Amiodarone

Category: pharmacological

Aliases: Cordarone, Pacerone

Pharmacological Mechanism

Class III antiarrhythmic — multi-channel blocker (K+, Na+, Ca²⁺, β-adrenergic). Inhibits CYP3A4, CYP2C9, CYP2D6, P-gp — broad DDI profile. Massive Vd (~60 L/kg) and extreme half-life (~40-50 days) require months for steady-state and washout. Pulmonary, hepatic, thyroid toxicity at chronic exposure.

Half-Life (t½)

PO: 1080h, IV: 1080h

Dosing Guidelines

PO: Typical 200 mg (Range: 100–400 mg)

Target Organ Systems

respiratory
endocrine
digestive

Interactions

Digoxin (major): P-glycoprotein inhibition. Santostasi 1987 (PMID:2438499): amiodarone 200 mg/d × 2 weeks raised digoxin oral bioavailability by 33-43% (n=6 healthy volunteers). Halve digoxin dose on amiodarone initiation; monitor levels.
Simvastatin (major): CYP3A4 inhibition (UPGRADE — prior edge had no kinetics). Becquemont 2007 (PMID:17301736) n=12 healthy crossover, simvastatin 40 mg PO ± amiodarone 400 mg/d × 3d: simvastatin acid AUC0-24h +73% (P=0.02), Cmax +100%. AUC ratio 1.73; Ki ≈ 2/(1.73−1) = 2.74 µM at Cp_perp 2 µM. Pravastatin unaffected (different transport). FDA limit: simva 20 mg with amio.
Warfarin (major): CYP2C9 inhibition (S-warfarin). Sanoski 2002 (PMID:11796427) n=43 stable warfarin patients starting amiodarone, ≥1y follow-up: peak interaction at 7 wk; mean 44% maximum dose reduction to maintain INR 2-3. Equivalent S-warfarin CL ratio 0.56 → AUC ratio 1.79; Ki ≈ 2/0.79 = 2.53 µM at Cp_perp 2 µM. INR/dose endpoint, not direct PK AUC — flagged.
Flecainide (major): CYP2D6 inhibition. Leclercq 1990 (PMID:2128031) n=78 cohort + chronic subset: flecainide trough C/D ratio 2.03→2.92 ng/mL/mg with amiodarone (1.44×). Ki ≈ 2/0.44 = 4.55 µM at Cp_perp 2 µM. Authors mandate 50% flecainide dose reduction with amiodarone. Css/dose proxy; not direct AUC.
Metoprolol (major): CYP2D6 inhibition. Werner 2004 (PMID:15541258) observational: amiodarone 1.2 g/d load × 6d "metoprolol plasma concentration is doubled" (ratio 2.0). Ki ≈ 2/(2-1) = 2.0 µM at Cp_perp 2 µM. CYP2D6-genotype-dependent magnitude. Additive bradycardia/AV block risk on top of plasma doubling.
Phenytoin (caution): CYP2C9 (+ CYP2C19 minor) inhibition. Nolan 1990 (PMID:2337037) verbatim: phenytoin "area under the serum concentration time curve ... increased from 208 +/- 82.8 ... to 292 +/- 108 mg.hr/liter (p = 0.015)". 7 healthy males, steady-state oral phenytoin 2-4 mg/kg/d × 14d before/after amiodarone 200 mg/d × 6 wk. AUC ratio 1.40×; Ki ≈ 2/0.40 = 4.95 µM. Phenytoin TDM critical — narrow TI and the rise compounds over weeks as amiodarone accumulates.

Pathways It Modulates

Cardiac action potential (inhibitor) — multi-channel (K+ class III dominant; also Na+/Ca²⁺/β)
Hypothalamic-pituitary-thyroid axis (inhibitor) — D1 deiodinase + iodine load (complex thyroid effects)
Warfarin metabolism (inhibitor) — CYP2C9 (S-warfarin path)

Chemical Identifiers

PubChem CID: 2157
Formula: C25H29I2NO3
Molecular weight: 645.31 g/mol
InChIKey: IYIKLHRQXLHMJQ-UHFFFAOYSA-N
SMILES: CCCCC1=C(C2=CC=CC=C2O1)C(=O)C3=CC(=C(C(=C3)I)OCCN(CC)CC)I