Pharmacodynamics: Drug-Receptor
Interactions
Drug Receptors
Receptor:
Synonym: Target molecule
Macromolecule (or macromolecular complex)
which binds agonists with high structural selectivity
with the consequence that a characteristic effect occurs
Or site of drug action responsible for the pharmacological
effect
The component of the organism with which the chemical
agent was presumed to interact.
Receptors can be any functional macromelecular
component of the organism
Drug Binding Sites
(Receptors and Acceptors)
Binding Site
Specific and Saturable
Receptor
Binding Site + Effect
Acceptor
Binding Site + no Effect
Types of Binding
Reversible
ionic attraction, hydrogen bonds, Van der
Waals interactions
Slowly reversible/irreversible
high affinity non-covalent binding,
covalent binding
Specific receptors and Non-specific drug
targets
Non-specific drug targets
- Water
- H+ ion, HO- ion
- Metal ions as relatively specific
receptors
Specific Receptors (drug receptors)
- Enzymes
- Membrane sterols / proteins
- DNA
Differences between
Specific Receptors and Non-specific Drug
Targets
Specific receptors
are stereoselective
can be selectively
blocked by antagonist
drugs
are occupied at
nanomolar or
micromolar
concentrations
Ligands (Receptor binding molecules)
Drugs or endogenous compounds binding to
receptors are described as Ligands.
Ligands are classified into 2 groups
Agonist:
Agonist molecule that binds to receptor and produces
similar response to that of the endogenous ligand.
Partial agonist: agonist that produce partial effect.
Antagonist:
Antagonist molecule that binds to a receptor, but
does not cause a response.
Competitive: reversible or weak binding
Non-competitive: non-reversible or strong binding
Ligands (Agonist and
Antagonist)
Affinity and Efficacy
Affinity: the attraction of the drug for
the receptor.
high affinity: low concentrations bind
low affinity: high concentrations bind
no affinity: does not bind
Efficacy: the intrinsic activity
Max. effect
efficacy = 1
Min. effect
efficacy = 0
Agonist and Antagonist
Agonist
Partial agonist
Antagonist
Competitive
Non-competitive
Affinity
yes
yes
Efficacy
high
low
low-medium
high
no
no
Classifications of Drug Receptors
Drug classification can be based on several
things
Classified by
General characteristics
Location
Consequence of interaction
Secondary chemical messenger involved in the
transduction pathway
Classifications of Drug Receptors
Based on General characteristics
Based on general characteristics, drug receptors
can be classified into 4 groups
Classical Receptors
Or Physiological receptors
Uptake carriers or Transport proteins
Ion channels
Enzymes
Classifications of Drug Receptors
Based on Location
Example 1 Receptors of the nervous system
Post-synaptic receptor: In postsynaptic cells, neurotransmitter receptors
receive signals that trigger an electrical signal, by regulating the activity of
ion channels.
Pre-synaptic receptor: On presynaptic cells the binding of a neurotransmitter
to a specific receptor provides feedback and mediates excessive
neurotransmitter release.
Example 2 Receptors that are on the surface and inside the cells
Cell-surface receptor
Ion-channel-linked receptors
G-protein-linked receptors
Enzyme-linked receptors
Intracellular receptor
Classifications of Drug Receptors
Based on Consequence of
Interaction
Stimulation or Inhibition
Of an enzyme
Of an organ activity
Stimulate or Inhibit heart contractility
Contraction or Relaxation of muscle
Classifications of Drug Receptors
Based on Secondary Messengers
Secondary messengers of the signal transduction
processes are in different kinds and can be used
to classify the receptors connected to them.
Drug
Receptors
Cyclic AMP
Cyclic GMP
Phosphoinositol
Arachidonic acid
Calcium ion
Effector or Target
Drug-Receptor Interaction
Structure specific
Drug + Receptor
Stereo-selective
Lock and key mechanism
Affinity
Drug-receptor complex
Transduction
pathways
Response
Efficacy
Potency
Receptor-mediated Mechanism of Action
drugs
beneficial effect
caused by the drugs ability to interact
with the receptor and change in
physiological
or biochemical
or pathological processes
Then termed mechanism of drug action
Intermediate Messengers or Second
Messengers
Activation of a receptor may initiate a series of
events mediated by intermediate messengers.
Drug
Binding Site
Signal transduction
intermediate
messengers
e.g. cyclic AMP
Effect
Mechanism of action
Classical Receptors
Drug actions on Classical receptors are based on
types of Ligands
Agonist
Antagonist
->
Stimulation
->
Inhibition
Neurotransmitter
norepinephrine (NE)
Hormones
angiotensin
Local hormones
histamine
receptor
receptor
receptor
action
action
action
Mechanism of action
Uptake Carriers
Uptake carriers or Transport
proteins can have a role in
regulation of drug action
Example: Norepinephrine (NE)
action
Drug
Uptake inactivation
Nerve Cell
NE
X
NE release from nerve
More NE
Receptors
Increase NE action
Neurotransmission
Uptake carrier
Reuptake
Rapid inactivation
Decrease NE action
Mechanism of action
Ion Channels
drug - ion channel
enhances /inhibits action
e.g.
Ca++ channel blocker (verapamil)
Mechanism of action
Enzymes
drug-enzyme interaction
inhibition of enzyme activity
Neostigmine inhibits acetyl cholinesterase
increased acetyl choline
Aspirin inhibits cyclooxygenase
decreased prostaglandins
Inhibition of Enzyme Activity Neostigmine
Mechanism of of action:
anti-cholinesterase
Inhibits activity of acetylcholinesterase
Effects: increase
Acetylcholine (ACh) levels
in the synapse.
Clinical use: treatment of
myasthenia gravis
Action of Neostigmine
Somatic Nervous
System (voluntary)
ACh
N
N
AChE
Skeletal
Muscle
N
Neostigmine
acetate
Nicotinic ACh
receptor
choline
Inhibition of Enzyme Activity
Aspirin
Mechanism of action: cyclo-oxygenase inhibitor
Pharmacological effects: prostaglandin release
pain and fever
Clinical use: treatment of pain and fever
Inflammation
and COX
Infection
Arachidonic Acid
(released from cell membrane)
Cyclooxygenase (COX)
Prostaglandins
Pain
Fever
Action of Aspirin
Infection
Arachidonic Acid (released from cell membrane)
Cyclooxygenase
Prostaglandins
Pain
Fever
Aspirin
