Principals of pharmacology

Question 1

Explain the receptor concept

Answer 1

• Drug receptor = specialised target macromolecule, binds to drug and mediates its pharmacological action
• Receptors: enzymes, nucleic acids or specialised membrane-bound proteins (all form drug receptor complex → biological response)
• Magnitude of response ∝ number of drug-receptor complexes
• Agonist: binds to receptor, produces response, can be drug or endogenous ligand for receptor
• ↑ concentration, ↑ response, until there are no more receptors or is maximal response have been reached
• Affinity = extent/ fraction which a drug binds to receptor at given drug concentration (best fit has highest affinity)
• Efficacy = maximum response possible to achieve
• Partial agonist = produces response but not 100%, even at high doses
• Active receptor state initiates signalling, has structural complementariness with coupling proteins that activate signal pathway (G-proteins/ G protein coupled receptor kinases)
• Antagonists bind to receptor, but no response, competitive antagonists prevent agonist binding so blocks response
• Antagonists possess affinity but no efficacy (some fit, no cellular effect)

Question 2

Agonists vs Antagonists

Answer 2

• Quantitative pharmacology: based on assumption drugs act by entering simple chemical relation with certain receptors, but this is not a concentration related effect as drugs have effect at small levels (high potency)
• Agonist binding is not always ∝ to occupancy (efficacy is important)
• Higher efficacy assumes a full agonist, low efficacy assumes a partial agonist
• Some highly efficacious agonists produce maximal response without binding to all available receptors (‘spare’ receptors)
• Inverse agonists: negative efficacy, drugs inhibit any intrinsic receptor that exist in absence of ligand, changes shape by itself and move to activated state, pushes activated receptor to deactivated states
• Competitive reversible antagonists: compete with agonist for same binding site or binds to overlapping adjacent site
• Irreversible competitive antagonists: compete for same binding site but irreversibly binds (partial agonist can act as competitive antagonist)
• Non-competitive antagonist: binds at different site, prevents effect of agonist without preventing binding, effect cannot be overcome by ↑ agonist
• Allosteric modulators: ligands bind to allosteric site, either ↑ or ↓ action produced by agonist
• Channel blockers: get into ion channel and block from inside, blocks ion passage (enhanced by receptor activation)
• Physiological antagonists: opposite effect on tissues, produce non-selective suppression of response