Clinical pharmacology, pharmacokinetics and therapeutic drug monitoring
This domain tests quantitative reasoning: can you predict what a dose will do in this patient, and interpret a measured concentration correctly?
Core pharmacokinetics
Volume of distribution (Vd), clearance (CL), half-life (t½ ≈ 0.693 × Vd/CL), bioavailability (F). Loading dose = (Vd × target concentration)/F; maintenance dose = (CL × steady-state concentration)/F. Steady state is reached after about 4–5 half-lives. First-pass metabolism lowers oral bioavailability; protein binding determines the free fraction, so hypoalbuminaemia raises free phenytoin and free valproate without changing the total level.
Special populations
Cockcroft-Gault for drug dosing, CKD-EPI for classification; augmented renal clearance in sepsis and burns can under-dose beta-lactams; obesity needs adjusted body weight for aminoglycosides; continuous renal replacement therapy clears small, poorly protein-bound drugs and needs higher-than-renal-failure doses.
Therapeutic drug monitoring
Indications: narrow therapeutic index, non-linear kinetics, toxicity overlapping with disease, organ failure, suspected non-adherence. Always interpret with sampling time, dose history, steady-state status and co-medication. Examples: vancomycin AUC/MIC 400–600 (trough sampling alone is a surrogate), once-daily aminoglycosides with a single level and nomogram, voriconazole trough 1–5.5 mg/L, tacrolimus trough 5–15 ng/mL by transplant protocol, phenytoin total 10–20 mg/L with free 1–2 mg/L, lithium 0.6–1.0 mmol/L.
Interactions and pharmacogenetics
CYP3A4 and P-gp interactions dominate in hospital practice; enzyme inhibition acts within days, induction over 1–2 weeks and persists after withdrawal. Thiopurine dosing depends on TPMT/NUDT15 status; abacavir requires HLA-B*57:01 screening.
Worked example
A 70 kg patient needs an oral phenytoin loading dose targeting 15 mg/L. Vd ≈ 0.65 L/kg → 45.5 L; F ≈ 0.9. Dose = (45.5 × 15)/0.9 ≈ 758 mg → give 750 mg in divided doses with monitoring. Do not apply linear maintenance calculations afterwards: phenytoin follows Michaelis-Menten kinetics, so a small dose increase can produce a large level increase.
Traps
- Interpreting a level without the sampling time.
- Using total rather than free concentrations in hypoalbuminaemia or uraemia.
- Applying linear dose scaling to phenytoin.
- Assuming renal failure always means lower doses - CRRT often needs higher ones.