Pharmacology Pharmacodynamic Mechanisms 3 ā Questions and Answers
Question 1: The therapeutic index (TI) is calculated as:
- ED50 / LD50
- LD50 / ED50 (Correct answer)
- Emax / EC50
- EC50 / Emax
Correct answer: LD50 / ED50
TI = LD50 / ED50; a larger ratio indicates a wider margin of safety between effective and lethal doses.
Question 2: Allosteric modulators differ from orthosteric ligands because they:
- Always activate the receptor maximally
- Bind at a site distinct from the endogenous ligand binding site (Correct answer)
- Competitively block endogenous agonist access
- Only function when the receptor is in the inactive state
Correct answer: Bind at a site distinct from the endogenous ligand binding site
Allosteric modulators bind to a topographically distinct site and alter receptor conformation to enhance or inhibit endogenous agonist activity.
Question 3: Which mechanism best explains the action of aspirin as an irreversible inhibitor of cyclooxygenase?
- Competitive active-site blockade
- Covalent acetylation of a serine residue (Correct answer)
- Allosteric distortion of the enzyme
- Chelation of a cofactor metal ion
Correct answer: Covalent acetylation of a serine residue
Aspirin covalently acetylates Ser530 of COX-1 and Ser516 of COX-2, permanently inactivating the enzyme for its lifespan.
Question 4: A patient's response to a drug increases rather than decreases with repeated administration. This is best described as:
- Tolerance
- Sensitization (reverse tolerance) (Correct answer)
- Tachyphylaxis
- Desensitization
Correct answer: Sensitization (reverse tolerance)
Sensitization refers to an augmented response following repeated drug exposure, seen with stimulants like cocaine and amphetamines.
Question 5: Which receptor family primarily signals through G-proteināmediated second messenger cascades?
- Ligand-gated ion channels
- Receptor tyrosine kinases
- G-proteinācoupled receptors (GPCRs) (Correct answer)
- Nuclear hormone receptors
Correct answer: G-proteinācoupled receptors (GPCRs)
GPCRs (7-TM receptors) couple to heterotrimeric G-proteins that modulate intracellular effectors such as adenylyl cyclase and phospholipase C.
Question 6: The concept of 'biased agonism' (functional selectivity) refers to:
- Different drugs acting on different receptor subtypes
- A single ligand preferentially activating one downstream pathway over another at the same receptor (Correct answer)
- Tissue-specific drug metabolism altering effective concentration
- A drug selectively blocking only one receptor subtype
Correct answer: A single ligand preferentially activating one downstream pathway over another at the same receptor
Biased agonists stabilize distinct receptor conformations that preferentially couple to G-protein vs. beta-arrestin pathways, enabling therapeutic selectivity.
Question 7: The Hill coefficient (n) greater than 1 in a dose-response curve indicates:
- Inverse agonism at high concentrations
- Negative cooperativity among binding sites
- Positive cooperativity or multiple binding sites (Correct answer)
- Reduced drug bioavailability
Correct answer: Positive cooperativity or multiple binding sites
A Hill coefficient >1 reflects cooperativity where binding of one ligand increases affinity at adjacent sites, steepening the dose-response curve.
Pharmacology Pharmacodynamic Mechanisms 3
The therapeutic index (TI) is calculated as: