GI Pharmacology Part 2 PDF

Gastrointestinal Pharmacology Part 2 Inflammatory Bowel Disease Ulcerative colitis Diffuse mucosal inflammation limited to the colon Bloody diarrhea, colicky pain, urgency, tenesmus Crohn’s Disease Patchy transmural inflammation May affect any part of GI tract Abdominal pain, diarrhea, weight loss,...

Gastrointestinal Pharmacology Part 2 Inflammatory Bowel Disease Ulcerative colitis Diffuse mucosal inflammation limited to the colon Bloody diarrhea, colicky pain, urgency, tenesmus Crohn’s Disease Patchy transmural inflammation May affect any part of GI tract Abdominal pain, diarrhea, weight loss, intestinal obstruction Inflammatory Bowel Disease Treatment - Resolve acute episodes and prolong remission Therapeutics: Aminosalicylates - for mild symptoms Corticosteroids - for moderate symptoms Thiopurines - for active and chronic symptoms Methotrexate - for active and chronic symptoms Cyclosporin - for active and chronic symptoms refractory to corticorsteroids- (significant side effects) Infliximab - antibody infusion Aminosalicylates Sulfasalazine (5-aminosalicylic acid and sulphapyridine as carrier substance) Mesalamine (5-ASA), eg Asacol, Pentasa Balsalazide (prodrug of 5-ASA) Olsalazine (5-ASA dimer cleaves in colon) Oral, rectal preparation Use Maintaining remission Active disease May reduce risk of colorectal cancer Adverse effects Nausea, headache, epigastric pain, diarrhea, hypersensitivity, pancreatitis, blood disorders, lung disorders, myo/pericarditis Caution in renal impairment, pregnancy, breast feeding Corticosteroids Anti-inflammatory agents for moderate to severe relapses Corticosteroids Inhibition of inflammatory pathways (↓IL transcription, suppression of arachidonic acid metabolism, lymphocyte apoptosis) Expression of anti-inflammatory proteins eg Prednisone, Hydrocortisone, eg Side effects Acne, moon face Sleep, mode disturbance Dyspepsia, glucose intolerance Cataracts, osteoporosis, myopathy… Thiopurines Purine antimetabolites immunosuppressants Azathioprine, mercaptopurine Deactivate key processes in T lymphocytes that lead to inflammation MOA - Inhibit ribonucleotide synthesis, thus inducing T cell apoptosis by modulating cell signaling Azathioprine metabolized to mercaptopurine and 6-thioguanine nucleotides (active) Use Active and chronic disease Steroid sparing Side effects Leucopoenia Monitor for signs of infection, sore throat Flu like symptoms after 2 to 3 weeks Liver, pancreas toxicity Methotrexate Inhibits dihydrofolate reductase Probably inhibition of T cell proliferation and cytokine and eicosanoid (PG, LT) synthesis Use Relapsing or active CD refractory or intolerant to AZA or thiopurine Side effects GI Hepatotoxicity, pneumonitis Cyclosporin Inhibition of the production of cytokines involved in the regulation of T-cell activation, in particular the transcription of interleukin 2 Nuclear factor of activated T cells (NFAT) proteins are a family of transcription factors whose activation is controlled by calcineurin, a Ca2+-dependent phosphatase. Use Active and chronic disease Steroid sparing Bridging therapy Side effects Tremor, paranesthesia, malaise, headache, abnormal LFT Gingival hyperplasia, hirsutism Major: renal impairment, infections, neurotoxicity Monitor Blood pressure, renal function Infliximab Anti TNF-α (a potent paracrine and endocrine mediator of inflammatory and immune functions) monoclonal antibody Potent anti-inflammatory effects Use Fistulizing CD Severe active CD refractory/intolerant of steroids or immunosuppression iv infusion Side effects Infusion reactions Sepsis Reactivation of TB, increased risk of TB Constipation Constipation Usually effectively treated with dietary modification. Only if this fails should laxatives be used. The #1 cause of constipation in laxative abuse! Treatments: 1. Bulking agents 2. Osmotic laxatives 3. Stimulant drugs 4. Stool softners Treatments Bulk Agents Increases bowel content and volume triggers stretch receptors in the intestinal wall Causes reflex contraction (peristalsis) that propels the bowel content forward Soluble, insoluble, non-absorbable, Non digestible, must be taken with lots of water! (or it will make constipation worse) Psyllium based (e.g., Metamucil) Methylcellulose, a synthetic fiber (e.g., Citrucel) Complex, non-absorbable starches such as calcium polycarbophil (e.g., Fibercon) Salts and Osmotic Laxatives Effective in 1-3 hours Used to purge intestine (e.g. surgery, poisoning) Fluid is drawn into the bowel by osmotic force, increasing volume and triggering peristalsis Nondigestible sugars and alcohols Lactulose (broken down by bacteria to acetic and lactic acid, which causes the osmotic effect) Salts Milk of Magnesia (Mg(OH)2) Epsom Salt (MgSO4) Glauber’s Salt (Na2SO4) Sodium Phosphates (used as enema) Sodium Citrate (used as enema) Polyethylene glycol (e.g., MiraLax) Stool Softners - Emollients Lubricates and softens the consistency of the stool Docusate sodium (surfactant and stimulant) Glycerin suppositories Docusate Irritant/Stimulant Laxatives Increases intestinal motility Irritate the GI mucosa and pull water into the lumen Indicated for severe constipation where more rapid effect is required (6-8 hours) Senna - Plant derivative Bisacodyl Lubiprostone -PGE1 derivative that stimulates chloride channels, producing chloride rich secretions (mucosal hydration/watery stool) Bisacodyl Senna Lubiprostone Laxative Abuse/Dependence Most common cause of constipation! Becomes a vicious cycle Longer interval needed to refill colon is misinterpreted as constipation => repeated use Enteral loss of water and salts causes release of aldosterone => stimulates reabsorption in intestine, but increases renal excretion of K+ => double loss of K+ causes hypokalemia, which in turn reduces peristalsis. =>This is then often misinterpreted as constipation => repeated laxative use Caused by: Diarrhea Toxins Microorganims (shigella, salmonella, E.coli, campylobacter, clostridium difficile) Antibiotic associated colitis Indications for treatment >2-3 days Severe diarrhea in the elderly or small children Chronic inflammatory disease When the specific cause has been determined Anti-motility Agents Anti-Diarrheal Agents Reduce peristalsis by stimulating opioid receptors in Loperamide the bowel (Morphine, Codeine) - Binds to the opiate receptor in the intestinal wall Allow time for more water to be - Reduces peristalsis and absorbed by the gut increases intestinal transit time Diphenoxylate/atropine - Increases the tone of the anal Centrally active opioid sphincter - reducing incontinence drug and urgency Used in combination drug - Poor CNS penetration - Schedule V, OTC with atropine for the treatment of diarrhea Diphenoxylate slows intestinal contractions Atropine prevents drug abuse Schedule V, Rx Loperamide Contraindications - Toxic Materials - Microorganisms (salmonella, E.coli) - AAD * Toxic colitis/ megacolon) Clostridium Difficile Spore-forming, Gram-positive anaerobic bacillus that produces two exotoxins: toxin A and toxin B The major cause of AAD and colitis (~20%). Distal aspect of colon Steps to infection Alteration of normal fecal flora Colonic colonization of C. difficile Growth and production of toxins Infection can lead to formation of colitis and toxic megacolon Pharmacological Treatment Discontinue offending antibiotic Metronidazole (contraindicated in patients with liver or renal impairment) Vancomycin (contraindicated in patients with renal impairment) Anti-Flatulence Drugs Used to relieve the painful symptoms associated with gas Simethicone (a detergent) Alters elasticity of mucus-coated bubbles, causing them to break Large bubbles -> smaller bubbles, less gas and less pain Simethicone Emesis (seeing something repulsive) (motion sickness) Pathophysiology Area postrema - AKA chemoreceptor trigger zone, located on the dorsal surface of the medulla oblongata - Stimulated directly or indirectly via: 1) Stomach/GI tract 2) Vestibular system 3) Cortex/ thalamus (Ingesting a toxin) Antiemetics Scopolamine Muscarinic M1 receptor antagonist Vestibular affection (motion sickness, BPPV) Side Effects: Dry Mouth, Dizziness, Restlessness, Dilated Pupils Allergic Reaction Contraindications Kidney or liver disease Enlarged prostate Difficulty in urination / bladder problems Heart Disease Glaucoma Antiemetics Phenothiazines Promethazine (Phenergan), Prochlorperazine (Compazine) Dopamine D2 receptor antagonist Histamine H1 blocking activity These drugs are neuroleptics (typical antipsychotics) Side Effects Blurred vision, Dry mouth Dizziness, Restlessness, Seizures Extrapyramidal effects - Tardive dyskinesia (long term treatment) Contraindications Glaucoma Liver disease Prostate / bladder problems Meclizine First-generation antihistamine (non-selective H1 antagonist) Also has central anticholinergic actions BPPV Metoclopramide Antiemetic action is due to its antagonist activity at D2 receptors in the chemoreceptor trigger zone in the central nervous system SE – Extrapyramidal effects Contraindication – Parkinson’s Dz Antiemetics Ondansetron (Zofran) Granisetron Serotonin 5-HT3 receptor antagonist Excellent for chemotherapy induced nausea and vomiting Side Effects Very few common side effects - usually well tolerated Headache Constipation Antiemetic Therapeutic Sites