, Volume 25, Issue 1 Supplement, pp 35-51
Date: 15 Oct 2012

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

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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.