| Indication |
For the prevention of nausea and vomiting associated with initial
and repeat courses of emetogenic cancer therapy (including high dose
cisplatin), postoperation, and radiation (including total body
irradiation and daily fractionated abdominal radiation). |
| Pharmacodynamics |
Granisetron is a selective inhibitor of type 3 serotonergic (5-HT3)
receptors. Granisetron has little or no affinity for other serotonin
receptors, including 5-HT 1 , 5-HT 1A , 5-HT 1B/C , or 5-HT 2 ; for
alpha 1 -, alpha 2 -, or beta-adrenoreceptors; for dopamine D 2
receptors; for histamine H 1 receptors; for benzodiazepine receptors;
for picrotoxin receptors; or for opioid receptors. In most human
studies, granisetron has had little effect on blood pressure, heart
rate, or electrocardiogram (ECG). The drug is structurally and
pharmacologically related to ondansetron, another selective inhibitor of
5-HT3 receptors. The serontonin 5-HT3 receptors
are located on the nerve terminals of the vagus in the periphery, and
centrally in the chemoreceptor trigger zone of the area postrema. The
temporal relationship between the emetogenic action of emetogenic drugs
and the release of serotonin, as well as the efficacy of antiemetic
agents suggest that chemotherapeutic agents release serotonin from the
enterochromaffin cells of the small intestine by causing degenerative
changes in the GI tract. The serotonin then stimulates the vagal and
splanchnic nerve receptors that project to the medullary vomiting
center, as well as the 5-HT3 receptors in the area postrema, thus
initiating the vomiting reflex, causing nausea and vomiting. |
| Mechanism of action |
Granisetron is a potent, selective antagonist of 5-HT3
receptors. The antiemetic activity of the drug is brought about through
the inhibition of 5-HT3 receptors present both centrally (medullary
chemoreceptor zone) and peripherally (GI tract). This inhibition of
5-HT3 receptors in turn inhibits the visceral afferent stimulation of
the vomiting center, likely indirectly at the level of the area
postrema, as well as through direct inhibition of serotonin activity
within the area postrema and the chemoreceptor trigger zone. |
| Absorption |
Absorption of is rapid and complete, though oral bioavailability is reduced to about 60% as a result of first pass metabolism. |
| Volume of distribution |
Not Available |
| Protein binding |
65% |
| Metabolism |
Primarily hepatic; undergoes N -demethylation and aromatic ring
oxidation followed by conjugation. Animal studies suggest that some of
the metabolites may have 5-HT 3 receptor antagonist activity. |
| Route of elimination |
The remainder of the dose is excreted as metabolites, 48% in the urine and 38% in the feces. |
| Half life |
4-6 hours in healthy patients, 9-12 hours in cancer patients |
| Clearance |
- 0.52 L/h/kg [Cancer Patients with 1 mg bid for 7 days]
- 0.41 L/h/kg [Healthy subject with a single 1 mg dose]
|
| Toxicity |
LD50>2000 mg/kg (rat, oral) |
