Pathophysiology
Clinical meaning
Understanding pharmacological mechanisms prevents life-threatening interactions. Serotonin toxicity: excessive 5-HT2A stimulation from combining reuptake inhibitors (SSRIs, SNRIs, tramadol), increased release (amphetamines), decreased metabolism (MAOIs, linezolid), or direct agonists (triptans). Most dangerous: MAOIs + any serotonergic agent. QT prolongation: hERG potassium channel blockade delays phase 3 repolarization, risking early afterdepolarizations and torsades de pointes — compounded by hypokalemia, hypomagnesemia, and bradycardia. Anticholinergic accumulation: multiple mild anticholinergic drugs create dangerous burden — tachycardia, urinary retention, constipation, confusion, hyperthermia ('Hot as a hare, blind as a bat, dry as a bone, red as a beet, mad as a hatter'). Hepatotoxicity: dose-dependent (acetaminophen/NAPQI depleting glutathione) vs. idiosyncratic (isoniazid, valproic acid).