Class III Antiarrhythmic Agents

Classification and mechanism of action

The group of Class III antiarrhythmics is pharmacologically heterogeneous. They are united by the ability to block potassium channels, which leads to the prolongation (slowing) of repolarization. As a result, the total action potential (AP) duration increases.

The 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 $\beta$-blockers).
• Selective blockers: ibutilide and nibentan.

Bretylium tosylate is considered separately as a quaternary ammonium compound with sympatholytic activity, which also prolongs the AP.

Amiodarone — a broad-spectrum drug

Amiodarone affects all parts of the heart and is used for all tachyarrhythmias (both ventricular and supraventricular). In addition to its antiarrhythmic effect, it exhibits antianginal action: it reduces myocardial oxygen demand (via $\beta_1$-receptor blockade) and increases its supply by dilating coronary vessels (through $\alpha$-receptor and calcium channel blockade).

Pharmacokinetic features:

• When taken per os, it is absorbed slowly, with bioavailability ranging from 20 to 50%.
• It exhibits pronounced material accumulation — it accumulates in tissues, which is why the maximum therapeutic effect is achieved only after several weeks.
• It is metabolized in the liver to form an active metabolite — N-desethylamiodarone.
• Elimination is biphasic and extremely slow (predominantly 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 profile of adverse reactions affecting various organ systems:

1. Cardiovascular system: bradycardia, hypotension, decreased myocardial contractility, and suppression of AV conduction. An arrhythmogenic effect is possible, although the risk of specific ventricular tachycardia such as torsades de pointes is lower than with quinidine-like agents.
2. 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.
3. Respiratory system: a severe complication is fibrous pneumonitis, which is often fatal.
4. Skin and metabolism: photosensitivity and lipofuscin deposition, giving the skin a blue-gray hue with prolonged use.
5. Other: microcrystal deposition in the corneal epithelium of the eye, tremor, ataxia, and inhibition of microsomal liver enzymes.

Sotalol and bretylium tosylate

Sotalol combines the properties of a $\beta$-blocker (suppresses sinus node automaticity and conduction) and a potassium channel blocker. It is effective in all types of tachyarrhythmias. Unlike amiodarone, it has high bioavailability (which, however, drops when taken with dairy products), does not bind to plasma proteins, is not metabolized, and is excreted unchanged by the kidneys.

Bretylium tosylate is used parenterally for ventricular arrhythmias resistant to other drugs. Its main side effect is arterial (including orthostatic) hypotension associated with pronounced sympatholytic activity.

Selective drugs (ibutilide, nibentan)

These agents work more selectively and are used only for supraventricular tachyarrhythmias (e.g., for cardioversion of paroxysms of atrial fibrillation and flutter).

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, which provides high conductivity. The blockade of these channels sharply lengthens the effective refractory period, preventing premature impulses from passing from the atria to the ventricles. Ibutilide is additionally capable of blocking sodium channels, suppressing phase 0 of the AP.

The drugs are administered strictly intravenously (dose adjusted by body weight) in a hospital setting under continuous ECG monitoring, as they have high arrhythmogenic activity.

Briefly: answers to topical questions

Class and exam questions

What else to study on this topic

• Mechanisms of "torsades de pointes" arrhythmia development
• Features of amiodarone metabolism and the role of N-desethylamiodarone
• Sympatholytic action of bretylium tosylate
• Electrophysiology of the bundle of His and action potential phases
• Drug interactions associated with the inhibition of microsomal liver enzymes

Other topics in the "Antiarrhythmic Agents" section

Prepared by WhiteCoat Pro faculty in accordance with the medical school curriculum. For educational purposes only.