HT3 antagonists

Arch Gen Psychiatry 42 1050-1055, 1985 Hodge CW, Kelley SP, Bratt AM, et al 5-HT3 receptor subunit is required for 5-HT3 antagonist-induced reductions in alcohol drinking. Neuropsychopharmacology 29 1807-1813, 2004... 

There have been few attempts to manipulate the monoamines in AzD and those using selegiline, the MOAb inhibitor, have shown little effect although the 5-HT3 antagonist, ondansetron, may give a slight improvement. 

Tetracyclic 2-adrenoceptor antagonist Mianserin Hi-antagonist, 5-HTi, 5-HT2 and 5-HT3 antagonist... 

For prophylaxis of acute chemotherapy-induced nausea and vomiting, the combination of a 5-HT3 antagonist and a corticosteroid is recommended for patients receiving highly eme-togenic cisplatin or non-cisplatin-based chemotherapy. 

Antiemetics can be administered either intravenously or orally in this situation, depending on patient characteristics such as ability to take oral medications, dosage form availability, and cost considerations.5,10 The intravenous and oral routes are equally effective. When used at equipotent doses, the 5-HT3 antagonists have similar efficacy in preventing acute CINV, despite pharmacokinetic and receptor binding affinity differences.5,10,36... 

The 5-HT3 antagonist palonosetron is the first 5-HT3 antagonist to be approved for prevention of both acute and delayed CINV.40 Compared to the other 5-HT3 antagonists, palonosetron has a longer serum half-life (40 hours compared to 4 to 9 hours) and a higher receptor binding affinity, which may contribute to its efficacy in preventing delayed CINV.41... 

Combinations of antiemetics may be the most effective method of preventing PONV for high-risk patients.7,42 Droperidol plus a 5-HT3 antagonist or dexamethasone plus a 5-HT3 antagonist are effective combinations.43,44 Three-drug combinations such as dexamethasone, droperidol, and a 5-HT3 antagonist have not been formally studied but may be a reasonable approach.42... 

Stimulation of 5-HT3 receptors triggers hypersensitivity and hyperactivity of the large intestine. Alosetron (Lotronex) is a selective 5-HT3 antagonist that blocks these receptors and is used to treat women with severe diarrhea-predominant IBS. Eligible patients should have frequent and severe abdominal pain, frequent bowel urgency or incontinence, and restricted daily activities. Alosetron has been shown to improve overall symptoms and quality of life. Alosetron can cause constipation in some patients. 

Apomorphine is approved for acute off episodes in patients with advanced stages of PD. The onset of effect is within 10 to 20 minutes and the duration of effect is about 60 minutes. It requires premedication with an antiemetic because it causes nausea and vomiting. Antiemetics that block central dopamine worsen the symptoms of PD, and 5-HT3 antagonists, such as ondansetron, can aggravate PD-related hypotension. Trimethobenzamide (300 mg three times daily) should be... 

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). 

Moderate, high, and very high likelihood of nausea/vomiting—5-HT3 antagonist (as above) and dexamethasone (as above) benzodiazepine Low likelihood of nausea/vomiting—Compazine Very low likelihood of nausea/vomiting—Compazine only if needed ... 

This discussion will be limited to the neural serotonin 5-HT3 receptors which came to the forefront with the advent of antiemetic agents exhibiting 5-HT3 antagonist properties. At the present time, there is no evidence that 5-HT, and 5-HT2 receptors play an important role in vomiting [64],... 

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 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. 

A functional relationship may exist between gastrointestinal responses and antiemetic action, because selected 5-HT3 antagonists, zacopride [17], BRL... 

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]. 

Recently, several 5-HT3 antagonists have been identified and found to be effective as antiemetics in animals (Table 7.2). These compounds as a class have been proven to be free of D2-dopamine blocking properties which are responsible for dystonic side-effects seen with metoclopramide. 

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