Michael J. Antonaccio

Pharmacology, pharmacodynamics and pharmacokinetics of sotalol.

Sotalol is a nonselective, water-soluble beta-adrenoceptor antagonist with no membrane-stabilizing activity or intrinsic sympathomimetic activity. Sotalol is, essentially, completely absorbed and is not metabolized. Consequently, bioavailability is close to 100%. Age and food have slight but unimportant effects on bioavailability. Cmax of sotalol is 2 to 3 hours with a t1/2 between 7 and 15 hours. Excretion of sotalol is primarily through the kidneys, with no metabolism by liver and no first-pass effect. Therefore, sotalol plasma levels and half-life are directly related to creatinine clearance and glomerular filtration rate. Appropriate dose adjustments must be made for patients with impaired renal function or increased renal blood flow, as in pregnancy. The beta-adrenoceptor antagonistic effects of sotalol are directly related to plasma levels, which, in turn, are directly related to dose. However, the beta-adrenoceptor antagonism t1/2 is longer than the sotalol plasma t1/2. As a consequence of its ability to prolong the action potential duration, sotalol also increases cardiac contractility in isolated ventricular, but not atrial, preparations by 20 to 40%. This positive inotropic effect is not blocked by beta or alpha blockade or reserpine pretreatment and seems to be related to sotalols effects on cardiac ionic currents. Like the effects of sotalol on action potential duration, the positive inotropic effects are inversely proportional to rate. The hemodynamics of sotalol indicate a relative lack of direct cardiac depressant activity in both animals and humans. The typical hemodynamic effects of sotalol in normotensive humans, even with depressed myocardial function, are a reduction in heart rate with little or no change in blood pressure, a reduction in cardiac output with no change in stroke volume, and little or no change in pulmonary wedge pressure and left ventricular end-diastolic pressure or volume, and little or no change in ejection fraction either at rest or during exercise.

Pharmacologic basis of the antiarrhythmic and hemodynamic effects of sotalol

Sotalol is a competitive beta adrenoceptor antagonist devoid of membrane-stabilizing activity and intrinsic sympathomimetic activity that has no preferential actions on beta 1 or beta 2 responses. No other tested receptor systems are affected by sotalol. In addition to having class II (beta blockade) effects, sotalol also has class III antiarrhythmic activity. It increases the action potential duration (APD) and prolongs atrial and ventricular repolarization. The effect on APD is independent of beta blockade; the same effect is seen with similar concentrations of the d stereoisomer of sotalol, which does not have beta-blocking activity. Sotalol prolongs the rate-corrected QT interval and ventricular and atrial refractoriness without affecting atrial, His-Purkinje, or ventricular conduction velocity. Atrioventricular nodal conduction is decreased, largely because of beta blockade. Sotalol increases the fibrillation threshold and decreases the defibrillation threshold. Sotalol is an effective antiarrhythmic in various animal models of arrhythmia (e.g., chloroform, hydrocarbon-catecholamine, ouabain, and coronary ligation). In addition, it reduces the severity and frequency of arrhythmias induced by programmed electrical simulation. By comparison, metoprolol is ineffective and d-sotalol is as effective as the racemate in this model, indicating that this effect is independent of beta blockade. Sotalol causes concentration-dependent increases in the contractility of isolated ventricular tissue that is not blocked by previous beta or alpha blockade or catecholamine depletion. The positive inotropic effect may be related to inhibition of time-dependent K+ current responsible for the increase in APD. Like propranolol, sotalol decreases contractile force, heart rate, arterial blood pressure, left ventricular dP/dt, and cardiac output in intact animals due to blockade of circulating catecholamines. Sotalol consistently reduces the heart rate to a greater degree than propranolol and causes significantly less cardiac suppression than propranolol at a given heart rate.

Dosing recommendations for encainide

The onset of antiarrhythmic action of encainide in patients with ventricular arrhythmias occurred within 3 hours after a single dose of 25 or 50 mg. No significant antiarrhythmic activity was noted after only 10 mg. After 14 days of daily dosing, both the 25- and 50-mg dose levels of encainide administered 3 times/day abolished or decreased ventricular arrhythmias in patients tested over a 24-hour period, whereas the 10-mg dose was ineffective. In 5 well-controlled studies involving 331 patients, encainide produced a dose-related decrease in the absolute number of ventricular arrhythmias as well as an increase in the percentage of responders (greater than 75% decrease in ventricular arrhythmias). Doses of 75 mg/day were required to obtain at least a 50% reduction in ventricular arrhythmias or 50% of patients responding or both. Three-times-a-day dosing was as effective as 4-times-a-day dosing. Further, doses greater than 200 mg/day gave little or no increase in incidence of efficacy. Important side effects were very low using doses of less than or equal to 150 mg/day and increased significantly at greater than or equal to 150 mg/day. It is recommended that encainide be initiated at 25 mg 3 times/day for 4 to 7 days, then carefully titrated upward, as needed, to 35 and 50 mg 3 times/day, respectively, every 4 to 7 days. If needed, 50 mg 4 times/day is an appropriate next dosage. Rapid dose escalation or doses greater than 200 mg are discouraged. Patients with severe life-threatening arrhythmias should receive encainide in a setting with cardiac monitoring and advanced life support systems.

Reduced contractile function after balloon denudation of rat carotid arteries

In rat carotid arteries isolated 2 weeks after balloon denudation, a significant neointima developed with little change in medial size. Associated with this neointimal hyperplasia was a marked decrease in contraction to various agents including angiotensins I and II, big endothelin-1, endothelin-1, norepinephrine, phenylephrine, and serotonin. Vasodilator responses to acetylcholine were significantly reduced. In contrast, vasodilator responses to nitroglycerin were unaffected. It is suggested that modulation of the neointimal cells to a more non-contractile phenotype may be responsible for the loss in contractile ability.

Electrophysiology, hemodynamic and arrhythmia efficacy model studies on encainide.

Encainide is a class IC agent possessing a broad spectrum of antiarrhythmic actions in a variety of animal models. It increases the ventricular fibrillation threshold of the perfused rabbit heart and in situ dog myocardium. Encainide suppresses atrial fibrillation resulting from topical application of aconitine in the anesthetized dog and ventricular fibrillation induced by chloroform asphyxiation in the mouse. In these latter 2 models, encainide is approximately 7 to 11 and 16 to 18 times more potent, respectively, on a milligram basis than quinidine. In anesthetized dogs encainide converts ouabain-induced tachyarrhythmias to normal sinus rhythm at a mean intravenous dose of 0.67 mg/kg. Single doses of 0.5 mg/kg intravenously or 1 mg/kg orally significantly reduced ventricular ectopy in conscious dogs 18 to 22 hours after 2-stage ligation of the left coronary artery. At doses and plasma concentrations exceeding efficacious therapeutic levels, encainide has no major negative inotropic effects and does not compromise cardiac function or hemodynamics. It is devoid of peripheral autonomic or mediator-evoked responses and, in particular, lacks anticholinergic actions. Encainide is rapidly absorbed by all routes of administration and extensively metabolized by the liver. The major metabolites, O-demethyl encainide and 3-methoxy-O-demethyl encainide, have been shown to have quantitatively different, but qualitatively similar, profiles of pharmacodynamic effects. Subacute and chronic administration of encainide at doses representing 11 times an effective oral human dose have produced no distinct or consistent toxicologic findings. Carcinogenicity and mutagenicity studies were negative.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of Ca2+ in the vascular contraction caused by a thrombin receptor activating peptide

Thrombin receptor activating peptide (TRAP) caused a slowly developing, sustained contraction of endothelium denuded rat aortic rings. Both nifedipine (10 microM) and removal of Ca2+ from the physiological salt solution (PSS) caused significant (60-75%) reductions in the contractile response to TRAP. In Ca(2+)-free PSS the response to both phenylephrine and TRAP were markedly reduced. Readministration of Ca2+ quickly restored the full response to phenylephrine. In contrast, readministration of Ca2+ only partially restored the TRAP response. Depletion of TRAP-sensitive intracellular Ca2+ stores had no effect on the phenylephrine response in Ca(2+)-free PSS. A threshold contracting concentration of TRAP (10 microM) enhanced contractions to the activator of voltage regulated Ca2+ channels Bay K 8644. Similarly, Bay K 8644 enhanced responses to TRAP. It is concluded that the contractile response of rat aortic rings to TRAP is largely mediated by influx of extracellular Ca2+. Furthermore, the intracellular Ca2+ pool(s) activated appears to be different from the phenylephrine-sensitive pools, which cannot be depleted by TRAP.

Enzyme inhibitors of the renin-angiotensin system.

The primary purpose of this review is to summarize new developments in the area of inhibitors of the renin-angiotensin system. Specifically, inhibitors of the two main enzymes involved in the generation of angiotensin II, renin and angiotensin-converting enzyme (ACE), will be examined. This review will concentrate primarily on novelty, either chemical or pharmacological, rather than cataloging anticipated and similar results of closely related analogs.

Effect of encainide, ODE, MODE, and flecainide on ADP/5-HT Induced platelet aggregation and in the anesthetized dog coronary artery stenosis-occlusion model of intravascular thrombosis

SummaryEncainide is a class 1C antiarrhythmic agent that is indicated for the treatment of life-threatening arrhythmias, such as sustained ventricular tachycardia. Furthermore, encainide possesses a moderate degree of antiserotonin activity, which was quantitated in this present study by determining displacement of [3H]spiperone binding from rat cortical 5-HT2 binding sites. The Ki for encainide in this model was 66.1 nM, compared to 2.6 nM for ketanserin. Two encainide metabolites, ODE and MODE, were also active, but were weaker than encainide. Additionally, these agents were found to inhibit platelet aggregation induced in vitro in human platelet-rich plasma by the combination of ADP and serotonin. In view of the fact that serotonin is one of a variety of humoral factors capable of activating blood platelets and has been recently implicated as playing a role in certain thrombotic syndromes, encainide, along with its two principal human metabolites, ODE and MODE, and another class 1C antiarrhythmic, flecainide, were evaluated in an in vivo model of intravascular thrombosis. Intraduodenal doses of 1 mg/kg of either encainide, ODE, or MODE significantly inhibited thrombosis in a canine model of coronary artery stenosis-occlusion.

Differences in kidney renin content between normotensive and spontaneously hypertensive rats: effect of captopril treatment

Kidney renin concentrations were significantly lower in spontaneously hypertensive rats (SHR) than in normotensive Wistar Kyoto (WKY) rats. After treatment of both SHR and WKY rats with captopril (100 mg/kg p.o. for 3 months), kidney renin concentration increased dramatically in SHR and slightly, but significantly, in WKY. After captopril treatment, kidney renin content of SHR was still significantly lower than WKY. Because of the lower content of kidney renin in SHR and the proportionately greater increase in kidney renin content in SHR after captopril treatment than in WKY, it is proposed that a fundamental difference(s) in the control of the renin-angiotensin system exists in SHR, an effect which may or may not be related to SHR hypertension.