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Pharmaceutisch Weekblad

, Volume 13, Issue 1, pp 1–6 | Cite as

Pathophysiology of cytotoxic drug-induced emesis: far from crystal-clear

  • C. Seynaeve
  • P. H. M. De Mulder
  • J. Verweij
Reviews

Abstract

Both radiotherapy and chemotherapy for cancer are capable of causing severe nausea and vomiting, which formerly often interfered with the patient's compliance to treatment. The basic pathway and pharmacological mechanisms involved in this are still poorly understood. The recent discovery, however, that 5-HT3 receptor antagonists can prevent or greatly reduce chemotherapy-induced emesis led to a re-evaluation of the sequence of events occurring in the protective emetic reflex, which are reviewed in this paper. The vomiting centre co-ordinates the incoming and outgoing information, and is thought to be represented by complex interactions between different adjacent areas in the brainstem. Whether the main role in the emetic reflex arch is accomplished by either the central part (chemoreceptor trigger zone) or the peripheral part (gastro-intestinal tract) needs further confirmation. A more important role, however, of the vagal nerve and the gastro-intestinal tract is generally accepted. The neurotransmitter serotonin (5-HT) appears to play a major role in chemotherapy-induced emesis via the 5-HT receptor. These indications could form the basis for further investigations into the involvement of other neurotransmitters, and the character of their interactions.

Keywords

Drug therapy Neoplasms Neurophysiology Pathology Receptors, dopamine Receptors, serotonin Vomiting 

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References

  1. 1.
    Davis CJ, Harding RR, Leslie RA, Andrews PLR. The organisation of vomiting as a protective reflex. In: Davis CJ, Lake-Bakaar GV, Grahame-Smith DG, eds. Nausea and vomiting: mechanisms and treatment. Berlin: Springer-Verlag, 1986:65–75.Google Scholar
  2. 2.
    Akwari OE. The gastrointestinal tract in chemotherapy induced emesis. Drugs 1983;25(Suppl 1):18–34.Google Scholar
  3. 3.
    Borison HL, Borison R, McCarthy LE. Role of the area postrema in vomiting and related functions. Fed Proc 1984;43:2955–8.Google Scholar
  4. 4.
    Borison HL. A 1983 neuropharmacologic perspective of space sickness. Brain Behav Evol 1983;23:7–13.Google Scholar
  5. 5.
    Morrow GR. The effect of a susceptibility to motion sickness on the side effects of cancer chemotherapy. Cancer 1985;55:2766–70.Google Scholar
  6. 6.
    Borison HL, Wang SC. Physiology and pharmacology of vomiting. Pharmacol Rev 1953;5:193–230.Google Scholar
  7. 7.
    Brizzee KR, Klara PM. Structure of the mammalian AP. Fed Proc 1984;43:2944–8.Google Scholar
  8. 8.
    Leslie RA. Comparative aspects of the area postrema: fine structures considerations help to determine its function. Cell Mol Neurobiol 1986;6:95–120.Google Scholar
  9. 9.
    Andrews PLR, Hawthorn J. Neurophysiology of vomiting. Clin Gastroenterol 1988;2:141–68.Google Scholar
  10. 10.
    McCarthy LE, Borison HL. Cisplatin induced vomiting eliminated by ablation of the AP in cats. Cancer Treat Rep 1984;68:401–4.Google Scholar
  11. 11.
    Borison HL, McCarthy LE. Neuropharmacology of cancer induced emesis. Drugs 1983;25(Suppl 1):8–17.Google Scholar
  12. 12.
    Lindstrom PA, Brizzee KR. Relief of intractable vomiting from surgical lesions in the area postrema. J Neurosurg 1962;19:288.Google Scholar
  13. 13.
    Carpenter DO, Briggs DB, Strominger N. Behavioral and electrophysiological studies of peptide-induced emesis in dogs. Fed Proc 1984;43:2952–4.Google Scholar
  14. 14.
    Schwartz JC, Agid Y, Bouthenet NL, et al. Neurochemical investigations into the human area postrema. In: Davis CJ, Lake-Bakaar GV, Grahame-Smith DG, eds. Nausea and vomiting: mechanisms and treatment. Berlin: Springer-Verlag, 1986:18–30.Google Scholar
  15. 15.
    Pedigo NW, Brizzee KR. Muscarinic cholinergic receptors in AP and brainstem areas regulating emesis. Brain Res Bull 1985;14:169–77.Google Scholar
  16. 16.
    Reynolds DJM, Leslie RA, Grahame-Smith DG, Harvey JM. Localization of 5-HT3 receptor binding sites in human dorsal vagal complex. Eur J Pharmacol 1989;174:127–30.Google Scholar
  17. 17.
    Higgins GA, Kilpatrick GJ, Bunce KT, Jones BJ, Tyers MB. 5HT3 receptor antagonists injected into the AP inhibit cisplatin induced emesis in the ferret. Br J Pharmacol 1989;97:247–55.Google Scholar
  18. 18.
    Willems JL, Lefebvre RA. Peripheral nervous pathways involved in nausea and vomiting. In: Davis CJ, Lake-Bakaar GV, Grahame-Smith DG, eds. Nausea and vomiting: mechanisms and treatment. Berlin: Springer-Verlag, 1986:56–64.Google Scholar
  19. 19.
    Andrews PLR, Rappeport WG, Sanger GJ. Neuropharmacology of emesis induced by anti-cancer therapy. TiPS 1988;9:334–41.Google Scholar
  20. 20.
    Mitchell EP, Schein PS. Gastrointestinal toxicity of chemotherapeutic agents. Semin Oncol 1982;9:52–63.Google Scholar
  21. 21.
    Gunning SJ, Hagan RM, Tyers MB. Cisplatin induces biochemical and histological changes in the small intestine of the ferret. Br J Pharmacol 1987;90(Suppl): 135P.Google Scholar
  22. 22.
    Allen SG, Smith SF. Small intestinal toxicity of cisplatin-comparison of effects of platinum analogues and dexamethasone. Br J Cancer 1986;53:355–60.Google Scholar
  23. 23.
    Cubbeddu LX, Hoffmann IS, Fuenmayor NT, Finn AL. Efficacy of ondansetron and the role of serotonin in cisplatin-induced nausea and vomiting. N Engl J Med 1990;322:810–6.Google Scholar
  24. 24.
    Miller AD, Wilson VJ. ‘Vomiting center’ reanalysed: an electrical stimulation study. Brain Res 1983;270:154–8.Google Scholar
  25. 25.
    Brizzee KR, Mehler WR. The central nervous connections in the vomiting reflex. In: Davis CJ, Lake-Bakaar GV, Grahame-Smith DG, eds. Nausea and vomiting: mechanisms and treatment. Berlin: Springer-Verlag, 1986:46–55.Google Scholar
  26. 26.
    Geldof H, Van der Schee EJ, Van Blankenstein M, Grashuis JL. Electrogastrographic study of gastric myoelectrical activity in patients with unexplained nausea and vomiting. Gut 1986;27:799–808.Google Scholar
  27. 27.
    Koch KL. The irritable gut (part II): the stomach. Motility 1988;6:4–6.Google Scholar
  28. 28.
    Stefanini E, Clement-Carmier Y. Detection of dopamine receptors in the area postrema. Eur J Pharmacol 1981:257–60.Google Scholar
  29. 29.
    Peroutka SJ, Snijder SH. Antiemetics: neurotransmitter receptor binding predicts antiemetic actions. Lancet 1982;1:658–9.Google Scholar
  30. 30.
    Peroutka SJ. Chemotherapeutic agents do not interact with neurotransmitter receptors. Cancer Chemother Pharmacol 1987;19:131–2.Google Scholar
  31. 31.
    Hamik A, Peroutka S. Different interactions of traditional and novel antiemetics with dopamine D2 and 5-hydroxytryptamine receptors. Cancer Chemother Pharmacol 1989;24:307–10.Google Scholar
  32. 32.
    McRitchie B, McClelland CM, Cooper SM, Turner DH, Sanger GJ. Dopamine antagonists as anti-emetics and as stimulants of gastric motility. In: Bennett A, Velo G, eds. Mechanisms of GI motility and secretion. New York: Plenum Press, 1984:287–301.Google Scholar
  33. 33.
    Harris AL. Cytotoxic therapy-induced vomiting is mediated via enkephalin pathways. Lancet 1982;1:714–6.Google Scholar
  34. 34.
    Edwards CM. Chemotherapy induced emesis — mechanisms and treatment: a review. J R Soc Med 1988;81:658–62.Google Scholar
  35. 35.
    Maxwell A, Gaffin SL, Wells MT. Radiotherapy, endotoxins and nausea. Lancet 1986;2:1148–9.Google Scholar
  36. 36.
    Miner WD, Sanger GJ, Turner DH. Evidence that 5-hydroxy-tryptamine receptors mediate cytotoxic drug- and radiation-evoked emesis. Br J Cancer 1987;56:159–62.Google Scholar
  37. 37.
    Humphrey PPA, Richardson BP. Classification of 5HT receptors and binding sites: an overview. In: Mylecharane EJ, Angus JA, eds. Serotonin: actions, receptors, pathophysiology. London: MacMillan Press, 1989:204–21.Google Scholar
  38. 38.
    Engel G, Buchheit KH, Richardson BP. 5HT3 receptors in the gastrointestinal tract. In: Mylecharane EJ, Angus JA, eds. Serotonin: actions, receptors, pathophysiology. London: MacMillan Press, 1989:241–8.Google Scholar
  39. 39.
    Tyers MB, Costall B, Naylor RT. 5HT3 receptors in the CNS. In: Mylecharane EJ, Angus JA, eds. Serotonin: actions, receptors, pathophysiology. London: MacMillan Press, 1989:95–100.Google Scholar
  40. 40.
    Costall B, Domeney AM, Naylor RJ, Tattersall FD. 5-Hydroxytryptamine-M receptor antagonism to prevent cisplatin-induced emesis. Neuropharmacology 1986;25:959–61.Google Scholar
  41. 41.
    Merrifield K, Chaffee BJ. Recent advances in the management of nausea and vomiting caused by antineoplastic agents. Clin Pharm 1989;8:187–99.Google Scholar
  42. 42.
    Costall B, Domeney AM, Naylor RJ, Tyers MB. Effects of a 5-HT3 receptor antagonist, GR38032F, on raised dopaminergic activity in the mesolimbic system of the rat and marmoset brain. Br J Pharm 1987;92:881–94.Google Scholar
  43. 43.
    Grunberg S. Oh, what a tangled web. J Clin Oncol 1989;7:691–3.Google Scholar

Copyright information

© Royal Dutch Association for Advancement of Pharmacy 1991

Authors and Affiliations

  • C. Seynaeve
    • 1
  • P. H. M. De Mulder
    • 2
  • J. Verweij
    • 1
  1. 1.Department of Medical OncologyRotterdam Cancer Institute, Dr. Daniel Den Hoed ClinicAE RotterdamThe Netherlands
  2. 2.Department of Medical OncologyUniversity Hospital Saint RadboudHB NijmegenThe Netherlands

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