Peptic Ulcers, GERD, and GI Drugs

• Drugs for treatment of gastrointestinal disorders
• Objectives include understanding pharmacological treatments for peptic ulcers and gastroesophageal reflux disease, identifying causes and treatments for common GI disorders, and discussing mechanisms of action, indications, and adverse effects of drugs for GI disorders

Peptic Ulcers and GERD

• Drugs utilized for peptic ulcers and gastroesophageal reflux disease
• Peptic ulcers are sores that develop on the lining of the stomach, lower esophagus, or small intestine
• Gastroesophageal Reflux Disease (GERD) is a digestive disorder where stomach acid frequently flows back into the esophagus
• Helicobacter pylori is present in 95% of duodenal ulcers and 80% of gastric ulcers
• H. pylori burrows into the gastric mucosa to escape gastric acid and produces urease, an enzyme that converts urea to ammonia and CO2
• Urease kills mucosal epithelial cells, which leaves the gut unprotected
• Testing for H. pylori includes breath tests for urea or serological culture
• Antisecretory or antibiotic treatments alone aren't as effective as combination therapy
• Two main causes for peptic ulcer are infection With H. Pylori and use of nonsteroidal anti-inflammatory drugs
• Increased HCl secretion and inadequate mucosal defense against gastric acid also contribute.
• Treatment options consists of eradicating H. pylori, reducing gastric acid secretion using PPIs or H2 receptor antagonists, and providing agents to protect the gastric mucosa from damage (misoprostol and sucralfate).

Antacids

• Weak bases react with gastric HCl to form water/salt, and thus lowers the acidity in the stomach
• A single dose of antacid given 1 hour after a meal neutralizes gastric acid for up to 2 hours
• All antacids may affect the absorption of other medications by binding the drug or by increasing the pH
• Antacids shouldn't be given within 2 hours of other drugs.
• Indications: dyspepsia and acid-peptic disorders
• Alkalotic urine increases the deposition of Ca2+ and PO43- to form a kidney stone (cranberry juice does the opposite)
• Increases blood sodium, which exacerbates hypertension
• Long-term use leads to osteoporosis
• Ricochet syndrome is acid rebound due to feedback regulation
• Constipation is common with Al3+ and diarrhea is often associated with Mg2+
• Systemic antacids includes NaHCO3
• Non-Systemic antacids include:, MgO, Mg(OH)2, Al(OH)3, and CaCO3

H2 Blockers

• H2 Blockers are competitive antagonists at the H2 receptor
• Blocks H2 receptors and reduce basal and meal-stimulated acid secretion in a dose-dependent manner
• Also inhibits gastric acid secretion stimulated by food, histamine, pentagastrin, caffeine, and insulin
• Indications: Peptic ulcers, acute stress ulcers, gastroesophageal reflux disease
• Can cause adverse reactions in less than 3% of patients (headaches, diarrhea, fatigue)
• Mental status changes may occur with IV administration in elderly
• Cimetidine inhibits the binding of dihydrotestosterone to androgen receptors and the metabolism of estradiol
• Chronic consumption of Cimetidine may cause gynecomastia or impotence in men and galactorrhea in women
• First generation H2 Blockers include Cimetidine
  • 50-60% reduction in acidity (moderate)
  • Binds to CYT P450; causes drug interaction (non-selective inhibition)
  • Binds to androgen receptors, which may cause gynecomastia, reduced libido, and impotence
• Second generation H2 Blockers include Ranitidine
  • More effective at reducing acid than Cimetidine (65-70%)
  • Less drug interaction
  • Does not bind androgen receptors
• Third generation H2 Blockers include Famotidine
  • More effective than Ranitidine, most potent
  • Does not bind CYT P450 at all
  • Limited adverse side effects
  • More effective at reducing acid secretion, best safety profile

Proton Pump Inhibitors

• Proton Pump Inhibitors (PPIs) are prodrugs with an acid-resistant enteric coating to protect them from degradation by gastric acid
• The alkaline duodenum removes the coating and the prodrug is absorbed and transported to the parietal cell
• It converts to an active drug, which creates a stable covalent bond with the H+/K+-ATPase enzyme
• It takes ~18 hours for the enzyme to be resynthesized to prevent acid secretion
• At standard doses, PPIs blocks basal and stimulated gastric acid secretion by more than 90%
• An oral product with omeprazole and antacids available for faster absorption
• Indications: Gastroesophageal Reflux Disease, Peptic ulcer disease, NonUcler, dyspepsia, Stress-induced gastritis, Gastrin-secreting tumors, and NSAID prevention of gastritis
• Side effects include nausea and diarrhea

Mucosal Protective Agents

• Sucralfate and bismuth coat ulcers/erosions to generate a protective layer against pepsin and acid
• Bismuth may also stimulate prostaglandin, mucus, and bicarbonate production
• Bismuth may have antimicrobial effects against H. Pylori
• Bismuth binds enterotoxins, which prevents or treats traveler's diarrhea
• Bismuth reduces stool frequency & liquidity in acute infectious diarrhea by salicylate inhibition of intestinal prostaglandins and chloride secretion, and creates"artificial” mucous
• Side Effects: constipation and/or black stool
• Misoprostol, a methyl PGE-1 analog, stimulates mucus & bicarbonate secretion by increasing mucosal blood flow, protects stomach by creating protective acid barrier
• Misoprostol binds to prostaglandin receptors on parietal cells, which reduces histamine-stimulated cAMP production from acid secretion
• Side effects include Prevention of NSAID induced (including aspirin)-induced gastric ulcers, abortion and birth defects, increased uterine contractions, and diarrhea

Antibiotics

• Antibiotics for GI Disorders, use of a PPI makes the micro-environment surrounding H. Pylori less acidic, shifts the bacteria into a replicative phenotype (more sensitive to amoxicillin and clarithromycin)
• Triple therapy includes PPI + 2 antibiotics (Amoxicillin and clarithromycin)
• Quadruple therapy includes PPI + 2 antibiotics + bismuth components

Emetics

• Nausea and vomiting occur in a variety of conditions (motion sickness, pregnancy, and GI illnesses), and are unpleasant for the patient. Nausea and vomiting produced by chemotherapeutic agents demands especially effective management
• Nearly 70%-80% of patients who undergo chemotherapy experience nausea and/or vomiting.
• Uncontrolled vomiting can produce dehydration, profound metabolic imbalances and nutrient depletion
• Selective 5-HT3 (serotonin) receptor antagonists
• Serotonin receptors of the 5-HT3 type are present both peripherally on vagal nerve terminals, centrally in the chemoreceptor trigger zone area postrema
• 5-HT3 receptors are expressed throughout central & peripheral nervous system, and are ligand-gated ion channel
• Ondansetron: a selective 5-HT3 (serotonin) receptor antagonists treatment for nausea related to cancer chemotherapy, prevention of postoperative nausea/vomiting
• Can cause side effects such as headaches, dizziness, and or constipation
• Reversible QT prolongation appears to be an effect produced by all members of this drug class
• Unlike some other medications, ondansetron is NOT dopamine antagonists
• Cytotoxic chemotherapy is thought to release serotonin from enterochromaffin cells of small intestine and stimulate the vagal afferent nerves through the 5-HT3 receptors (the vomiting reflex).

Diarrheals

• Diarrhea is frequent liquid stool (sign of an intestinal disorder) with multiple causes, from foods, bacteria, virus, protozoa, drug side effect, laxative abuse, malabsorption syndrome stress, and/or bowel tumor
• Severity of diarrhea can be life threatening (dehydration)
• Simple treatment includes clear liquids and/or a change in diet
• Antidiarrheals include Loperamide, an antimotility agent
• Loperamide is an agonist for peripheral mu opioid receptors
• Loperamide does not cross the blood-brain barrier; and it is a nonanalgesic/addictive
• It inhibits the release of acetylcholine/prostaglandins, reduces peristalsis, increases intestinal transit time, and favors water/electrolyte movement through the bowel.
• Loperamide increases the tone of the anal sphincter, reduces incontinence and urgency
• Loperamide is used to treat of mild to moderate diarrhea, or diarrhea associated with Inflammatory Bowel Disease
• Loperamide has no analgesic effects and no potential for addiction
• High doses of loperamide may prolong the QTc and QRS intervals, which increases the risk for Torsade de Pointes and life-threatening ventricular tachycardia

Constipation and Laxatives

• Constipation is a disorder resulting in infrequent/uncomfortable bowel movements, resulting small amounts of hard, dry stool (usually fewer than 3 times a week)
• Laxatives includes stimulate the intestine and increase smooth muscle
• Senna, Castor Oil, and Bisacodyl all stimulate intestinal walls and the enteric nervous system (causing the increase smooth muscle contraction and peristalsis, which leads to increased electrolyte and water secretion)
• Generally produces a bowel movement in 6-12 hours.
• Can cause abdominal cramps, nausea, vomiting and diarrhea
• Senna can cause melanosis coli and bisacodyl has risk of atonic colon

Irritable Bowel Syndrome (IBS)

• IBS is a common "idiopathic," poorly understood bowel disorder, in absence of identifiable organic cause
• Characterized by chronically recurring abdominal discomfort (pain, bloating, cramps), diarrhea, and constipation
• The most commonly diagnosed GI condition, accounting for ~30% of gastroenterologist referrals
• Approximately 10-20% of adults/adolescents have overlapping symptoms.
• Peripheral Mechanisms, Dysregulation Brain-Gut, altered microflora, and Intestinal Irrltants
• Treatment is symptomatic and include treatment for diet, exercise, laxatives for constipation, Antidiarrheals, Antibiotics and relief for abdominal pain.

Inflammatory Bowel Disease (IBD)

• Mediated by Immunity and leads to chronic intestitial conditions.
• Includes the major diseases of Ulcerative Colitis and Crohn's Disease.
• The disease typically onset between the ages of 15 and 30 and appears again in individuals 60 to 80 years old.
• Treatment of IBD include Biologics: Anti-TNF, Anti-Integrin, Immunomodulators, Corticosteroids, Antibiotics and Aminosalicylates.