Flashcards in PD Deck (10):
tendency of a drug to bind to a specific receptor (the concentration at which half the available receptors are bound) – which is Kd for agonists and Ki¬ for antagonists
the ability of a drug to produce a response as a result of the receptor being occupied
Agonist activity is referenced against themselves. Antagonists are said to have zero efficacy (they reduce the number of receptors available for agonists to bind). Partial agonists are referenced against the maximal efficacy of a named agonist.
dose required to produce the desired biological response (the smallest dose required the higher the potency)
• Agonist potency is the drug concentration at which 50% of the maximal response is obtained. This is the EC50. Because the response downstream of the receptor isn’t necessarily linear (there is redundancy in the receptors), it doesn’t always equal Kd.
• Antagonist potency is the concentration of drug that reduces maximal activation of a receptor by 50% (can only really be measured in vitro). You can get both competitive and non-competitive antagonism.
Describe non-competitive and competitive antagonism and how potency changes
Competitive antagonism – antagonist competes with agonist for receptor sites – can reduce effect by increasing agonist concentration. EC50 changes but maximal effect stays the same
Non-competitive – maximal effect is depressed proportionally to the degree of antagonist present, EC50 stays the same
• Can bind at the site for agonist binding (irreversibly or unbinding very slowly)
• Or bind allosterically
Describe how drug interactions affect the absorption of a drug
Agents affecting gut motility, or absorption from the gut.
Metoclopramide (acts as an antiemetic and gastro pro-kinetic) increases rate of gastric emptying and uptake from the small bowel
Describe how drug interactions affect the distribution of a drug
Competition between drugs at protein binding sites (usually offset by increased clearance)
Phenytoin – non-linear pharmacokinetics and a narrow therapeutic window can lead to serious toxicity
drugs with greater Vd have lower plasma concs as they spread further throughout the body and are therefore less likely to interact with other drugs
Describe how drug interactions affect the metabolism of a drug
Induction of CYP450 enzymes (increases transcription or translation, or slows degradation), leading to more rapid elimination and higher clearance. This usually takes 1-2 weeks.
- don’t withdraw the inducer without altering the dose of drugs that will now be metabolised slower – you risk toxicity
- may increase production of a toxic metabolite
Inhibition of CYP450 enzymes – this increases the half-life. Usually sets in over a few days.
Inducers – Pheytoin, Carbamazepine, Barbituates, Rifampicin, Alcohol (chronic use), Sulphonylureas, St John’s Wort
Inhibiters – Omeprazole, Disulfiram, Erythromycin, Valproate, Isoniazid, Cimetidine, Ciprofloxacin, Ethanol, Sulphonamides, Grapefruit Juice, Cranberry Juice
Describe how drug interactions affect the excretion of a drug
Inhibition of tubular secretion
Changes in urine flow/pH
Describe how drug disease interaction occur
• Renal disease –
Reduced GFR increased time to clear and so can stay in system longer and build up.
GFR can be further reduced by NSAIDs/ACEi so drugs are nephrotoxic.
Damaged kidneys can cause electrolyte disturbances interacting with drugs.
• Hepatic disease –
Reduced CYP450 activity so drugs have longer half-lives and accumulate leading to adverse effects.
Hypoalbuminaemia so higher free conc of drugs.
• Cardiac disease –
Heart failure leading to oedema allows drugs to accumulate in gut so it’s not distributed or accumulate elsewhere causing excessive effects.
Reduced hepatic and renal blood flow leads to problems with renal and hepatic disease discussed above.