Pharmacology — pharmacokinetics, CYP interactions, toxicology
**Pharmacokinetics (ADME):** • **Absorption** — bioavailability F; first-pass hepatic metabolism for oral. • **Distribution** — Vd. Vd = total dose / plasma conc. • **Metabolism** — phase I (oxidation/reduction/hydrolysis; CYPs), phase II (conjugation: glucuronidation, sulfation). • **Excretion** — renal (↓ in CKD, adjust digoxin, aminoglycosides, vancomycin), hepatic.
**Half-life (t½) = 0.693 × Vd / CL.** 5 half-lives to reach steady state or for >96% elimination.
**Pharmacodynamics:** agonist (full/partial), antagonist (competitive — surmountable, shifts EC50 right; non-competitive — unsurmountable, ↓Emax). Therapeutic index TI = TD50/ED50.
**CYP450 (clinically tested):** • **Inducers** — rifampin, phenytoin, carbamazepine, phenobarbital, St. John's Wort, chronic EtOH, smoking (CYP1A2). Lower drug levels — e.g., OCP failure, INR drop on warfarin. • **Inhibitors** — azole antifungals, macrolides (not azithromycin), grapefruit, cimetidine, amiodarone, ritonavir, fluoxetine/paroxetine. Higher drug levels.
**Classic toxidromes / antidotes:** • Acetaminophen — N-acetylcysteine; Rumack-Matthew nomogram. • Opioids — naloxone. • Benzos — flumazenil (caution, can precipitate seizure). • Organophosphate — atropine + pralidoxime. • TCA — sodium bicarbonate (widened QRS). • β-blocker — glucagon + calcium + insulin-glucose. • Digoxin — digoxin-specific Fab. • Iron — deferoxamine. • Lead — dimercaprol/EDTA/succimer. • Methanol/ethylene glycol — fomepizole + dialysis. • CO — 100% O₂ (hyperbaric if severe/pregnancy).
**FDA pregnancy categories** (replaced 2015 by PLLR — narrative risk summary on labels). Teratogens: ACEi (renal), warfarin (fetal warfarin syndrome), isotretinoin, valproate (NTD), lithium (Ebstein), methotrexate, thalidomide, tetracyclines.