Skip to main content
SpringerLink
Log in

The Pharmacology and Clinical Effectiveness of Phenothiazines and Related Drugs for Managing Chemotherapy-induced Emesis

  • Published:
Drugs Aims and scope Submit manuscript

Summary

The phenothiazines are a group of chemical agents with neuroleptic, antiemetic, antihistaminic, anticholinergic and sedative activities. Their main pharmacological response is determined by variations in the chemical structure of the side-chain at position 10 of the phenothiazine ring. The most widely used antiemetics contain a basic amino group incorporated into a piperazine ring. These compounds have decreased autonomic activity but the greatest extrapyramidal effects of all the phenothiazine subgroups. Their antiemetic action is primarily due to inhibition of dopaminergic transmission in the chemoreceptor trigger zone. They also demonstrate some effect at the vomiting centre through inhibition of peripheral autonomic afferent impulses via the vagus nerve.

The phenothiazines are well absorbed orally although their bioavailability varies from 27 to 67% because of gut wall and first-pass liver metabolism. Plasma concentrations are increased 3- to 4-fold via the parenteral route of administration. They demonstrate a biphasic elimination curve with a distribution half-life of approximately 2 hours and an elimination half-life of 16 to 30 hours with wide intra- and interpatient variations in elimination. These drugs are highly lipophilic and protein bound. Their main route of elimination is via liver metabolism. There have been no specific correlations made between plasma concentration and efficacy, therefore individualisation of dosages is necessary.

The phenothiazines demonstrate some degree of efficacy in the prevention of nausea and vomiting secondary to a variety of causes such as anaesthetics, radiation, cancer and drug toxicity. There is little difference between them in antiemetic effectiveness within a similar group of patients. For patients undergoing treatment with chemotherapeutic drugs having moderate to strong emetic stimuli, phenothiazines are significantly better than placebo in the prevention of emesis. In comparative trials, prochlorperazine is the most widely studied phenothiazine. It has been shown to be equally or less effective than droperidol, ‘low-dose’ metoclopramide, tetrahydrocannabinol, nabilone or ‘high-dose’ metoclopramide. Only a few patients preferred the phenothiazine to the newer antiemetics regardless of the outcome of the study. Other phenothiazines such as thiopropazate, thiethylperazine, metopimazine and fluphenazine in combination with nortriptyline have been shown to be significantly better than placebo in limited trials. Compounds structurally related to the phenothiazines such as chlorprothixene, the butyrophenones and domperidone show antiemetic effects superior to placebo and are at least as effective as the phenothiazines.

Adverse reactions to the phenothiazines can be classified as extrapyramidal reactions, autonomic responses, hypersensitivity reactions and hormonal dysfunction. They may also enhance the effects of central nervous system depressants. Withdrawal of the drug is the most appropriate treatment for any of these side effects. Extrapyramidal reactions can be alleviated more quickly by the administration of diphenhydramine or certain anticholinergic drugs used in the treatment of Parkinsonism. In the vast majority of studies evaluating the antiemetic effect of the phenothiazines, the most common adverse reaction was oversedation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Arnold, D.J.; Ribiero, V. and Bulkin, W.: Metoclopramide (MCP) vs. prochlorperazine (PCP) in the prevention of vomiting from diamminedichloroplatinum (DDP). Proceedings of American Society of Clinical Oncology 21: 344 (1980)

    Google Scholar 

  • Baker, J.J.; Lokey. J.L.; Price, N.A.; Bowen, J. and Winokur, S.H.: Comparison of dexamethasone plus prochlorperazine to placebo plus prochlorperazine as antiemetics for cancer chemotherapy. Proceedings of American Society of Clinical Oncology 21: 339 (1980)

    Google Scholar 

  • Bardfield, P.A.: A controlled double-blind study of trimethobenzamide, prochlorperazine, and placebo. Journal of the American Medical Association 196: 116–118 (1966)

    Google Scholar 

  • Blatchford, E.; Studies of antiemetic drugs: A comparative study of cyclizine (Marzine), pipamazine (Momidine), trimethobenzamide (Tigan), and hyoscine. Canadian Anesthesia Society Journal 8: 159–274 (1961)

    Article  Google Scholar 

  • Boyd, C.E.; Boyd, E.M. and Cassell, W.A.: Prevention of apomorphine-induced vomiting (dimethyl amino-l-n-propyl-3)-N-(2-chloro)-phenothiazine hydrochloride. Federation Proceedings 12: 303 (1953)

    Google Scholar 

  • Carr, B.; Pulone, B.; Bertrand, M.; Browning, S.; Doroshow, J.; Klein, L.; Presant, C. and Change, F.F.: A double-blind comparison of metoclopramide (MCP) and prochlorperazine (PCP) for cis-platinum (DDP)-induced emesis. Proceedings of the American Society of Clinical Oncology 1: 66 (1982)

    Google Scholar 

  • Cohen, R.; Sheehan, A.P.; Ruckdeschel, J.C.; Blanchard, E.G.; Hall, V.I.; Poleto, M.A.; Cassidy, M.H. and Horton, J.: Patient treatment factors in the development of chemotherapy-related nausea and vomiting. Proceedings of the American Society of Clinical Oncology 22: 418 (1981)

    Google Scholar 

  • Daniels, T.C. and Jorgensen, E.C.: Central nervous system depressants; in Wilson, Gisvold and Doerge (Eds) Textbook of Organic Medicinal and Pharmaceutical Chemistry (J.B. Lippincott Co., Philadelphia 1971

    Google Scholar 

  • Deberdt, R.: Compatibility of high doses of both oral domperidone and neuroleptics in chronic psychotics. Postgraduate Medical Journal 55 (Suppl. 1): 48–49 (1979)

    PubMed  Google Scholar 

  • Delay, J. and Deniker, P.: Characteristiques psycho-physiologiques des medicaments neuroleptiques; in Garattini and Ghetti (Eds) Psychotropic Drugs (Elsevier, New York 1957

    Google Scholar 

  • Drapkin, R.L.; Sokol, G.H.; Paladine, W.J.; Polackwich, R. and Lyman, G.: The antiemetic effect and dose response of dexamethasone in patients receiving cis-platinum. Proceedings of the American Society of Clinical Oncology 1: 61 (1982)

    Google Scholar 

  • D’Souza, D.P.; Reyntjens, A. and Thornes, R.D.: Domperidone in the prevention of nausea and vomiting induced by anti-neoplastic agents: A three-fold evaluation. Current Therapeutic Research 27: 384–390 (1980)

    Google Scholar 

  • Ducrot, R. and Koetschet, P.: Propriètes antiemetiques d’un nouveau derivé de la phenoethiazine, la chloro-3-(N-methyl-piperazinyl-3propyl)-10 phenothiazine (P.P. 6140(Antiemetic properties of a new phenothiazine derivative, the 2-chloro-10-(3-N-methylpiperazinyl-propyl) phenothiazine (R.P. 6140-SKF 4657-I). Abstracts of Communications of the XXth International Physiological Congress, Brussels, p.258 (1956)

    Google Scholar 

  • Edmonds-Seal, J. and Prys-Robert, C: Pharmacology of drugs used in neuroleptanalgesia. British Journal of Anaesthesia 42: 207–216 (1970)

    Article  PubMed  CAS  Google Scholar 

  • Friend, D.G. and Cummings, J.F.: New antiemetic drug: Preliminary report. Journal of the American Medical Association 153: 480 (1953)

    Article  PubMed  CAS  Google Scholar 

  • Frytak, S. and Moertel, C.G.: Management of nausea and vomiting in the cancer patient. Journal of the American Medical Association 245: 393–396 (1981)

    Article  PubMed  CAS  Google Scholar 

  • Frytak, S.; Moertel, C.G. and O’Fallon, J.R.: Delta-9-tetrahydrocannabinol as an antiemetic for patients receiving cancer chemotherapy. Annals of Internal Medicine 91: 825–830 (1979)

    PubMed  CAS  Google Scholar 

  • Gralla, R.J.; Itri, L.M.; Pisko, S.E.; Squillante, A.E.; Kelsen, D.P.; Braun, Jr., D.W.; Bordin, L.A.; Vraun, T.J. and Young, C.W.: Antiemetic efficacy of high-dose metoclopramide: Randomized trials with placebo and prochlorperazine in patients with chemotherapy-induced nausea and vomiting. New England Journal of Medicine 305: 905–909 (1981)

    Article  PubMed  CAS  Google Scholar 

  • Gralla, E.J.; Sabo, J.P.; Hayden, D.W.; Yochmowitz, M.G. and Mattsson, J.L.: The effect of selected drugs on first-stage radioemesis in beagle dogs. Radiation Research 78: 286–295 (1979)

    Article  PubMed  CAS  Google Scholar 

  • Grossman, B.; Lessin, L.S. and Cohen, P.: Droperidol prevents nausea and vomiting from cis-platinum. New England Journal of Medicine 301: 47 (1979)

    PubMed  CAS  Google Scholar 

  • Hamers, J.: Cytostatic therapy-induced vomiting inhibited by domperidone. A double-blind cross-over study. Biomedicine 29: 242–244 (1978)

    PubMed  CAS  Google Scholar 

  • Herman, T.S.; Einhorn, L.H.; Jones, S.E.; Hagy, C.; Chester, A.B.; Dean, J.C.; Furnas, B.; Williams, S.D.; Leigh, S.A.; Dorr, R.T. and Moon, T.E.: Superiority of nabilone over prochlorperazine as an antiemetic in patients receiving cancer chemotherapy. New England Journal of Medicine 300: 1295–1297 (1979)

    Article  PubMed  CAS  Google Scholar 

  • Hollister, L.E.: Psychiatric disorders; in Avery (Ed.) Drug Treatment, pp.1062–1066 (ADIS Press, Sydney and New York 1980

    Google Scholar 

  • Huys, J.: Cytostatic-associated vomiting effectively inhibited by domperidone (R 33812). Cancer Chemotherapy Pharmacology 1: 215–218 (1978)

    Article  CAS  Google Scholar 

  • Israel, L. and Rodary, C.: Treatment of nausea and vomiting related to anti-cancerous multiple combination chemotherapy. Journal of International Medicine Research 6: 235–240 (1978)

    CAS  Google Scholar 

  • Jacobs, A.J.; Deppe, G. and Cohen, C.J.: A comparison of the antiemetic effects of droperidol and prochlorperazine in chemotherapy with cis-platinum. Gynecologic Oncology 10: 55–57 (1980)

    Article  PubMed  CAS  Google Scholar 

  • Joss, R.A.; Goldhirsch, A.; Brunner, K.W. and Galeazzi, R.L.: Sudden death in cancer patient on high-dose domperidone. Lancet 1: 1019 1982

    Article  PubMed  CAS  Google Scholar 

  • Levitt, M.; Wilson, A.; Burman, D.; Fairman, C; Kernel, S.; Krepart, G.; Schipper, H.; Weinerman, B. and Weinerman, R.: Dose vs. response of tetrahydrocannabinol (THC) vs. prochlorperazine (PCPZ) as chemotherapy antiemetics. Proceedings of the American Society of Clinical Oncology 22: 419811981

    Google Scholar 

  • Loeser, E.A.; Bennett, G.; Stanley, T.H. and Machin, R.: Comparison of droperidol, haloperidol and prochlorperazine as postoperative antiemetics. Canadian Anaesthesia Society Journal 26: 125–127(1979)

    Article  CAS  Google Scholar 

  • Long, A.; Mioduszewski, J. and Natale, R.: A randomized double-blind cross-over comparison of the antiemetic activity of levonantradol and prochlorperazine. Proceedings of the American Society of Clinical Oncology 1: 57 (1982)

    Google Scholar 

  • Lowenbraun, S.; Cunitz, G.; Benton, R.; and Birch, R.: Double-blind comparison of the antiemetic effects of chlorpromazine (C) alone vs. chlorpromazine + secobarbital (C+S) vs. chlorpromazine + secobarbital + methylprednisolone (C+S+M) in patients (PTS) receiving chemotherapy (Chemo). Proceedings of the American Society of Clinical Oncology 1: 67 (1982)

    Google Scholar 

  • Marks, J.H.: Use of chlorpromazine in radiation sickness and nausea from other causes. New England Journal of Medicine 250: 999–1001 (1954)

    Article  PubMed  CAS  Google Scholar 

  • McCabe, M.; Smith, F.P.; Goldberg, D.; Macdonald, J.; Woolley, P.V.; Warren, R.; Brodeur, R. and Schein, P.S.: Comparative trial of oral 9-tetrahydrocannabinol (THC) and prochlorperazine (PCPZ) for cancer chemotherapy-related nausea and vomiting. Proceedings of the American Society of Clinical Oncology 22: 416 (1981)

    Google Scholar 

  • Mehrotra, S.; Rosenthal, C.J.; Barile, B.; Dotan, S. and Alfonso, A.: A comparison between droperidol (DP) and prochlorperazine (PCP) in combination with trimethobenzamide (TMB) as antiemetics for antineoplastic combination chemotherapy (CCT). Proceedings of the American Society of Clinical Oncology 22: 417 (1981)

    Google Scholar 

  • Mellencamp, E. and Wang, R.I.H.: The patient with nausea III. Cancer, pregnancy or surgery. Drug Therapy 7(6): 102–112 (1977)

    Google Scholar 

  • Moertel, C.G. and Reitemeier, R.J.: Controlled clinical studies of orally administered antiemetic drugs. Gastroenterology 57: 262–268 (1969)

    PubMed  CAS  Google Scholar 

  • Moertel, C.G. and Reitemeier, R.J.: Controlled studies of metopimazine for the treatment of nausea and vomiting. Journal of Clinical Pharmacology 13: 283–287 (1973)

    PubMed  CAS  Google Scholar 

  • Moertel, C.G.; Reitemeier, R.J. and Gage, R.P.: A controlled clinical evaluation of antiemetic drugs. Journal of the American Medical Association 186: 116–118 (1963)

    Article  PubMed  CAS  Google Scholar 

  • Morran, C.; Smith. D.C.; Anderson, D.A.; McArdle, C.S.: Incidence of nausea and vomiting with cytotoxic chemotherapy; A prospective randomized trial of antiemetics. British Medical Journal 1: 1223–1224(1979)

    Google Scholar 

  • Mover, J.H.: Effective antiemetic agents. Medical Clinics of North America 41: 405–432 (1957)

    Google Scholar 

  • Neidhart, J.A.; Gagen, M.; Young, D. and Wilson, H.E.: Specific antiemetics for specific cancer chemotherapeutic agents. Cancer 47: 1439–1443 (1981)

    Article  PubMed  CAS  Google Scholar 

  • Nogarede, J.; Closon, M.Th.; Clarysse, A.; Longueville, J.; Derouaux, M.; Ferrant, A. and Drochmans, A.: Domperidone (R 33812) in the prophylactic treatment of chemotherapy-induced emesis. Drug Research 28: 686–688 (1978)

    PubMed  CAS  Google Scholar 

  • Orr. L.E.; McKernan, J.F. and Bloome, B.: Antiemetic effect of tetrahydrocannabinol compared with placebo and prochlorperazine in chemotherapy-associated nausea and emesis. Archives of Internal Medicine 140: 1431–1433 (1980)

    Article  PubMed  CAS  Google Scholar 

  • Paladine, W.; Price, L.; Sokol, G.; Kriz, E. and Ayres, V.: Antiemetic trial of droperidol. Proceedings of the American Society of Clinical Oncology 21: 380 (1980)

    Google Scholar 

  • Petracek, F.J.; Bier, J.H.; Bopp, B. and Mitchell, B.: Chemistry and structure activity relationships of psychotropic drugs; in Clarke, W.G. and del Guidice, J. (Eds) Principles of Psychopharmacology (Academic Press, New York 1978

    Google Scholar 

  • Plotkin, D.A.; Plotkin, D. and Okun, R.: Haloperidol in the treatment of nausea and vomiting due to cytotoxic drug administration. Current Therapeutic Research 15: 599–602 (1973)

    PubMed  CAS  Google Scholar 

  • Purkis, I.E.: The action of thiethylperazine (Torecan), a new antiemetic compared with perphenazine (Trilafon), trimethobenzamide (Tigan) and a placebo in the suppression of postanaesthetic nausea and vomiting. Canadian Anaesthesia Society Journal 12: 595–607 (1965)

    Article  CAS  Google Scholar 

  • Sallan, S.E.; Cronin, C.; Zelan, M. and Zinberg, N.E.: Antiemetics in patients receiving chemotherapy for cancer: A randomized comparison of delta-9-tetrahydrocannabinol and prochlorperazine. New England Journal of Medicine 302: 135–138 (1980)

    Article  PubMed  CAS  Google Scholar 

  • Scagna, D. and Smalley, R.: Chemotherapy-induced nausea and vomiting. American Journal of Nursing 9: 1562–1564 (1979)

    Article  Google Scholar 

  • Siegel, L.J. and Longo, D.L.: The control of chemotherapy-induced emesis. Annals of Internal Medicine 95: 352–359 (1981)

    Google Scholar 

  • Sicher, K. and Backhouse, T.W.: An assessment of thiethylperazine (Torecan) in the control of radiation-induced nausea and vomiting. Clinical Radiology 19: 238–240 (1968)

    Article  PubMed  CAS  Google Scholar 

  • Snyder, S.H.: Receptors, neurotransmitters and drug responses. New England Journal of Medicine 300: 465–472 (1979)

    Article  PubMed  CAS  Google Scholar 

  • Solan, M.J.: Prochlorperazine and irradiation sickness. British Medical Journal 2: 1068–1069 (1959)

    Article  PubMed  CAS  Google Scholar 

  • Steele, N.; Gralla, R.J.; Braun, D.W. and Young, C.W.: Double-blind comparison of the antiemetic effects of nabilone and prochlorperazine on chemotherapy-induced emesis. Cancer Treatment Reports 64: 219–224 (1980)

    PubMed  CAS  Google Scholar 

  • Stoll, B.A.: Radiation sickness: An analysis of over 1,000 controlled drug trials. British Medical Journal 2: 507–510 (1962)

    Article  PubMed  CAS  Google Scholar 

  • Swann, I.L.; Thompson, E.N. and Qureshi, K.: Domperidone or metpclopramide in preventing chemotherapeutically induced nausea and vomiting. British Medical Journal 2: 1188 (1979)

    Article  PubMed  CAS  Google Scholar 

  • Williams, C.J.; Bolton, A.; de Pemberton, R. and Whitehouse, J.M.: Antiemetics for patients treated with antitumor chemotherapy. Cancer Clinical Trials 3: 363–367 (1980)

    PubMed  CAS  Google Scholar 

  • Wilson, J.; Weltz, M.; Solimando, D.; Perry, D.; Baldwin, P. and Kimball, D.: Continuous infusion droperidol: Anti-emetic therapy for cis-platinum (DDP) toxicity. Proceedings of American Society of Clinical Oncology 22: 421 (1981)

    Google Scholar 

  • Wyman, J.B. and Wick, M.R.: The vomiting patient. American Family Physician 21: 139–143 (1980)

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Medical College of Virginia, Richmond, Virginia

    Galen Wampler

Authors
  1. Galen Wampler
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wampler, G. The Pharmacology and Clinical Effectiveness of Phenothiazines and Related Drugs for Managing Chemotherapy-induced Emesis. Drugs 25 (Suppl 1), 35–51 (1983). https://doi.org/10.2165/00003495-198300251-00005

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00003495-198300251-00005

Keywords

Search

Navigation