29 Mitemcinal Antiemetic Agents 5HT3 receptor antagonists

The introduction of 5HT3 receptor antagonists into clinical practice as antiemetic agents revolutionized the treatment of patients undergoing therapy for malignancy. Once again, metoclopramide was at the vanguard, with high doses of this agent being an effective antiemetic in dog82 and human.83 The antiemetic efficacy of selective 5HT3 receptor antagonists was first demonstrated in the ferret.84 In these studies, tropisetron and bemesetron profoundly inhibited the emetic response evoked by the chemotherapeutic agent cisplatin. Additional 5HT3 receptor antagonists ondansetron and granisetron prevented emesis evoked by high-dose cisplatin or cyclophosphamide or x-irradiation. ' These antagonists were not only able to prevent the onset of emesis, but were also able to abolish established emesis, raising the possibility of using these agents as interventional therapies once emesis was established or following the failure of agents administered earlier.

The precise locus for the antiemetic activity of the 5HT3 receptor antagonists remains unclear. There is debate over whether the most important site of receptor blockade lies within the central or the peripheral nervous system, or indeed whether receptor blockade at both sites is important. What is clear is that many chemotherapeutic agents evoke a significant release of 5HT from small intestinal enterochromaffin cells. 5HT so released stimulates 5HT3 receptors located on vagal afferent nerve fibers that project into dorsomedullary structures in the brainstem. These sensory fibers also appear to have 5HT3 receptors on their central terminals, which modulate the release of neurotransmitters in this important modulatory region, and may represent an important site of drug activity.

Ondansetron, granisetron, and tropisetron are effective antiemetic agents in patients undergoing treatment with a wide range of chemotherapeutic agents87,88 and with radiotherapy.89 Additional 5HT3 receptor antagonists include dolasetron (30), ramosetron (31), and palonosetron (32). These agents vary in their affinity for 5HT3 receptors and in their routes of metabolism, and hence while they have broadly similar antiemetic profiles, individual responses to these agents may differ.

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