Drug-receptor Interactions Flashcards
Why is a sigmoid curved graph better?
Because:
- Easier to draw by hand
- Represent a wider range of concentrations
What is the dissociation equilibrium constant?
A measure of affinity —> how tightly a ligand binds to its target
What is the difference between full and partial agonists?
Full - have maximal response
Partial - even at high concentration can’t produce full response.
They differ in efficacy - their ability to activate the receptor
What is potency of an agonist?
Expressed as EC50 - the concentration of agonist that causes 50% of maximum response.
A partial agonist can have a higher potency than a full agonist, I.e. have lower EC50
Why don’t we use agonists to classify receptors?
Potency and EC50 are not direct estimates of binding, or off affinity of the drug. Relationship between receptor occupancy and biological effect is complex
Name the 4 ways antagonists act without affecting the receptor of the agonist?
Chemical antagonism
Functional/physiological antagonism
Pharmacokinetic antagonism
Indirect antagonism
What is chemical antagonism?
Rare
Antagonist combines directly with substance being antagonised
E.g. chelating agent EDTA used to treat inorganic lead poisoning
What is functional or physiological antagonism?
Antagonist produces an opposite biological effect to the substance being antagonised e.g. adrenaline relaxes bronchial smooth muscle. So reduces bronchoconstriction caused by histamine and the leukotrienes
What is pharmacokinetic antagonism
Reduces concentration of active drug at its site if action. E.g. repeated administration of phenobarbitone induces an increase in the activity of hepatic enzymes that inactivate the anticoagulant warfarin. Hence phenobarbitone reduces plasma concentration of warfarin and therefore it’s activity.
What is indirect antagonism?
Interferes with one or more of the cellular processes that link receptor activation to the final response observed. E.g. propranolol acts on beta blockers to block effect of tyramine which releases noradrenaline. Therefore stopping the effect of released tyramine and not acting on its receptors.
What are antagonist mechanisms using receptor macromolecule?
- Direct blockage of the agonist binding site (competitive)
- antagonist binds to agonist binding site (without producing a response)
- prevents agonist from binding (if agonist bound hen antagonist cannot bind)
- binding need to be reversible for it to be truly competitive
E.g. atropine competitively blocks action of Ach on muscarinic receptors
- Not involving the agonist binding site
- antagonist prevents receptor activation by becoming attached to another site in receptor macromolecule (can be overlapping sites)
- both agonist and antagonist can be bound at same time
E.g. hexamethiniun reduces action of synaptically released Ach on autonomic ganglia by blocking the ion channel which is intrinsic to nicotinic receptor.
- non competitive
Describe what happens to a concentration-response curve when antagonist is added?
- because reversible increasing conc will overcome the blocking effect
- curve shifted to the right without any change in slope it maximal response
- because effect of antagonist is to increase the apparent dissociation constant of for the agonist (Ka) in:
Ka = (1+(B/KB))
How can the extent of shift be expressed?
Dose Ratio (defined as factor by which the agonist concentration must be increased to restore a given response in the presence of the antagonist)
Measure distance between shift as parallel shift
Measuring dose ratio as a function of antagonist concentration enables us to measure affinity of the antagonist for the receptors
Affinity of pure competitive antagonist depends only on structure of receptor and antagonist - useful in clarifying receptors.
Drugs with some selectivity for different receptor types are the basis of many therapeutic advances
What is the Shild equation?
R-1 = (b)/kB
- plot of r-1 against B should give KB as revircproal of slope
- more commonly log(r-1) against Log B and log Kb obtained from intercept on x axis.
How do partial agonists act?
Behave as antagonist to full agonist
N.b antagonist have very low efficacy
How do you measure therapeutic index?
Maximum tolerated dose/minimum minimum effective dose
Equation for receptor occupancy?
P = A/Ka + A
