Comparison of the potassium channel blocker tedisamil with the beta‐adrenoceptor blocker esmolol and the calcium antagonist gallopamil in patients with coronary artery disease

Abstract

Background: Tedisamil is a new bradycardic agent proven to exert anti‐ischemic and antiarrhythmic effects by blockade of the different cardiac and vascular K+ currents. Hypothesis: It was the aim of the present study to compare the favorable anti‐ischemic effects of tedisamil, with two long established representatives in the treatment of coronary artery disease (CAD), namely, the beta1 blocker esmolol and the Ca2 antagonist gallopamil. Methods: The hemodynamic and neurohumoral effects of the new potassium channel blocker tedisamil, an agent with negative chronotropic and class III antiarrhythmic properties, were compared with the ultra‐short‐acting beta1‐selective adrenoceptor blocker esmolol and the calcium antagonist gallopamil. A total of 22 patients with angiographically proven CAD and reproducible ST‐segment depression in the exercise electrocardiogram was included in two studies with an almost identical design and inclusion criteria. The investigation was carried out using right heart catheterization and bicycle ergometry. A subgroup of 8 patients receiving 0.3 mg/kg body weight tedisamil intravenously (IV) in an open dose‐finding study was compared with a group of 14 patients who had received esmolol (IV bolus of 500 μg/kg, maintenance dose 200 μg/kg/min) and gallopamil (initial dose 0.025 mg/kg, maintenance dose 0.0005 mg/kg/h) in a second intraindividual comparison. Results: Tedisamil and esmolol reduced heart rate at rest by 13% (p < 0.001), and 6% (p < 0.05), and at maximum working levels by 8% (p>0.01) and 9% (p>0.05), respectively. Gallopamil increased heart rate at rest by 7% (p < 0.05), with only slight changes occurring during exercise. Corresponding findings for each drug were observed for cardiac output both at rest and during exercise [tedisamil: at rest ‐10% (NS), max. exercise ‐ 8%; esmolol: at rest ‐14% (NS), max. exercise ‐18% (NS); gallopamil: no significant changes]. Compared with tedisamil, stroke volume was reduced by esmolol [at rest and max. workload: ‐9% (NS)] and gallopamil [rest: ‐6% (NS), max. exercise: ‐2% (NS)]. Of the indirect parameters of ventricular function, that is, mean capillary wedge pressure (PCWPm) and right ventricular ejection fraction, only PCWPm demonstrated significant differences between tedisamil and gallopamil (+18% and ‐6% at rest, + 17% and ‐21% during exercise, respectively; p>0.001). Compared with gallopamil, both tedisamil and esmolol were superior in their effects on rate‐pressure product, myocardial oxygen consumption, and ST‐segment depression, whereas plasma lactate concentration was more reduced by tedisamil and gallopamil. Tedisamil led to a fall in norepinephrine levels in particular. Conclusion: Tedisamil and esmolol showed almost equipotent anti‐ischemic effects at the doses administered. Tedisamil acts mainly by reductions in heart rate, and esmolol, though to a lesser degree, also by reductions in systolic blood pressure. The mechanism of gallopamil is to reduce afterload and to improve coronary perfusion. At the doses applied, however...

Effects of Tedisamil on Cardiovascular Tissues Isolated from Normoand Hypertensive Rats

“…Tedisamil did not alter cardiac contractility ontractions were calin patients with coronary disease (2). Tedisnd aorta contractions amil contracts the rat aorta (this study) and…”

“…Tedisamil is a bradycardic agent that is in clinical trial for angina (2,3) and heart failure (4). Inhibition of the transient outward potassium current (Ito) of human atrial myocytes (5) probably underlies the bradycardic effect of tedisamil.…”

Potassium Channel Openers and Blockers in Coronary Artery Disease Comparison to Betablockers and Calcium Antagonists

“…Bradycardic and antiischemic effects could be demonstrated following both intravenous and oral administration in in-vitro and in-vivo animal studies [7,15] as well as in humans [16,17,28]. In patients with coronary artery disease, the antiischemic effects of intravenous tedisamil were first described in an acute open-label dose-finding study [16,17] and compared to the beta-adrenoceptor blocker esmolol and the calcium antagonist gallopamil in patients with coronary artery disease [18]. Tedisamil and esmolol showed no difference in their negative chronotropic effect with the exception that tedisamil produced a greater reduction in heart rate at rest.…”

Clinically Important Interaction Between Tedisamil and Verapamil

“…The class III antiarrhythmic action of tedisamil shows reverse rate dependency because the prolongation of the duration of action potentials increases at lower heart rates 3 . Tedisamil has linear pharmacokinetics, is orally bioavailable (F ∼50%), and is eliminated as unchanged drug via the renal route 4 , 5 . Tedisamil is a substrate for the pleiotropic drug efflux pump P‐glycoprotein.…”

“…Tedisamil was initially developed for its antiischemic properties, and phase II results have confirmed beneficial hemodynamic and antiischemic effects in patients with ischemic heart disease 5 , 8 , 9 . Dose‐finding studies in patients with stable angina pectoris determined that doses of 50 to 100 mg bid are well tolerated and clinically effective 10 .…”