Linaclotide (Linzess) Pharmacology

Linaclotide (Linzess)

• Used to treat IBS with constipation and opioid-induced constipation
• Acts locally on the apical membrane of the gastrointestinal tract to increase intestinal fluid secretion and improve fecal transit

Lubiprostone (Amitiza)

• Used to treat IBS with constipation and opioid-induced constipation
• Chloride channel activator that increases intestinal fluid secretion and improves fecal transit
• Not approved for males with IBS-C

Lactulose

• Used to treat constipation (osmotic laxative)
• Bacteria in the colon degrade lactulose into lactic acid, increasing osmotic pressure and acidifying intestinal contents
• Softens stool by promoting stool water content
• Alters colonic flora to decrease ammonia production
• Used to treat hepatic encephalopathy

Metoclopramide (Reglan)

• Used to treat GERD, diabetic gastroparesis, and hiccups
• Dopamine antagonist that blocks dopamine receptors and enhances the response to acetylcholine in the upper GI tract
• Contraindications: GI obstruction, perforation or hemorrhage, history of seizure, use with other drugs causing EPS
• Side effects: drowsiness, insomnia, extrapyramidal symptoms, depression, neuroleptic malignant syndrome, tardive dyskinesia

Sucralfate (Carafate)

• Used to treat duodenal ulcers
• Antiulcer activity is the result of formation of an ulcer-adherent complex that covers the ulcer site and protects it against further attack by acid, pepsin, and bile salts

Sodium/Potassium/Magnesium (Suprep Bowel Kit)

• Used for colonoscopy preparation
• Sulfate salts provide sulfate anions, which are poorly absorbed, causing water retention in the GI tract
• Contraindications: GI obstruction, bowel perforation, gastric retention, ileus, toxic colitis
• Side effects: discomfort, abdominal distention/pain, N/V, fluid/electrolyte abnormalities, cardiac arrhythmia, seizure

Diphenoxylate/Atropine (Lomotil)

• Used to treat diarrhea
• Diphenoxylate inhibits excessive GI motility and GI propulsion
• Contraindications: obstructive jaundice, diarrhea associated with pseudomembranous enterocolitis or enterotoxin-producing bacteria
• Side effects: drowsiness, euphoria, N/V, flushing, paralytic ileus, toxic megacolon, anaphylaxis, anticholinergic effects, respiratory depression

Loperamide (Imodium)

• Used to treat diarrhea
• Acts directly on circular and longitudinal intestinal muscles to inhibit peristalsis and prolong transit time
• Reduces fecal volume, increases viscosity, and diminishes fluid and electrolyte loss
• Demonstrates antisecretory activity
• Contraindications: children younger than 2 years, abdominal pain without diarrhea, acute dysentery, active ulcerative colitis, bacterial enterocolitis
• Side effects: dizziness, abdominal pain, constipation, torsades de pointes

Esomeprazole (Nexium)

• Used to treat difficile infection
• Somatostatin analog that inhibits serotonin release and the secretion of gastrin, VIP, insulin, glucagon, secretin, motilin, and pancreatic polypeptide
• Interacts with Pylera, Risedronate DR, CYP2C19 inx, Clopidogrel, Atazanavir, and Rilpivirine

Dexlansoprazole (Dexilant)

• Interacts with Pylera, Risedronate DR, CYP2C19 inx, Clopidogrel, Atazanavir, and Rilpivirine

Polyethylene glycol (Miralax)

• Used to treat constipation
• Osmotic laxative that causes water retention in the stool, increasing stool frequency

Docusate (Colace)

• Used to treat constipation
• Stool softener that draws water into stool, softening the stool and achieving ease in bowel movement

Alosetron (Lotronex)

• Used to treat irritable bowel syndrome

• Selective 5-HT3 receptor antagonist

• Contraindications: constipation, colitis, intestinal obstruction, Crohn's disease, severe hepatic impairment

• Side effects: constipation, abdominal pain, ischemic colitis### Acromegaly Treatment

• Octreotide (Sandostatin) decreases growth hormone (GH) and IGF-1 in acromegaly, available in IV and PO forms

• Common side effects of octreotide include hyperhidrosis, abdominal pain, and headache

• Serious side effects of octreotide include bradyarrhythmia, hyper/hypoglycemia, and cholelithiasis

Antispasmodic

• Dicyclomine (Bentyl) blocks the action of acetylcholine at parasympathetic sites in smooth muscle, secretory glands, and the CNS
• Dicyclomine is used to treat functional bowel/IBS, available in PO and IM forms
• Contraindications of dicyclomine include obstructive disease of GI tract, severe ulcerative colitis, glaucoma, Myasthenia gravis, and breast feeding in infants
• Common side effects of dicyclomine include anticholinergic effects and lightheadedness
• Serious side effects of dicyclomine include tachyarrhythmia, psychosis, and dyspnea

COPD Treatment

• Roflumilast (Daliresp) is used to treat COPD, available in PO form
• Common side effects of roflumilast include weight loss, diarrhea, nausea, and decrease in appetite
• Serious side effect of roflumilast is suicidal thoughts
• Contraindication of roflumilast is moderate-severe liver impairment (Child Pugh B or C)

Systemic Glucocorticoids

• Systemic glucocorticoids cause inhibition of inflammatory response, suppress neutrophil migration, and decrease inflammatory mediators
• Glucocorticoids reverse capillary permeability and have immunosuppressive effects
• Dexamethasone (DexPak) is available in PO, IV, and ophthalmic forms
• Hydrocortisone (Cortef, Solucortef) is available in PO, rectal, and injectable forms
• Methylprednisolone (Medrol, Solumedrol) is available in PO and injectable forms
• Prednisone (Deltasone) is available in PO form
• Prednisolone (Millipred) is available in PO and ophthalmic forms
• Common side effects of systemic glucocorticoids include increased appetite, weight gain, Na/H2O retention, hypokalemia, CNS effects, indigestion, HTN, and hyperglycemia
• Chronic side effects of systemic glucocorticoids include Cushing's syndrome, dermal thinning, diabetes, glaucoma, cataracts, amenorrhea, growth retardation, acne, and pancreatitis
• Relative potency of glucocorticoids: dexamethasone 0.75 mg, methylprednisolone 4 mg, hydrocortisone 20 mg, prednisone/prednisolone 5 mg

Respiratory Agents

• Inhaled steroids inhibit inflammatory responses in airways and increase beta-2 receptor sensitivity
• ICS/LABA combination improves pulmonary function and control by combining corticosteroid and LABA
• Corticosteroids have anti-inflammatory, immunosuppressive, and antiproliferative actions
• LABAs relax bronchial smooth muscle by acting on beta-2 receptors
• Short-acting muscarinic antagonists work on M3 receptors, decreasing secretions and causing bronchodilation
• Long-acting muscarinic antagonists induce bronchodilation by inhibiting M3 receptors on airway smooth muscle
• Short-acting beta agonists relax bronchial smooth muscle and inhibit mediator release from mast cells by activating beta-2 receptors
• Leukotriene modifiers, such as montelukast, inhibit leukotriene receptors, facilitating bronchodilation
• Phosphodiesterase 4 inhibitors increase cAMP levels, reducing lung inflammation

Thyroid Hormones and Antithyroid Agents

• Thyroid hormones increase cellular metabolism and play a role in growth, development, CNS, and bone functions
• Antithyroid agents inhibit the synthesis of thyroid hormones

Gastrointestinal Agents

• Antihistamines (H1 receptor antagonists) block H1 receptors, decreasing histamine actions
• Histamine (H2) receptor antagonists competitively inhibit histamine at H2 receptors, reducing gastric acid secretion
• Proton pump inhibitors decrease acid secretion by inhibiting (H+, K+)-ATPase enzyme system
• Osmotic laxatives, such as polyethylene glycol, cause water retention in stool, increasing stool frequency
• Selective 5-HT3 receptor antagonists block 5-HT3 receptors on enteric neurons in the GI tract
• Guanylate cyclase agonists bind to guanylate cyclase-C, increasing intracellular and extracellular cGMP, and decreasing GI transit time
• Chloride channel activators increase intestinal fluid secretion and improve fecal transit
• Ammonium detoxicants, such as lactulose, soften stool by promoting stool water content
• Dopamine antagonists block dopamine receptors, enhancing tissue response to acetylcholine in the upper GI tract
• Sucralfate has antiulcer activity, forming an ulcer-adherent complex that protects against acid, pepsin, and bile salts
• Bowel prep agents, such as sulfate salts, provide sulfate anions that cause water retention in the GI tract
• Antidiarrheal agents, such as diphenoxylate and loperamide, inhibit excessive GI motility and propulsion
• Somatostatin analogs mimic natural somatostatin, inhibiting serotonin release and secretion of various hormones
• Antispasmodics block the action of acetylcholine at parasympathetic sites in smooth muscle, secretory glands, and the CNS

Cardiovascular Agents

• Direct thrombin inhibitors directly inhibit thrombin, binding to the active thrombin site
• Factor Xa inhibitors reversibly and selectively inhibit Factor Xa, resulting in decreased thrombin generation and thrombus formation
• Glycoprotein IIb/IIIa inhibitors specifically bind to GPIIb/IIIa, preventing fibrinogen-mediated platelet aggregation
• Unfractioned heparin binds to antithrombin, which inactivates thrombin and Factor Xa
• Low molecular weight heparin binds to antithrombin, inhibiting Factor Xa more than thrombin
• Vitamin K antagonists competitively inhibit vitamin K reductase, reducing vitamin K epoxide and depleting clotting factors
• NSAIDS inhibit platelet function by acetylating platelet cyclooxygenase, blocking thromboxane A2 formation
• P2Y12 inhibitors irreversibly inhibit P2Y12 receptors on platelets, preventing platelet activation and aggregation
• Fibrinolytics break down clots by binding to fibrin and converting plasminogen to plasmin
• Antidiuretic hormone analogs stimulate V1 to increase systemic vascular resistance and mean arterial blood pressure, and V2 to increase water permeability in renal tubules

Insulin Regulation

• Insulin is a hormone secreted by pancreatic beta cells, essential for reducing blood glucose levels.
• It promotes cellular glucose uptake, particularly in muscles and fat tissues.
• Insulin facilitates glycogenesis, converting glucose to glycogen in the liver and muscles for storage.
• It enhances lipid storage and suppresses gluconeogenesis, the process of generating glucose from non-carbohydrate substrates.
• Insulin release is triggered by increased blood glucose levels following meals.

Glycogen Storage

• Glycogen serves as the stored form of glucose, primarily found in liver and muscle tissues.
• Glycogenesis, the conversion of glucose into glycogen, is stimulated by insulin.
• The liver's glycogen acts to maintain blood glucose levels, while muscle glycogen is utilized for energy during physical activity.
• Glycogen stores are depleted during fasting, exercise, and when glucose availability is low.

Glucagon Function

• Glucagon is produced by alpha cells in the pancreas and acts to elevate blood glucose levels.
• It stimulates glycogenolysis, the process where glycogen is broken down into glucose in the liver.
• Glucagon encourages gluconeogenesis, creating glucose from non-carbohydrate sources like amino acids.
• Its secretion is triggered by low blood glucose levels and during fasting states.

Homeostatic Feedback Mechanisms

• A negative feedback loop regulates blood glucose levels: high levels stimulate insulin secretion, lowering glucose and subsequently decreasing insulin release.
• Conversely, low glucose levels trigger glucagon secretion, raising glucose and leading to reduced glucagon production.
• This feedback ensures blood glucose remains stable within a narrow range, typically between 70-100 mg/dL.

Glycolysis Pathway

• Glycolysis is a key metabolic process that converts glucose into pyruvate, yielding energy in the form of ATP.
• It consists of three phases:
  • Investment Phase: ATP is utilized to phosphorylate glucose, enhancing its reactivity.
  • Cleavage Phase: The 6-carbon glucose molecule is split into two 3-carbon molecules.
  • Payoff Phase: Produces ATP and NADH, converting the 3-carbon derivatives into pyruvate.
• Under aerobic conditions, pyruvate enters the Krebs cycle; under anaerobic conditions, it is converted to lactate in animals or ethanol in yeast.
• Glycolysis is crucial for energy production and plays a significant role in cellular respiration.

This quiz covers the mechanism of action, effects, and side effects of Linaclotide (Linzess) in treating IBS with constipation.