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Pharmacotherapeutic group: Antiemetics and antinauseants, Serotonin (5-HT3) antagonists. ATC code: A04AA02.
Pharmacology: Pharmacodynamics: Neurological mechanisms, serotonin-mediated nausea and vomiting: Serotonin is the main neurotransmitter responsible for emesis after chemo- or radio-therapy. The 5-HT3 receptors are located in three sites: vagal nerve terminals in the gastrointestinal tract and chemoreceptor trigger zones located in the area postrema and the nucleus tractus solidarius of the vomiting center in the brainstem. The chemoreceptor trigger zones are located at the caudal end of the fourth ventricle (area postrema). This structure lacks an effective blood-brain barrier, and will detect emetic agents in both the systemic circulation and the cerebrospinal fluid. The vomiting centre is located in the brainstem medullary structures. It receives major inputs from the chemoreceptor trigger zones, and a vagal and sympathetic input from the gut.
Following exposure to radiation or catotoxic substances, serotonin (5-HT) is released from enterochromaffine cells in the small intestinal mucosa, which are adjacent to the vagal afferent neurons on which 5-HT3 receptors are located. The released serotonin activates vagal neurons via the 5-HT3 receptors which lead ultimately to a severe emetic response mediated via the chemoreceptor trigger zone within the area postrema.
Mechanism of action: Granisetron is a potent anti-emetic and highly selective antagonist of 5-hydroxytryptamine (5-HT3) receptors. Radioligand binding studies have demonstrated that granisetron has negligible affinity for other receptor types including 5-HT and dopamine D2 binding sites.
Chemotherapy- and radiotherapy-induced nausea and vomiting: Granisetron administered intravenously has been shown to prevent nausea and vomiting associated with cancer chemotherapy in adults and children 2 to 16 years of age.
Post-operative nausea and vomiting: Granisetron administered intravenously has been shown to be effective for prevention and treatment of post-operative nausea and vomiting in adults.
Pharmacological properties of granisetron: Interaction with neurotropic and other active substances through its activity on P 450-cytochrome has been reported (see Interactions).
In vitro studies have shown that the cytochrome P450 sub-family 3A4 (involved in the metabolism of some of the main narcotic agents) is not modified by granisetron. Although ketoconazole was shown to inhibit the ring oxidation of granisetron in vitro, this action is not considered clinically relevant.
Although QT-prolongation has been observed with 5-HT3 receptor antagonists (see Precautions), this effect is of such occurrence and magnitude that it does not bear clinical significance in normal subjects. Nonetheless it is advisable to monitor both ECG and clinical abnormalities when treating patients concurrently with drugs known to prolong the QT (see Interactions).
Paediatric population: Clinical application of granisetron was reported by Candiotti et al. A prospective, multicentre, randomized, double-blind, parallel-group study evaluated 157 children 2 to 16 years of age undergoing elective surgery. Total control of postoperative nausea and vomiting during the first 2 hours after surgery was observed in most patients.
Pharmacokinetics: Pharmacokinetics of the oral administration is linear up to 2.5-fold of the recommended dose in adults. It is clear from the extensive dose-finding program that the antiemetic efficacy is not unequivocally correlated with either administered doses or plasma concentrations of granisetron.
A fourfold increase in the initial prophylactic dose of granisetron made no difference in terms of either the proportion of patient responding to treatment or in the duration of symptom control.
Distribution: Granisetron is extensively distributed, with a mean volume of distribution of approximately 3 L/kg. Plasma protein binding is approximately 65%.
Biotransformation: Granisetron is metabolized primarily in the liver by oxidation followed by conjugation. The major compounds are 7-OH-granisetron and its sulphate and glycuronide conjugates. Although antiemetic properties have been observed for 7-OH-granisetron and indazoline N-desmethyl granisetron, it is unlikely that these contribute significantly to the pharmacological activity of granisetron in man.
In vitro liver microsomal studies show that granisetron's major route of metabolism is inhibited by ketoconazole, suggestive of metabolism mediated by the cytochrome P-450 3A subfamily (see Interactions).
Elimination: Clearance is predominantly by hepatic metabolism. Urinary excretion of unchanged granisetron averages 12% of dose while that of metabolites amounts to about 47% of dose. The remainder is excreted in faeces as metabolites. Mean plasma half-life in patients by the oral and intravenous route is approximately 9 hours, with a wide inter-subject variability.
Pharmacokinetic relationship(s): Renal failure: In patients with severe renal failure, data indicate that pharmacokinetic parameters after a single intravenous dose are generally similar to those in normal subjects.
Hepatic impairment: In patients with hepatic impairment due to neoplasic liver involvement, total plasma clearance of an intravenous dose was approximately halved compared to patients without hepatic involvement. Despite these changes, no dosage adjustment is necessary (see Dosage & Administration).
Elderly: In elderly subjects after single intravenous doses, pharmacokinetic parameters were within the range found for non-elderly subjects.
Paediatric population: In children, after single intravenous doses, pharmacokinetics are similar to those in adults when appropriate parameters (volume of distribution, total plasma clearance) are normalized for body weight.
Toxicology: Preclinical safety data: Non-clinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, reproductive toxicity and genotoxicity. Carcinogenicity studies revealed no special hazard for humans when used in the recommended human dose. However when administered in higher doses and over a prolonged period of time the risk of carcinogenicity cannot be ruled out.
A study in cloned human cardiac ion channels has shown that granisetron has the potential to affect cardiac repolarisation via blockade of HERG potassium channels. Granisetron has been shown to block both sodium and potassium channels, which potentially affects both depolarisation and repolarisation through prolongation of PR, QRS, and QT intervals. This data helps to clarify the molecular mechanisms by which some of the ECG changes (particularly QT and QRS prolongation) associated with this class of agents occur. However, there is no modification of the cardiac frequency, blood pressure or the ECG trace. If changes do occur, they are generally without clinical significance.
