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Amitriptyline accumulation in tissues after coated activated charcoal hemoperfusion—a randomized controlled animal poisoning model

  • Tejs JansenEmail author
  • Lotte C. G. Hoegberg
  • Thomas Eriksen
  • Kim P. Dalhoff
  • Bo Belhage
  • Sys S. Johansen
Original Article
  • 7 Downloads

Abstract

Amitriptyline poisoning (AT) is a common poisoning, and AT possess the ability to promote life-threatening complications by its main action on the central nervous and cardiovascular systems. The pharmacokinetic properties might be altered at toxic levels compared to therapeutic levels. The effect of coated activated charcoal hemoperfusion (CAC-HP) on the accumulation of AT and its active metabolite nortriptyline (NT) in various tissues was studied in a non-blinded randomized controlled animal trial including 14 female Danish Land Race piglets. All piglets were poisoned with amitriptyline 7.5 mg/kg infused in 20 min, followed by orally instilled activated charcoal at 30 min after infusion cessation. The intervention group received 4 h of CAC-HP followed by a 1-h redistribution phase. At study cessation, the piglets were euthanized, and within 20 min, vitreous fluid, liver tissue, ventricle and septum of the heart, diaphragm and lipoic and brain tissues were collected. AT and NT tissue concentrations were quantified by UHPLC-MS/MS. A 4-h treatment with CAC-HP did not affect the tissue accumulation of AT in the selected organs when tested by Mann-Whitney U test (p values between 0.44 and 0.73). For NT concentrations, p values were between 0.13 and 1.00. Although not significant, an interesting finding was that data showed a tendency of increased tissue accumulation of AT and NT in the CAC-HP group compared with the control group. Coated activated charcoal hemoperfusion does not significantly alter the tissue concentration of AT and NT in the AT-poisoned piglet.

Keywords

Amitriptyline Poisoning Activated charcoal hemoperfusion Cardiotoxicity UHPLC-MS/MS Tissue concentrations Forensic medicine 

Notes

Acknowledgements

The study was supported by the Aase and Ejnar Danielsen Foundation—a general private foundation who supports free medical research. The foundation was not involved in the trial or paper finalizing. The study was supported by the Research Foundation at Bispebjerg University Hospital, Copenhagen. The Research Foundation was not involved in the conduction of the trail or production of the paper.

Authors’ contributions

All authors have contributed throughout the process of this paper. TJ: Tejs Jansen, LCGH: Lotte CG Hoegberg, TE: Thomas Eriksen, KPD: Kim Peder Dalhoff, BB: Bo Belhage, SSJ: Sys S Johansen. TJ, LCCH, TE, KPD and BB conceived and designed the research. TJ, LCGH and TE conducted experiments. SSJ And TJ conducted the analytical work. TJ, LCGH, TE, BB and KPD analysed the data. TJ, LCCH, TE, KPD, BB and SSJ wrote the manuscript. All authors read and approved the manuscript.

Compliance with ethical standards

The study protocol was approved by the Danish Experimental Animal Expectorate (2014-15-0201-00190), and it complies with the NIH guide for care and use of laboratory animals, eighth edition, and was conducted in the animal research facilities at the Department of Experimental Medicine and Institute for Forensic Medicine, both at the Faculty of Health and Medical Sciences, Copenhagen University

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

210_2019_1669_MOESM1_ESM.docx (37 kb)
ESM 1 (DOCX 36 kb)

References

  1. Abeyaratne DD, Liyanapathirana C, Gamage A, Karunarathne P, Botheju M, Indrakumar J (2016) Survival after severe amitriptyline poisoning with prolonged ventricular tachycardia and cardiac arrest. BMC Res Notes 9:167.  https://doi.org/10.1186/s13104-016-1963-0 CrossRefGoogle Scholar
  2. Agarwala R, Ahmed SZ, Wiegand TJ (2014) Prolonged use of intravenous lipid emulsion in a severe tricyclic antidepressant overdose. J Med Toxicol 10:210–214.  https://doi.org/10.1007/s13181-013-0353-4 CrossRefGoogle Scholar
  3. Amiri H, Zamani N, Hassanian-Moghaddam H, Shadnia S (2016) Cardiotoxicity of tricyclic antidepressant treated by 2650 mEq sodium bicarbonate: a case report. JRSM Cardiovasc Dis 5:2048004016682178.  https://doi.org/10.1177/2048004016682178 Google Scholar
  4. Amitai Y, Kennedy EJ, DeSandre P, Frischer H (1993) Distribution of amitriptyline and nortriptyline in blood: role of alpha-1-glycoprotein. Ther Drug Monit 15:267–273CrossRefGoogle Scholar
  5. Amitriptyline (n.d.) www.drugbank.ca/drugs/DB00321 (2019 (Accessed January 31, 2019)) https://www.drugbank.ca/drugs/DB00321. Accessed January 31, 2019 13:19
  6. Bek K et al (2008) Charcoal haemoperfusion in amitriptyline poisoning: experience in 20 children. Nephrology (Carlton, Vic) 13:193–197.  https://doi.org/10.1111/j.1440-1797.2008.00922.x CrossRefGoogle Scholar
  7. Bjork MK, Simonsen KW, Andersen DW, Dalsgaard PW, Sigurethardottir SR, Linnet K, Rasmussen BS (2013) Quantification of 31 illicit and medicinal drugs and metabolites in whole blood by fully automated solid-phase extraction and ultra-performance liquid chromatography-tandem mass spectrometry. Anal Bioanal Chem 405:2607–2617.  https://doi.org/10.1007/s00216-012-6670-7 CrossRefGoogle Scholar
  8. Boehnert MT, Lovejoy FH Jr (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.  https://doi.org/10.1056/NEJM198508223130804 CrossRefGoogle Scholar
  9. Brady WJ, Skiles J (1999) Wide QRS complex tachycardia: ECG differential diagnosis. Am J Emerg Med 17:376–381CrossRefGoogle Scholar
  10. Bronstein AC, Spyker DA, Cantilena LR Jr, Green JL, Rumack BH, Dart RC (2011) 2010 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 28th Annual Report. Clin Toxicol (Philadelphia, Pa) 49:910–941.  https://doi.org/10.3109/15563650.2011.635149 CrossRefGoogle Scholar
  11. Chan CY, Waring WS (2007) Images in cardiovascular medicine. Tricyclic cardiotoxicity treated with sodium bicarbonate. Circulation 115:e63–e64.  https://doi.org/10.1161/CIRCULATIONAHA.106.657247 Google Scholar
  12. Danos O, Davies K, Lehn P, Mulligan R (2010) The ARRIVE guidelines, a welcome improvement to standards for reporting animal research. J Gene Med 12:559–560.  https://doi.org/10.1002/jgm.1472 CrossRefGoogle Scholar
  13. Dargan PI, Colbridge MG, Jones AL (2005) The management of tricyclic antidepressant poisoning: the role of gut decontamination, extracorporeal procedures and fab antibody fragments. Toxicol Rev 24:187–194CrossRefGoogle Scholar
  14. Ghannoum M, Laliberte M, Nolin TD, MacTier R, Lavergne V, Hoffman RS, Gosselin S (2015) Extracorporeal treatment for valproic acid poisoning: systematic review and recommendations from the EXTRIP workgroup. Clin Toxicol (Philadelphia, Pa) 53:454–465.  https://doi.org/10.3109/15563650.2015.1035441 CrossRefGoogle Scholar
  15. Han E, Kim E, Hong H, Jeong S, Kim J, in S, Chung H, Lee S (2012) Evaluation of postmortem redistribution phenomena for commonly encountered drugs. Forensic Sci Int 219:265–271.  https://doi.org/10.1016/j.forsciint.2012.01.016 CrossRefGoogle Scholar
  16. Harrigan RA, Brady WJ (1999) ECG abnormalities in tricyclic antidepressant ingestion. Am J Emerg Med 17:387–393CrossRefGoogle Scholar
  17. Heinonen JA, Litonius E, Backman JT, Neuvonen PJ, Rosenberg PH (2013) Intravenous lipid emulsion entraps amitriptyline into plasma and can lower its brain concentration--an experimental intoxication study in pigs. Basic Clin Pharmacol Toxicol 113:193–200.  https://doi.org/10.1111/bcpt.12082 CrossRefGoogle Scholar
  18. Hilberg T, Bugge A, Beylich KM, Ingum J, Bjorneboe A, Morland J (1993) An animal model of postmortem amitriptyline redistribution. J Forensic Sci 38:81–90CrossRefGoogle Scholar
  19. Hilberg T, Ripel A, Smith AJ, Slordal L, Morland J, Bjorneboe A (1998) Postmortem amitriptyline pharmacokinetics in pigs after oral and intravenous routes of administration. J Forensic Sci 43:380–387CrossRefGoogle Scholar
  20. Hoegberg LCG GA (2015) Techniques used to prevent gastrointestinal absorption. In: Hoffman RSHM, Lewin NA, Nelson LS, Goldfrank LR (eds) Goldfrank’s Toxicologic Emergencies, vol 10th edt. McGraw-Hill Companies, Inc., USAGoogle Scholar
  21. Hoegberg LC, Groenlykke TB, Abildtrup U, Angelo HR (2010) Combined paracetamol and amitriptyline adsorption to activated charcoal. Clin Toxicol (Philadelphia, Pa) 48:898–903.  https://doi.org/10.3109/15563650.2010.524649 CrossRefGoogle Scholar
  22. Hoffman JR, Votey SR, Bayer M, Silver L (1993) Effect of hypertonic sodium bicarbonate in the treatment of moderate-to-severe cyclic antidepressant overdose. Am J Emerg Med 11:336–341CrossRefGoogle Scholar
  23. Hurst HE, Jarboe CH (1981) Clinical findings, elimination pharmacokinetics, and tissue drug concentrations following a fatal amitriptyline intoxication. Clin Toxicol 18:119–125.  https://doi.org/10.3109/15563658108990017 CrossRefGoogle Scholar
  24. Irman-Florjanc T, Kuzner J, Drevensek G, Budihna MV (2002) Amitriptyline and citalopram, two different types of antidepressant drugs, relax histamine-contracted porcine coronary artery. Inflamm Res [et al] 51(Suppl 1):S25–S26Google Scholar
  25. Islek I, Degim T, Akay C, Turkay A, Akpolat T (2004) Charcoal haemoperfusion in a child with amitriptyline poisoning. Nephrol Dial Transplant 19:3190–3191.  https://doi.org/10.1093/ndt/gfh232 CrossRefGoogle Scholar
  26. Jansen T, Petersen H, Malskaer CM, Gabel-Jensen C, Dalhoff K, Eriksen T, Belhage B, Hoegberg LCG (2016) Activated charcoal hemoperfusion in the treatment of experimental amitriptyline poisoning in pigs - the effect on amitriptyline plasma concentration and hemodynamic. Parameters Basic Clin Pharmacol Toxicol 120:491–497.  https://doi.org/10.1111/bcpt.12704 CrossRefGoogle Scholar
  27. Kawasaki CI, Nishi R, Uekihara S, Hayano S, Kragh-Hansen U, Kawasaki CI, Otagiri M (2005) How tightly can a drug be bound to a protein and still be removable by charcoal hemoperfusion in overdose cases. Clin Toxicol (Philadelphia, Pa) 43:95–99CrossRefGoogle Scholar
  28. de Lange DW, Sikma MA, Meulenbelt J (2013) Extracorporeal membrane oxygenation in the treatment of poisoned patients. Clin Toxicol (Philadelphia, Pa) 51:385–393.  https://doi.org/10.3109/15563650.2013.800876 CrossRefGoogle Scholar
  29. Lavergne V, Hoffman RS, Mowry JB, Cormier M, Gosselin S, Roberts DM, Ghannoum M (2016) Why are we still dialyzing overdoses to tricyclic antidepressants? A subanalysis of the NPDS database. Semin Dial 29:403–409.  https://doi.org/10.1111/sdi.12520 CrossRefGoogle Scholar
  30. Levitt MA, Sullivan JB Jr, Owens SM, Burnham L, Finley PR (1986) Amitriptyline plasma protein binding: effect of plasma pH and relevance to clinical overdose. Am J Emerg Med 4:121–125.  https://doi.org/10.1016/0735-6757(86)90155-5 CrossRefGoogle Scholar
  31. Liebelt EL (2015) Cyclic antidepressants. In: Hoffman RSHM, Lewin NA, Nelson LS, Goldfrank LR (eds) Goldfrank’s toxicologic emergencies, 10th edn. McGraw Hill Education, New York, pp 972–982Google Scholar
  32. Malallah MA, Al-Shaiji TF (2015) Pharmacological treatment of pure stress urinary incontinence: a narrative review. Int Urogynecol J 26:477–485.  https://doi.org/10.1007/s00192-014-2512-9 CrossRefGoogle Scholar
  33. Margalho C, Barroso M, Gallardo E, Monsanto P, Vieira DN (2007) Massive intoxication involving unusual high concentration of amitriptyline. Hum Exp Toxicol 26:667–670.  https://doi.org/10.1177/0960327107076813 CrossRefGoogle Scholar
  34. Nielsen MK, Johansen SS (2012) Simultaneous determination of 25 common pharmaceuticals in whole blood using ultra-performance liquid chromatography-tandem mass spectrometry. J Anal Toxicol 36:497–506.  https://doi.org/10.1093/jat/bks054 CrossRefGoogle Scholar
  35. Ojanpera I, Kriikku P, Vuori E (2016) Fatal toxicity index of medicinal drugs based on a comprehensive toxicology database. Int J Legal Med 130:1209–1216.  https://doi.org/10.1007/s00414-016-1358-8 CrossRefGoogle Scholar
  36. Pentel PR, Keyler DE (1988) Effects of high dose alpha-1-acid glycoprotein on desipramine toxicity in rats. J Pharmacol Exp Ther 246:1061–1066Google Scholar
  37. Ramasubbu B, James D, Scurr A, Sandilands EA (2016) Serum alkalinisation is the cornerstone of treatment for amitriptyline poisoning. BMJ Case Rep.  https://doi.org/10.1136/bcr-2016-214685
  38. Seaberg DC, Weiss LD, Yealy DM, Kaplan RM, Krenzelok EP, Stiller RL (1991) Effects of alpha-1-acid glycoprotein on the cardiovascular toxicity of nortriptyline in a swine model. Vet Hum Toxicol 33:226–230Google Scholar
  39. Wong J, Motulsky A, Abrahamowicz M, Eguale T, Buckeridge DL, Tamblyn R (2017) Off-label indications for antidepressants in primary care: descriptive study of prescriptions from an indication based electronic prescribing system. BMJ (Clin Res Ed) 356:j603.  https://doi.org/10.1136/bmj.j603 CrossRefGoogle Scholar
  40. Woolf AD, Erdman AR, Nelson LS, Caravati EM, Cobaugh DJ, Booze LL, Wax PM, Manoguerra AS, Scharman EJ, Olson KR, Chyka PA, Christianson G, Troutman WG (2007) Tricyclic antidepressant poisoning: an evidence-based consensus guideline for out-of-hospital management. Clin Toxicol (Philadelphia, Pa) 45:203–233.  https://doi.org/10.1080/15563650701226192 CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Anaesthesia and Intensive CareCopenhagen University Hospital BispebjergCopenhagenDenmark
  2. 2.Department of Veterinary Clinical Sciences, University Hospital for Companion Animals, Faculty of Health and Medical SciencesUniversity of CopenhagenFrederiksbergDenmark
  3. 3.Department of Clinical PharmacologyCopenhagen University Hospital BispebjergCopenhagenDenmark
  4. 4.Department of Forensic Medicine, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark

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