Experimental amitriptyline intoxication: treatment of cardiac toxicity with sodium bicarbonate.

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)

Mechanism of reversal of toxic effects of amitriptyline on cardiac Purkinje fibers by sodium bicarbonate.

Alkalinization with NaHCO3 can effectively reverse ventricular arrhythmias caused by amitriptyline intoxication, but the mechanism is unclear. To test whether alkalinization per se is important or whether increases in extracellular Na concentration also contribute, we exposed Purkinje fibers to 500 ng/ml (1.8 microM) of amitriptyline and then superfused them with three different test solutions, viz. 1) high Na-Tyrode's, 2) high NaHCO3-Tyrode's and 3) high pH-low pCO2-Tyrode's. Amitriptyline significantly depressed action potential amplitude and Vmax without altering resting membrane potential and abbreviated action potential duration at all phases of repolarization. Effects on phase 0 were accompanied by a depression of conduction velocity. All three test solutions produced significant hyperpolarization and improvement in action potential amplitude and Vmax. However, the magnitude of improvement of phase 0 characteristics was significantly greater after high NaHCO3 and resulted in significant improvement of conduction velocity in fibers depressed by amitriptyline. The effects of amitriptyline on phase 0 were rate-dependent. Reversal of this effect by NaHCO3 was equally effective at all rates. Improvement of Vmax was partly related to a shift of the Vmax-membrane potential relationship in the depolarizing direction. NaHCO3 had minimal and variable effects on action potential duration. The results suggest that the beneficial effects of NaHCO3 are related to a reversal of drug effects on phase 0 characteristics and that this effect is due both to alkalinization and to increases in extracellular Na concentration.

Evidence against a role for lipoxygenase-derived products of arachidonic acid in the lamb ductus arteriosus.

The effects of leukotrienes, the leukotriene antagonist FPL55712 (sodium 7-(3-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-2-hydroxypropoxy)-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylate), and inhibitors of arachidonate lipoxygenase and cyclo-oxygenase (compound BW755C, 3-amino-1-(m-(trifluoromethyl)-phenyl)-2-pyrazoline; ETYA, 5,8,11,14-eicosatetraynoic acid) were studied in an isolated preparation of ductus arteriosus from mature foetal lambs. Leukotrienes (LT) C4 and D4 produced a modest relaxation of the ductus but only at the highest concentrations tested (10(-7) to 10(-6) M) and under hypoxic conditions (PO2, 6--9 Torr (1 Torr = 133.322 Pa)). LTB4 had no effect at any concentration tested. BW755C (10(-6) to 10(-5) M) and FPL55712 (10(-5) M) contracted the hypoxic ductus; however, their action was abolished by pretreatment of the tissue with the cyclooxygenase inhibitor indomethacin (2.8 x 10(-6) M). Indomethacin-treated preparations were also unresponsive to ETYA 3 x 10(-5) M. The contraction of hypoxic tissues to either BW755C or FPL55712 increased further upon raising the oxygen tension of the medium (PO2 591--691 Torr). These findings indicate that leukotrienes and allied compounds formed from lipoxygenase-catalysed reactions do not contribute to prenatal patency of the ductus and are unlikely to have a role in its closure at birth. It is also confirmed that prostaglandin E2 is essential for keeping the vessel patent in the foetus.