Class+II+antiarrhythmics

Class II 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 reevaluate 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]

The V-W class II antiarrhythmic agents consist of the beta-adrenergic blocking drugs. In 1948, Ahlquist hypothesized that the physiologic effects of catecholamines were mediated by the activation of specific receptors, namely alpha and beta.[303] This led to the development of drugs that could act as antagonists at these receptors, thereby attenuating or blocking the effects of catecholamines. The first beta-receptor antagonist marketed was propranolol in 1967. Subsequent to the discovery of propranolol, beta1- and beta2-selective agents, as well as drugs with intrinsic sympathomimetic activity within each subset, were developed. Although it was initially believed that beta2-receptors were not located on myocardial tissue, it is now accepted that, despite the relative predominance of beta1-receptors found on cardiac muscle, beta2-receptors are also located on myocardial cells and are important regulators of cardiac activity and are therefore pharmacologic targets. Considering the dispersion of beta-receptors in the human body and the variety of beta-receptor antagonists that are available, the therapeutic role of beta-receptor antagonists is likely to continue to grow.


 * Mechanism of Action:** Beta-adrenergic antagonists compete with adrenergic neurotransmitters (i.e., catecholamines) for binding at sympathetic receptor sites. The primary beneficial pharmacodynamic/electrophysiologic effects of the beta-blocking agents generally are considered to be the direct antagonism of adrenergic stimulation of the AV and SA nodes. The beta-blocking agents would then be most desirable for arrhythmias caused primarily by a defect at these sites.[304] Pharmacologically, these drugs can increase AV nodal refractoriness, decrease automaticity, and slow conduction.[302]


 * Distinguishing Features:** Generally speaking, the use of beta-blockers as antiarrhythmics is reserved for patients who require only control of ventricular rate during atrial tachyarrhythmias or who have mildly symptomatic ventricular arrhythmias. Furthermore, agents of other V-W classes also might possess beta-blocking activity in addition to their primary classified electrophysiologic activity. Drugs with secondary or additional beta-antagonist activity include propafenone, sotalol, and amiodarone.[304]


 * Adverse Reactions:** The adverse effects of beta-blockers are generally mild and temporary; they usually occur at the onset of therapy and diminish over time.

Most adverse reactions of beta-blockers are manifestations of their therapeutic effects. Bradycardia and hypotension are rarely serious and can be reversed with IV atropine, if necessary. AV block, secondary to depressed conduction at the AV node, can necessitate sympathomimetic and/or pressor therapy or the use of a temporary pacemaker.

Congestive heart failure is more likely to occur in patients with preexisting left ventricular dysfunction and usually will respond to discontinuation of beta-blocker therapy.

Adverse CNS effects include dizziness, fatigue, and depression. Although much less common with hydrophilic beta-blockers, CNS depression, resulting in mental depression, fatigue, and, in some cases, vivid dreams, can occur.

Diarrhea and nausea/vomiting are the most common GI adverse effects during therapy with beta-blockers.

Bronchospasm and dyspnea are more likely to occur with nonselective beta-blockers or with high doses of cardioselective agents because the beta selectivity of the drug is lost. Patients with preexisting bronchospastic disease are at greater risk.

Both hypoglycemia and hyperglycemia can occur during beta-blocker therapy. Beta-blockers can interfere with glycogenolysis to cause hyperglycemia, and they also can mask signs of hypoglycemia. Beta-blockers should be used cautiously in brittle diabetics.