Vasopressor challenges during chronic MAOI or TCA treatment in anesthetized dogs

Ten male mongrel dogs were treated in Phase I with tranylcypromine, 6 mg/kg IM b.i.d., for 21 days. Dogs were anesthetized at weekly intervals before, during, and up to four weeks after drug treatment with a combination of amylbarbital, 25 mg/kg, 1% enflurane in 70:30 N₂0:0₂) and fentanyl, 500 mcg. Bolus IV injections of norepinephrine, 0.1–0.6 mcg/kg, and ephedrine, 0.03–0.12 mg/kg were given while continuously recording arterial blood pressure, lead II of the ECG, heart rate, and rectal temperature. Awakening times were noted. In Phase II, the dogs were given imipramine, 25 mg/kg IM b.i.d., for 21 days. During Phase III, 14 days of tranylcypromine, 7 days of tranylcypromine plus imipramine, and 7 days of imipramine were administered. Anesthetic techniques were repeated in phases II and III. The fourth phase consisted of tranylcypromine injections, 6 mg IM b.i.d., and anesthesia with amylbarbital 25 mg/kg, 2.5% enflurane in 70:30 N₂0:0₂. Vasopressor challenges were repeated during each phase of the study. Following induction of anesthesia and prior to fentanyl challenge, baseline blood pressures and heart rates did not differ from control in Phase I, II, and III of this study. Responses to norepinephrine during all of the tranylcypromine phases were not significantly different from control but ephedrine responses were prolonged, peaking by the second week of treatment. During Phase II, dysrhythmias occurred following norepinephrine and ephedrine with one lethality following norepinephrine, 0.2 mcg/kg. Responses to norepinephrine and awakening times were significantly greater during Phase II compared to Phase I. In Phase III, during the first week of combined therapy the responses to norepinephrine were significantly greater than any other week of this phase. During Phase IV, resting blood pressure and the ephedrine responses were significantly increased during tranylcypromine when the anesthesia regimen did not include fentanyl. These results suggest that during initial treatment with tranylcypromine or imipramine, cardiovascular responses to vasopressor challenges were predicted by the pharmacology of the antidepressant. During tranylcypromine phases, we did not observe exaggerated cardiovascular effects during anesthesia and vasopressor challenges as had been previously reported.

The use of monoamine oxidase inhibitors (MAOIs), alone or in combination with tricyclic antidepressants (TCAs), has been increasing over the last few years because they appear to be more effective than TCAs alone in treating resistant affective disorders. (1,2) However, reluctance to use MAOIs has persisted because of reports of interactions with various foods and drugs. (3–6) In recent years, cell membrane receptor studies have shown that chronic treatment (greater than 14 to 21 days) with either MAOIs of TCAs results in physiological adaptations that partially reduce the interactions between drugs and their receptors. (7,8) Attenuation of arrhythmogenicity has been described in dogs after six weeks of TCA treatment. (9) Clinically, patients on chronic MAOI therapy have undergone elective surgery, including open-heart surgery, without adverse responses. (10,11) The cardiovascular response to analgesics, anesthetics, and vasopressors during the initial phase (less than 14 to 21 days) of treatment with MAOIs compared to TCAs has yet to be addressed. Therefore, the purpose of this study was to examine the cardiovascular responses of analgesic, anesthetic, and vasopressor agents before, during, and after the first three weeks of MAOI and TCA administration in dogs.