Drugs Acting On Gastrointestinal Tract Gastrointestinal Tract Professor Kassim Al-Saudi, M.B.,Ch.B.,Ph.D.

OBJECTIVES Identify classes of drugs used to improve GI function. Identify uses and varying actions of these drugs. Identify how these drugs are absorbed, distributed, metabolized, and excreted. Identify drug interactions and adverse reactions to these drugs. Be familiar with drug-induced hepatotoxicity

DRUGS AND THE GI SYSTEM Classes of drugs used to improve GI function include: Peptic ulcer drugs Antiemetic and emetic drugs Antidiarrheal drugs Laxative drugs

Peptic Ulcer The term “peptic ulcer” refers to an ulcer in the lower Oesophagus, stomach, duodenum (commonly), jujenum and ileum (rarely) Gastric and duodenal ulcers may be acute or chronic Acute ulcer shows no evidence of fibrosis Both penetrate the muscularis mucosae Erosions do not penetrate the muscularis mucosae

Aetiology : 1- Infection – Helicobacter pylori (Gm –ve) - 50% Industrialized - 90% Developing (Childhood) - Majority symptoms free - 90% of DU patients and 70% of GU patients are infected with H. pylori 2- Acid and Pepsin secretion 3- Mucosal defensive mechanism

Pathogenesis of Ulcers Aggressive Factors Acid, pepsin Acid, pepsin Bile salts Bile salts Drugs (NSAIDs) Drugs (NSAIDs) H. pylori H. pylori Defensive Factors Mucus, bicarbonate layer Mucus, bicarbonate layer Blood flow, cell renewal Blood flow, cell renewal Prostaglandins Prostaglandins Phospholipid Phospholipid Free radical scavengers Free radical scavengers Therapy is directed at enhancing host defense or eliminating aggressive factors; i.e., H. pylori.

Aim of Treatment Relief Symptoms Heal Ulcer Prevent recurrence Prevent complications

Lifestyle measures Raise the head of the bed Decrease fat intake Avoid certain foods Avoid lying down for 3 hours after eating Stop smoking Lose weight if appropriate

PEPTIC ULCER DRUGS Aimed at either eradicating H. pylori or restoring balance between acid and pepsin secretions and the GI mucosal defense. Aimed at either eradicating H. pylori or restoring balance between acid and pepsin secretions and the GI mucosal defense. These drugs include: systemic antibiotics, antacids, Histamine-2 (H2)-receptor antagonists, proton pump inhibitors, and other peptic drugs such as misoprostol and sucralfate. These drugs include: systemic antibiotics, antacids, Histamine-2 (H2)-receptor antagonists, proton pump inhibitors, and other peptic drugs such as misoprostol and sucralfate.

Eradication of H. pylori

Tests For Initial Diagnosis of Infection Urea Breath Test and Stool Assay Urea Breath Test and Stool Assay  Non-invasive, sensitive and specific Serology Serology  O.K. for initial diagnosis  Fair sensitivity and specificity Endoscopy Not necessary for diagnosis Endoscopy Not necessary for diagnosis

Who Should Be Treated For H. pylori Infection? Patients who have documented H. pylori infection and: Patients who have documented H. pylori infection and:  Definitely had or has a duodenal or stomach ulcer  Have had stomach lymphoma or family hx of stomach cancer Consider treatment if:  Presence of “severe histologic” gastritis and H. pylori infection  Ulcer-like dyspepsia in the absence of an ulcer or prior to endoscopy in a young patient

FDA-Approved Treatment Regimes for H. pylori Infection Omeprazole 20 mg BID + Clarithromycin 500 mg BID + Amoxicillin 1 g BID for 10 days Lansoprazole 30 mg BID +Clarithromycin 500 mg BID + Amoxicillin 1 g BID for 10 days Bismuth subsalicylate (Pepto Bismol) 525 mg QID + Metronidazole 250 mg QID + Tetracycline 500 mg QID X 14 days + H 2 receptor antagonist x 4 wks

Known Factors Which Determine Success of H. pylori Therapy Patient compliance or non-compliance  Medicine complications or side effects Antimicrobial resistance of infecting H. pylori strains Duration of Therapy Correct dosing Clearance of H. pylori infection is not equivalent to eradication.

Drugs Affecting Gastric Acid Secretion

PROTON PUMP INHIBITORS Disrupt chemical binding in stomach cells to reduce acid production, lessening irritation and allowing peptic ulcers to heal. These drugs include: Omeprazole (Prilosec) Rabeprazole (Aciphex) Pantoprazole (Protonix) Lansoprazole (Previcid) Esomaprazole (Nexium)

PROTON PUMP INHIBITORS Pharmacokinetics: Pharmacokinetics: Given orally in enteric-coated form to bypass the stomach and are dissolved and absorbed in the small intestine. Given orally in enteric-coated form to bypass the stomach and are dissolved and absorbed in the small intestine. Highly protein-bound and are extensively metabolized by the liver; eliminated in the urine. Highly protein-bound and are extensively metabolized by the liver; eliminated in the urine.

PROTON PUMP INHIBITORS Pharmacodynamics: Pharmacodynamics: Block the last step in the secretion of gastric acid by combining with hydrogen, potassium, and adenosine triphosphate in the parietal cells of the stomach. Block the last step in the secretion of gastric acid by combining with hydrogen, potassium, and adenosine triphosphate in the parietal cells of the stomach.

PROTON PUMP INHIBITORS Pharmacotherapeutics: Pharmacotherapeutics: Indicated for: Indicated for: Short term treatment of gastric ulcers Short term treatment of gastric ulcers Active duodenal ulcers and peptic ulcers (H. pylori) Active duodenal ulcers and peptic ulcers (H. pylori) Erosive esophagitis Erosive esophagitis GERD GERD Hypersecretory states Hypersecretory states

PROTON PUMP INHIBITORS Drug interactions: Drug interactions: May interfere with the metabolism of diazepam, phenytoin, and warfarin. May interfere with the metabolism of diazepam, phenytoin, and warfarin. May also interfere with drugs that depend on gastric pH for absorption. May also interfere with drugs that depend on gastric pH for absorption. Adverse reactions: Adverse reactions: Abdominal pain, diarrhea, nausea, and vomiting Abdominal pain, diarrhea, nausea, and vomiting

Pharmacological therapy – PPIs Significantly more effective than H2RAs for both symptom resolution and healing of erosive esophagitis Significantly more effective than H2RAs for both symptom resolution and healing of erosive esophagitis Also effective in more severe cases of GERD Also effective in more severe cases of GERD Most patients respond well to standard therapy, but some require prolonged and/or high-dose treatment Most patients respond well to standard therapy, but some require prolonged and/or high-dose treatment

% esophagitis cases healed Weeks of treatment 12 PPIs H 2 RAs Placebo p < PPIs are the most effective drugs for the initial treatment of GERD

H2-RECEPTOR ANTAGONISTS Commonly prescribed anti-ulcer drugs include: Commonly prescribed anti-ulcer drugs include: Cimetidine (Tagamet) Cimetidine (Tagamet) Ranitidine (Zantac) Ranitidine (Zantac) Famotidine (Pepcid) Famotidine (Pepcid) Nizatidine (Axid) Nizatidine (Axid)

H2-RECEPTOR ANTAGONISTS Pharmacokinetics: Absorbed rapidly and completely except for famotidine; food and antiacids may reduce absorption; distributed widely throughout the body; metabolized by the liver; excreted primarily in the urine. Pharmacodynamics: Block histamine from stimulating the acid- secreting parietal cells of the stomach.

H2-RECEPTOR ANTAGONISTS Pharmacotherapeutics: Used therapeutically to: Promote healing of duodenal and gastric ulcers. Provide long-term treatment of pathological GI hypersecretory conditions. Reduce gastric acid production and prevent stress ulcers.

H2-RECEPTOR ANTAGONISTS Drug interactions: Drug interactions: Cimetidine inhibits metabolism of ethyl alcohol in the stomach resulting in higher blood alcohol levels. Cimetidine inhibits metabolism of ethyl alcohol in the stomach resulting in higher blood alcohol levels. Adverse reactions: Adverse reactions: Headache, diarrhea, and rash Headache, diarrhea, and rash

Prevention of ulcers in NSAID Users * * * p< 0.05

Antimuscarinic drugs Pirenzepine, telenzepine M1 receptors antagonists : M1 receptors antagonists : Pirenzepine, telenzepine (a more potent analog), reduce gastric acid secretion with fewer adverse effects than atropine and others. Contraindicated in some gastric ulcers as they Contraindicated in some gastric ulcers as they may slow gastric emptying and prolong the may slow gastric emptying and prolong the exposure of the ulcer bed to acid. exposure of the ulcer bed to acid.

ANTACIDS Over-the-counter medications that include: Magnesium hydroxide and aluminum hydroxide Sodium bicarbonate Calcium carbonate Simethicone

ANTACIDS Pharmacokinetics: Pharmacokinetics: Work locally in the stomach by neutralizing gastric acid. Work locally in the stomach by neutralizing gastric acid. Distributed throughout the GI tract; eliminated primarily in the feces. Distributed throughout the GI tract; eliminated primarily in the feces. Pharmacodynamics: Pharmacodynamics: Reduce the total amount of acid in the GI tract. Reduce the total amount of acid in the GI tract.

ANTACIDS Pharmacotherapeutics: Prescribed to relieve pain and promote healing in peptic ulcer disease. Also used to relieve symptoms of acid indigestion, heart-burn, dyspepsia, or GERD. Also used to prevent stress ulcers, GI bleeding, and hyperphosphatemia in kidney failure.

ANTACIDS Drug interactions: All antacids can interfere with the absorption of oral drugs given at the same time. All antacids can interfere with the absorption of oral drugs given at the same time. Adverse reactions: Diarrhea, constipation, electrolyte imbalances Diarrhea, constipation, electrolyte imbalances

Antacids

Antacids may be no more effective than placebo Placebo Mean increase in time to reproduce heartburn with Bernstein test x 4.1 x 2.9 x 0 x 1 x 2 x 3 x 4 x 5 Antacid * * *p < 0.05 versus pre- treatment

Mucosal Protective Agents

 Tripotassium dicitratobismuthate is a bismuth chelate effective in healing gastric & duodenal ulcers.  Low absorption has been reported  Colloidal Bismuth Subcitrate (CBS) is used in the management of gastric and duodenal ulcers, and in combination with two antibacterials for the eradication of H. pylori. Bismuth Compounds:

Sucralfate It is a complex of aluminium hydroxide and sulphated sucrose but has minimal antacid properties. May act by protecting the mucosa from acid-pepsin attack in gastric and duodenal ulcers.

OTHER PEPTIC ULCER DRUGS Misoprostol (Cytotec) - Protects against peptic ulcers caused by NSAIDs by reducing the secretion of gastric acid and by boosting the production of gastric mucus. Misoprostol (Cytotec) - Protects against peptic ulcers caused by NSAIDs by reducing the secretion of gastric acid and by boosting the production of gastric mucus.

NSAID Use in the Arthritis Patient with a History of Bleeding Ulcer Treating H. pylori is likely to be of benefit if there was a duodenal ulcer; test and treat for H. pylori is recommended. Use COX2 Inhibitor Add a PPI or Misoprostol