Methoctramine, a cardioselective muscarinic cholinergic antagonist, prevents fentanyl‐induced bradycardia in the dog

Abstract

A controlled study examining the effects of the cardioselective muscarinic cholinergic antagonist methoctramine on fentanyl-induced bradycardia was performed in six dogs. Five doses of methoctramine (6, 10, 20, 30 and 60 micrograms/kg) followed by fentanyl (20 micrograms/kg) were administered randomly on separate days. Fentanyl caused a significant reduction in heart rate from baseline values. Moreover, fentanyl produced a variety of arrhythmogenic actions indicative of vagal hyperactivity, including sinus bradycardia, second-degree atrioventricular block and ventricular and supraventricular escape beats. Administration of methoctramine 5 min before fentanyl injection prevented the bradycardic effects of fentanyl in a dose-dependent manner, with high doses of methoctramine causing sinus tachycardia. Using regression analysis, the dose of methoctramine necessary to prevent fentanyl-induced bradyarrhythmias without causing tachycardia was calculated as 14.4 micrograms/kg. The study confirmed that fentanyl administration in the conscious dog causes profound bradycardia with bradyarrhythmias. The cardioselective muscarinic antagonist agent methoctramine prevented the bradycardic effects of fentanyl.

In vivo measurement of QT prolongation, dispersion and arrhythmogenesis: application to the preclinical cardiovascular safety pharmacology of a new chemical entity

“…3 additional, indirect effects of an NCE on neurogenic mechanisms, such as vagal stimulation or drug‐induced histamine release, not detected by in vitro screens, as with Mu opioid agonists or some antibiotic compounds [15–17].…”

“…Classic examples illustrating such limitations of in vitro testing are verapamil, potently blocking IKr in transfected cells without deleterious effect on cardiac repolarization in vivo, possibly via an additional attenuation of ICa 2+ L [14,15], Mu opioid agonists, inducing vagal hyperactivity and cholinergically mediated bradycardia with cardiac conduction disturbances at high doses [16,17] or fluoroquinolone antibiotics inducing histamine release with repercussions on cardiac electrophysiology, at least in experimental animals [18].…”

Effects of a muscarinic type-2 antagonist on cardiorespiratory function and intestinal transit in horses anesthetized with halothane and xylazine

“…The dosing range for methoctramine was based on results of a preliminary study a and dose-response studies 18,24 performed in dogs. For each horse, we attempted to control the HR response by administering boluses (10 µg/kg) every 10 minutes until HR was increased by at least 30% above baseline or until a total cumulative dose of 30 µg/kg had been administered.…”

“…17,20,21 Because of their selective cardiac effects at doses that do not interfere with other parasympathetically mediated functions in vitro and in vivo, the term cardioselective antagonist has been used to designate M 2 receptor antagonists. 18,[22][23][24] Methoctramine, a cardioselective muscarinic antagonist, can prevent fentanyl-induced bradycardia in dogs when administered at a dosage of 14.4 µg/kg. 24 In a preliminary in vitro study, a it was determined that the M 2 antagonist methoctramine had a relatively low potency for antagonizing the effects of acetylcholine on equine longitudinal jejunal smooth muscle, compared with the effects for the M 3 antagonist 4-DAMP.…”

“…18,[22][23][24] Methoctramine, a cardioselective muscarinic antagonist, can prevent fentanyl-induced bradycardia in dogs when administered at a dosage of 14.4 µg/kg. 24 In a preliminary in vitro study, a it was determined that the M 2 antagonist methoctramine had a relatively low potency for antagonizing the effects of acetylcholine on equine longitudinal jejunal smooth muscle, compared with the effects for the M 3 antagonist 4-DAMP. Despite the potential clinical application of cardioselective muscarinic antagonists in the treatment of horses with intraoperative bradycardia, we are not aware of any studies conducted to evaluate the effects of methoctramine in an experimental model of bradycardia during general anesthesia in horses.…”