UCLA UCLA Previously Published Works Title Cardiotoxicity of amitriptyline and doxepin. Permalink https://escholarship.org/uc/item/80v5m0x9 Journal Clinical pharmacology and therapeutics, 29(3) ISSN 0009-9236 Authors Tobis, JM Aronow, WS Publication Date 1981-03-01 DOI 10.1038/clpt.1981.49 License https://creativecommons.org/licenses/by/4.0/ 4.0 Peer reviewed eScholarship.org Powered by the California Digital Library University of California Cardiotoxicity of amitriptyline and doxepin The cardiotoxicity of the tricyclic antidepressants amitriptyline and doxepin were compared in an animal with acute overdose. The mean repetitive extrasystole threshold (RET) decreased 71.5% with amitriptyline and 27.5% with doxepin (mean blood levels 933 nglml and 1889 nglm1). Physostigmine reversed these effects. Sodium bicarbonate had a variable effect on the lowered RET. The toxic arrhythmogenic effects of the tricyclic antidepressants can be measured by RET and are partly reversed by autonomic tone manipulation. In the same blood level range, doxepin is less toxic than amitriptyline. Jonathan M. Tobis, M.D., and Wilbert S. Aronow, M.D. Irvine, Calif Department of Medicine, University of California There is controversy over the relative car- Because of the life-threatening effects of diotoxicity of various tricyclic antidepressant overdose in humans, we were limited to the drugs.° Some believe that doxepin is less car- animal model to analyze the effect of amitrip- diotoxic than amitriptyline or imipramine.8 On tyline and doxepin overdose on repetitive ex- the other hand, there are several reports of fatal trasystole threshold (RET). We chose a dog intoxication from doxepin alone.' Vohra et al.' with acute drug overdose and constantly infused studied the effects on bundle of His conduction drug to maintain blood levels at toxic concen- of several tricyclic antidepressants in overdose tration. Electrical vulnerability was tested by victims.' They found prolonged HV conduction measuring ventricular fibrillation threshold di- time in seven of eight patients who had taken rectly or by measuring the current required to nortriptyline, amitriptyline, or imipramine but produce a repetitive extrasystole. Matta et al.6 normal bundle of His studies in six patients af- found that the RET is a good marker of the ter doxepin. Most of the deaths from tricyclic ventricular fibrillation threshold in 91% of the antidepressant overdose are from ventricular dogs they studied; single repetitive extrasystoles tachycardia that develops into ventricular fibril- occurred when 66% of the fibrillation current lation. Conduction abnormalities demonstrated was delivered and multiple extrasystoles at 82% by His studies suggest that electrical vulner- of the fibrillation current. In those animals with ability to ventricular tachycardia may be a dis- a significant fall in RET (taken arbitrarily as tinct characteristic. We therefore examined the >50% reduction in RET from baseline), several effect of amitriptyline and doxepin on electrical potential antidotes to the cardiotoxicity of instability. tricyclic antidepressants were tested. We have reported on the effect of amitriptyline on RET and its reversibility with sodium bicarbonate, Received for publication Oct. 27, 1980. physostigmine, propranolol, or left stellate Accepted for publication Nov. 18, 1980. ganglionectomy .7 We report here on our com- Reprint requests to: Jonathan M. Tobis, M.D., University of California, Irvine, 101 City Dr. South, Orange, CA 92668. parison of the effect of doxepin on electrical 0009-9236/81/030359+06$00.60/0 C) 1981 The C. V. Mosby Co. 359 360 Tobis and Aronovv Clin Pharmacol. Ther. March 1981 40- Table I. Effect of doxepin on RET and doxepin blood levels 36 - R ET Doxepin RET after doxepin blood level control (mA) (tnA) (ng Iml 32- Group A* 33.3 ± 4.7 31.4 7.2 1,614 ± 785 28 Group Bt 33.0 4.5 6.8 3.9t 2,379 921§ 24 - *RET after doxepin was not lowered more than 50% of control RET. tRET after doxepin was lowered more than 50% of control RET. < 0.01 RET before and after doxepin in group B. 20 - a §p < 0.05 Dozepin blood level reached in group B compared E _ with group A. 16 into the right femoral vein for injection of drugs. The left femoral artery was cannulated 12- with a 16-gauge polyethylene catheter and used to measure systemic blood pressure and to ob- 8- tain arterial blood samples. A Statham P23 Dc transducer and a Grass Polygraph recorder, were to 4 - Model 7, used record systemic blood pressure. An electrocardiogram was recorded on the Grass Polygraph using a standard limb lead. CONTROL AMITRIPTYLJNE DOXEPIN Electrical testing of the heart was performed Fig. 1. Comparison of amitriptyline and doxepin on as follows. The chest was opened by a thoracot- RET. omy on the right. Two Cordis sutureless epicar- dial electrodes, Model 324-856, were placed 2 vulnerability and the results of sodium bicar- cm apart on the right ventricle midway between bonate or physostigmine to reverse the car- the apex and the atrioventricular groove. The diotoxic effects. electrodes were connected through a stimulus isolation unit (Grass SIU-5A) and a constant Methods current unit (Grass CCU-1A) to a Grass S-44 We used 26 healthy mongrel dogs weighing square-wave pulse generator. The output of this 16 to 27 kg. Anesthesia was introduced in- assembly was calibrated with an oscilloscope. A travenously with sodium thiamylal 4 mg/kg and separate pacemaker was placed in line with the alpha chloralose 40 to 80 mg/kg at a concentra- Grass stimulator and was set at 200 beats per min tion of 5 mg/ml dissolved in heated normal to overcome any tachycardia induced by the an- saline. Additional alpha chloralose 20 to 50 ticholinergic effect of tricyclic antidepressants. mg/kg was given during the experiment if The heart was paced at 2 mA with a 2-msec necessary to maintain anesthesia. The dogs impulse. The pulse generator was able to deliver were intubated and ventilated with a Harvard a premature impulse with variable delay after the pump using a mixture of room air and 100% last paced beat. The pacemaker would then shut oxygen. The ventilator was adjusted to stabilize off for 3 sec, during which the effect of the the arterial blood pH at 7.30 to 7.45. Lights premature extrastimulus was observed on the were used to maintain body temperature. A electrocardiogram. 16-gauge polyethylene catheter was inserted The RET was obtained in the manner de- Volume 29 A mitriptyline and doxepin cardiotoxicitv 361 Number 3 scribed by Matta et al.6 Electrical diastole was 40-. scanned in 5-msec decrements, beginning at the end of the T wave and ending at the border of 36 - the strength interval curve, i.e., where no de- 32 polarization could be induced with the extrasys- tole. The current of the extrasystole impulses 28 - was set at 2 mA and was increased in incre- ments of 1 or 2 mA. The T wave was scanned at 24 - each successive current until a repetitive ex- trasystole was obtained. The RET was defined 20 - as the current required to induce at least one extra depolarization after the premature elec- 16 - trical input. The RET was verified by obtain- ing extrasystoles in at least two of three trials. 12 - The maximum output of our generator was 40 mA. 8 - Experimental interventions. After the base- 4 - line RET was obtained and reproduced 15 to 30 min later, amitriptyline or doxepin was infused. Each animal received only one of the drugs. CONTROL I BICARBONATE I COXEPIN Doxepin was given at a rate of 10 to 15 mg/kg A M ITR I PTYUNE CONTROL BICARBONATE over 30 min, followed by a constant infusion of Fig. 2. Comparison of amitriptyline and doxepin on 0.01 to 0.03 mg/kg/min. Amitriptyline was RET and effect of sodium bicarbonate in cases where given as an initial intravenous bolus of 3 to 10 fixed doses of drug decreased RET. mg/kg over 30 min, followed by constant infu- sion of 0.015 to 0.025 mg/kg/min. A constant Statistical analyses were by Student's t test for infusion was used to maintain blood levels. The paired or independent means. RET was obtained 15 min after the initial bolus and was verified as stable up to 60 min later. If Results the RET did not change significantly after the Three animals were tested for up to 3 hr for initial bolus, a second or even a third 10-mg/kg control levels and stability of the RET. The dose of drug was given. Blood levels of amitrip- baseline RET was 31 ± 1 mA and remained at tyline or doxepin were obtained at the time RET 30 ± 3 mA up to 3 hr later, with measurements was established. Blood levels were analyzed by taken every 30 to 60 min. After the control val- gas chromatography at Bio-Science Labor- ues were established in these three animals, 2 atories (Van Nuys, Calif.) mg physostigmine was given intravenously. The methods and results of administering po- The repeat mean RET was 30.6 ± 5.4 mA tential antidotes to amitriptyline have been re- (control not significantly different). For the ported.7 Ten dogs received doxepin. In those control animals and at various stages during the animals where the RET fell more than 50%, 44 intervention experiments, the ventricular fibril- mEq sodium bicarbonate was given intrave- lation threshold (VFT) was compared with the nously, and the RET was reperformed within 10 RET. The RET was 90.8% of the VFT. How- min. Arterial pH was measured before and after ever, during 1.5% of the trials the VFT oc- bicarbonate. In four dogs equilibrium was es- curred at the same current level as the RET.