Ann Emerg Med. 1986 Sep;15(9):1052-9.
Experimental amitriptyline intoxication: treatment of cardiac toxicity with sodium bicarbonate.

Sasyniuk BI, Jhamandas V, Valois M.

Overdose with amitriptyline and other tricyclic antidepressants can result in ventricular conduction abnormalities as well as severe ventricular arrhythmias. The arrhythmogenic effects of these compounds may be attributed to their direct local anesthetic actions in blocking sodium channels in cardiac membranes. Thus tricyclic-induced ventricular arrhythmias usually do not respond well to therapy with standard Class I antiarrhythmic drugs that also have the same direct local anesthetic action and may potentiate the adverse effects of tricyclic antidepressants. Cardiac toxicity was produced in dogs by the administration of amitriptyline, both orally and IV. At serum concentrations less than 2,000 ng/mL, sinus tachycardia occurred with widened QRS complexes. At higher concentrations, QRS duration became more markedly prolonged and was followed by ventricular tachyarrhythmias. Occurrence of ventricular tachyarrhythmias was associated with QRS durations of more than 0.11 second. Sodium bicarbonate (18 to 36 mEq) administered IV over either 30 seconds or two minutes rapidly converted ventricular tachycardia to normal sinus rhythm. Conversion was associated with abbreviation of the QRS complex and was accompanied by a rise in both systolic and diastolic pressures. The duration of sodium bicarbonate effect paralleled the duration of the changes in arterial pH and plasma bicarbonate concentrations. In vitro studies in cardiac Purkinje fibers suggested that reversal of amitriptyline-induced cardiac membrane effects by sodium bicarbonate may be attributed not only to alkalinization but also to increased in extracellular sodium concentration, diminishing the local anesthetic action of amitriptyline and resulting in less sodium channel block.(ABSTRACT TRUNCATED AT 250 WORDS)

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J Cardiovasc Pharmacol. 1984 Jan-Feb;6(1):83-9.
Experimental amitriptyline intoxication: electrophysiologic manifestations and management.

Nattel S, Keable H, Sasyniuk BI.

Amitriptyline intoxication can result in severe ventricular arrhythmias that may be refractory to medical management. The mechanisms of these arrhythmias are unclear, and their optimal management is problematic. We studied the cardiac effects of amitriptyline infusion in anesthetized and awake dogs. Amitriptyline significantly increased heart rate, QRS duration, and AH and HV intervals. The concentration-response curves for these effects were, however, quite different, with significant changes beginning at a concentration of 1.5 +/- 0.4 mg/L for heart rate, compared with 2.4 +/- 0.4 mg/L for QRS and HV intervals and 3.7 +/- 0.5 mg/L for the AH interval. Ventricular tachyarrhythmias developed after marked QRS widening had occurred, and appeared in all six awake dogs and five of the six anesthetized dogs studied. Sodium bicarbonate was given to seven animals with ventricular tachyarrhythmias, and it rapidly reversed the arrhythmia in all instances. The benefit from sodium bicarbonate could not be attributed to changes in serum potassium or amitriptyline concentrations. It may have been due to alkalinization or changes in serum sodium concentration. These experiments suggest that: (a) amitriptyline intoxication frequently produces ventricular tachyarrhythmias, if high enough drug concentrations are achieved; (b) these arrhythmias are associated with marked slowing of intraventricular conduction; and (c) sodium bicarbonate is effective therapy for amitriptyline-induced ventricular arrhythmia.

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Encephale. 1990 Jan-Feb;16(1):43-5.
[Valpromide-amitriptyline interaction. Increase in the bioavailability of amitriptyline and nortriptyline caused by valpromide]

[Article in French]

Bertschy G, Vandel S, Jounet JM, Allers G.

Clinique de Neurologie et de Psychiatrie, C.H.U. Saint-Jacques, Besancon.

Valpromide is largely used in the therapy of affective disorders for its presumed thymoregulating activity. So, it is often associated with tricyclic antidepressant treatment. Previous clinical studies lead us to consider the possibility of an interaction between valpromide and tricyclic antidepressants, interaction which could result in an increase of antidepressant plasma concentrations. But no pharmacokinetic study has been realized up to now in order to clearly demonstrate such a phenomenon. The authors studied amitriptyline and nortriptyline plasma levels in two groups of ten patients receiving 125 mg amitriptyline, once a day, during 20 days. In the second group, patients also received 600 mg valpromide daily after ten days on amitriptyline. In the first group amitriptyline and nortriptyline plasma concentrations remained stable between the tenth and the twentieth day. In the second group, addition of valpromide resulted in a significant increase of antidepressant plasma levels: from 70.5 +/- 35 to 105.5 +/- 49 ng/ml (p less than 0.0003) for amitriptyline, and from 61.0 +/- 34 to 100.5 +/- 65 ng/ml (p less than 0.01) for nortriptyline.

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Pharmacol Biochem Behav. 1977 Aug;7(2):159-65.
Mechanisms of amitriptyline induced hypothermia in the rat.

Lee HK, Chai CY, Wayner MJ, Chung PM, Cheng JT.

Effects of amitriptyline on rectal temperature of male rats were studied at the ambient temperature of 25 degrees C. Drugs were administered intraperitoneally. Amitryptyline elicited a dose related hypothermia. The hypothermia was attenuated by phenoxybenzamine 10 mg/kg, haloperidol 2 mg/kg, diphenhydramine 5 mg/kg, atropine 20 mg/kg, and cyproheptadine 5 mg/kg. Propranolol, at a dose of 5 mg/kg, had no effect on the hypothermia. Theophylline 50 mg/kg and dibutyryl cyclic AMP 20 mg/kg inhibited the hypothermia produced by anitriptyline. Pretreatment with parachloroamphetamine (PCA), 2 or 5 mg/kg daily for 3 days, strongly antagonized the hypothermia. In addition, pretreatment with parachlorophenylalanine (PCPA), 100 mg/kg daily for three days, reduced the brain 5-hydroxytryptamine (5-HT) concentration to 20% of the control level and completely blocked the hypothermia response. When brain 5-HT concentration recovered to 50% of the control level in PCPA treated rats following the administration of 10 mg/kg 5-hydroxytryptophan (5-HTP) the hypothermia induced by amitriptyline was restored. However, the administration of 5-HT, 5 mg/kg, to PCPA treated rats did not increase brain 5-HT concentration or restore the amitriptyline induced hypothermia (AIH). Results suggest that amitriptyline interacts with several transmitter substances to produce hypothermia. Since the ability of amitriptyline to produce hypothermia was correlated with brain 5-HT content, 5-HT might play an important role in the mediation of AIH.

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Lancet. 1988 Jul 9;2(8602):90-2.
Blood disorders and suicide in patients taking mianserin or amitriptyline.

Inman WH.

Drug Safety Research Unit, North Croft House, Botley, Southampton.

26,781 patients who had been prescribed mianserin and 42,082 prescribed amitriptyline were followed up by means of a questionnaire addressed to their general practitioners. No patient had aplastic anaemia, agranulocytosis, or leucopenia severe enough to endanger life, and in only 2 patients in each group was a causal association likely. If either drug dose cause leucopenia, the incidence is likely to be in the range of 1 in 10,000 to 1 in 100,000 patients. Among patients who were reported to have attempted suicide, 56 of 246 survivors of amitriptyline overdoses required intensive care, compared with none of 92 patients who overdosed with mianserin. 4 patients who overdosed with amitriptyline alone died, compared with none of the patients who overdosed with mianserin alone. Both drugs are associated with a low risk of blood disorders, but mianserin is appreciably safer than amitriptyline because of its low toxicity in overdosage.

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Biol Psychiatry. 1979 Jun;14(3):485-97.
Epileptic phenomena induced in the cat by the antidepressants maprotiline, imipramine, clomipramine, and amitriptyline.

Koella WP, Glatt A, Klebs K, Durst T.

The epileptogenic properties of four tricyclic antidepressant drugs: maprotiline, imipramine, clomipramine, amitriptyline, were investigated in locally anesthetized cats immobilized with gallamine and supplied with neocortical, hippocampal, and reticular recording electrodes. The drugs were infused intravenously at a constant rate (0.5 or, in some cases, 0.25 mg/kg per min) up to a final dose of 45 mg/kg. Already in small doses (1 to 5 mg/kg) all four antidepressants produced local signs of epileptiform pathology. Generalized sustained discharges occurred, on the average, at between 20 and 25 mg/kg with all four drugs. Imipramine and amitriptyline, after the first or first few generalized discharges, led to a pattern of repeated short generalized seizures alternating with silent periods. Maprotiline invariably produced this later alternating pattern only after a 10- to 30-min period of a seminormal high amplitude pattern. Clomipramine assumed a position between maprotiline on the one hand and imipramine and amitriptyline on the other. Starting at doses of 2-4 mg/kg, imipramine, clomipramine and amitriptyline, all three being norepinephrine and serotonin uptake inhibitors, induced a high amplitude "sleep" pattern. Maprotiline, a norepinephrine uptake inhibitor, which is thought devoid of serotonin-uptake inhibiting properties, led to high amplitude slow waves only with doses of at least 12.5 to 15 mg/kg.

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Hum Toxicol. 1984 Jun;3(3):165-71.
Lidocaine and amitriptyline interaction during experimental haemoperfusion.

Heath A, Lofstrom B, Martensson E.

Displacement of amitriptyline by lidocaine was studied during haemoperfusion (HP) in five beagle dogs. Clearance of amitriptyline during HP was 0.93, although the amount of amitriptyline removed was only 2% of the given dose. Lidocaine does therefore not improve amitriptyline yield during HP. Clearance of lidocaine during HP was 0.99. Almost 13% of the lidocaine given intravenously was removed by HP. Lidocaine did not improve myocardial performance during HP in amitriptyline-intoxicated dogs. At necropsy the highest concentrations of amitriptyline in this model were found in the brain and the lung. The amitriptyline/nortriptyline ratio was lowest in the liver and lung, suggesting that these two organs are major sites of metabolism.

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