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Substrates of Human CYP2D6
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
Dolasetron is a 5-HT3 receptor antagonist, which is used for the treatment of chemotherapy-induced emesis (Balfour and Goa 1997). It is rapidly reduced by carbonyl reductase to form its major pharmacologically active metabolite, reduced dolasetron (Shah et al. 1995). Reduced dolasetron appears in plasma within 10 min after intravenous or oral administration (Dempsey et al. 1996). Reduced dolasetron underwent oxidation of the indole aromatic ring at positions 5, 6, and 7 and also N-oxidation. Reduced dolasetron accounts for 17%–54% of the dose in urine, and hydroxylated metabolites of reduced dolasetron represent up to 9% of the dose in urine (Figure 3.37) (Reith et al. 1995). Most of the remaining urinary radioactivity consists of conjugated metabolites of reduced dolasetron and hydroxylated reduced dolasetron. Hydroxylation of reduced dolasetron is mediated by CYP2D6, and its N-oxidation is catalyzed by CYP3A4 (Sanwald et al. 1996a).
Neurotransmitters and pharmacology
Published in Mark J. Ashley, David A. Hovda, Traumatic Brain Injury, 2017
Ronald A. Browning, Richard W. Clough
The 5-HT3 family was originally identified in the periphery.121 These receptors are unique among the monoamine receptors in that, instead of being G-protein linked receptors (GPCRs), they are ligand-gated ion channels similar to the nicotinic ACh receptor. The 5-HT3 receptor is a nonselective cation channel that allows Na+ and K+ to enter the cell when 5-HT is bound to it. Thus, the 5-HT3 receptor produces excitation when activated. Originally, the 5-HT3 receptor was identified primarily by its affinity for specific agonists and antagonists,121,122 but it has now been cloned.39 Indeed, at least two subtypes of 5-HT3 receptors have now been identified (known as 3A and 3B), and there may be others. These subtypes differ in the protein subunit composition, much like the nicotinic ACh receptor or the GABAA receptor.123 The 5-HT3 receptors are present in the area postrema and autonomic afferent nerves where they play a role in promoting nausea and vomiting. Indeed, the 5-HT3 antagonists ondansetron (Zofran®), granisetron (Kytril®), and dolasetron (Anzetmet®) are widely used to treat the nausea and vomiting associated with cancer chemotherapy. Another 5-HT3 antagonist, Alosetron (Lotronex®), has been approved for the treatment of diarrhea associated with irritable bowel syndrome.109 It is likely that, in the future, we will see 5-HT3 antagonists used in the treatment of psychiatric disorders as drugs that are more selective for subtypes of the receptor become available.
Gastroparesis syndromes: emerging drug targets and potential therapeutic opportunities
Published in Expert Opinion on Investigational Drugs, 2023
Le Yu Naing, Matthew Heckroth, Prateek Mathur, Thomas L Abell
5-HT3 receptors differ from all other 5-HT receptors in that they are ligand-gated ion channels, whereas the others are G-protein linked receptors. Activation of 5-HT3 receptors inhibits gastric secretions, stimulates migrating motor complexes, and increases intestinal secretions, accelerating small bowel transit. They also stimulate gastric antral contractions and vagal afferent nerves initiating the vomiting reflex[31]. 5-HT3 receptor antagonists are potent antiemetics often used to treat the symptoms of Gp. They block serotonin both peripherally on vagal nerve terminals in the GI tract, as well as centrally in the area postrema and nucleus tractus solitarius. Available 5-HT3 receptor antagonists include ondansetron (Zofran), granisetron (Kytril), tropisetron (Navoban), dolasetron (Anzamet), ramosetron (Nasea), and palonosetron (Aloxi). Some of them have been associated with QT prolongation on EKG, and it is recommended that patients with congenital long QT syndrome need to be cautious with their use. For patients with significant electrolyte abnormalities, congestive heart failure, or those taking other medications that prolong the QT interval, monitoring with serial EKGs is recommended.
An update on the use of pharmacotherapy for opioid-induced bowel dysfunction
Published in Expert Opinion on Pharmacotherapy, 2023
Taraneh Mousavi, Shekoufeh Nikfar, Mohammad Abdollahi
Antiemetic agents used to manage opioid-induced nausea include prokinetic agents (e.g. metoclopramide), 5-HT3 receptor antagonists (e.g. ondansetron, granisetron, palonosetron, and dolasetron), anticholinergics (e.g. trimethobenzamide, scopolamine, and promethazine), antihistamines (e.g. meclizine, diphenhydramine, dimenhydrinate, and hydroxyzine), and corticosteroids (e.g. dexamethasone), cannabinoids (e.g. dronabinol and nabilone). In some cases, benzodiazepines (e.g. lorazepam) and neuroleptics (e.g. prochlorperazine, chlorpromazine, haloperidol, and olanzapine) might be used as well [68,69]. For instance, switching to neuroleptics is preferred in refractory cases or those with advanced cancer [70,71]. Additionally, using antihistamines and metoclopramide is reasonable for patients who suffer from nausea associated with vertigo or postprandial vomiting.
Improving recovery after microvascular decompression surgery for hemifacial spasm: experience from 530 cases with enhanced recovery after surgery (ERAS) protocol
Published in British Journal of Neurosurgery, 2021
Dongliang Wang, Jixia Fang, Jiayu Liu, Qingpei Hao, Hu Ding, Bo Liu, Zhi Liu, Haidong Song, Jia Ouyang, Ruen Liu
PONV is common after general anesthesia and can cause distress, dehydration, electrolyte imbalance, pulmonary aspiration, and prolonged hospital stay.14 Recent studies among craniotomy patients have determined that MVD poses a high risk of PONV.15–18 Most worrying in these cases is that the physical act of vomiting may result in increased intracranial and arterial pressures, thereby potentially increasing the risk of intracranial hemorrhage, especially during the first 24 h after surgery. Kathirvel et al. have reported that more than 60% of MVD patients had PONV within 24 h postoperatively despite the use of ondansetron,19 and the incidence of PONV in the patients in our control group (55.7%) was similar. The combination of dexamethasone plus dolasetron or haloperidol has already been shown to be superior to monotherapy in PONV treatment,20 and our ERAS protocol also calls for administration of an oral carbohydrate load with amino acid solution 2 h before surgery, which may alleviate postoperative hunger and thirst and help to attenuate PONV. To further mitigate PONV, propofol was the preferred agent for maintaining general anesthesia, and the use of opioids was limited.21,22 Finally, a combination of methylprednisolone and tropisetron was administered prophylactically prior to the end of surgery, and of course, postoperatively if necessary. Therefore, the rate of PONV was significantly reduced in the ERAS group.