Classification and Mechanism of Action
Class III antiarrhythmics are pharmacologically diverse. They share the ability to block potassium channels, which leads to prolonged (slowed) repolarization. As a result, the total duration of the action potential (AP) increases.
Drugs are divided into two main subgroups:
- Mixed-action agents: amiodarone (possesses properties of all four antiarrhythmic classes) and sotalol (combines Class III effects and $\beta$-blockade).
- Selective blockers: ibutilide and nibentan.
Bretylium tosylate is considered separately as a quaternary ammonium compound with sympatholytic activity that also prolongs the AP.
Amiodarone: A Broad-Spectrum Agent
Amiodarone affects all parts of the heart and is used for all types of tachyarrhythmias (both ventricular and supraventricular). In addition to its antiarrhythmic properties, it exerts an antianginal effect: it reduces myocardial oxygen demand (via $\beta_1$-receptor blockade) and increases oxygen delivery by dilating coronary vessels (via $\alpha$-receptor and calcium channel blockade).
Pharmacokinetic Features:
- Absorbed slowly when taken per os, with bioavailability ranging from 20% to 50%.
- Exhibits marked tissue accumulation, causing the maximum therapeutic effect to appear only after several weeks.
- Metabolized in the liver to form an active metabolite, N-desethylamiodarone.
- Elimination is biphasic and extremely slow (primarily via the gastrointestinal tract): the half-life reaches 10–50 days.
Side Effects of Amiodarone
Due to its complex mechanism of action, the drug has an extensive adverse effect profile affecting multiple organ systems:
- Cardiovascular System: Bradycardia, hypotension, decreased myocardial contractility, and suppression of AV conduction. An arrhythmogenic effect is possible, though the risk of specific torsades de pointes ventricular tachycardia is lower than with quinidine-like agents.
- Endocrine System: The molecule contains iodine, which stimulates TSH production by the adenohypophysis. This can cause hypo- or hyperthyroidism, as well as a goitrogenic effect.
- Respiratory System: A severe complication is fibrous pneumonitis, which is frequently fatal.
- Skin and Metabolism: Photosensitization and lipofuscin deposition, giving the skin a bluish-gray tint with long-term use.
- Other: Corneal microdeposits, tremor, ataxia, and inhibition of hepatic microsomal enzymes.
Sotalol and Bretylium Tosylate
Sotalol combines the properties of a $\beta$-blocker (suppressing sinus node automaticity and conduction) and a potassium channel blocker. It is effective for all types of tachyarrhythmias. Unlike amiodarone, it has high oral bioavailability (which decreases when taken with dairy products), does not bind to plasma proteins, undergoes no hepatic metabolism, and is excreted unchanged by the kidneys.
Bretylium tosylate is administered parenterally for ventricular arrhythmias refractory to other drugs. Its main side effect is arterial (including orthostatic) hypotension related to pronounced sympatholytic activity.
Selective Agents (Ibutilide, Nibentan)
These agents act more selectively and are used exclusively for supraventricular tachyarrhythmias (e.g., termination of atrial fibrillation and flutter paroxysms).
Their target is the fibers of the bundle of His, whose membranes are rich in potassium channels. Normally, phase 3 of the AP is short here, allowing high conduction velocity. Blockade of these channels sharply prolongs the effective refractory period, preventing premature impulses from passing from the atria to the ventricles. Ibutilide can additionally block sodium channels, depressing phase 0 of the AP.
These drugs are administered strictly intravenously (weight-based dosing) in an inpatient setting under continuous ECG monitoring due to their high arrhythmogenic potential.