Linaclotide

Linaclotide

Linaclotide (marketed as Linzess) is a guanylate cyclase-C agonist medication primarily employed for the management of chronic constipation and irritable bowel syndrome (IBS).

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Schematic representation of Linaclotide

Linaclotide

Overview

Linaclotide is a synthetic 14 amino acid peptide that acts as an agonist of the guanylate cyclase C receptors in the intestine, facilitating improved bowel movements and relief from symptoms associated with chronic constipation and IBS.

Indications

Linzess is indicated in adults for the treatment of:

• irritable bowel syndrome with constipation (IBS-C).
• Chronic idiopathic constipation (CIC), where the cause of the constipation is unidentified.

Mechanism of Action

Linaclotide's therapeutic action is based on its interaction with guanylate cyclase C receptors in the intestine:

• The agonistic action on this receptor escalates cyclic guanosine monophosphate levels, triggering the secretion of chloride and bicarbonate into the intestinal lumen. This, in turn, boosts fluid secretion, fostering intestinal transit.
• Linaclotide predominantly acts on the luminal side of enterocytes in the upper intestine, with minimal absorption into the bloodstream.
• Clinical trials have underscored its efficacy in increasing spontaneous bowel movements, refining stool consistency, and alleviating symptoms linked to chronic constipation and IBS.

Contraindications

Linaclotide is contraindicated in:

• Infants and toddlers below 2 years due to potential severe dehydration risks.
• Patients with identified or suspected mechanical gastrointestinal obstruction.

Drug Interactions

As of current knowledge, no formal drug interaction studies have been undertaken with Linzess.

FDA Approval

The FDA greenlit linaclotide for usage in the U.S. in 2012, marking its approval for treating IBS with constipation and idiopathic chronic constipation.

Dosage and Administration

IBS with Constipation

• Recommended dose: 290 mcg orally once daily.

Chronic Idiopathic Constipation

• Recommended dose: 145 mcg orally once daily. Depending on individual tolerance, a 72 mcg daily dose might be preferable.

General guidelines:

• Administer Linzess as prescribed by a healthcare provider.
• It should be taken on an empty stomach, roughly 30 minutes prior to the day's first meal.
• In case a dose is skipped, the next dose should be taken as scheduled without doubling up.
• Linzess capsules must be consumed whole and not be crushed or chewed.
• For adults who find swallowing the capsules challenging, it's permissible to sprinkle the beads over applesauce or mix with bottled water before ingestion.
• The compatibility of Linzess with other foods or liquids remains unverified.

Available Forms and Branding

Linaclotide is available in the following dosages as capsules:

• 72 mcg
• 145 mcg
• 290 mcg

Branding:

• Linzess

Side Effects

Common side effects:

• Gas formation
• Abdominal discomfort or pain
• Abdominal swelling or a sensation of fullness or pressure (distention)

Serious side effects:

• Diarrhea

Precautions

• Should not be administered to children below 2 years of age.
• Diarrhea is a commonly reported side effect in Linzess users. If severe diarrhea is encountered, the drug should be discontinued and the patient should be rehydrated.

Overdose

Symptoms suggestive of an overdose predominantly include:

• Severe diarrhea

Pregnancy

Data regarding Linzess's safety during pregnancy is currently insufficient to deduce any association with major birth defects or miscarriage risks.

Pediatric Use

Linzess is not advised for children under 2 years. Its safety and efficacy in those under 18 years remain inconclusive.

Ingredients

Active ingredient:

• Linaclotide

Inactive ingredients for 145 mcg and 290 mcg capsules:

• Calcium chloride dihydrate, hypromellose, L-leucine, and microcrystalline cellulose. Capsule's composition: gelatin and titanium dioxide.

Inactive ingredients for 72 mcg capsules:

• Calcium chloride dihydrate, L-histidine, microcrystalline cellulose, polyvinyl alcohol, and talc. Capsule's composition: gelatin and titanium dioxide.

Manufacturers and Distributors

Brand: Linzess® is a trademark of Ironwood Pharmaceuticals, Inc.

• Distributed by: Allergan USA, Inc., Madison, NJ
• Promoted by: Allergan USA, Inc., Madison, NJ and Ironwood Pharmaceuticals, Inc., Boston, MA

Storage and Disposal

• Store Linzess within a temperature range of 68°F to 77°F (20°C to 25°C).
• Retain the medicine in its original bottle, which comes with a desiccant packet to keep the medication dry.
• The bottle should be securely closed and stored in a dry setting.

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.

• Cholestyramine
• Colesevelam
• Colestipol
• Crofelemer
• Difenoxin
• Diphenoxylate
• Kaolin
• Loperamide
• Methylcellulose
• Octreotide
• Pectin
• Rifamycin
• Rifaximin
• Somatostatin
• Telotristat

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

• Hyoscyamine, Methscopolamine, Scopolamine

Antihistamines

• Cyclizine, Dimenhydrinate, Hydroxyzine, Meclizine, and Promethazine

Cannabinoid Receptor Agonists

• Dronabinol, Nabilone, Tetrahydrocannabinol
• Phenothiazines [See Antipsychotic Agents]
• Chlorpromazine, Prochlorperazine

Serotonin 5-HT3 Receptor Antagonists

• Alosetron, Dolasetron, Granisetron, Ondansetron, Palonosetron

Substance P/Neurokinin 1 Receptor Antagonists

• Aprepitant, Fosaprepitant, Rolapitant

Miscellaneous

• Dexamethasone, Metoclopramide, Trimethobenzamide

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

• Dexlansoprazole, Esomeprazole, Lansoprazole, Omeprazole, Pantoprazole, Rabeprazole

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.

• Bisacodyl
• Cascara Sagrada
• Castor Oil
• Docusate
• Fiber, Bran
• Lactulose
• Magnesium Sulfate
• Methylcellulose
• Naldemedine (Opioid Antagonist)
• Naloxegol (Opioid Antagonist)
• Plecanatide (for Chronic Idiopathic Constipation)
• Prucalopride (for Chronic Idiopathic Constipation)
• Senna

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

• Balsalazide, Mesalamine, Olsalazine, Sulfasalazine

Immunosuppressive Agents

• Azathioprine, Mercaptopurine, Methotrexate

Tumor Necrosis Factor Antagonists

• Adalimumab, Certolizumab, Golimumab, Infliximab

Miscellaneous

• Metronidazole, Natalizumab, Vedolizumab

Irritable Bowel Syndrome Agents Antimuscarinics/Antispasmodics [See Anticholinergic agents

• Dicyclomine, Glycopyrrolate, Hyoscyamine, Methscopolamine

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

Other

• Eluxadoline

• Dailymed label info on Linaclotide
• FDA Linaclotide

Linaclotide Resources
Latest articles Most recent articles Ongoing trials	Wikipedia

Resources

Latest articles - Linaclotide

• Most recent articles
• Ongoing trials

Source: Data courtesy of the U.S. National Library of Medicine. Since the data might have changed, please query MeSH on Linaclotide for any updates.

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