Abstract
In the Cardiac Arrhythmia Suppression Trial antiarrhythmic drug therapy with slow kinetic sodium channel blockers (class Ic antiarrhythmic drugs) was associated with excess mortality, presumably due to drug induced proarrhythmia. It has been suggested that the degree of rate-dependent conduction slowing produced by agents that have sodium channel blocking properties may be related to the proarrhythmic propensity of these agents.
In the present study, rate-dependent conduction slowing by the antidepressants amitriptyline and maprotiline was investigated in anesthetized guinea pigs. After electrical ablation of the sinus node the left atrium was stimulated at cycle lengths between 200 ms and 500 ms. His bundle electrograms were registered by means of an epicardial electrode. Drugs were administered by i.v. infusion of 0.2 mg kg−1 min−1 for 30 min followed by 0.1 mg kg−1 min−1 for up to 30 min. Both drugs produced substantial rate-dependent conduction slowing within the His-Purkinje-system. The relationship between pacing rate and conduction slowing was well fitted by linear regression. The steepness of the regression line was significantly greater for amitriptyline than for maprotiline (slope factors: 9.10×10−4±7.85 × 10−5, n = 6, vs. 6.29×10−4±2.97×10−5, n=6, P<0.001), indicating that conduction slowing by amitriptyline exhibits a greater degree of rate-dependence than conduction slowing by maprotiline. On abruptly changing the driving cycle length from 500 ms to 300 ms, conduction slowing reached a new steady state with rate constants of 0.83±0.093 beat−1 (amitriptyline) and 0.14±0.05 beat−1 (maprotiline, P<0.001). Following interruption of rapid pacing at a cycle length of 250 ms, conduction slowing recovered with time constants of 332.4±52.8 ms (amitriptyline) and 1088.1 ± 143.5 ms (maprotiline, P = 0.001). Thus, amitriptyline exhibited fast kinetic properties similar to class Ib antiarrhythmic action while the slower kinetic properties of maprotiline resembled those of class Ia agents.
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References
Balcioglu A, Bozkurt A, Kayaalp SO (1991) Comparison of the cardiovascular effects of amineptine with those of amitriptyline and imipramine in anaesthetized rats. Arch Int Pharmacodyn Ther 309:64–74
Baldessarini RJ (1990) Drugs and the treatment of psychiatric disorders. In: Gilman AG, Rall TW, Nies AS and Taylor P (eds) The pharmacological basis of therapeutics, 8th edn. Pergamon Press, New York, pp 383–435
Biggs JT, Spiker DG, Petit JM, Ziegler VE (1977) Tricyclic antidepressant overdose: Incidence of symptoms. J Am Med Assoc 238:135
Boehnert MT, Lovejoy FH (1985) Value of the QRS duration versus the serum drug level in predicting seizures and ventricular arrhythmias after an acute overdose of tricyclic antidepressants. N Engl J Med 313:474–479
Campbell TJ (1983) Importance of physico-chemical properties in determining the kinetics of the effects of class I antiarrhythmic drugs on maximum rate of depolarization in guinea-pig ventricle. Br J Pharmacol 80:33–40
Campbell TJ (1992) Subclassification of Class-I antiarrhythmic drugs — enhanced relevance after CAST. Cardiovase Drugs Ther 6:519–528
Dollery C (1991a) Therapeutic drugs, vol 1. Amitriptyline (hydrochloride). Churchill Livingstone, London, pp A95-A100
Dollery C (1991b) Therapeutic drugs, vol 2. Maprotiline hydrochloride. Churchill Livingstone, London, pp M9-M12
Edwards JG, Goldic A (1983) Mianserin, maprotiline and intracardiac conduction. Br J Clin Pharmacol 15:249S-254S
Eschenhof E, Rieder J (1969) Untersuchungen über das Schicksal des Antidepressivums Amitriptylin im Organismus der Ratte und des Menschen. Arzneimittelforschung 19:957–966
Hashimoto H, Nishimoto M, Ozaki T, Ohara K, Nakashima M (1990a) Comparison of the cardiac electrophysiologic effects of amitriptyline and clomipramine in the dog after myocardial infarction. Arch Int Pharmacodyn Ther 304:181–195
Hashimoto H, Nishimoto M, Ozaki T, Oohara K, Nakashima M (1990b) Comparative effects of antidepressants, amitriptyline, and maprotiline on intraventricular conduction, effective refractory period, and incidence of ventricular arrhythmias induced by programmed stimulation in dog hearts after myocardial infarction. J Cardiovasc Pharmacol 16:693–701
Igawa O, Kotake H, Kurata Y, Saitoh M, Fujimoto Y, Hasegawa J, Mashiba H (1988) Electrophysiological effects of maprotiline, a tetracyclic antidepressant agent, on isolated cardiac preparations. J Cardiovasc Pharmacol 11:167–173
Macfarlane PW, Veitch Lawrie TD (1989) The normal electrocardiogram and vectorcardiogram. In: Macfarlane PW, Veitch Lawrie TD (eds) Comprehensive electrocardiology. Theory and practice in health and disease. Pergamon Press, New York, pp 407–457
Marshall JB, Forker AD (1982) Cardiovascular effects of tricyclic antidepressant drugs: therapeutic usage, overdose and management of complications. Am Heart J 103:401–414
Martyn R, Somberg JC, Kerin NZ (1993) Proarrhythmia of nonantiarrhythmic drugs. Am Heart J 126:201–205
Nattel S (1985) Frequency-dependent effects of amitriptyline on ventricular conduction and cardiac rhythm in dogs. Circulation 72: 898–906
Nesterenko VV, Lastra AA, Rosenshtraukh LV, Starmer CF (1992) A proarrhythmic response to sodium channel blockade — modulation of the vulnerable period in guinea pig ventricular myocardium. J Cardiovasc Pharmacol 19:810–820
Niemann JT, Bessen HA, Rothstein RJ, Laks MM (1986) Electrocardiographic criteria for tricyclic antidepressant cardiotoxicity. Am J Cardiol 57:1154–1159
Riess W (1976) The relevance of blood level determinations during the evaluation of maprotiline in man. In: Murphy J (ed) Research and clinical investigations in depression. Cambridge Medical Publications, Northhampton, pp 19–38
Spach MS, Dolber PC, Heidlage JF (1988) Influence of the passive anisotropic properties on directional differences in propagation following modification of the sodium conductance in human atrial muscle. A model of reentry based on anisotropic discontinuous propagation. Cite Res 62:811–832
Spiker DG, Weiss AN, Chang SS, Ruwitch JF, Biggs JT (1975) Tricyclic antidepressant overdose: Clinical presentation and plasma levels. Clin Pharmacol Ther 18:539–546
Starmer CF, Lastra AA, Nesterenko VV, Grant AO (1991) Proarrhythmic response to sodium channel blockade. Theoretical model and numerical experiments. Circulation 84:1364–1377
Starmer CF, Lancaster AR, Lastra AA, Grant AO (1992) Cardiac instability amplified by use-dependent Na channel blockade. Am J Physiol 262:H1305-H1310
Symanski JD, Gettes LS (1993) Drug effects on the electrocardiogram. A review of their clinical importance. Drugs 46:219–248
Szeless S, Kleinberger G, Kotzaurek R, Pall H, Pichler M, Raberger G (1975) Fatal self-poisoning with the tetracyclic antidepressive drug, Ludiomil®. Wien Klin Wochenschr 87:254–258
The Cardiac Arrhythmia Suppression Trial (CAST) Investigators (1989) Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. N Engl J Med 321:406–412
Thorstrand C (1976) Clinical features in poisonings by tricyclic antidepressants with special reference to the ECG. Acta Med Scand 199:337
Todt H, Raberger G (1992) Epicardial His bundle recordings in the guinea pig in vivo. J Pharmacol Methods 27:191–195
Todt H, Krumpl G, Krejcy K, Raberger G (1992) Mode of QT correction for heart rate: Implications for the detection of inhomogeneous repolarization after myocardial infarction. Am Heart J 124: 602–609
Todt H, Krumpl G, Zojer N, Krejcy K, Raberger G (1993a) Effect of ajmaline on sustained ventricular tachycardia induced by programmed electrical stimulation in conscious dogs after myocardial infarction. Naunyn-Schmiedeberg's Arch Pharmacol 348:290–297
Todt H, Zojer N, Raberger G (1993b) Kinetics of rate-dependent slowing of intraventricular conduction by the class Ib antiarrhythmic agent tocainide in vivo. Br J Pharmacol 110:145–150
Wang Z, Pelletier LC, Talajic M, Nattel S (1990) Effects of flecainide and quinidine on human atrial action potentials. Role of rate-dependence and comparison with guinea pig, rabbit, and dog tissues. Circulation 82:274–283
Weirich J, Antoni H (1990) Differential analysis of the frequency-dependent effects of class 1 antiarrhythmic drugs according to periodical ligand binding: Implications for antiarrhythmic and proarrhythmic efficacy. J Cardiovasc Pharmacol 15:998–1009
Whitcomb DC, Gilliam FR, Starmer CF, Grant AO (1989) Marked QRS complex abnormalities and sodium channel blockade by propoxyphene reversed with lidocaine. J Clin Invest 84:1629–1636
Williams DO, Scherlag BJ, Hope DR, El-Sherif N, Lazzara R, Samet P (1976) Selective versus non-selective His bundle pacing. Cardiovasc Res 10:91–100
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Todt, H., Zojer, N., Djamshidian Tehrani, S. et al. Frequency-dependent effects of amitriptyline and maprotiline on conduction in the guinea pig His-Purkinje-system in vivo. Naunyn-Schmiedeberg's Arch Pharmacol 350, 670–676 (1994). https://doi.org/10.1007/BF00169373
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DOI: https://doi.org/10.1007/BF00169373