Clinical Pharmacology and Therapeutics
Core concepts
Pharmacokinetics: absorption, distribution (volume of distribution), metabolism (phase I cytochrome P450, phase II conjugation) and excretion. First-order kinetics eliminates a constant fraction per unit time and reaches steady state after 4–5 half-lives; zero-order kinetics (phenytoin, ethanol, high-dose salicylate, theophylline) eliminates a constant amount, so small dose increments cause disproportionate rises. Loading dose = volume of distribution × target concentration ÷ bioavailability; maintenance dose depends on clearance. Enzyme inducers (rifampicin, carbamazepine, phenytoin, St John's wort, smoking) lower drug levels; inhibitors (macrolides, azoles, grapefruit, ritonavir, cimetidine) raise them. Therapeutic drug monitoring is useful for digoxin, lithium, phenytoin, vancomycin, gentamicin, ciclosporin and theophylline. Adverse reactions: type A (dose-related, predictable) versus type B (idiosyncratic, such as anaphylaxis or Stevens-Johnson syndrome). Antidotes: paracetamol - acetylcysteine; opioid - naloxone; benzodiazepine - flumazenil; warfarin - vitamin K and prothrombin complex; heparin - protamine; digoxin - specific antibody; methanol and ethylene glycol - fomepizole; iron - desferrioxamine; organophosphate - atropine plus pralidoxime; methotrexate - folinic acid; cyanide - hydroxocobalamin.
Traps
Forgetting that rifampicin reduces oral contraceptive and antiretroviral efficacy. Confusing renally cleared drugs (gentamicin, digoxin, metformin, DOACs) with hepatically cleared ones. Missing serotonin syndrome with SSRIs, tramadol, triptans, linezolid or MAOIs. Using flumazenil in a mixed overdose, which risks seizures.
Rule of thumb
A drug reaches steady state in 4–5 half-lives and takes the same time to clear after stopping. For a drug with a 24-hour half-life, that is roughly a week.