Tegaserod

Tegaserod is a 5-HT4 receptor partial agonist that was formerly marketed under the brand name Zelnorm. It was initially approved for the treatment of irritable bowel syndrome with constipation (IBS-C) in women and chronic constipation. Tegaserod works by stimulating the 5-HT4 receptors in the gastrointestinal tract, which enhances peristalsis and increases intestinal fluid secretion, thereby alleviating constipation and associated symptoms.

Mechanism of Action:

Tegaserod binds to the 5-HT4 receptors located in the enteric nervous system. Activation of these receptors triggers a cascade of events that ultimately lead to increased release of neurotransmitters like acetylcholine and calcitonin gene-related peptide (CGRP). This, in turn, stimulates peristaltic reflexes, accelerating gastrointestinal transit and promoting bowel movements.

Medical Uses:

Tegaserod was primarily used for the short-term treatment of IBS-C in women whose symptoms did not respond adequately to other treatments. It was also indicated for the treatment of chronic idiopathic constipation (CIC).

Adverse Effects and Safety Concerns:

While generally well-tolerated, tegaserod was associated with several potential adverse effects, including diarrhea, abdominal pain, nausea, and headache. More serious concerns arose from post-marketing studies, which indicated a possible increased risk of cardiovascular events, such as stroke and myocardial infarction (heart attack), in patients taking tegaserod.

Regulatory History and Availability:

Due to concerns about the increased risk of cardiovascular events, the U.S. Food and Drug Administration (FDA) initially requested the manufacturer to voluntarily withdraw tegaserod from the market in 2007. Subsequently, in 2019, the FDA approved a limited reintroduction of tegaserod for IBS-C in women under a Risk Evaluation and Mitigation Strategy (REMS) program. This REMS program restricts the use of tegaserod to patients meeting specific criteria and requires prescribers and pharmacies to be certified. It is also available only to those under the direct care of a certified prescriber and who meet specific eligibility requirements including being under 65 years old and free of any existing cardiovascular conditions. As a result of these restrictions, availability is limited.

Contraindications:

Tegaserod is contraindicated in patients with a history of ischemic cardiovascular disease, stroke, transient ischemic attack (TIA), or uncontrolled hypertension. It is also contraindicated in patients with severe renal impairment, severe hepatic impairment, or a history of bowel obstruction.

Pharmacokinetics:

Tegaserod is rapidly absorbed after oral administration. It undergoes extensive first-pass metabolism in the liver. The drug is primarily eliminated through renal excretion.