TRC: 5-HT4 agonists

5-HT4 agonists

5-HT4 agonists such as cisapride (Prepulsid®) may increase the efficacy of therapy in reflux disease when combined with PPIs or H2 receptor antagonists. Cisapride increases LES pressure, improves oesophageal body motility (more rapid clearance of acid), and accelerates gastric emptying. Cisapride has no effect on colonic motility, and is thus not used as a laxative. Another 5-HT4-agonist is prucalopride.

It has recently been demonstrated that cisapride prolongs the QT interval and may cause cardiac arrhythmias (torsades de pointes) when given with other CP450 inhibiting agents (e.g. erythromycin). Because of these potentially serious complications, the use of cisapride is restricted.

The mechanism of action is displayed in the left upper corner of the figure. 5-HT4 receptors are located on the myenteric neurons. When agonists bind to the stimulatory receptor, the production of the second messenger cAMP via the adenylate cyclase enzyme is enhanced. The increase in cytosolic cAMP concentration stimulates the release of acetylcholine (ACh) from the neuron. This will result in increased GI motility and increased sphincter tone.

I. Stimulation of a Gs coupled receptor causes an increase in cellular concentration of cAMP.

II. Serotonin is the only ligand that can increase intracellular cAMP levels.

Extra info: GI motility can be stimulated by a number of substrates, any of which will increase cAMP and stimulate acetylcholine-induced muscle contraction.

Option explanation:

I is true and II is false

I is true and II is true

I is false and II is false

I is false and II is true

I Cisapride is effective for reflux by inhibiting gastric acid secretion.

II The combination of cisapride and erythromycin is contraindicated.

Extra info: Cisapride has little effect on gastric acid secretion. It is also a substrate for cP450 isoenzymes. So when administered with erythromycin (inhibitor of cP450 isoenzyme), cisapride reaches toxic levels and leads to torsades de pointes (arrhythmia).

Option explanation:

I is true and II is false

I is true and II is true

I is false and II is false

I is false and II is true

5-HT4 agonists

5-HT4 agonists

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