Pharmacology 2a – Mechanisms of Drug action 2
Anil Chopra
1. Briefly explain what you understand by the term 'structure-activity relationship'.
2. Differentiate between the four principal types of drug antagonism. Give one
example of each type of antagonist.
3. Name the four main families of receptors. On what basis are they distinguishable?
4. Describe the different types of receptor-linked transduction mechanisms and give
examples of receptors which utilise each signal transduction pathway.
5. Explain the functional consequences of different signal transduction pathways e.g.
the different time-courses of observed responses.
6. Define 'drug tolerance'. Briefly describe the five different cellular mechanisms
that may account for, or contribute to, this phenomenon.
Drug – receptor interactions:
Antagonists
-
-
affinity but no efficacy
2 types
o Competitive
 Same site as agonist
 Surmountable
 Shift the dose-response curve RIGHT
 Eg. Atropine. Propanolol (beta blocker)
o Irreversible
 Binds tightly or to a different site on the receptor but still
blocks the response to the receptor.
 Insurmountable – cannot be overcome by increasing agonist
concentration.
 E.g. hexamethonium (anti-hypertensive drug)
 Shifts the dose-response curve right and reduces the maximum
response.
Receptor reserve
o Where in some tissues, you don’t need to stimulate 100% of the
receptors to get 100% response. E.g. smooth muscle
o Increases the sensitivity of the tissue.
o Increases the speed of response.
Types of Drug Antagonism
-
-
Receptor blockade:
o This is where the antagonist literally blocks the binding site i.e. has
affinity but no efficacy. Normally they are competitive and
irreversible.
o This can be overcome with high doses of agonist
o Resulting in a parallel shift of the dose depended curve to the right.
Physiological Antagonism
o Bind to different receptors which produce the opposite effects of the
same tissue e.g. Noradrenaline vs. histamine (effect on blood pressure)
NA causes constriction, histamine causes vasodilation.
-
-
Chemical antagonism
o Interaction in solution
o E.g. dimercaprol  binds to heavy metal ions to form a complex
which is easy to excrete. It is used with people who have metal
poisoning (e.g. lead poisoning).
Pharmacokinetic antagonism
o Antagonist reduces the concentration of the active drug at site of
action.
o Decrease absorbtion / increase metabolism / increase excretion
o E.g. barbiturates – enzyme inducers in the liver. Leads to increased
metabolism and therefore reduces the effects of drugs if coadministered.
Drug Tolerance
Gradual reduction in responsiveness to a drug over a period of (days/weeks) with
regular administration. If the decrease occurs quickly  tachyphylaxis.
e.g. benzodiazepines (good at stopping seizures but if given over a period of time, the
anti-seizure effectiveness is lost)
1. Pharmacokinetic Factors
-
Increase rate of metabolism the more you take it.
E.g. barbiturates (liver enzyme inducers) / alcohol.
2. Loss of Receptors
-
By membrane endocytosis, because the cell thinks that the cell is being overstimulation
Receptor “down-regulation”
β – adrenoreceptors.
NB – receptor up-regulation also exists.
3. Change in receptors
-
Receptor desensitisation
o Conformation change of the receptor such that the receptor doesn’t
bring about response any more.
o E.g. Acetylcholine receptors at neuromuscular junction
4. Exhaustion of Mediator Stores
-
Amphetamines (comes into contact with Noradrenaline neurones in the brain
so then Noradrenaline leaks out into the synaptic cleft)
5. Physiological Adaptation
-
-
Bodies homeostatic responses shift response of antagonists e.g. increase in
blood pressure by drugs is cancelled out by bodies homeostatic response by
lowering blood pressure
Can also cause development of tolerance to side effects of drugs.
Receptor Families
4 types based on
 Molecular structure
 Signal transduction systems
Type 1: Ion channel-linked receptors
 Fast responses (m secs)
 nAChR; GABAA
Type 2: G-protein-coupled receptors
 Slower responses (secs)
 1-adrenoceptors (heart)
Type 3: Tyrosine kinase-linked type
 insulin/growth factors (mins)
Type 4: Intracellular steroid type receptors
 steroids/thyroid hormones (hrs)
 regulate DNA transcription
Type 1
Type 2
Type 3
Type 4
Ion-Channel
Linked
Receptors
G-protein
Coupled
Receptor
TyrosineKinase Linked
Receptors
Receptors
Linked to Gene
Transcription
(nuclear
receptors)
Location
Membrane
Membrane
Intracellular
Effector
Channel
Enzyme
Gene transcription
Coupling
Direct
Membrane
Enzyme or
channel
G-protein
Direct or Indirect
Via DNA
Timescale
M secs
Secs
Hours
Structure
Many different
sub-units,
generally 4-5
forming a
single protein
A single protein
with no subunit.
Has 7
transmembrane
α-helices as the
binding domain
with an intracellular G-protein
coupling domain
Examples
Nicotinic ACh
GABAA
Muscarinic ACh
Adrenoceptors
Mins
A single α-helix
which passes
through the
membrane. The
catalytic domain
contains the
tyrosine kinase
which
phosphorylates
tyrosine
Insulin Receptor
Cytokine
Receptors
Close to nucleus
and causes
changes in DNA
transcription. Has a
binding domain and
a DNA-bindning
domain (“zinc
fingers”)
Steroid receptors
Thyroid Hormone
receptors