Class+III+antiarrhythmics

Class III antiarrhythmics
 * Background:** The publication of the results of the Cardiac Arrhythmia Suppression Trial in 1989[296] and 1992[297] and other studies suggesting increased mortality associated with the use of antiarrhythmic drugs caused the medical community to re-evaluate the choice and use of pharmacologic agents for the management of many serious arrhythmias. As a result, antiarrhythmic agents have been replaced in some cases (e.g., life-threatening ventricular arrhythmias) by implantable defibrillator devices. Antiarrhythmic drugs are still used as primary therapy for many supraventricular arrhythmias, but their use as primary therapy for ventricular arrhythmias has declined since the publication of the trials mentioned above.

The Vaughan-Williams (V-W) classification system traditionally has been used to classify antiarrhythmic drugs.[298] This scheme places the available agents into one of four classes: I, II, III, or IV. The V-W system, however, has two limitations. First, although all drugs within a single class might possess a similar electrophysiologic action, they do not necessarily exert all of the same actions. The second limitation of the V-W classification system is that some agents have multiple electrophysiologic activities that complicate the placement of a drug into a single (e.g., amiodarone) or any (e.g., adenosine) category.[299]


 * Mechanism of Action:** Amiodarone, bretylium, and sotalol are the three primary drugs that compose the class III antiarrhythmic group, although other drugs possess class III activity. All class III antiarrhythmics, at least as their primary electrophysiologic effect, exert their antiarrhythmic activity via prolongation of the action-potential duration throughout the myocardium, consequently prolonging the effective refractory period. Of the antiarrhythmic classes, the mechanism of action of the class III agents is the least understood. In addition, many of the agents in this class have different and multiple pharmacologic and electrophysiologic effects.[304]

Some researchers believe that class III electrophysiologic effects are achieved primarily via blockade of potassium ion channels.[305] In general, class III activity is not believed to be a result of blockade of sodium channels or decreases in conduction velocity or automaticity.

Despite what is known about the mechanisms of class III activity, much remains to be researched. Many class III agents have multiple electrophysiologic actions. For example, amiodarone possesses electrophysiologic characteristics typical of all classes of the V-W classification scheme: potent sodium-channel blocking properties (class I), noncompetitive alpha- and beta-blockade (class II), unique class III activity unlike bretylium or sotalol, and calcium-channel blocking activity (class IV). Furthermore, because amiodarone was originally designed and tested as an anti-anginal compound, it possesses both coronary and peripheral vasodilatory activity.[306] Sotalol has both class III and class II pharmacology, pharmacodynamics, and electrophysiology.[295] Disopyramide, while classified as a Ia agent, also possesses class III activity.

Bretylium, originally investigated as an antihypertensive agent, initially causes a release of norepinephrine from sympathetic nerve terminals that is followed by anti-adrenergic activity. By being taken up and concentrated within the same nerve terminals, bretylium prevents further release of norepinephrine. The mechanism by which this process occurs is similar to that of guanethidine, with the ultimate pharmacologic effect being indirect beta-blockade.[306] The pharmacology of bretylium is unique in that it initially induces the release of norepinephrine from adrenergic nerve terminals, an event that may actually be beneficial in reestablishing coronary blood flow and altering the development of the arrhythmia in a manner similar to the use of epinephrine in resuscitation situations.


 * Distinguishing Features:** Amiodarone is unique in that it is the most potent and "broad-spectrum" antiarrhythmic compound currently available, possesses multiple electrophysiologic effects, has an extremely long elimination half-life (up to 100 days), has impressive efficacy in suppressing both supraventricular and ventricular arrhythmias, and causes severe adverse reactions. Bretylium, unlike amiodarone and perhaps sotalol, is not effective in treating supraventricular arrhythmias, but might be effective in treating ventricular fibrillation in conjunction with cardioversion. Bretylium is also unique when compared with its other class III agents because it is effective as an antifibrillatory agent, lowering the fibrillation threshold, while amiodarone and sotalol are more effective antitachycardia agents.[304] Sotalol is unique in that its pharmacology can be dictated by its enantiomeric conformation. The class III activity of sotalol is due to the d-isomer (currently available only in Europe), while the beta-blocking activity of sotalol is due to the l-isomer. In the United States, however, sotalol is currently available only as the racemic compound, so its class II and III effects cannot be separated.


 * Adverse Effects:** Like all antiarrhythmic drugs, class III agents can induce proarrhythmic events, including life-threatening ventricular arrhythmias, or can worsen preexisting ventricular arrhythmias, which can lead to sustained ventricular fibrillation, sustained ventricular tachycardia, and/or torsade de pointes. It often is difficult to distinguish between an underlying malignant arrhythmia and a drug-induced arrhythmia, unless a clear precipitating event occurred such as an electrolyte imbalance or AMI. Use of antiarrhythmic drugs has been associated with sudden death, and patients are continually at risk, not just during the initiation of therapy as was once believed. Careful monitoring of QT intervals and electrolyte balance is critical with all antiarrhythmic therapy in order to minimize potentially lethal adverse events.

Despite its superior efficacy as an antiarrhythmic agent, amiodarone's use is limited by its multitude of adverse effects. Amiodarone is more toxic than other class III agents and other drugs in general. Overall, approximately 70% of patients taking amiodarone will experience some type of adverse reaction, with 5—20% being of sufficient severity to warrant discontinuation of the drug. In general, the major adverse effects of amiodarone are cumulative and dose-related, and therefore tend to occur after long-term therapy and/or with higher doses.

The most severe potential adverse effects of amiodarone therapy are pulmonary reactions. These reactions can be fatal (10% of cases) and might result from amiodarone-induced pulmonary interstitial pneumonitis, hypersensitivity pneumonitis, pulmonary fibrosis, or ARDS.

Although quite rare, fatal hepatotoxicity (cirrhosis, hepatitis) has occurred secondary to amiodarone therapy and is accompanied by severe elevations in hepatic enzymes.

Cardiovascular effects of amiodarone are difficult to differentiate from extensions of its normal pharmacologic activity. Amiodarone can cause AV block, sinoatrial block, and/or intraventricular block, precipitating serious new cardiac arrhythmias. It also can exacerbate existing arrhythmias.

Patients receiving amiodarone therapy can experience peripheral neuropathy.

Amiodarone-induced hypothyroidism appears to be slightly more common than hyperthyroidism. In some, but not all, cases of thyroid disease, discontinuation of amiodarone is necessary.

Photosensitivity, the most common dermatologic adverse effect of amiodarone, can occur in 10% of patients. Long-term administration of amiodarone infrequently can result in blue-gray skin discoloration, which could be more likely to occur in patients with fair skin or in those with frequent, unprotected exposure to sunlight.

Gastrointestinal disturbances are quite common during amiodarone therapy, particularly during the loading phase, but usually do not warrant discontinuance of the drug. Adverse GI symptoms occur in about 25% of patients receiving amiodarone and include nausea/vomiting, anorexia, constipation, and abdominal pain.

Visual disturbances, including halo vision, blurred vision, photophobia, and dry eyes, occur in as many as 10% of patients receiving amiodarone therapy. Asymptomatic corneal deposits (microdeposits) occur in virtually all patients who receive amiodarone for at least 6 months, although they can occur sooner, and are usually unrelated to adverse ocular disturbances.

The side effects most often reported, which have led to withdrawal of sotalol treatment, include: fatigue, bradycardia, asthenia, diarrhea, and dizziness. Patients with preexisting bronchospastic disease are at high risk for exacerbation of asthma, dyspnea, or bronchospasm because sotalol may inhibit endogenous catecholamines that cause bronchodilation via their beta-antagonist activity. Both hypoglycemia and hyperglycemia can occur during sotalol therapy. Sotalol can interfere with glycogenolysis to cause hyperglycemia, and it also can mask signs of hypoglycemia. Sotalol should be used cautiously in brittle diabetics.

Hypotension, both supine and postural, is the most common adverse effect of bretylium. Postural hypotension includes symptoms of vertigo, dizziness, lightheadedness, faintness, and syncope. Brief hypertension can occur due to the initial bretylium-induced release of norepinephrine from the sympathetic ganglia. Bradycardia, a sensation of substernal pressure, and precipitation of angina also have been reported.