The Pharmacology and Clinical Effectiveness of Phenothiazines and Related Drugs for Managing Chemotherapy-induced Emesis
- First Online:
- 18 Downloads
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.
Unable to display preview. Download preview PDF.
- 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
- 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 1971Google Scholar
- Delay, J. and Deniker, P.: Characteristiques psycho-physiologiques des medicaments neuroleptiques; in Garattini and Ghetti (Eds) Psychotropic Drugs (Elsevier, New York 1957Google 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
- 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)PubMedCrossRefGoogle 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)PubMedCrossRefGoogle Scholar
- Hollister, L.E.: Psychiatric disorders; in Avery (Ed.) Drug Treatment, pp.1062–1066 (ADIS Press, Sydney and New York 1980Google 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)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: 419811981Google 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
- 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
- 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
- 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 1978Google Scholar
- Siegel, L.J. and Longo, D.L.: The control of chemotherapy-induced emesis. Annals of Internal Medicine 95: 352–359 (1981)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