drug-drug interaction

**Definition:** A clinically significant change in the effect of one drug caused by co-administration of another drug (also applies to drug-food/herbal interactions).

**1. Pharmacokinetic interactions** - **Absorption:** Chelation (tetracyclines/fluoroquinolones + Ca2+, Mg2+, Al3+, Fe → reduced absorption); antacids/PPIs raise gastric pH (decrease absorption of ketoconazole, itraconazole, atazanavir); cholestyramine binds warfarin, digoxin, thyroid hormone. - **Distribution:** Displacement from albumin (e.g., sulfonamides, NSAIDs, or valproate displacing warfarin or phenytoin) is usually transient and rarely clinically significant alone. - **Metabolism (most testable): CYP450** - **Inducers** (↑ metabolism of other drugs → ↓ levels/efficacy; take days to weeks to develop): **"Guiness, PCR chugs":** Griseofulvin, Phenytoin, Carbamazepine, Rifampin, Phenobarbital, St. John's wort, Chronic alcohol, Nevirapine, Modafinil. Consequences: failure of OCPs, warfarin, and transplant immunosuppressants (cyclosporine, tacrolimus). - **Inhibitors** (↓ metabolism → ↑ levels/toxicity; onset is rapid, often within days): **"SICKFACES.COMICS":** Sodium valproate, Isoniazid, Cimetidine, Ketoconazole, Fluconazole, Alcohol (acute), Chloramphenicol, Erythromycin/clarithromycin, Sulfonamides, Ciprofloxacin, Omeprazole, Metronidazole, Amiodarone, Grapefruit juice, Ritonavir/protease inhibitors, Quinidine. (Mnemonics vary by source.) - Classic examples: clarithromycin or azole + simvastatin → rhabdomyolysis; rifampin + warfarin → subtherapeutic INR; ritonavir "boosting" of other HIV drugs (intentional use); CYP3A4 inhibitors + cyclosporine/tacrolimus → nephrotoxicity. - Prodrugs (clopidogrel via CYP2C19, codeine via CYP2D6) have *reduced* effect when the activating enzyme is inhibited (e.g., omeprazole + clopidogrel; fluoxetine/paroxetine + codeine/tamoxifen). - Xanthine oxidase inhibition: allopurinol + azathioprine/6-MP → toxicity (myelosuppression). - **Excretion:** Competition for renal tubular secretion (probenecid ↑ penicillin and methotrexate levels); NSAIDs, ACEi/ARBs, and thiazides ↑ lithium levels; urine pH changes (bicarbonate alkalinizes urine to ↑ salicylate excretion); quinidine, verapamil, amiodarone ↑ digoxin levels (↓ renal clearance and P-gp inhibition). - **P-glycoprotein:** Inhibitors (verapamil, amiodarone, quinidine) ↑ digoxin; inducers (rifampin, St. John's wort) ↓ levels.

**2. Pharmacodynamic interactions** - **Additive/synergistic:** CNS depressants (benzodiazepines + opioids + alcohol → respiratory depression); ACEi + K-sparing diuretics → hyperkalemia; "triple whammy" (NSAID + diuretic + ACEi/ARB → AKI); aminoglycosides + loop diuretics → ototoxicity; multiple QT-prolonging drugs (macrolides, fluoroquinolones, antipsychotics, class IA/III antiarrhythmics, ondansetron) → torsades de pointes; warfarin + NSAIDs/aspirin → bleeding. - **Serotonin syndrome:** SSRIs/SNRIs/TCAs/MAOIs/linezolid/tramadol/meperidine/triptans/St. John's wort/dextromethorphan combined → hyperthermia, clonus, hyperreflexia, agitation, diarrhea. Treat with cyproheptadine, benzodiazepines, and stopping offending agents. - **MAOI + tyramine or sympathomimetics** → hypertensive crisis. - **Nitrates + PDE-5 inhibitors (sildenafil)** → severe hypotension (contraindicated). - **Antagonistic:** β-blockers blunt albuterol effect; protamine reverses heparin; vitamin K reverses warfarin; naloxone reverses opioids; flumazenil reverses benzodiazepines. - **Disulfiram-like reaction:** Alcohol + metronidazole, certain cephalosporins (cefotetan), procarbazine, sulfonylureas → flushing, nausea, headache (inhibits acetaldehyde dehydrogenase).

**3. Clinical significance and management** - Highest risk with narrow therapeutic index drugs: warfarin, digoxin, lithium, phenytoin, theophylline, cyclosporine/tacrolimus, aminoglycosides. - Risk factors: polypharmacy, elderly patients, hepatic/renal impairment, genetic polymorphisms (e.g., CYP2D6, CYP2C19 poor/ultrarapid metabolizers). - Management: avoid the combination, choose an alternative (e.g., a non-interacting statin like pravastatin or rosuvastatin), adjust dose, monitor drug levels or INR, separate administration times (for chelation), and use EHR interaction alerts and pharmacist review. - Some interactions are used therapeutically: ritonavir/cobicistat boosting, probenecid + penicillin, carbidopa + levodopa, and amoxicillin + clavulanate.

**Board pearl:** If a stem says a patient on a stable chronic drug (warfarin, OCP, cyclosporine) develops a problem shortly after starting a new drug, think CYP450 induction or inhibition, then identify the new agent (e.g., rifampin, an azole, a macrolide, or an anticonvulsant).