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GASTROINTESTINAL PHARMACOLOGY

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Presentation on theme: "GASTROINTESTINAL PHARMACOLOGY"— Presentation transcript:

1 GASTROINTESTINAL PHARMACOLOGY
Charles Nichols, PhD Department of Pharmacology & Experimental Therapeutics LSUHSC, New Orleans, LA

2 The Gastrointestinal Tract

3 GASTROINTESTINAL DISORDERS
Gastroesophageal Reflux Disease (GERD) Peptic Ulcer Disease (PUD) Duodenal Ulcer Nausea Emesis IBS Diarrhea Constipation

4 Stomach

5 Stomach Lining Basics

6 Gastric Gland

7 Gastric Mucosal Barrier
Surface mucosa cells in the pyloric region secrete a thick, alkaline-rich mucus that protects the epithelium of the stomach and duodenum from harsh acid conditions of the lumen. This is known as the gastric mucosal barrier. These cells are stimulated by mechanical and chemical irritation and parasympathetic inputs. This protective mucus barrier can be damaged by bacterial and viral infection, certain drugs, and aspirin.

8 Parietal Cell: Gastric Acid Secretion
H+

9 Chief Cell: Synthesis and Activation of Pepsin
HCl +HCl Pepsin Pepsin

10 Serotonin (5-Hydroxytryptamine)
Key neurotransmitter in the intestine Present in abundance within the gut Most is stored in enterochromaffin cell granules Released by many stimuli - most potently by mucosal stroking Serotonin stimulates enteric nerves to initiate secretion and propulsive motility

11 Serotonin in the Gut

12 Serotonin Dysfunction in the Gut

13 Gastroesophageal Reflux Disease (GERD)
Backflow of stomach acid into the esophagus Esophagus is not equipped to handle stomach acid => scaring Usual symptom is heartburn, an uncomfortable burning sensation behind the breastbone (MI often mistaken for GERD !) More severe symptoms: difficulty swallowing, chest pain Reflux into the throat can cause sore throat Complications include esophageal erosions, esophageal ulcer and narrowing of the esophagus (esophageal stricture) In some patients (~10%), the normal esophageal lining or epithelium may be replaced with abnormal (Barrett's) epithelium. This condition (Barrett's esophagus) has been linked to cancer of the esophagus.

14 Gastroesophageal Reflux Disease (GERD)
Endoscope of Barrett’s Esophagus (can become malignant - needs monitoring)

15 Gastroesophageal Reflux Disease (GERD)
Precipitants: Food (fatty food, alcohol, caffeine) Smoking Obesity Pregnancy Usually chronic relapsing course

16 Peptic Ulcer Disease Benign PUD: Normal gastric acid pro-
duction however the mucosal barrier is weak. Malignant PUD: Excessive secretion of gastric Acid that overwhelms the mucosal barrier.

17 Treatment of Heartburn, GERD and PUD
Antacids H2 Receptor Blockers Mucosal Protective Agents Proton Pump Inhibitors Anti-cholinergics Prostaglandin Analogs Anti-microbial Agents

18 Antacids Systemic Antacid: Sodium Bicarbonate Nonsystemic Antacid:
Aluminum Hydroxide + Magnesium Hydroxide Combinations (Maalox and Mylanta) Contraindicated in patients with impaired renal function Magnesium may cause diarrhea Calcium Carbonate (Tums) Calcium may cause constipation

19 ANTACID NEUTRALIZING CAPACITY (ANC)
Amount of 1N HCl(meq) brought to pH 3.5 by an antacid solution within 15 min. FDA requires a Min=5 meq/dose As the ANC number increases the neutralizing capacity of an antacid increases. Maalox TC=28 Mylanta DS=23 Tums EX=15

20 Histamine H2 Receptor Blockers
Inhibit secretion of gastric acid through competitive inhibition of Histamine H2 receptors Prevention & tx of PUD, Esophagitis, GI bleeding, stress ulcers, and Zollinger- Ellison Syndrome May alter the effects of other drugs through interactions with CYP450 (especially cimetidine) Very few side effects (except for cimetidine - inhibits metabolism of estrogen) Suppresses 24 hour gastric secretion by 70% Cimetidine Famotidine Ranitidine Nizatidine

21 Proton Pump Inhibitors
Strong inhibitors of gastric acid secretion through irreversible inhibition of proton pump, preventing “pumping” or release of gastric acid (24 hr action) Indicated in PUD, Gastritis, GERD, & Zollinger-Ellison syndrome Faster relief and healing than H2 receptor blockers Decreases acid secretion by up to 95% for up to 48 hours 4-8 week course of treatment Omeprazole Lansoprazole Rebeprazole Esomeprazole Pantoprazole

22 Prostaglandins Misoprostol Misoprostol PGE1 analog
Stimulates Gi pathway, leading to decrease in gastric acid release For treatment of NSAID induced injury Side effects include diarrhea, pain, and cramps (30%) Do not give to women of childbearing years unless a reliable method of birth control can be DOCUMENTED Can cause birth defects, and premature birth Misoprostol

23 Anticholinergics Pirenzipine
Muscarinic M1 acetylcholine receptor antagonist Blocks gastric acid secretions About as effective as H2 blockers Rarely used, primarily as adjunct therapy Anticholinergic side effects (anorexia, blurry vision, constipation, dry mouth, sedation)

24 Summary of Acid Reduction therapeutics
Antacids H+ Cl-

25 Mucosal Protective Agents
Sucralfate (carafate) Can be used to prevent & treat PUD It requires an acid Ph to activate Forms sticky polymer in acidic environment and adheres to the ulcer site, forming a barrier May bind with other drugs and interfere with absorption Give approximately 2 hours before or after other drugs Take on an empty stomach before meals Chelated Bismuth Protects the ulcer crater and allows healing Some activity against H. pylori Should not be used repeatedly or for more than 2 months at a time Can cause black stools, constipation

26 Helicobacter pylori H. pylori are bacteria able to attach to the epithelial cells of the stomach and duodenum which stops them from being washed out of the stomach. Once attached, the bacteria start to cause damage to the cells by secreting degradative enzymes, toxins and initiating a self-destructive immune response. nobel/2005/images/invasion.jpg

27 Anti-H.pylori Therapy >85% PUD caused by H. pylori
Antibiotic Ulcer Therapy - Used in Combinations Bismuth - Disrupts bacterial cell wall Clarithromycin - Inhibits protein systhesis Amoxicillin - Disrupts cell wall Tetracycline - Inhibits protein synthesis Metronidazone - Used often due to bacterial resistance to amoxicillin and tetracycline, or due to intolerance Triple Therapy - 7 day treatment - Effective 80-85% Proton pump inhibitor + amoxicillin/tetracycline + metronidazone/clarithomycin Quadruple Therapy - 3 day treatment, as efficacious as triple therapy - Add Bismuth to triple therapy

28 Moving down the system...

29 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

30 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

31 Aminosalicylates Sulfasalazine (5-aminosalicylic acid and sulfapyridine as carrier substance) Mesalazine (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 10-45% Nausea, headache, epigastric pain, diarrhoea, hypersensitivity, pancreatitis, blood disorders, lung disorders, myo/pericarditis Caution in renal impairment, pregnancy, breast feeding

32 Corticosteroids Anti-inflammatory agents for moderate to severe relapses eg 40mg Prednisolone Inhibition of inflammatory pathways (↓IL transcription, suppression of arachidonic acid metabolism, lymphocyte apoptosis) Side effects Acne, moon face Sleep, mode disturbance Dyspepsia, glucose intolerance Cataracts, osteoporosis, myopathy…

33 Thiopurines Azathioprine, mercaptopurine Use Side effects
Inhibit ribonucleotide synthesis Inducing T cell apoptosis by modulating cell signalling Azathioprine metabolised to mercaptopurine and 6-thioguanine nucleotides Use Active and chronic disease Steroid sparing Side effects Leucopaenia (myelotoxic) Monitor for signs of infection, sore throat Flu like symptoms after 2 to 3 weeks, liver, pancreas toxicity

34 Methotrexate Inhibits dihydrofolate reductase
Probably inhibition of cytokine and eicosanoid synthesis Use Relapsing or active CD refractory or intolerant to AZA or thiopurine Side effects GI Hepatotoxicity, pneumonitis

35 Cyclosporin Inhibitor of calcineurin, preventing clonal expansion of T cell subsets Use Active and chronic disease Steroid sparing Bridging therapy Side effects Tremor, paraesthesiae, malaise, headache, abnormal LFT Gingival hyperplasia, hirsutism Major: renal impairment, infections, neurotoxicity Monitor Blood pressure, FBC, renal function

36 Infliximab Anti TNF-α 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

37 Constipation

38 Constipation Usually effectively treated with dietary modification.
Only if this fails should laxatives be used. The #1 cause of constipation in laxative abuse! Therapy: 1. Bulking agents 2. Osmotic laxatives 3. Stimulant drugs 4. Stool softners

39 Laxatives

40 Bulk Laxatives Psyllium Bran Methylcellulose
Increase in bowel content volume triggers stretch receptors in the intestinal wall Causes reflex contraction (peristalsis) that propels the bowel content forward Psyllium Bran Methylcellulose Insoluble and non-absorbable Non digestible Must be taken with lots of water! (or it will make constipation worse)

41 Saline 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

42 Stool Softners - Emollients
Docusate sodium (surfactant and stimulant) Liquid Paraffin (oral solution) Glycerin suppositories Docusate

43 Irratant/Stimulant Laxatives-Cathartics
-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) Castor Oil - From the Castor Bean Senna - Plant derivative Bisacodyl Lubiprostone -PGE1 derivative that stimulates chloride channels, producing chloride rich secretions Bisacodyl Senna Lubiprostone

44 Laxative Abuse Most common cause of constipation!
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

45

46 Diarrhea

47 Diarrhea Caused by: Indications for treatment 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

48 Anti-Diarrheal Agents
Anti-motility Agents Reduce peristalsis by stimulating opioid receptors in the bowel Allow time for more water to be absorbed by the gut Morphine Codeine Diphenoxylate Loperamide 40-50x more potent than morphine Poor CNS penetration Increases transit time and sphincter tone Antisecretory against cholera toxin and some E.coli toxin T½ 11 hours, dose: 4 mg followed by 2mg doses (16mg/d max) Overdose: paralytic ileus, CNS depression Caution in IBD (toxic megacolon) Contraindications for antidiarrheals Toxic Materials Microorganisms (salmonella, E.coli) Antibiotic associated Loperamide

49 Clostridium Difficile
The major cause of diarrhea and colitis in patients exposed to antibiotics (~20%). Fecal - oral route of transmission Three 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)

50 Antiflatulants (Le Pétomane)

51 Antiflatulants Simethicone
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, and less pain Used often, but limited data regarding effectiveness Simethicone

52 Emesis (Vomiting)

53 Emesis (seeing something repulsive) (motion sickness)
(Ingesting a toxin)

54 Syrup of Ipecac Emetic Prepared from the root of the ipecacuanha plant
Induces emesis Side effects include drowsiness, diarrhea, and stomach ache Acceptable for use when: There is no contraindication to the use of ipecac There is substantial risk of serious toxicity to the victim There is no alternative therapy available or effective to decrease gastrointestinal absorption (e.g., activated charcoal) There will be a delay of greater than 1 hour before the patient will arrive at an emergency medical facility and ipecac syrup can be administered within minutes of the ingestion Ipecac syrup administration will not adversely affect more definitive treatment that might be provided at a hospital

55 Antiemetic Therapuetics
Muscarinic M1 receptor antagonist Scopolamine Side Effects: Dry Mouth Dizziness Restlessness Dilated Pupils Delirium at high doses Allergic Reaction Contraindications Kidney or liver disease Enlarged prostate Difficulty in urination / bladder problems Heart Disease Glaucoma

56 Antiemetic Therapuetics
Histamine H1/Dopamine D2 receptor antagonist Phenothiazines Promethazine (Phenergan) Prochlorperazine (Compazine) Side Effects These drugs are neuroleptics (typical antipsychotics) Blurred vision Dry mouth Dizziness Restlessness Seizures Extrapyramidal effects - Tardive dyskinesia (long term treatment) Contraindications Allergy to phenthiazines Glaucoma Liver disease Prostate / bladder problems

57 Antiemetic Therapuetics
Serotonin 5-HT3 receptor antagonist Ondansetron (Zofran) Granisetron Excellent for chemotherapy induced nausea and vomiting Side Effects Very few common side effects - usually well tolerated Headache Constipation Rarely Hiccups Itchiness Transient blindness

58 Antiemetic Therapeutic Sites - Summary
Cancer Chemotherapy Drugs Dopamine agonists Chemoreceptor Trigger Zone (CTZ) Scopolamine H1 Antihistamines Ondansetron Phenothiazines All Ondansetron

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