Pure class III agents for prevention of sudden cardiac death.

The results of clinical trials in postmyocardial infarction patients using type I antiarrhythmic drugs have been disappointing. There was optimism that IKr blockers might result in a reduction in sudden cardiac death in postinfarct population. Four trials are reviewed here, and the results are variable. The four drugs reviewed--d,l-sotalol, d-sotalol, dofetilide, and azimilide--all share IKr-blocking properties. In addition, d,l-sotalol is a beta-blocker and azimilide is an IKs blocker. The primary uses of d,l-sotalol, dofetilide, and, if approved, azimilide are currently for treatment of atrial fibrillation. Thus, the mortality trials reviewed here are primarily used as support of safety in high-risk patients, because none has achieved a mortality reduction in postinfarction patients. These trials play pivotal roles for regulatory approval of these drugs for use in atrial fibrillation.

Developmental toxicity in the pregnant rabbit by the class III antiarrhythmic drug sotalol.

The purpose of this study was to investigate the potential of sotalol to cause developmental toxicity in the pregnant rabbit. Sotalol is a beta-adrenoceptor blocking drug which also has class III antiarrhythmic properties via Ikr channel blockade. EXPERIMENT 1: Nine pregnant New Zealand White rabbits were given doses of either 300, 225, or 150 mg/kg of sotalol during gestational days, called Days, 13-16 which resulted in total litter loss. EXPERIMENT 2: A single dose of sotalol, 100 or 150 mg/kg was administered during Days 8-17 to 15 rabbits. Dosing on Day 8, 9, or 10 resulted in a slightly higher incidence of embryonic death compared to historical controls. There was marked increased embryonic death of 55-90% (four does with total litter loss), decreased number of live foetuses per litter, and elevated mean foetal weight after dosing during Days 12-16. EXPERIMENT 3: 16 pregnant rabbits were administered single doses of sotalol of either 100, 85, 75, 60 or 50 mg/kg on Day 14. The main finding was increased embryonic death, which ranged from total litter loss to approximately 30% at 50 mg/kg. At 50 mg/kg, the maternal Cmax, AUC(1-24 hr), and t1/2 were approximately 45 microM, 340 micromol x hr/l, and 6 hr, respectively. In conclusion, sotalol treatment resulted in embryonic death in the rabbit in early pregnancy in the same way as has been seen for other drugs with Ikr blocking properties (class III antiarrhythmics) in rodents. The observed developmental toxicity in the rabbit is most likely secondary to embryonic arrhythmia as has been shown in rodent studies. The results may indicate that Ikr blocking agents are developmental toxicants across species including man.

[Drug therapy of ventricular arrhythmias]. / Medikamentöse Therapie ventrikulärer Arrhythmien.

In patients with no or only mild structural heart disease, spontaneous ventricular ectopy which causes symptoms is being treated with beta receptor antagonists, sotalol, or in rare cases with class I substances. For primary prevention of sudden death, for instance in survivors of myocardial infarction, beta receptor antagonists are the only substances for which benefit has been demonstrated in large scale trials. In contrast, class I agents are contraindicated for this purpose. In secondary prevention of sudden death in patients with a history of sustained ventricular tachycardia or ventricular fibrillation, treatment with sotalol or amiodarone can be considered. However, nonpharmacological therapy by means of implantable defibrillators is increasingly applied in this patient population.

Sotalol hydrochloride (Betapace): a new antiarrhythmic drug.

Sotalol hydrochloride (Betapace), recently released by the Food and Drug Administration for general use, is used to treat a variety of ventricular and supraventricular tachyarrhythmias. The drug's dominant action is the result of combined nonselective beta-adrenergic antagonism (Class II effect) and monophasic action potential duration prolongation in all cardiac tissues (Class III effect). It causes less left ventricular depression than propranolol and has a low incidence of toxicity. It is a useful addition to the antiarrhythmic drug armamentarium. This article reviews the drug's pharmacokinetic, pharmacodynamic and electrophysiologic properties, clinical uses and potential side effects. Reports on the drug's use as an antianginal and antihypertensive agent are also discussed.

[New anti-arrhythmia agents]. / Neue Antiarrhythmika.

Use of class-I antiarrhythmic agents (encainide, flecainide or moricizine) to suppress asymptomatic ventricular premature depolarizations does not decrease, but rather increases mortality from cardiac events after myocardial infarction. These patients should not be treated with antiarrhythmic drugs until improved survival is shown in a controlled clinical trial. In other clinical conditions such as symptomatic tachyarrhythmias class-I agents should only be used if the expected benefit outweighs the risk of an adverse cardiac effect. The development of new class-I drugs does not seem promising. Esmolol is the first intravenous and ultrashort-acting beta-adrenoceptor blocker that can be used to treat supraventricular arrhythmias in the critical care setting; in addition, it displays high cardioselectivity. Specific class-III antiarrhythmic agents including sematilide and dofetilide have been shown to be effective against ventricular tachyarrythmias in preclinical studies, but their clinical value remains to be established. Torsades de pointes arrhythmia is an undesirable side-effect closely coupled to specific class-III action that may limit their future use. The known pharmacological profiles and limited controlled clinical studies make amiodarone and sotalol promising candidates for drugs that may improve survival of patients at risk for sudden cardiac death.