Amiodarone

Mechanism

Pharmacologic Class and Drug Group

Broad-spectrum antiarrhythmic belonging to Class III of the Vaughan-Williams classification (Potassium Channel Blockers). Structurally, it is a benzofuranic derivative that contains a high percentage of iodine in its molecular composition (approximately 37% of its total weight).

Mechanism of Action

Although classified as a Class III antiarrhythmic, amiodarone exhibits electrophysiological properties representative of the four classes of the Vaughan-Williams classification concurrently, acting in a multichannel manner.

Multichannel Electrophysiological Mechanism of Amiodarone

1. Potassium Channel Blockade (Main Class III Effect): Potently inhibits outward potassium currents during cardiac repolarization, mainly the fast and slow rectifying potassium current (I_{Kr currents} y I_Ks). This prolongs the duration of the action potential and the effective refractory period in the atrial and ventricular tissue and in the Purkinje fibers:

Inhibition of I_{Kr currents} Prolongation of ventricular repolarization ↑ QT interval on ECG

2. Sodium Channel Blockade (Class I Effect): Blocks voltage-gated sodium channels in their inactive state, reducing the maximum rate of phase 0 depolarization in fast atrial and ventricular tissues in a manner similar to Class I antiarrhythmics.

3. Calcium Channel Blockade (Class IV Effect): Non-competitively inhibits slow L-type channels (Cav1.2), decreasing nodal conduction and exerting mild negative inotropic effects with a stabilizing profile.

4. Non-Competitive Antagonism of Adrenergic Receptors (Class II Effect): Non-selectively antagonizes the α and β adrenergic receptors of the cell membrane in a non-competitive manner, attenuating the effects of sympathetic overstimulation.

Pharmacokinetics

High-Resolution Pharmacokinetics

• Absorption and Bioavailability: Slow, incomplete and highly variable oral absorption (bioavailability 30% to 50%). Taking it with fatty food approximately doubles drug exposure, requiring a consistent pattern of administration.
• Distribution: Marked lipid affinity, with substantial accumulation in adipose tissue, liver, lung, myocardium and cornea. This produces an exceptionally large apparent volume of distribution of approximately 5000 a 7000 L at baseline). Very high plasma protein binding (99.9%).
• Metabolism: Extensive hepatic oxidative metabolism mediated selectively by cytochrome isoenzymes CYP3A4 and CYP2C8 to form its principal active metabolite, desethylamiodarone (DEA), which has potent antiarrhythmic properties.
• Excretion: Negligible renal excretion. The drug and its metabolites are eliminated through bile and faeces following slow active biliary elimination. Not removed by dialysis.
• Half-life (t_1/2): Because of substantial lipid storage and slow tissue elimination, it has a very long biological half-life of 20 to 100 days. This explains why amiodarone's clinical effects may persist for months after discontinuation. Loading doses over several weeks are used to saturate tissue stores.

Indicators and dose

Clinical Indications and Uses

• Atrial Fibrillation (Conversion to Sinus Rhythm and Prevention of Recurrences): Of choice for long-term maintenance of rhythm control in patients with hypertrophic cardiomyopathy or heart failure with depressed LVEF (where other antiarrhythmics are contraindicated).
• Sustained Ventricular Tachycardia and Prevention of Sudden Death: Antiarrhythmic of choice in life-threatening ventricular arrhythmias.
• Cardiac Arrest due to Refractory Ventricular Fibrillation: Rapid start intravenous bolus administration after failure of the protocol electrical defibrillation shocks.

Dosage and Clinical Adjustment

• Oral Loading Phase (Depot Saturation): 600 mg to 800 mg per day orally in 2 or 3 divided doses over a 2-week period, reducing to 400 mg per day during the third week.
• Chronic Maintenance Phase: 100 mg to 200 mg once daily orally in the morning continuously, using the lowest effective dose to reduce tissue accumulation.
• Arrhythmic Emergency in Cardiac Arrest (VF/pulseless VT): Initial rapid intravenous bolus of 300 mg diluted in 20 mL of 5% dextrose solution to be passed quickly. An additional 150 mg bolus may be given if the arrhythmia is refractory.
• Renal/Hepatic Adjustment: No adjustment is required in renal failure since it is not eliminated through this route. Monitor rigorously in liver failure.

Security

Absolute and Relative Contraindications

Absolute Contraindications

• Second or third degree atrioventricular block without normal functional permanent pacemaker.
• Severe sinus bradycardia or sinus node dysfunction.
• Prolongation of the corrected baseline QT interval superior a 500 ms de base (riesgo elevado de inducir taquicardia helicoidal de torsades de pointes).
• Known hypersensitivity to amiodarone or iodine.
• Severe underlying uncontrolled thyroid dysfunction.

Relative Contraindications

• Previous diffuse interstitial lung disease or pulmonary fibrosis (amiodarone is associated with severe pulmonary toxicity with high mortality).
• Moderate to severe liver failure.

Adverse Effects and Specific Toxicity

• Amiodarone is associated with a complex systemic toxicity profile linked to the use of long-term cumulative doses, of biochemical origin and direct tissue deposition:
• Thyroid Dysfunction (Hyper or Hypothyroidism 10%): Each 200 mg tablet contains approximately 75 mg of molecularly bound iodine, rather than free iodine. Iodine release exceeds daily physiological needs and can affect thyroid function through two opposing mechanisms:

Amiodarone-Related Thyroid Pathophysiology (Wolff-Chaikoff and Jod-Basedow Effects)

1. Amiodarone-induced hypothyroidism (AIH): Caused by the Wolff-Chaikoff effect, in which excess iodine temporarily inhibits new thyroid hormone synthesis. In susceptible patients, the thyroid cannot escape this inhibition, resulting in clinical hypothyroidism. Levothyroxine replacement may be used without discontinuing amiodarone when it remains essential.

2. Amiodarone-induced hyperthyroidism (TIA): Two clinically distinct types require different management:

• TIA Type I: Increased iodine-induced hormone synthesis in autonomous thyroid tissue or latent Graves disease; associated with Jod-Basedow Effect. Excess iodine provides substrate for increased hormone synthesis in pre-existing nodular goitre. Treated with high-dose antithyroid medication such as methimazole.
• TIA Type II: A destructive inflammatory thyroiditis caused by direct amiodarone toxicity to follicular cells, releasing preformed hormone into the circulation. Treat with glucocorticoids such as prednisone; cardiology and endocrinology should jointly decide whether to continue amiodarone according to cardiac risk.

• Pulmonary Toxicity (Fibrosing Interstitial Pneumonitis 1% - 5%): A potentially fatal complication of amiodarone involving alveolar phospholipid accumulation and immune-mediated injury. Features include progressive exertional dyspnea, non-productive cough, fever and bilateral crackles. Suspected toxicity requires prompt assessment, consideration of withdrawal and corticosteroid treatment according to severity.
• Microbiliary Corneal Deposits (90%): Usually asymptomatic and benign; do not generally require discontinuation. Resolve slowly after treatment is stopped.
• Hepatotoxicity: Asymptomatic transaminase elevation. Can progress to microvesicular liver injury or steatohepatitis.
• Blue-grayish discoloration of the skin (Photo-sensitivity): Related to melanin and amiodarone metabolite deposits in sun-exposed facial areas.

Relevant Drug Interactions

• Strong CYP3A4 and P-Glycoprotein Inhibitors (Digoxin, Warfarin, Statins): Amiodarone reduces the clearance of these drugs. It can double digoxin concentrations, often requiring a reduction in digoxin dose, and increase warfarin's anticoagulant effect and INR.
• Drugs that Prolong the QT interval (Erythromycin, Haloperidol, Moxifloxacin): Additive QT prolongation increases the risk of potentially fatal torsades de pointes.