Emesis, antagonists

The most widely used emetic is syrup of ipecac, containing the alkaloids, emetine and cq haeline. Emetine induces vomiting by activation of sensory neurons in the vagus and sympathetic nerves to the stomach and centrally in the medulla, possibly at the CTZ. The release of serotonin and SP may be involved as 5-HT3 and NKi receptor antagonists prevent emesis induced... 

Dronabinol (tetrahydrocannabinol), the active principle from cannabis and synthetic cannabinoids, nabilone and levonantradol are effective in treating nausea and vomiting in cancer chemotherapy. The mode of action is unclear but appears to involve cannabinoid CBi receptors. Cannabinoids have been shown to reduce acetylcholine release in the cortex and hippocampus, and have been suggested to inhibit medullary activity by a cortical action. Inhibition of prostaglandin synthesis and release of endorphins may also be involved in the antiemetic effect. A review of trials of dronabinol, nabilone or levonantradol concluded that while the cannabinoids were superior to placebo or dopamine receptor antagonists in controlling emesis... 

Aapro MS 5-HT3 receptor antagonists an overview of their present status and future potential in cancer therapy-induced emesis. Drugs 42 551-568, 1991... 

DA antagonists are anti-emetic, elevate plasma prolactin and have major motor and behavioural effects. Thus DA must be involved in the initiation of vomiting, the secretion of prolactin and control of motor and behavioural activity. Its role in emesis and as the prolactin release inhibitory factor have been adequately covered above. Its motor and behavioural function will now be considered. 

Fever, rigors, chills, malaise headaches, myalgia Nausea, emesis Neutropenia Hepatic enzyme elevation Cutaneous—alopecia, transient, mild rashlike reaction Acetaminophen (APAP). NSAID if APAP is not effective. Meperidine for severe chills and rigors. Bedtime administration. 5-HT3 antagonist, prochlorperazine, metoclopramide, fluids Weekly complete blood count reduce dose by 30-50% Liver function tests (LFTs) weekly withhold treatment until LFTs normalize restart at 30-50% dose reduction reversible on dose reduction or cessation. Interferon is contraindicated in patients with psoriasis because exacerbation of psoriasis has been noted during IFN therapy. 

HT3 antagonist, prochlorperazine for emesis (avoid corticosteroids), H2 blocker for gastritis, antidiarrheal as needed (loperamide, diphenoxylate/atropine, codeine). 

An important advance in this field has been made by the discovery of selective serotonin (5-HT3) receptor antagonists that are effective inhibitors of cytotoxic drug-induced emesis in laboratory animals. The new agents have been found to be free of the undesirable side-effects associated with dopaminergic blockade and have shown significant protection from emesis in early clinical trials. 

In general, ketones, alcohols and ethers of formula (3) showed comparable protection against cisplatin-induced emesis in the dog and ferret with that of metoclopramide. Erythro (cis) alcohols (3c, 3g, 3i) were found to be more potent than the corresponding threo-(trans) isomers (3d, 3h, 3j). Optical isomer (.R) (3e) was found to be somewhat more potent than its (S )-enantiomer (3f) as an antagonist of cisplatin-induced emesis in the ferret. In the dog, both isomers showed similar activity. A number of heterocyclic analogues were also studied but with the exception of (3k), all were inferior in potency as antiemetic agents compared with other compounds (3) shown in Table 7.1. Lead compound, BMY 25801, batanopride, (3a) is presently under clinical investigation. 

Another approach combined modification of the 2-substituent yielding dihy-drobenzofuran and pyrrolidinemethyl side-chain with unsubstituted (secondary) nitrogen to give ADR 851 (24) and ADR 847 (25) [18]. Both were reported to be somewhat more effective than metoclopramide as antagonists of cisplatin-induced emesis in the dog. In addition, ADR 847 enhanced gastric emptying [19]. 

Parallel with the developments in the benzamide area, progress was also made in several nonbenzamide series of compounds. MDL 72222 (26) [20], atropine ester of 3,5-dichlorobenzoic acid, was the first selective 5-HT3 receptor antagonist and a potent antagonist of cisplatin-induced emesis in the ferret [21]. ICS 205-930 (27) [22,23 ], the tropine ester of 3-indolecarboxylic acid, exhibited similar pharmacological and antiemetic profiles. 

Metoclopramide, administered at doses higher than those required to inhibit apomorphine-induced emesis, was more effective than haloperidol in antagonizing cisplatin-induced emesis in dogs [80]. This was observed despite the fact that metoclopramide was considerably weaker than haloperidol as a D2-dopamine antagonist [43]. Subsequently, antiemetic efficacy of metoclopramide administered at high doses has been reported in cancer patients... 

There are a few reports on possible sites of action of 5-HT3 antagonists. Low doses of zacopride administered directly into the fourth ventricle (i.c.v.) antagonized cisplatin (i.v.[-induced emesis in the cat [108]. A similar antagonism was demonstrated when routes of drug administration were interchanged. Similarly, GR 38032F, GR 65630 and MDL 72222, administered i.c.v. onto the area postrema at very low doses, antagonized cisplatin-induced... 

It had been reported that 5-HT and 2-Me-5-HT released DA in striatal slices [112]. The functional importance of this response is unknown, because the D2-dopamine antagonists are not efficient antiemetics against radiation- or chemotherapy-induced emesis. 

It can be concluded that direct evidence linking endogenous 5-HT to emesis is not convincing. On the other hand, selective effectiveness of 5-HT3 antagonists as antiemetic agents and presence of 5-HT3 receptors in the area postrema and vagus nerve do implicate 5-HT mechanisms. 

Domperidone [133], one of the most potent D2-dopamine blockers and antagonists of apomorphine-induced emesis with limited brain-blood barrier permeability, did not establish a position as an antiemetic, especially against cisplatin [134], Recently, the use of domperidone as a parenteral antiemetic has been discontinued because of serious cardiovascular toxicity. 

Metoclopramide may be considered as a prototype 5-HT3 antagonist because its antiemetic efficacy both in animals and man could not be adequately explained by D2-dopamine blockade. In fact, metoclopramide was considerably weaker as a D2-antagonist than haloperidol or domperidone and yet it was effective against emesis induced by anticancer agents both in animals [43, 80] and cancer patients [135]. 

Chapter 7 outlines the basic mechanism and treatment of emesis, and in particular, that induced by chemotherapy of cancer. Finally, the chemistry, pharmacology and clinical applications of antagonists of the platelet-activating factor (PAF), an important mediator of many physiological and pathological conditions, are reviewed in Chapter 8. 

A direct reaction of activation is exemplified by the NK receptor antagonist L-754,030 (9.78) developed as an i.v. drug against emesis, migraine, and chronic pain. Because the compound has a low water solubility unfavorable for i.v. administration, a phosphoramidate prodrug (9.77) has been examined [152], This compound hydrolyzed rapidly under acidic conditions. More importantly, it was rapidly converted to L-754,030 in rat blood but was... 

Reddy, G.K., Gralla, R.J. and Hesketh, P.J., Novel neurokinin-1 antagonists as antiemetics for the treatment of chemotherapy-induced emesis. Support. Cancer Ther., 2006, 3, 140-142. 

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