Simultaneous assessment of the hemodynamic, cardiomechanical, and electrophysiological effects of terfenadine on the in vivo canine model.
Prolongation of the QT interval, sometimes leading to torsades de pointes, has been clinically reported during terfenadine treatment. However, information regarding the cardiovascular profile of terfenadine is still limited, particularly in in vivo animal models. In the current study, we examined the cardiovascular effects of terfenadine using halothane-anesthetized, closed-chest in vivo canine models (n = 6) to better simulate the clinical situation. Intravenous infusion of 0.3 mg/kg of terfenadine over 10 min, which would attain the antihistaminic plasma concentration, reduced the heart rate and left ventricular contractility and prolonged the repolarization period as well as the ventricular effective refractory period. An additional infusion of a ten times higher dose of terfenadine over 10 min caused hypotension and increased left ventricular preload and atrioventricular conduction time, in addition to potentiating the changes observed by the lower dose. A reverse use-dependent prolongation of the repolarization period was observed after the higher dose infusion. Moreover, early afterdepolarization-like potential was detected in four out of six experiments. Since each suppressive effect can become deleterious during terfenadine overdose, caution must be taken for those patients with potential cardiac dysfunction and with the risk of elevated plasma drug concentrations.
Usui
T
T
Second Department of Internal Medicine, Shinshu University School of Medicine, Nagano, Japan.
Sugiyama
A
A
Ishida
Y
Y
Satoh
Y
Y
Sasaki
Y
Y
Hashimoto
K
K
D000704:Analysis of Variance; D000818:Animals; D002320:Cardiovascular Physiological Phenomena; D002319:Cardiovascular System / Q000187:drug effects*; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D004594:Electrophysiology; D005260:Female; D006439:Hemodynamics / Q000187:drug effects*; D006634:Histamine H1 Antagonists / Q000008:administration & dosage* / Q000097:blood; D007275:Injections, Intravenous; D008297:Male; D011897:Random Allocation; D012016:Reference Values; D016593:Terfenadine / Q000008:administration & dosage* / Q000097:blood