TUMIFLO 2MG

Indications

• Chronic constipation

Dosage

Adults: 2 mg once daily. If there is no response after 4 weeks, review treatment. For elderly patients, the initial dose is 1 mg once daily, which may be increased to 2 mg once daily if necessary.

Mechanism of action

Prucalopride selectively stimulates 5-HT4 receptors located in the gastrointestinal tract, particularly in smooth muscle cells and myenteric plexus. This stimulation leads to the release of acetylcholine, which is the major excitatory neurotransmitter in the gut. The drug promotes colonic motility through contractions of the muscle layer and relaxation of the circular muscle layer, facilitating the propulsion of luminal contents.

Pharmacodynamics

In animal studies, prucalopride has demonstrated a dose-dependent increase in contractile activity in the proximal colon while inhibiting contractions in the distal colon. It enhances giant migratory contractions, which are essential for initiating the urge to defecate. Clinical trials have shown prucalopride to significantly increase spontaneous bowel movements and improve colonic transit times without adversely affecting anorectal function.

Pharmacokinetics

Prucalopride has a molecular formula of C18H26ClN3O3. It is absorbed well after oral administration, with peak plasma concentrations occurring after approximately 2 hours. The drug is primarily eliminated through renal pathways, necessitating dose adjustments in patients with renal impairment. The half-life of prucalopride is about 24 hours, allowing for once-daily dosing.

Contra-indications

• Intestinal obstruction
• Intestinal perforation
• Toxic megacolon
• Crohn's disease
• Ulcerative colitis

Adverse effects

• Decreased appetite
• Diarrhea
• Dizziness
• Fatigue
• Gastrointestinal discomfort
• Gastrointestinal disorders
• Headache
• Nausea
• Vomiting
• Anorectal hemorrhage
• Fever
• Malaise
• Palpitations
• Tremor
• Increased urinary frequency

Precautions

• History of arrhythmias
• Ischaemic heart disease
• Renal impairment
• Caution in elderly patients
• Monitor renal function before starting treatment in patients at risk of fluid and electrolyte disturbances

Pregnancy

Manufacturer advises avoiding use due to limited data available.

Breast-feeding

Manufacturer advises avoiding use as prucalopride is present in milk.

Storage

Store in a cool, dry place away from direct sunlight.

Formulations

• Oral solution
• Tablets

Mechanism of action

Prucalopride acts as a selective stimulator of the 5-HT4 receptors while having no interaction with hERG channel or 5-HT1 receptors which reduces significantly the cardiovascular risk found in other similar drugs. 5-HT4 receptors can be found throughout the gastrointestinal tract primarily in smooth muscle cells, enterochromaffin cells, and myenteric plexus. Its activation produces the release of acetylcholine which is the major excitatory neurotransmitter in the GI tract. Hence, prucalopride stimulates motility by interacting specifically with 5-HT4 receptors in the GI tract which causes a release of acetylcholine and further contraction of the muscle layer of the colon and relaxation of the circular muscle layer leading to the propulsion of luminal content.

Pharmacodynamics

In animal studies, prucalopride induced a dose-dependent stimulation of contractile activity in the proximal colon and inhibition of the contractility in the distal colon. As well it has been shown that prucalopride stimulates and amplifies giant migratory contraction which is the high-amplitude type of contraction that initiates the urge to defecate. Thus, prucalopride not only accelerates the colonic transit but also accelerates gastric emptying and small bowel transit. In supratherapeutic concentrations, prucalopride can be observed to interact with hERG potassium channels and L-type calcium channels. In clinical trials, prucalopride showed to significantly increase the spontaneous bowel movements with a standardized mean difference of about 0.5 after the use of 1 mg when compared with the placebo group. In this studies as well, it was observed a numerical improvement in mean colonic transit time and a significant increase in spontaneous complete bowel movement without marked changes in the anorectal function. In phase III clinical trials, 86% of the tested individuals opted to continue with the open-label study and based on Patients Assessments, 67% of the patients increase more than one point improvement in their satisfaction. In the final set of clinical trials for approval, there was a significant increase in the number of patients that reached over 3 complete spontaneous bowel movements per week when compared with the placebo.