🧪 absorption & bioavailability
−- Bioavailability (f) — fraction of dose reaching systemic circulation
- IV administration: f = 1 (100%)
- Oral drugs: reduced by first‑pass hepatic extraction
- First‑pass effect
- Portal blood → liver → extensive metabolism before systemic distribution
- High‑extraction drugs: lidocaine (IV), nitroglycerin (sublingual) avoid first‑pass
- Redistribution
- Lipophilic drugs → fat stores; prolongs effect after repeated doses
- Initial CNS effect duration often reflects redistribution, not half‑life
- 💡 IV bolus AUC is the reference for bioavailability; oral AUC is compared to IV.
⚗️ biotransformation
−- Goal — increase water solubility for renal excretion
- Phase I (functionalization): oxidation, reduction, hydrolysis
- Microsomal (CYP450): require O₂ & NADPH; many isozymes
- Nonmicrosomal: esterases, amidases, MAO, alcohol dehydrogenase
- Phase II (conjugation): glucuronidation, acetylation, GSH conjugation
- Glucuronidation: inducible; enterohepatic recirculation possible
- Acetylation: genetic polymorphism (slow acetylators → higher risk for hydralazine/INH SLE)
- GSH depletion → acetaminophen hepatotoxicity
- ⚠️ CYP3A4 & 2D6 are responsible for most drug interactions; inducers (rifampin) & inhibitors (azole antifungals, grapefruit) alter clearance.
| isozyme | substrate example | inducer | inhibitor |
|---|---|---|---|
| 1A2 | theophylline, acetaminophen | smoking, cruciferous veg | quinolones, fluvoxamine |
| 2C9 | warfarin, NSAIDs | rifampin, St. John's wort | azole antifungals, amiodarone |
| 2C19 | PPIs, clopidogrel (prodrug) | rifampin, carbamazepine | omeprazole, cimetidine |
| 2D6 | β‑blockers, SSRIs | rifampin | amiodarone, haloperidol |
| 3A4 | statins, steroids, warfarin | rifampin, phenytoin | macrolides, grapefruit, ritonavir |
🧬 elimination & clearance
−- First‑order kinetics — elimination rate ∝ plasma concentration
- t½ constant; most drugs follow this pattern
- Renal elimination = GFR + active secretion − reabsorption
- Filtration: free drug only (protein‑bound not filtered)
- Clearance (Cl) = volume of blood cleared per unit time
- If no secretion/reabsorption and no binding: Cl = GFR (~120 mL/min)
- Half‑life t½ = 0.7 × Vd / Cl
- 🧠 Inulin clearance = gold standard for GFR (neither reabsorbed nor secreted).
📈 steady‑state principles
−- Plateau principle — time to steady state depends only on t½ (not dose or interval)
- 50% steady state: 1 × t½
- 90%: 3.3 × t½
- 95%: 4–5 × t½
- Mathematical steady state: >7 × t½
- Infusion — higher rate → higher Cpss, but same time to plateau
- Loading dose — rapidly achieve effective Cp
- LD = (Vd × Cp) / f
- If dosing every half‑life and target Cp = Cpss, LD = 2 × maintenance dose
- ⚠️ Clinical steady state is accepted at 4–5 half‑lives, though mathematical steady state takes longer.
rate in = rate out
→
Cpss constant
🧮 key pharmacokinetic equations
−
single dose
- Vd = D / C⁰
- t½ = 0.7 × Vd / Cl
multiple / infusion
- k₀ (infusion rate) = Cl × Css
- LD = (Vd × Cp) / f
- MD = (Cl × Css × τ) / f
- 📐 Maintenance dose = (Css × Cl × τ) / f ; loading dose = (Vd × Cp) / f
🩺 clinical pearls & exam traps
−- Active metabolites — diazepam → nordiazepam (long‑acting sedative)
- Prodrugs — clopidogrel (CYP2C19); omeprazole reduces its activation
- Low therapeutic index — warfarin, theophylline; monitor levels
- Slow acetylators — higher risk of drug‑induced SLE (hydralazine > procainamide > INH)
- Gray baby syndrome — chloramphenicol due to immature glucuronidation
- Ethanol metabolism — genetic polymorphism in dehydrogenases
- ⚠️ Classic CYP inducers: rifampin, carbamazepine, St. John's wort. Classic inhibitors: azole antifungals, macrolides, grapefruit, ritonavir.