Skip to main content
PMC home page
British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 1977 May;60(1):11–19. doi: 10.1111/j.1476-5381.1977.tb16741.x

Plasma concentrations and cardiotoxic effects of desipramine and protriptyline in the rat

G Bianchetti, Aurora Bonaccorsi, A Chiodaroli, R Franco, S Garattini, R Gomeni, PL Morselli
PMCID: PMC1667180  PMID: 884382

Abstract

1 Desipramine and protriptyline were administered to anaesthetized rats by two consecutive intravenous infusions in order to obtain a peak level (first infusion) followed by lower steady state concentrations (second infusion) (Wagner, 1974). Theoretical plasma level time courses were confirmed experimentally.

2 Desipramine and protriptyline were measured in atria and ventricles. Increasing infusion rates led to proportional increases in plasma and atrial concentrations. The tissue/medium ratio ranged from 57 to 21 for desipramine and from 43 to 11 for protriptyline according to the time of determination during infusions.

3 Heart rate changes, deviation of the electrical axis of the heart and prolongation of atrioventricular conduction were recorded at fixed times during infusion.

4 Positive chronotropic effects were noted at plasma concentrations ranging from 0.035 to 0.1 μg/ml for desipramine and from 0.04 to 1.2 μg/ml for protriptyline. At higher plasma concentrations the positive chronotropic effect decreased and bradycardia developed. Both drugs induced right rotation of the electrical axis of the heart. Threshold plasma levels giving 40° rotation were 1.35 μg/ml (desipramine) and 1.75 μg/ml (protriptyline). Atrioventricular conduction was prolonged at threshold plasma concentrations of 2.2 μg/ml for desipramine and 3.6 μg/ml for protriptyline.

5 Desipramine is more cardiotoxic than protriptyline. This difference is discussed in relation to the plasma and heart concentration of the two drugs.

Full text

PDF
13

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Alexander C. S., Niño A. Cardiovascular complications in young patients taking psychotropic drugs. A preliminary report. Am Heart J. 1969 Dec;78(6):757–769. doi: 10.1016/0002-8703(69)90442-6. [DOI] [PubMed] [Google Scholar]
  2. Alexanderson B. Pharmacokinetics of nortriptyline in man after single and multiple oral doses: the predictability of steady-state plasma concentrations from single-dose plasma-level data. Eur J Clin Pharmacol. 1972 Mar;4(2):82–91. doi: 10.1007/BF00562502. [DOI] [PubMed] [Google Scholar]
  3. Asberg M., Crönholm B., Sjöqvist F., Tuck D. Relationship between plasma level and therapeutic effect of nortriptyline. Br Med J. 1971 Aug 7;3(5770):331–334. doi: 10.1136/bmj.3.5770.331. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Asberg M. Plasma nortriptyline levels--relationship to clinical effects. Clin Pharmacol Ther. 1974 Jul;16(1):215–229. [PubMed] [Google Scholar]
  5. Babulova A., Bareggi S. R., Bonaccorsi A., Garattini S., Morselli P. L., Pantarotto C. Correlation between desipramine levels and (-)-noradrenaline uptake and chronotropic effect in isolated atria of rats. Br J Pharmacol. 1973 Jul;48(3):464–474. doi: 10.1111/j.1476-5381.1973.tb08354.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Barth N., Muscholl E. The effects of the tricyclic antidepressants desipramine, doxepin and iprindole on the isolated perfused rabbit heart. Naunyn Schmiedebergs Arch Pharmacol. 1974;284(3):215–232. doi: 10.1007/BF00500343. [DOI] [PubMed] [Google Scholar]
  7. Baum T., Shropshire A. T., Rowles G., Gluckman M. I. Antidepressants and cardiac conduction: iprindole and imipramine. Eur J Pharmacol. 1971;13(3):287–291. doi: 10.1016/0014-2999(71)90216-0. [DOI] [PubMed] [Google Scholar]
  8. Borgå O., Garle M. A gas chromatographic method for the quantitative determination of notriptyline and some of its metabolites in human plasma and urine. J Chromatogr. 1972 May 31;68(1):77–88. doi: 10.1016/s0021-9673(00)88765-8. [DOI] [PubMed] [Google Scholar]
  9. CAIRNCROSS K. D., GERSHON S. A pharmacological basis for the cardiovascular complications of imipramine medication. Med J Aust. 1962 Sep 8;49(2):372–375. [PubMed] [Google Scholar]
  10. CARLSSON A., WALDECK B. INHIBITION OF 3H-METARAMINOL UPTAKE BY ANTIDEPRESSIVE AND RELATED AGENTS. J Pharm Pharmacol. 1965 Apr;17:243–244. doi: 10.1111/j.2042-7158.1965.tb07653.x. [DOI] [PubMed] [Google Scholar]
  11. CURRY A. S. SEVEN FATAL CASES INVOLVING IMIPRAMINE IN MAN. J Pharm Pharmacol. 1964 Apr;16:265–267. doi: 10.1111/j.2042-7158.1964.tb07454.x. [DOI] [PubMed] [Google Scholar]
  12. Di Salle E., Baker K. M., Bareggi S. R., Watkins W. D., Chidsey C. A., Frigerio A., Morselli P. L. A sensitive gas chromatographic method for the determination of propranolol in human plasma. J Chromatogr. 1973 Sep 26;84(2):347–353. doi: 10.1016/s0021-9673(01)91714-5. [DOI] [PubMed] [Google Scholar]
  13. Elonen E., Linnoila M., Lukkari I., Mattila M. J. Concentration of tricyclic antidepressants in plasma, heart and skeletal muscle after their intravenous infusion to anaesthetized rabbits. Acta Pharmacol Toxicol (Copenh) 1975 Oct;37(4):274–281. doi: 10.1111/j.1600-0773.1975.tb00845.x. [DOI] [PubMed] [Google Scholar]
  14. Elonen E., Mattila M. J., Saarnivaara L. Cardiovascular effects of amitriptyline, nortriptyline, protriptyline and doxepin in conscious rabbits. Eur J Pharmacol. 1974 Sep;28(1):178–188. doi: 10.1016/0014-2999(74)90130-7. [DOI] [PubMed] [Google Scholar]
  15. FEKETE M., BORSY J. ON THE ANTIARRHYTHMIC EFFECT OF SOME THYMOLEPTICS (AMITRIPTYLINE, IMIPRAMINE, TRIMEPROPIMINE AND DESMETHYLIMIPRAMINE). Med Exp Int J Exp Med. 1964;10:93–102. doi: 10.1159/000135401. [DOI] [PubMed] [Google Scholar]
  16. Franco R., Bonaccorsi A., Castelli M. G., Garattini S., Morselli P. L. Relationships between chronotropic effect, 1-3H-noradrenaline uptake and tissue concentrations of desipramine, protripyline and doxepin in rat isolated atria. Arch Int Pharmacodyn Ther. 1976 Nov;224(1):55–65. [PubMed] [Google Scholar]
  17. Greeff K., Wagner J. Cardiodepressive und lokalanaesthetische Wirkungen der Thymoleptica. Vergleichende Untersuchungen mit Imipramin, Desipramin, Amitriptylin, Notriptylin und Melitracen. Arzneimittelforschung. 1969 Oct;19(10):1662–1664. [PubMed] [Google Scholar]
  18. Jefferson J. W. A review of the cardiovascular effects and toxicity of tricyclic antidepressants. Psychosom Med. 1975 Mar-Apr;37(2):160–179. doi: 10.1097/00006842-197503000-00006. [DOI] [PubMed] [Google Scholar]
  19. Langslet A., Johansen W. G., Ryg M., Skomedal T., Oye I. Effects of dibenzepine and imipramine on the isolated rat heart. Eur J Pharmacol. 1971 May;14(4):333–339. doi: 10.1016/0014-2999(71)90186-5. [DOI] [PubMed] [Google Scholar]
  20. Lechat P., Auclair M. C., Fontagné J., Prudhommeaux J. L. Etude expérimentale comparée de la toxicité cardiaque de la protriptyline et de l'imipramine. Therapie. 1969 Mar-Apr;24(2):263–272. [PubMed] [Google Scholar]
  21. MULLER O. F., GOODMAN N., BELLET S. The hypotensive effect of imipramine hydrocloride in patients with cardiovascular disease. Clin Pharmacol Ther. 1961 May-Jun;2:300–307. doi: 10.1002/cpt196123300. [DOI] [PubMed] [Google Scholar]
  22. Marmo E., Coscia L., Cataldi S. Cardiac effects of antidepressants. Jpn J Pharmacol. 1972 Jun;22(3):283–293. doi: 10.1254/jjp.22.283. [DOI] [PubMed] [Google Scholar]
  23. Rasmussen J. Amitriptyline and imipramine poisoning. Lancet. 1965 Oct 23;2(7417):850–851. doi: 10.1016/s0140-6736(65)92478-5. [DOI] [PubMed] [Google Scholar]
  24. SIGG E. B., OSBORNE M., KOROL B. CARDIOVASCULAR EFFECTS OF IMIPRAMINE. J Pharmacol Exp Ther. 1963 Aug;141:237–243. [PubMed] [Google Scholar]
  25. Schmitt H., Cheymol G., Gilbert J. C. Effets anti-arythmisants et hémodynamiques de l'imipramine et de la chlorimipramine. Arch Int Pharmacodyn Ther. 1970 Mar;184(1):158–174. [PubMed] [Google Scholar]
  26. Spiker D. G., Weiss A. N., Chang S. S., Ruwitch J. F., Jr, Biggs J. T. Tricyclic antidepressant overdose: clinical presentation and plasma levels. Clin Pharmacol Ther. 1975 Nov;18(5 Pt 1):539–546. doi: 10.1002/cpt1975185part1539. [DOI] [PubMed] [Google Scholar]
  27. Thorstrand C. Cardiovascular effects of poisoning with tricyclic antidepressants. Acta Med Scand. 1974 Jun;195(6):505–514. doi: 10.1111/j.0954-6820.1974.tb08179.x. [DOI] [PubMed] [Google Scholar]
  28. Vohra J. K. Cardiovascular abnormalities following tricyclic antidepressant drug overdosage. Drugs. 1974;7(5):323–325. doi: 10.2165/00003495-197407050-00002. [DOI] [PubMed] [Google Scholar]
  29. Wagner J. G. A safe method for rapidly achieving plasma concentration plateaus. Clin Pharmacol Ther. 1974 Oct;16(4):691–700. doi: 10.1002/cpt1974164691. [DOI] [PubMed] [Google Scholar]
  30. Williams R. B., Jr, Sherter C. Cardiac complications of tricyclic antidepressant therapy. Ann Intern Med. 1971 Mar;74(3):395–398. doi: 10.7326/0003-4819-74-3-395. [DOI] [PubMed] [Google Scholar]
  31. YATES C. M., TODRICK A., TAIT A. C. Aspects of the clinical chemistry of desmethylimipramine in man. J Pharm Pharmacol. 1963 Jul;15:432–439. doi: 10.1111/j.2042-7158.1963.tb12810.x. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Pharmacology are provided here courtesy of The British Pharmacological Society

RESOURCES