dronedarone

**Mechanism:** Structurally similar to amiodarone but lacks iodine (less thyroid toxicity) and has a methane-sulfonyl group (less lipophilic, shorter half-life ~13–19 h vs weeks-months for amiodarone). Blocks K+ channels (IKr, IKs, IK-ACh, IK1; class III, prolongs repolarization/QT), Na+ channels (class I), beta-adrenergic receptors (class II, noncompetitive antisympathetic), and L-type Ca2+ channels (class IV). Net effect: slows ventricular rate, prolongs AV node conduction and refractory period, increases PR and QT intervals.

**Indication:** Maintenance of sinus rhythm / reduction of AF-related hospitalization in non-permanent AF (paroxysmal or persistent) with recent AF episode. Less effective than amiodarone for rhythm maintenance (DIONYSOS), but with fewer extracardiac toxicities. ATHENA trial: reduced CV hospitalization/death in AF patients.

**Contraindications / Boxed warning:** - Permanent AF (PALLAS: increased stroke, MI, systemic embolism, CV death) - NYHA class IV HF or symptomatic HF with recent decompensation requiring hospitalization (ANDROMEDA: increased mortality) - Second/third-degree AV block or sick sinus syndrome without pacemaker; bradycardia <50 bpm - Concomitant strong CYP3A4 inhibitors (ketoconazole, clarithromycin, ritonavir), QT-prolonging drugs (class I/III antiarrhythmics, phenothiazines, TCAs, macrolides) - Baseline QTc ≥500 ms or PR >280 ms - Severe hepatic impairment; prior amiodarone-related liver or lung toxicity - Pregnancy (Category X)

**Adverse effects:** GI (diarrhea, nausea), bradycardia, QT prolongation, rash, **increased serum creatinine** (~0.1 mg/dL via inhibition of tubular creatinine secretion, with no true GFR drop), rare hepatotoxicity (including acute liver failure; monitor LFTs), pulmonary toxicity (pulmonary fibrosis, rarer than amiodarone), and HF worsening.

**Pharmacokinetics/interactions:** Substrate of CYP3A4; also inhibits CYP3A4, CYP2D6, and P-glycoprotein. Increases digoxin levels (reduce digoxin dose by ~50%), dabigatran, statins (simvastatin), and beta-blockers/CCBs (diltiazem, verapamil: additive bradycardia). Take with food (bioavailability increases ~2-3x).

**Boards pearls:** - "Amiodarone without iodine": less thyroid dysfunction, but is not free of pulmonary/hepatic toxicity risk. - Dronedarone is NOT for permanent AF or decompensated HF. - The creatinine bump is benign (tubular secretion), so do not mistake it for AKI. - Other class III agents: amiodarone, sotalol, dofetilide, ibutilide. - Amiodarone's toxicities (pulmonary fibrosis, hypo-/hyperthyroidism, corneal deposits, blue-gray skin, hepatotoxicity, optic neuropathy) are largely attributable to iodine content and long half-life/tissue accumulation.