Effect of amitriptyline antidotes on repetitive extrasystole threshold
The effect ofamitriptyline that leads to ventricular tachycardia was evaluated hy the repetitive extrasystole threshold (RET) technique in 18 dogs. The RET was 28.8 ± 7.9 mamp before and 8.2 ± 5.3 mamp after amitriptyline. p < 0.001. Physostigmine. propranolol. sodium bicarbonate, and left stellate ganglionectomy reversed the effect of amitriptyline on RET. We conclude that amitriptyline overdose predisposes to sudden death by lowering the ventricular fibrillation threshold. This cardiotoxic effect is mediated partly through the central nervous system and can be inhibited by increased plasma binding (bicarbonate), cholinergic stimulation (physostigmine), beta adrenergic blockade (propranolol), and sympathetic denervation (left stellate ganglionectomy).
Jonathan M. Tobis, M.D., and Wilbert S. Aronow, M.D. Irvine, Calif. Cardiology Section and Medical Service, University of California, Irvine, and Long Beach Veterans Administration Medical Center
The mechanism of tricylic antidepressant ac tyline on the repetinve extrasystole threshold tion is not established. The cardiotoxic proper (RET), Matta et al." have shown that the RET ties have been established.?- II, 14 The most was a good marker of the ventricular fibrillation common serious clinical arrhythmia is ventricu threshold in 91% of the animals they studied. A lar tachycardia." Several antidotes have been single repetitive extrasystole occurred when reported as successful in reversing the central 66% of the fibrillation current was delivered, nervous system and cardiac manifestations oftri and repeated extrasystoles were induced at 82% cyclic antidepressant overdose, i.e., physo of the fibrillation current. stigmine, propranolol, and sodium bicarbon We then explored the effect of several poten ate,3-5, 10. 12. I:l but there is no agreement on tial antidotes. To elucidate the mechanism of their mechanism of action or efficacy. I, 2 action of the tricyclics, we manipulated sympa We investigated some of the cardiotoxic thetic and parasympathetic nervous system ac properties of amitriptyline. Because of the life tivity with physostigmine and propranolol and threatening effects of an overdose in humans, by cutting the left stellate ganglion. We also we thought we were limited to the animal model studied the effect of sodium bicarbonate, to analyze the effect of an overdose of amitrip- Methods Eighteen healthy mongrel dogs of both sexes, Received for publication Oct. 26, 1979. weighing 16 to 27 kg, were used. Anesthesia Accepted for publication Dec. 8. 1979. was induced intravenously with sodium thi Reprint requests to: Jonathan M. Tobis, M.D., Assistant Profes amylal 4 mg/kg and alpha chloralose 40 to 80 sor of Medicine, University of California, Irvine, !OI City Dr. So., Orange, CA 92668. mg/kg at a concentration of 5 mg/ml in heated
602 Volume 27 Antidotes to amitriptyline poisoning 603 Number 5
normal saline. Additional alpha chloralose 20 to ments of I or 2 mamp until there was a repeti 50 mg/kg was given if required during the ex tive extrasystole. The RET was defined as the periment to maintain anesthesia. The dogs were current required to induce at least one extra de intubated and ventilated with a Harvard pump polarization after the premature electrical input. with a mixture of room air and 100% oxygen. The RET was verified by obtaining extrasys The ventilator was adjusted to stabilize the ar toles in at least 2 of 3 trials. The maximum terial blood pH at 7.30 to 7.45. Overhead lights output of our generator was 40 mamp. were used to maintain body temperature. A 16 F Experimental interventions. After the base polyethylene catheter was inserted percutane line RET was obtained and reproduced 15 to 30 ously into the right femoral vein for drug admin min later, amitriptyline was given as a bolus istration. The left femoral artery was cannulated infusion of 10 to 20 mg/kg over 30 min in 9 percutaneously with a 16 F polyethylene cathe dogs. In 7 other dogs an amitriptyline bolus of 3 ter and used to measure systemic blood pressure to 10 mg/kg was injected intravenously and fol and obtain arterial blood samples. A Statham D lowed by a constant infusion of 0.015 to 0.025 23 De transducer and a Grass Polygraph re mg/kg/min. The RET was obtained IS min corder model 7 were used to record systemic after the initial bolus of amitriptyline and was blood pressure. An electrocardiogram was re verified as stable up to 60 min later. corded on the Grass Polygraph using a standard In 6 dogs physostigmine was given intrave limb lead. nously as a 2-mg bolus 30 to 45 min after the Electrical testing of the heart was performed amitriptyline bolus or during continuous ami as follows. The chest cavity was opened by triptyline infusion. Another RET was obtained right thoracotomy. A midline sternotomy was 10 to IS min after physostigmine. performed in the series of left stellate gan In 5 dogs propranolol 2 mg was given intra glionectomy experiments. Two Cordis suture venously 30 to 45 min after the amitriptyline less epicardial electrodes, model 324-856, were bolus or during continuous amitriptyline infu placed 2 em apart on the right ventricle midway sion. The RET was determined 10 to IS min between the apex and the atrioventricular after propranolol. groove. The electrodes were connected through In 5 dogs a midline sternotomy was per a stimulus isolation unit (Grass SIU-5A) and a formed. The RET was determined at baseline constant-current unit (Grass CCU-2A) to a and then during an amitriptyline infusion of Grass S-44 square-wave pulse generator. The 0.015 to 0.025 mg/kg/min after an initial intra output of this assembly was calibrated with an venous bolus of 3 to 10 mg/kg. A left stellate oscilloscope. The pulse generator was set at 200 ganglionectomy was performed through the bpm to overcome any tachycardia induced by sternotomy incision. During constant infusion the anticholinergic effect of amitriptyline. The of amitriptyline the RET was again obtained. heart was paced with a 2-msec impulse. The In 2 dogs sternotomy was performed, fol pulse generator had the ability to deliver a pre lowed by baseline determination of RET. These mature impulse with variable delay after the last dogs then had a left stellate ganglionectomy paced beat. The pulse generator would then shut prior to any drug administration. After the off for 3 sec, during which the effect of the postganglionectomy RET was performed, an premature extrastimulus could be observed on amitriptyline bolus of IS mg/kg was followed the electrocardiogram. by a 0.015- or 0.025-mg/kg/min infusion in The RET was obtained in the manner de travenously, and RET was repeated. scribed by Matta et al.? Electrical diastole was In 4 dogs RET was determined before and scanned in 5-msec decrements, beginning at the during intravenous amitriptyline infusion. RET end of the T wave and ending at the border of was repeated after 44 mEq sodium bicarbonate the strength interval curve, i.e., where no de was given intravenously over 5 min. Arterial polarization could be induced with the extrasys pH was determined before and after bicarbonate tole. The current of the extrasystole impulse while RET was being determined. was set at 2 mamp and was increased in incre- Several amitriptyline blood samples were 604 Tobis and Aronow Clin. Pharmacal. Ther. May 1980
40 40
36 36
32 32
28 28
24 24
""E 20 20 -c E
16 16
12 12
Control Amitriptyline Physostigmine Control Amitriptyline Propranolol
Fig. 1. Repetitive extrasystole threshold before Fig. 2. Repetitive extrasystole threshold before amitriptyline, after amitriptyline, and after physo amitriptyline, after amitriptyline, and after proprano stigmine. rnA, Milliampere (mamp). lol. rnA, Milliampere (mamp). drawn during each experiment to ensure ade triptyline followed by left stellate ganglionec quate toxic blood levels. Amitriptyline and tomy. Mean RET was 28.4 ± 7.5 mamp before nortriptyline plasma levels were determined by and 9.4 ± 3.8 mamp after amitriptyline, p < Bio-Science Laboratories. 0.005, and 27.6 ± 9.8 mamp after left stellate ganglionectomy (control not significantly dif Results ferent). For the entire group of 16 dogs RET ± 1 SD Fig. 4 shows RET in the 4 dogs given ami was 28.8 ± 7.9 mamp during the control pe triptyline followed by sodium bicarbonate. riod and 8.2 ± 5.3 mamp after amitriptyline, Mean RET was 25.3 ± 4.0 mamp before and p < 0.001. Average blood level at the time of 5.8 ± 3.3 mamp after amitriptyline, p < 0.01, RET determination was 933 ± 562 ng/ml. and 21.3 ± 16.0 mamp after sodium bicarbon Fig. 1 shows RET in the 6 dogs given ami ate (control not significantly different). Mean triptyline followed by physostigmine. Mean arterial pH was 7.26 ± 0.08 before and 7.39 ± RET was 23.5 ± 5.7 mamp before and 9.8 ± 0.08 after an average dose of 44 mEq sodium 6.0 rna after amitriptyline, p < 0.001, and bicarbonate. 26.7 ± 6.8 mamp after physostigmine (control In the 2 dogs with left stellate ganglionec not significantly different). tomy before amitriptyline infusion, the ventricu Fig. 2 shows RET in the 5 dogs given ami 1M fibrillation threshold (VFT) was measured triptyline followed by propranolol. Mean RET directly rather than RET, because ventricu was 35.6 ± 6.1 mamp before and 5.0 ± 5.2 lar fibrillation developed in the control periods mamp after amitriptyline, p < 0.001, and during RET measurement. Control VFT was 38.0 ± 2.8 mamp after propranolol (control not 33.0 ± 7.5 mamp before and 37.0 ± 0.0 significantly different). mamp after left stellate ganglionectomy (p not Fig. 3 shows RET in the 5 dogs given ami- significant) and 37.8 ± 4.5 mamp after amitrip- Volume 27 Antidotes to amitriptyline poisoning 605 Number 5
40 40
36 36
32 32
28 28
24 24
20 20 « E -c E 16 16
12 12
Control Amitriptyline left Stellate Control Amitriptyline Bicarbonate Ganglionectomy Fig. 4. Repetitive extrasystole threshold before Fig. 3. Repetitive extrasystole threshold before amitriptyline, after amitriptyline, and after sodium amitriptyline, after amitriptyline, and after left stel bicarbonate. rnA, Milliampere (mamp). late ganglionectomy. rnA, Milliampere (mamp). tyline (p not significant). At the time of VFT the which leads to early excess of catecholamines mean level of amitriptyline was 971 ± 526 with resultant hypertension and tachycardia. (3) ng/m!. With continued blockage of catechol uptake there is catecholamime depletion with sub Discussion sequent hypotension and bradycardia. (4) There Our data demonstrated that amitriptyline may also be direct myocardial depression by consistently reduced RET in anesthetized dogs. tricyclic antidepressants, perhaps accounting These dogs were given alpha chloralose to di for decreased contractility and heart block. minish the effects of anesthesia on myocardial The most common serious arrhythmia that electrical properties. The lowered RET is con tricyclic antidepressant overdose victims de sistent with the clinical finding that tricyclic an velop is sinus tachycardia, often with a broad tidepressant overdoses predispose to ventricular QRS, followed by ventricular tachycardia. One tachycardia. This effect on RET was countered of the questions we sought to answer was by physostigmine, propranolol, and left stellate whether this cardiotoxic effect is a direct action ganglionectomy. of tricyclic antidepressants on myocardial cells Clinical manifestations in victims of tricyclic or whether there is some indirect action through antidepressant overdose suggest that there are 4 the central nervous system. major mechanisms of action.P (l) There are Our hypothesis is that tricyclic antidepressant early signs of anticholinergic effects, e.g., cardiotoxicity is the result of imbalance of au mydriasis, diminished secretions, tachycardia, tonomic tone to the myocardium, which induces decreased gastrointestinal tract motility, and uri dispersion of repolarization (evidenced by pro nary retention. (2) Tricyclic antidepress longed QT interval) and predisposes to ventricu ants have been shown to block the re-uptake lar tachycardia and ventricular fibrillation. Thus, of catecholamines at neuromuscular junctions, antidotes to tricyclic antidepressant poisoning 606 Tobis and Aronow Clin. Pharmacal. Ther. May 1980
may work if they reestablish normal autonomic propranolol, and sodium bicarbonate in the tone. treatment of severe tricyclic antidepressant Because tricyclic antidepressants have an an overdose. ticholinergic action, physostigmine may coun teract cardiotoxic manifestations by increasing cholinergic tone, and propranolol may block References unopposed sympathetic tone to equalize the I. Bigger, JT, Kantor SJ, Glassman AH, Perel JM: neural input ot the myocardium and thereby Letters: Is physostigmine effective for cardiac toxicity of tricyclic antidepressant drugs? JAMA counteract the cardiotoxic effect of tricyclics. 237:1311, 1977. The data from our experiments indicate that 2. Biggs JT, Spiker DG, Petit JM, Ziegler VE: both physostigmine and propranolol counteract Tricyclic antidepressant overdose. JAM A the effect of amitriptyline on RET. 238:135-138, 1977. The experiments with left stellate ganglio 3. Brown KGE, McMichen HUS, Briggs DS: Tachyarrhythmia in severe imipramine overdose nectomy suggest that the cardiotoxic properties controlled by practolol. Arch Dis Child 47: of amitriptyline are centrally mediated. The 104-106, 1972. partial sympathectomy reversed the toxic ef 4. Brown TCK, Barker GA, Dunlop ME, Lough fects of amitriptyline on RET. When amitrip nan PM: The use of sodium bicarbonate in the tyline was given after left stellate ganglionec treatment of tricyclic antidepressant-induced ar rhythmias. Anaesth Intensive Care 1:203-21 0, tomy, there was no RET decrease despite toxic 1973. blood levels of amitriptyline (x = 971 ng/ml). 5. Duvoisin RC, Katz R: Reversal of central an This blood level of amitriptyline consistently ticholinergic syndrome in man by physostig lowered RET before left stellate ganglionec mine. JAMA 206:1963-1965, 1968. tomy. These blood levels of amitriptyline are 6. Fouron JC, Chicoine R: ECG changes in fatal imipramine (Tofranil) intoxication. Pediatrics associated clinically with severe overdoses with 48:777-781,1971. frequent episodes of ventricular tachycardia." 7. Hollister LE: Tricyclic antidepressants. N Eng J The question arose as to whether physostig Med 299: 1106-1109, 1168-1172, 1978. mine, propranolol, and left stellate ganglionec 8. Jefferson JW: A review of the cardiovascular tomy are nonspecific for counteracting tricyclic effects and toxicity of tricyclic antidepressants. Psychosom Med 37:160-174,1975. antidepressant toxicity and will tend to raise 9. Matta RJ, Verrier RL, Lown B: Repetitive ex RET under any circumstance. We showed that trasystole as an index of vulnerability to ven there is no increase in baseline RET when left tricular fibrillation. Am J Physiol 230:1439 stellate ganglionectomy is performed before 1473, 1976. amitripty line. 10. Munoz RA, Kuplic JB: Large overdose of tricyclic antidepressants treated with physo Sodium bicarbonate has been shown to in stigmine salicylate. Psychosomatics 16:77-78, crease the plasma binding of tricyclics by rais 1975. ing arterial pH. There are case reports of its 11. Noble J, Matthew H: Acute poisoning by tricyc clinical efficacy. In 2 dogs there was a dramatic lic antidepressants: Clincal features and man increase in RET after 44 mEq sodium bicar agement of 100 patients. Clin Toxicol 2:403 421, 1969. bonate. In 2 other dogs RET did not increase 12. Rumack BH: Anticholinergic poisoning: Treat despite adequate elevation of arterial pH. There ment with physostigmine. Pediatrics 52:449 are not enough clinical reports to suggest the 451, 1973. frequency with which sodium bicarbonate is ef 13. Siovis TL, Ott JE, Teitelbaum DT, Lipscomb fective in reversing toxic tricyclic antidepres W: Physostigmine therapy in acute tricyclic an tidepressant poisoning. Clin Toxicol 4:451-459, sant properties. 1971. In the clinical application of experiments, 14. Tobis J, Das BN: Cardiac complications in caution must be exercised in extending results amitriptyline poisoning. JAMA 235:1474-1476, from laboratory animals to humans. Data from 1976. our study suggest a rationale to pharmacologic 15. Winters WD, Johnson M: The tricyclic antide pressant overdosed patient, in Rumack B, Tem intervention in humans with life-threatening ar ple A, editors: Management of the poisoned pa rhythmias resulting from amitriptyline. We rec tient. Princeton, NJ, 1977, Science Press, pp. ommend the cautious use of physostigmine, 62-76.