Amiodarone

Mechanism

Pharmacological Class and 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 and 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 of 30% to 50%). Administration together with fatty foods netly doubles the area under the curve of the drug, requiring regularity in the intake pattern.
• Distribution: It has an extreme affinity for lipids, accumulating massively in adipose tissue, liver, lung, myocardium and cornea. This results in an extraordinarily large apparent volume of distribution (approximately 5000 to 7000 L of base). Very high binding to plasma proteins (99.9%).
• Metabolism: Extensive hepatic oxidative metabolism mediated selectively by the cytochrome isoenzymes CYP3A4 and CYP2C8 to form its main active metabolite, desethylamiodarone (DEA), which has potent antiarrhythmic properties.
• Excretion: Virtually zero renal excretion. The drug and its metabolites are eliminated exclusively via the bile and fecal route after slow active biliary elimination. It is not removed by dialysis.
• Half-life (t_1/2): Due to its massive lipid deposition and slow tissue elimination, it has an extraordinarily long biological half-life of 20 to 100 days. This explains why the clinical effect of amiodarone persists for months after its formal discontinuation. It requires high loading doses for weeks to saturate the reserve tanks.

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 greater than 500 ms at baseline (high risk of inducing torsades de pointes helical tachycardia).
• 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 75 mg of organic free iodine. Once in the body, it releases iodine in quantities much higher than the daily physiological requirement, altering the thyroid axis through two opposite mechanisms:

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

1. Amiodarone-induced hypothyroidism (AIH): It is generated by the Wolff-Chaikoff Effect, where organic excess of iodine temporarily inhibits the synthesis of de novo thyroid hormones. In susceptible patients, the thyroid is unable to "escape" this inhibition, resulting in clinical hypothyroidism that is managed with replacement levothyroxine without forcing the suspension of amiodarone if it is essential.

2. Amiodarone-induced hyperthyroidism (AIT): It is classified into two clinically differentiated types that are difficult to manage:

• TIA Type I: Of immunological origin due to Jod-Basedow Effect. Excess iodine acts as an accelerating substrate for the synthesis of hormones in previous nodular goiters. It is treated with high doses of antithyroid drugs (methimazole).
• TIA Type II: Of destructive inflammatory origin. This is thyroiditis due to direct toxicity of amiodarone on the thyroid follicular cells, causing a massive release of preformed hormone into the capillary plasma. It is treated with glucocorticoids (prednisone) and usually requires definitive discontinuation of the antiarrhythmic.

• Pulmonary Toxicity (Fibrosing Interstitial Pneumonitis 1% - 5%): It is the most lethal complication of amiodarone. It is due to a dual mechanism of phospholipid accumulation in alveolar pneumocytes and lymphocytic immunotoxicity. It presents with progressive dyspnea on exertion, non-productive cough, fever and bilateral crackles. It requires immediate suspension of the drug and initiation of rapid immunosuppressive therapy with high-potency systemic corticosteroids.
• Microbiliary Corneal Deposits (90%): Practically universal, asymptomatic, benign in nature that do not require suspension. They disappear slowly when treatment is stopped.
• Hepatotoxicity: Asymptomatic elevation of transaminases. It can progress to microvesicular cirrhosis or de novo steatohepatitis.
• Blue-grayish discoloration of the skin (Photo-sensitivity): Due to deposits of melanin and amiodarone metabolites exposed to ultraviolet radiation from the sun in exposed areas of the face.

Relevant Drug Interactions

• Strong CYP3A4 and P-Glycoprotein Inhibitors (Digoxin, Warfarin, Statins): Amiodarone decreases the clearance of these drugs. It doubles the plasma concentration of digoxin (requires reducing the digoxin dose by half when starting amiodarone) and displaces warfarin, critically increasing the anticoagulation INR value.
• Drugs that Prolong the QT interval (Erythromycin, Haloperidol, Moxifloxacin): Critical synergism of QT prolongation, multiplying the possibility of lethal helical ventricular arrhythmias.