliminated

 4t ½ = 93.75% of the drug is eliminated

 Nearly complete drug elimination occurs in 4-5 half lives

 For drugs eliminated by first order kinetics t 1/2 remains

constant because Vd and CL do not change with dose

 Zero order kinetics t1/2 increase with dose because CL

progressively decreases as dose is increased

 Pharmacokinetic parameters
 Volume of distribution V = DOSE / Co

 Plasma clearance Cl = Kel .Vd

 Plasma half-life (t1/2) directly from graph

or t1/2 = 0.693 / Kel

 Bioavailability (AUC)x/ (AUC)iv

 Multiple dosing
121

 Usually the amount of drug in the body rises to a

maximum until the rate of elimination becomes equal to
the rate of absorption and then decreases

 If the drug is given at regular intervals the amount

absorbed from each dose will surmount the amounts
remaining previous dose

 On continuous steady administration of a drug, plasma

concentration will rise fast at first then more slowly and reach a
plateau, where:
rate of administration = rate of elimination ie.
steady state is reached.
 Multiple dosing

 Therefore, at steady state:

Dose (Rate of Administration) = clearance x plasma
conc.
Or
If you aim at a target plasma level and you know
the
clearance, you can calculate the dose required.
 Concentration at steady state is dependent on two factors:
 CLEARANCE and DOSE
 Dose can be determined from desired steady
concentration and clearance.
 Dose=Css*Cl
 Steady State concentration
123

 Steady State: the amount of drug administered is

equal to the amount of drug eliminated within one
dosing interval resulting in a plateau or constant
serum drug level
 Drugs with short half-life reach steady state rapidly;
drugs with long half-life take days to weeks to reach
steady state
 Time to Reach Steady State
 The time to reach steady is solely dependent on
half-life
 From a clinical/practical perspective steady state
is reached in 4-5 half-lives

Number of Half-Lives % of steady state achieved

1 50
2 75
3 87.5
4 93.75
5 96.875
 Loading Dose

 A single or a few quickly repeated dose given in the beginning

to attain target concentration rapidly.
 Loading dose = target Cp X Vd/F

 Loading dose is given only by Vd not by CL or t ½

 For example the half-life of lidocaine is 1 to 2 hrs

 Arrhythmias encountered after myocardial infarction

obviously may be life-threatning and one cannot wait 4 to 8
hrs to achieve a therapeutic concentration.
 Maintenance Dose

 The dose of the drug which will be repeated at specified

intervals to maintain a steady state of drug in the body.

 At Cpss, dosing rate = rate of elimination

 If intermittent dose are given, the maintenance dose is

calculated from:

 Maintenance dose = dosing rate X dosing interval

Methods of prolonging the duration
of action of a drug
127

1. Delaying drug absorption

 Reduction in vascularity
 Adrenaline with local anesthetics
 Reduction in the solubility of the drug
 Protamine zinc insulin

 Procaine pencillin

 Implantation of drug pellets in Sc

 Levonorgestrel

 The use of sustained release tablets

 Administration of drug in oily suspension
 Vasopressin tannate suspension
 Methods of prolonging…
128

 Delaying drug metabolism in the liver

 Enzyme inhibition

 Not yet applicable

 Delaying renal excretion of the drug

 Probenecid delays penicillin excretion

 Increasing PPb of the drugs

 Long acting sulphonamides are bound to PP much more
extensively than short acting ones
 129

THANK YOU ALL!!!

2/29/2024