Session 8

Question 0

Explain what is meant by the terms intrinsic activity, antagonist, functional antagonism, reversible competitive antagonism, irreversible competitive antagonism, non-competitive antagonism

Answer 0

Intrinsic activity - ability to produce an active form of the receptor
Antagonist - when a binding molecule produces no response
Functional antagonism - not antagonising receptor, different mechanism
Reversible competitive antagonism - inhibition is surmountable, can be overcome by addition of agonist, cause a parallel shift to the right of the agonist concentration-response curve (Naloxene vs. Heroin)
Irreversible competitive antagonism - antagonist dissociates slowly or not at all, non surmountable, cause a parallel shift to the right of the agonist concentration-response curve, suppress maximal response at higher concentrations (Phenoxybenzamine in pheochromocytoma)
Non-competitive antagonism - allosteric binding of an antagonist to a receptor (not orthosteric site)

Question 1

Explain what is meant by the terms ligand, affinity, efficacy, agonist, potency, partial agonist

Answer 1

Ligand - any molecule that binds specifically to a receptor site
Affinity - likelihood of a ligand binding to its target
Efficacy - likelihood of activation
Agonist - when a binding molecule produces a response
Potency - a combination of affinity and efficacy, measured by EC50
Partial agonist - some drugs cannot produce a maximal response even with full receptor occupancy

Question 2

Discuss affinity and efficacy in a clinical setting

Answer 2

In asthma the treatment goal is to activate b2-adrenoceptors to relax the airways. However there are b-adrenoceptors elsewhere in the body e.g. b1 in heart increase force and contraction.
Salbutamol is a b2-adrenoagonist. It has a higher affinity for b2-adrenoceptors, so b2 selective efficacy and route of administration (oral spray) limits b1 activation and side effects.
Salmeterol is a longer acting b2-adrenoagonist than salbutamol. It has no selective efficacy, preventing b1 activation and side effects through differences in affinity. Salmeterol has much greater affinity for b2 than b1.

Question 3

Explain the concept of spare receptors

Answer 3

Less than 100% receptor occupancy will give 100% response. Tissues that have more receptors than required to produce a maximum response have spare receptors.
Spare receptors increase sensitivity, allowing for responses at low concentrations of agonist.

Question 4

Discuss the clinical use of partial agonists

Answer 4

Opioids are used for pain relief but can also cause respiratory depression leading to death.
Morphine is a full agonist of the receptor, buprenorphine is a partial agonist with a higher affinity but lower efficacy than morphine. It provides adequate pain control with less respiratory depression.

Question 5

List some mechanisms that may underlie receptor desensitisation

Answer 5

Change in receptor properties (conformational, phosphorylation, binding of inhibitor protein)
Loss of receptors - irreversible/reversible receptor internalisation
Exhaustion of mediators
Increased breakdown of drug

Question 6

Explain the terms homologous and heterologous desensitisation

Answer 6

Homologous - only the signal from the stimulated receptor is reduced, mechanism probably involves a specific effect on one receptor
Heterologous - receptors for other agonists become less effective even when only one receptor has been continually stimulated, mechanisms likely to involve negative feedback on some signalling pathway component common to both receptors