Pharmacology of the class III antiarrhythmic agent sematilide in patients with arrhythmias.
Sematilide, a close structural analog of N-acetylprocainamide, prolongs cardiac action potentials in vitro, whereas it does not depress maximum action potential upstroke slope, a "class III" action. This report outlines an evaluation of the clinical pharmacologic actions of sematilide in 14 patients with chronic high-frequency nonsustained ventricular arrhythmias. In all, 36 intravenous infusions (range 0.15 to 1.5 mg/kg over 15 minutes) were administered in a dose-ranging, placebo-controlled study design. Sematilide prolonged rate-corrected QT (QTc) in a dose- and concentration-related fashion, did not alter PR or QRS, and slowed heart rate at high concentrations (greater than or equal to 2 micrograms/ml). The relations between dose and total area under the time-concentration curve, dose and peak plasma concentration, and peak plasma concentration and increase in QTc were linear (r = 0.66 to 0.92; p less than 0.001). QTc increases of approximately equal to 25% were seen at plasma concentrations of approximately equal to 2.0 micrograms/ml. The mean elimination half-life (+/- SD) was 3.6 +/- 0.8 hours, and most of a dose (77 +/- 13%) was recovered unchanged in the urine. Plasma concentrations greater than or equal to 0.8 micrograms/ml suppressed arrhythmias (5 patients) or aggravated them (3), including 1 patient who needed cardioversion for an episode of torsades de pointes (2.7 micrograms/ml). Thus, sematilide exerts class III actions in patients. Further studies to evaluate the role of this antiarrhythmic mode of action should be conducted at doses designed to limit QTc increases.
Wong
W
W
Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee.
Pavlou
H N
HN
Birgersdotter
U M
UM
Hilleman
D E
DE
Mohiuddin
S M
SM
Roden
D M
DM
D000889:Anti-Arrhythmia Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D006207:Half-Life; D006801:Humans; D011342:Procainamide / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D016171:Torsades de Pointes / Q000139:chemically induced
D000889:Anti-Arrhythmia Agents; C062818:sematilide; D011342:Procainamide