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Linaclotide

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Information about Linaclotide

Linaclotide is a minimally absorbed agonist of guanylate cyclase C receptors in the intestine and is used for treatment of chronic constipation and irritable bowel syndrome.

Linaclotide
Linaclotide

Liver safety of Linaclotide

Linaclotide has not been linked to serum enzyme elevations during treatment or to episodes of clinically apparent liver injury.

Mechanism of action of Linaclotide

Linaclotide (lin ak’ loe tide) is 14 amino acid peptide that acts as an agonist of the guanylate cyclase C receptors in the intestine. Activation of this receptor increases cyclic guanosine monophosphate levels which lead to secretion of chloride and bicarbonate into the intestinal lumen, thus increasing fluid secretion and promoting intestinal transit. Linaclotide acts locally on the luminal side of enterocytes in the upper intestine and is minimally absorbed. Several clinical trials have shown that linaclotide increases the number of spontaneous bowel movements, improves stool consistency and can alleviate symptoms of chronic constipation including the constipation of irritable bowel syndrome. Linaclotide was approved for use in the United States in 2012 for irritable bowel syndrome with constipation as well as idiopathic chronic constipation.

Dosage and administration for Linaclotide

Linaclotide is available in capsules of 145 and 290 mcg under the brand name Linzess. The recommended dose for chronic idiopathic constipation is 145 mcg once daily and for irritable bowel syndrome with constipation is 290 mcg once daily. It is contraindicated in children below the age of 6 years and is not recommended for use in children below the age of 18 years.

Side effects of Linaclotide

Side effects include diarrhea (~20%), abdominal pain, bloating, flatulence and headache.

Antidiarrheal agents

Antidiarrheal agents include bulk forming agents, hydroscopic agents, bile acid resins, bismuth, inhibitors of intestinal motility, non-absorbed antibiotics and hormones. Bulk forming agents include methylcellulose; hydroscopic agents include pectin and kaolin; bile acid resins are cholestyramine, colestipol and colesevalam; inhibitors of intestinal motility include opioids such as diphenoxylate and loperamide. Antibiotics include rifamycin and rifaximin which are non-absorbed and are used for travelers' diarrhea. Hormones with antidiarrheal activity include octretide and somatostatin. Most antidiarrheal agents are active locally in the small intestine and colon and are largely not absorbed. Some, however, have been implicated in rare causes of liver injury (senna, cascara, cholestyramine). Telotristat is a relatively new agent that inhibits the synthesis of serotonin and is used specifically for the diarrhea of carcinoid syndrome.

Antiemetics are a diverse group of medications that act at different points in the pathways that regulate nausea and vomiting. These include antihistamines, anticholinergic agents, phenothiazines, serotonin type 3 receptor blockers, centrally acting benzamides, cannabinoid receptor agonists, substance P antagonists and miscellaneous.

Anticholinergic Agents

Antihistamines

Cannabinoid Receptor Agonists

Serotonin 5-HT3 Receptor Antagonists

Substance P/Neurokinin 1 Receptor Antagonists

Miscellaneous

Acid peptic disease/antiulcer agents that include antacids, the histamine type 2 receptor blockers (H2 blockers), and the proton pump inhibitors (PPIs). These agents are some of the most commonly taken medications and are very well tolerated, most being available both by prescription and over-the-counter. While many of these drugs are approved for use in duodenal and gastric ulcer disease, their major use is for acid reflux and indigestion.

Histamine H2 Receptor Antagonists (H2 Blockers) Cimetidine, Famotidine, Nizatidine, Ranitidine

Proton Pump Inhibitors

Cathartics, laxatives or agents for constipation include bulk forming agents, osmotic agents, stool wetting agents, nonspecific stimulants, prokinetic agents and agents that increase fluid secretion. Many of these therapies are not systemically absorbed and none are considered particularly hepatotoxic. Naldemedine and naloxegol are opioid antagonists and are used to treat the constipation associated with opioid use.

Inflammatory bowel disease encompasses several disorders, most commonly ulcerative colitis and Crohn colitis. Agents can be classified as 5-aminosalicyclic acid (5-ASA) based agents, immunosuppressive drugs, antitumor necrosis factor agents, corticosteroids, antibiotics and miscellaneous.

5-Aminosalicyclic Acid (5-ASA) Derivatives

Immunosuppressive Agents

Tumor Necrosis Factor Antagonists

Miscellaneous

Irritable Bowel Syndrome Agents Antimuscarinics/Antispasmodics [See Anticholinergic agents

Prokinetic Agents - See Serotonin 5-ht4 receptor agonists Alosetron, Cisapride, Domperidone, Linaclotide, Lubiprostone, Metoclopramide, Plecanatide, Prucalopride, Tegaserod

Other

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