Pharmacogenetics: CYP variants, drug protein binding, free fraction

CYP2D6 converts codeine to morphine. Phenotypes: poor metabolizer (codeine doesn't work), intermediate, normal, ultra-rapid metabolizer (UM, 1-7%; up to 30% in some Mediterranean groups). UMs convert codeine to morphine MUCH faster — documented infant deaths from breastfeeding mothers who were UMs. FDA black-box on codeine in children <12 and breastfeeding mothers reflects this. Tramadol has the same problem (CYP2D6 → O-desmethyltramadol).

CYP3A4 metabolizes ~50% of commonly used drugs — including fentanyl, alfentanil, midazolam, lidocaine, methadone, most statins. Inducers (rifampin, phenytoin, carbamazepine, St. John's wort) lower drug levels — fentanyl wears off faster. Inhibitors (azoles, macrolides, grapefruit juice, ritonavir) raise levels — midazolam given to a patient on diltiazem stays around much longer. Always ask about HIV meds, antifungals, and grapefruit.

Acidic + neutral drugs (NSAIDs, warfarin, phenytoin, propofol) bind to albumin. Basic drugs (lidocaine, beta-blockers, opioids) bind to α1-acid glycoprotein. ONLY THE FREE FRACTION IS ACTIVE — crosses membranes, reaches receptors, gets metabolized. Free fraction is usually small (warfarin is 99% bound, 1% free). When free fraction surprises you: hypoalbuminemia (cirrhosis, nephrotic syndrome, burns) → more free phenytoin → toxicity at 'therapeutic' total levels. Drug displacement: warfarin + sulfa, or warfarin + NSAIDs → more free warfarin → bleeding even at therapeutic INR.

Vd is the apparent volume the drug distributes into. Lipophilic drugs (fentanyl, propofol) have HUGE Vd — hide in fat, slowly redistribute back. Hydrophilic drugs (rocuronium, vasopressors) have small Vd (~10-20 L). High Vd drives a relatively large loading bolus. It also drives 'context-sensitive half-time' — the time to drop 50% of plasma drug after stopping an infusion — which gets LONGER for high-Vd drugs as infusion duration increases.