Amiodarone

Mechanism of Action (Pharmacodynamics)

Amiodarone possesses a polyvalent (mixed) mechanism of action, uniquely combining the electrophysiological properties of all four classes of antiarrhythmic agents (I, II, III, and IV).

• Primary effect (Class III): Blockade of potassium ($K^+$) channels. This leads to delayed (prolonged) repolarization, an increase in the total duration of the action potential (AP), and the effective refractory period (ERP).
• Additional effects: The drug blocks sodium ($Na^+$) channels (preventing cell membrane depolarization), calcium ($Ca^{2+}$) channels, as well as $\beta$-adrenoceptors.

Due to this broad spectrum of action on ionic currents, the drug affects all parts of the heart.

Pharmacokinetics and Metabolism

The drug is characterized by complex, prolonged pharmacokinetics and the ability to accumulate in the body.

• Absorption: Slow and incomplete upon oral administration. Bioavailability varies widely, ranging from 20% to 50%.
• Distribution: Characterized by high plasma protein binding (96%). Amiodarone is prone to marked tissue accumulation. Because of this, there is a prolonged latent period: several weeks are required for the maximum therapeutic effect to develop.
• Metabolism: Occurs in the liver with the formation of an active metabolite, N-desethylamiodarone. The drug itself is a substrate for CYP3A4 and CYP3A5 isoenzymes.
• Elimination: Occurs predominantly via the gastrointestinal tract and is very slow. The elimination pattern is biphasic: the initial phase lasts about 10 days, and the terminal phase lasts up to 100 days. The half-life ($T_{1/2}$) ranges from 10 to 50 days, ensuring prolonged circulation in the bloodstream.

Drug Interactions (Cytochrome P450 System)

Amiodarone is a clinically significant inhibitor of several hepatic isoenzymes, which necessitates dose adjustments during combination therapy:

• CYP2D6 inhibition: Slows down the metabolism of psychotropic drugs (haloperidol, clozapine, tricyclic antidepressants), cardiological agents (metoprolol, timolol), opioids (codeine), and proton pump inhibitors (omeprazole).
• CYP3A4/CYP3A5 inhibition: Affects the metabolism of a vast number of drugs, including statins (lovastatin), macrolides, immunosuppressants (cyclosporine), and other antiarrhythmics.

Indications for Use

In clinical practice, amiodarone is positioned as a universal antiarrhythmic.

1. Rhythm disorders: Highly effective for both ventricular and supraventricular tachyarrhythmias and premature beats of any localization.
2. Ischemic heart disease: Used for stable exertional angina and vasospastic angina. In this case, it works as a mixed-acting agent: it simultaneously reduces myocardial oxygen ($O_2$) demand and increases its delivery (similar to nicorandil).

Side Effects

The specific toxicity profile is largely due to tissue accumulation of the drug:

• Cardiac effects: Development of bradycardia, impaired atrioventricular (AV) conduction.
• Extracardiac effects:
• Thyroid dysfunction (can manifest as either hypothyroidism or hyperthyroidism).
• Specific deposit localization: deposition of drug microcrystals in the corneal epithelium (so-called "corneal deposits").

Formulations and Administration Guidelines

According to reference prescribing data, the drug is used in the following dosages:

• Oral (200 mg tablets): The initial dose is 0.6–0.8 g per day. This dose should be divided into 3–4 intakes and taken after meals.
• Parenteral (5% solution in 3 mL ampoules): Administered via slow intravenous injection. Before administration, the contents of the ampoule must be pre-diluted in 40 mL of 5% glucose solution.