Clinical Pharmacology and Therapeutics
Pharmacokinetics
For first-order drugs a constant fraction is eliminated per unit time, so half-life determines time to steady state (about 4–5 half-lives), and loading dose = volume of distribution × target concentration while maintenance dose = clearance × target concentration. Zero-order kinetics (phenytoin, ethanol, high-dose salicylate) means a small dose increase produces a disproportionate rise in level.
Therapeutic drug monitoring
Monitor digoxin (toxicity: nausea, visual disturbance, arrhythmia; hypokalaemia and renal impairment predispose), lithium (tremor, ataxia, confusion; avoid NSAIDs, thiazides and ACE inhibitors), vancomycin, phenytoin, theophylline and ciclosporin. Interpret levels with timing relative to the dose.
Interactions
CYP3A4 inhibitors (macrolides, azole antifungals, grapefruit) raise levels of statins, ciclosporin and many others; inducers (rifampicin, carbamazepine, phenytoin) lower them. Additive effects matter: NSAID plus ACE inhibitor plus diuretic causes triple-whammy AKI; serotonergic combinations risk serotonin syndrome; QT-prolonging drugs stack.
Antidotes to know
Paracetamol - N-acetylcysteine; opioid - naloxone; benzodiazepine - flumazenil (with caution); warfarin - vitamin K and prothrombin complex; dabigatran - idarucizumab; heparin - protamine; methanol - fomepizole; tricyclic - sodium bicarbonate; organophosphate - atropine and pralidoxime; methotrexate - folinic acid.
Rule of thumb: steady state is reached after about five half-lives - roughly one day for a 5-hour half-life, a week for a 36-hour half-life. Adjust doses for renal function using eGFR, and remember that some drugs (e.g. metformin, NSAIDs, contrast) need stopping when eGFR falls sharply.