PH1.1-13 | General Pharmacology Foundations — Graded Quiz

Correct. This is the classic irreversibility trap. Aspirin's plasma half-life is ~15–20 minutes, but since it irreversibly acetylates platelet COX-1 and platelets are anucleate (cannot synthesise new protein), the antiplatelet effect persists for the platelet's entire lifespan (~7–10 days). Standard surgical guidance is to stop aspirin 7–10 days before elective procedures.

Aspirin's antiplatelet effect outlasts the drug's plasma half-life (~15–20 min) because COX-1 inhibition is irreversible. Anucleate platelets cannot synthesise new protein. Platelet turnover takes 7–10 days to fully replace the affected population.

Incorrect. A drug's duration of action is NOT simply its plasma half-life. Aspirin irreversibly inhibits COX-1 — platelets, being anucleate, cannot synthesise new enzyme. The effect lasts the platelet's lifespan (7–10 days), not the drug's 15-minute plasma t½.

Correct. Efficacy (Emax) determines the maximum achievable response. For severe bronchospasm requiring maximal bronchodilation, Drug X's higher efficacy is clinically decisive — it can achieve a greater maximal bronchodilation regardless of the dose required. Potency determines the dose needed, not the ceiling effect.

Efficacy (Emax) is the maximum response a drug can produce. Potency (EC50) is the concentration needed for half-maximal response. For achieving maximal effect, efficacy is the critical determinant — not potency.

Incorrect. Potency (EC50) tells you the dose needed for half-maximal effect — it does not set the ceiling. Efficacy (Emax) sets the maximum possible response. When maximum effect is needed, efficacy is the key criterion.

Correct. Hepatic cirrhosis reduces functional hepatocyte mass, impairing Phase II conjugation (glucuronidation). The drug accumulates as biotransformation slows, plasma half-life increases, and toxic levels may be reached at standard doses. Dose reduction and careful monitoring are required.

Hepatic cirrhosis reduces the functional hepatocyte mass available for Phase II conjugation enzymes (UDP-glucuronosyltransferases). This slows biotransformation, prolongs half-life, and raises plasma drug levels — requiring dose reduction.

Incorrect. Phase II conjugation (glucuronidation) is a hepatic process dependent on functional hepatocytes. Cirrhosis impairs this conjugation, so the parent drug accumulates. The kidneys do not perform glucuronidation and cannot compensate.

Correct. Bioequivalent generics have met regulatory PK standards (AUC and Cmax within 80–125% of the reference). Using generic (INN) names avoids brand duplication errors, supports cost-effective prescribing, and is the basis of the WHO Essential Medicines concept — core principles of rational drug use.

Rational drug use and EBM support generic prescribing: bioequivalent generics have demonstrated PK equivalence, use the INN (preventing brand-name confusion), reduce cost (improving access), and the WHO Model List of Essential Medicines is entirely generic-name based.

Incorrect. Generics are not chemically superior — they contain the same active molecule. Branded drugs do not universally have higher bioavailability. Generic substitution is appropriate for all bioequivalent drugs — the decision is based on regulatory approval, not therapeutic index category.

Correct. Pregnancy increases renal GFR by approximately 50%, increasing clearance of drugs like TMP-SMX that are renally excreted. Near term, sulfonamides displace bilirubin from albumin in the neonate, increasing free bilirubin and the risk of kernicterus. TMP is also a folate antagonist — particularly hazardous in the first trimester.

Pregnancy increases renal blood flow and GFR by ~50%, increasing clearance of renally-excreted drugs. TMP-SMX near term competes with bilirubin for albumin binding → neonatal hyperbilirubinaemia → kernicterus risk, and trimethoprim is a folate antagonist (teratogenic risk in first trimester; neural tube defects).

Incorrect. Pregnancy INCREASES (not reduces) GFR by ~50%, increasing clearance of many drugs. Sulfonamides near term cause kernicterus risk by bilirubin displacement — not cardiac arrhythmia or nephrotoxicity. This is a clinically critical distinction.

Correct. Fluconazole potently inhibits CYP2C9 (and CYP2C19, CYP3A4). Since phenytoin is primarily metabolised by CYP2C9, inhibition dramatically reduces its clearance, causing plasma level accumulation and phenytoin toxicity (nystagmus, diplopia, ataxia, encephalopathy). This interaction also works bidirectionally — phenytoin induces CYP3A4, reducing fluconazole efficacy.

Phenytoin is primarily metabolised by CYP2C9 (and CYP2C19). Fluconazole is a potent CYP2C9 inhibitor. Inhibition reduces phenytoin clearance, raising plasma levels into the toxic range (nystagmus, ataxia, confusion). This is also a bidirectional interaction — phenytoin induces CYP3A4, reducing fluconazole levels.

Incorrect. Fluconazole is a CYP2C9 INHIBITOR, not inducer. Inhibition of CYP2C9 reduces phenytoin metabolism, leading to drug accumulation and toxicity — not reduced levels. Additionally, phenytoin induces CYP3A4, which reduces fluconazole levels.

Correct. Simvastatin is highly dependent on CYP3A4 for first-pass and systemic clearance. Erythromycin inhibits CYP3A4, reducing simvastatin metabolism and causing accumulation. Elevated simvastatin levels cause dose-dependent myopathy, which can progress to rhabdomyolysis and acute kidney injury if not recognised.

Simvastatin is extensively metabolised by CYP3A4 to inactive metabolites. CYP3A4 inhibitors (erythromycin, clarithromycin, ketoconazole, grapefruit juice) increase simvastatin plasma levels, raising the risk of myopathy and rhabdomyolysis — a well-documented class hazard.

Incorrect. The interaction is pharmacokinetic — CYP3A4-mediated. Erythromycin inhibits the CYP3A4 enzyme that metabolises simvastatin, causing drug accumulation. Protein displacement rarely causes clinically significant interactions of this magnitude.

Correct. EBM, as formalised by Sackett and colleagues, integrates three elements: best available external evidence, clinical expertise, and patient values/preferences. The evidence hierarchy acknowledges that RCTs are the gold standard for efficacy, but observational studies, registries, and expert consensus remain valid when RCT data are absent, impractical, or unethical to obtain.

EBM does NOT mean RCT-only. The hierarchy of evidence prioritises RCTs and systematic reviews for efficacy, but observational data, cohort studies, case-control studies, and expert consensus all have roles — especially for rare harms, long-term outcomes, and conditions where RCTs are impractical or unethical. EBM also mandates integration of clinical expertise and patient values.

Incorrect. EBM is NOT limited to RCT evidence. It integrates the best available evidence — which may include observational studies when RCTs are impossible (e.g., rare diseases, long-term outcomes, surgical interventions). Clinical expertise is also a core pillar, not a bias source.

Correct. TI = TD50/ED50 — the ratio of the dose toxic in 50% of subjects to the dose effective in 50% of subjects. A high TI (e.g., penicillin TI ≈ 1000) provides a wide safety margin. A narrow TI (digoxin TI ≈ 2, lithium TI ≈ 2–3) means there is a small margin between therapeutic and toxic levels, necessitating plasma level monitoring and patient-specific dosing.

Therapeutic index (TI) = TD50/ED50. A narrow TI (e.g., digoxin, lithium, warfarin, phenytoin, aminoglycosides) means the toxic dose is only slightly above the therapeutic dose, requiring plasma level monitoring and precise dosing.

Incorrect. TI = TD50/ED50. It is NOT bioavailability/t½. A NARROW TI (not wide) requires tighter monitoring. A low TI means the drug is LESS safe — the toxic dose is close to the effective dose.

Correct. Beta-lactam antibiotics (e.g., piperacillin) inhibit cell-wall synthesis, and aminoglycosides (e.g., gentamicin) inhibit protein synthesis — different targets, complementary bactericidal mechanisms. This combination produces true pharmacodynamic synergism (greater kill than the sum of individual effects). Toxicity profiles are largely distinct (allergic vs nephrotoxic/ototoxic), making this more acceptable than combining two drugs with additive toxicity.

Rational drug combinations exploit complementary mechanisms to achieve synergistic therapeutic effects while minimising overlapping toxicity. Beta-lactam + aminoglycoside is the classic synergistic antibiotic combination. Dual ACE inhibitor + ARB in CKD is an example of an IRRATIONAL combination — increased hyperkalaemia and renal failure risk without additional benefit (shown in ONTARGET).

Incorrect. Rational combination therapy requires complementary mechanisms AND non-overlapping toxicity. Combining two drugs with the same mechanism of action (two beta-blockers) adds nothing. Combining two nephrotoxic agents doubles nephrotoxicity risk. Dual ACE inhibitor + ARB in CKD has been shown to INCREASE harm (ONTARGET) without added benefit.