Drug action and receptors

1. Drug action and receptors Dave Hallsworth, StR2 SMH

2. “Tell me how drugs exert their action on the body.”

3. Simples! A drug is an exogenous agent administered to create a physiological effect dependant on: Physicochemical properties of the drug, Enzyme inhibition, or Receptor interaction

4. Physicochemical properties Manitol – plasma tonicity Antacids – e.g. Sodium citrate Chelating agents – eg. Penicillamine in Wilson’s disease and mercury poisoning.

5. Enzyme inhibition Increase the concentration of substrates and decrease the level of products, e.g. ACEi AChE inhibitors NSAIDs

6. Receptor binding “What is a receptor?” A receptor is a protein molecule which is usually located in the cell membrane and contains a specific ligand binding site. Binding of a ligand initiates a conformation change in the receptor-ligand complex, leading to a physiological action. In broad terms, ligand binding either opens an ion channel or activates a second messenger system. There are also ‘intracellular receptors’ not bound to the membrane. Ligand binding opens a DNA / RNA binding domain and causes changes in gene transcription / translation.

7. When Vivas go bad.... What can you tell me about drug-receptor interactions....?

8. Drug-receptor interaction The two properties of a drug that determine the nature of its interaction with the receptor are it’s: AFFINITY This is how avidly the ligand binds the receptor At equilibrium INTRINSIC ACTIVITY (IA) Refers to the magnitude of effect the drug has when bound and takes a value between 0 and 1 (an inverse agonist may have a value of -1; more later.......)

9. What is an agonist? An agonist has significant receptor affinity and full intrinsic activity (IA=1) i.e. causes a maximal response

10. Dose-response curve Hyperbolic Dose for 50% receptor occupance = Ka or EC50 Log[dose]-response curve Semi-logarithhmic Sigmoidal Allows comparison of drugs How does potency affect the curve? What is it? How does efficacy effect the curve? What is it?

11. Potency Reciprocal of EC50 Increasing potency shifts left Efficacy Analogous to maximal effect

12. What is a partial agonist? A partial agonist has significant receptor affinity, but only partial intrinsic activity. Maximum response not never elicited despite increasing concentration and full receptor occupancy e.g. Buprenorphine acting at the OP3 receptor

13. So a partial agonist always acts as an ‘agonist’? True? NO! Partial agonist alone = yes Partial agonist + low dose full agonist = yes Partial agonist + high dose of full agonist = NO!!

15. What is an inverse agonist? Inverse agonists have a significant receptor affinity and IA, but their effect is OPPOSITE to the endogenous agonist. -1 < IA < 0 Example: atropine, certain benzodiazepines Muscarinic receptors have a constitutive activity. An agonist ‘activates’ the receptor (muscarinic effect). An inverse agonist ‘deactivates’ the receptor (anti-muscarinic effects)

16. What is an inverse agonist?

17. What is an antagonist? Define and classify. Antagonists can be: Chemical, e.g. Dexferrioxamine and iron Pharmacokinetic, e.g. Rifampicin and OCP Pharmacodynamic, occurring at a: Common receptor Irreversible Reversible Competitive Non-competitive Allosteric modulators Different receptor (e.g. physiological antagonism) Common receptor antagonists have significant receptor affinity but an intrinsic activity of zero

18. Competitive reversible antagonism Antagonist competes with same receptor site, but their effect can be overcome by increasing the concentration of agonist e.g. Non-depolarising muscle relaxants, beta-blockers and norad Log[dose] vs response curve is shifted to the right pA2 value = -log[conc] of antagonist required to produce dose ratio of 2

19. Rocuronium is 1/5th as potent as vecuronium but in our daily practice is faster acting. Why? Because it is given in 5x the dose (0.5mg/kg versus 0.1mg/kg; an equipotent dose), therefore there is a higher concentration gradient driving molecules into the NMJ (Roc&Vec have a similar VD) and greater concentration at the synaptic cleft. ‘Bowman’s Principle’

20. Non-competitive reversible antagonists Bind at a different receptor site and cause a conformational change. Action cannot be overcome by increasing [agonist] Example ketamine antagonises glutamate at the NMDAR

21. Allosteric modulators Not all drugs fit the categorisation! Some bind at sites distant to the agonist but still modulate the agonist binding These may have negative or positive effects Example: benzodiazepines are positive allosteric modulators of GABA at the GABAA receptor

22. Irreversible antagonists May bind at the same or distant site but do not dissociate and cannot be overcome by increasing the agonist concentration. Effect is terminated by synthesising a new receptor molecule. Examples Phenoxybenzamine at the alpha-receptor Aspirin at the COX-1 receptor

23. Tachyphylaxis, desensitisation and tolerance They are not addiction! Tachyphylaxis Rapid decrease in response over a short period of time Usually due to depletion of transmitter Ephedrine (indirect sympathomimetic) depletes noradrenaline stores Desensitisation Loss of response over a longer period May be due to change in receptor numbers or modulation of affinity E.g. Loss of myocardial beta-receptors with chronic exposure to adrenaline or dobutamine

24. Tolerance Refers to the phenomenon whereby larger doses of the agonist is required to create the same response. E.g. Chronic opioid use