Medical Pharmacology Topics   

GI Pharmacology: Gastric Motility

Introduction missing

Prokinetic Drugs

Prokinetic drus enhance coordinated gastrointestinal motility and transit of materials in the GI tract. Most of them do not stimulated GI smooth muscle directly (except cholinergic drus) but rather influence the activation of inervation to the gut, thereby maintaining coordination of propulsive function.

Prokinetic drugs may be dopamine antagonists, serotonin agonists and motilin-mimetics. Although cholinergic agonists and acetylcholinesterase inhibitors were used as prokinetics, they are now obsolete.

Metoclopramide is a seratonin agonist, mostly at 5-HT4 receptors. It increases tone of the lower sphageal sphincter, stimulates antral and small intestine contractions and facilitates gastric empyting. The main side effects are in the CNS: extrapyramidal and tardive dyskinesias.

Dompridone is a D2 ntagonist that inhibits acetylcholine release and emesis via the central triger zone (CTZ), without extrapyramidal effects. Erythromycin has a motilin-like effect on GI smooth muscle and improves gastric emptying in conditions like diabetic gastroparesis.

Laxatives

Laxatives act by either increasing fluid secretion, decreasing absorption of fluid or increasing osmolality. Agents that inrease fluid secretion include anthraquinones, diphenylmethanes, dioctyl sodium succinate and castor oil.

The anthraquinones include aloe, rhubarb, cascara sagrada and senna. They are effective 8-12 hous after ingestion because they are activated in the colon. They often cause cramping and may get into the breast milk. Lazy bowel syndrome is associated with abuse of anthraquinones.

Bisacodyl is the only available diphenylmethane, and requires hydrolisis to be active, and may cause inflamation of the bowel. Dioctyl sodium succinate is a surfactant used as a stool softener.

The use of castor oil as a laxative should be considered obsolete although the agent is still vailable. Castor oil is a triacylglyceride of ricinoleic acid, which is toxic and can be released by hydrolysis cayalyzed by pancretic lipase. Castor oil promotes cAMP-mediated fluid secretion.

Among the agents that decrease the absorption of fluids in the colon are mineral oil and fiber hydrophobic colloids. Mineral oil lubricates but has a short-term effet. Adverse effects seen with long-term use of mineral oil include inflammatin, aspiration pneumonia, decreased absorption of fat-soluble vitamins and leakage.

The fiber colloids include bran, methylcellulose, psyllum and agar. They are not digested nor absorbed, and will swell in the prescence of water, stimulating peristalsis. The fiber colloids do not prduce cramps, lazy bowel or dependance, but may cause impaction.

Agents tht increase osmolality include saline (magnesium sulfate, sodium citrate, etc.), lactulose, sorbitol and mannitol. The saline is hyperosmoyic, thus draws fluid from the extracellular fluid around the gut and induces rapid peristalsis. Lactulose and the other osmotic agents are hydrolized in the gut to organic acids and create a hyperosmotic environment, with results similar to saline.

Anti-emetics

Drugs used as antiemetics include the H1 antagonists (antihistamines), phenothiazine, metoclopramide, ondansetron, marijuana and glucocorticoids.

The antihistamines, dimenhydrinate, diphenhydramine and meclizine, depress labyrinth excitability and are used to treat motion sickness. Phenothiazine and metoclopramine block dopamine receptors in the CTZ. Ondansetron blocks seratonin receptors in the CTZ. The mechanisms of action of marijuana (or its synthetic derivative dronabinol) and glucocorticoids are not known.

Antidiarrheals

Agents used as antidiarrheals include intraluminal agents and antimotility/antisecretory agents. Opioids like loperamide, diphenoxylate and difenoxin are the preferred antimotility/antisecretory agents. They do not cross the blood-brain barrier thus do not have the CNS effects of other opids.

The intraluminal agents include bulk-forming/hygroscopic agents and bismuth. Bulk agents like psyllum (Metamucid) are used for mild diarrhea and irritable bowel syndrome. Kaolin/pectin (kaopectolin) is another hygroscopic agent. Bismuth subsalicylate (Pepto-Bismol) is thought to be antisecretory, anti-nflammatory and antibactericidal, and is commonly used to treat traveler's diarrhea.

Irritable Bowel Disease

Agents used in the treatment of irritable bowel disease (IBD) include glucocorticoids, 5-aminosalicylates (5-ASA) and ifliximab. The 5-aminosalicylates include sulfasalazine, olsalazine, balsalazine and mesalamine, and they inhibit COX and LOX, reducing the production of inflamatory mediators like leukotrienes (LTB4 and 5-HETE), among other posible actions.

Sulfsalazine is a 5-ASA/sulfapyridine conjugate, and is cleaved into its components by bacterial azoreductases in the colon. Its derivative sulfapyridine causes most of the advers effects. Sulfasalazine is not the preferred drug to treat IBD.

Olzalazine and basalazine are also conjugates cleaved by pH-dependent bacterial azo reduction in the colon. Olsalazine releses 2 molecules of 5-ASA. Mesalamine suppositories contain 5-ASA in a wax matrix for rectal administration.

Infliximab is a monoclonal antibody directed at TNFa. A single infusion may induce remission in refractory moderate to severe Crohn's disease. Folloup infusions reduce the number of draining fistulas. A single treatment costs about $2000.

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