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DRUGS USED IN  GASTROINTESTINAL DISEASES

Dewi Selvina Rosdiana

Outline
• • • • • • • Drugs used in acid‐peptic diseases Prokinetic agent Antiemetic Antidiarrheals Laxatives Antispasmodic Drug used for miscellaneous GI disorder

DRUG USED IN ACID‐PEPTIC DISEASE
• Acid neutralizing agents • Acid production inhibitor ƒ H2 antagonist ƒ Proton-pump inhibitors • Mucosal protective agents • Other acid suppressant

Schematic model for physiologic control of hydrogen ion (acid) secretion by the parietal cells of the gastric fundic glands

Acid neutralizing agents: Antacids
Combination of Al(OH)3, Mg(OH)2, CaCO3 (+simethicone) Pharmacodynamics:
y Form salt and water y Promote mucosal defense by stimulation of PG production

Drug interaction:
y Inhibit absorption of digoxin, phenytoin, cimetidine, fluoroquinolone y Some Al can be absorbed

Acid neutralizing agents: Antacids

H2 receptor antagonists
Cimetidine, ranitidine, nizatidine, famotidine Pharmacodynamic: y Reduce acid secretion in 2 ways: competitive inhibition H2 receptor & modulate PC’s response to gastrin & Ach y Reduce 90% (at night) and 60-80% (daytime)

H2 receptor antagonists
Pharmacokinetic: y rapidly absorbed in intestinal lumen y Undergo 1st pass metabolism Æ F = 50% y T1/2: 1-4 hrs, and d.o.a depend on dose, 10 hrs in recommended dose y Elimination: hepatic metab., glomerular filtration filtration & renal tubular secretion y Cross the placenta, secreted into breast milk

H2 receptor antagonists
Safety: ƒ Extremely safe ƒ SE: ¾ diarrhea, constipation, headache, fatigue, myalgia ¾ Gynaecomastia ¾ Blood dyscrasi ¾ Avoid from pregnant and nursing women Drug interaction: ¾ cimetidine prolong half-lives drugs that are substrate for CYP: warfarin, theophylline, phenitoin, lidocaine, quinidine, b-blockers, Ca-channel blockers, benzodiazepines ¾Compete with procainamide for renal tubular secretion

H2 receptor antagonists

Proton‐pump inhibitors
Omeprazole, esomeprazole, lansoprazole, pantoprazole, rabeprazole Pharmacodynamic: y Protonated & concentrated in PC canaliculi y The reactive cation binds covalently with H/K ATPase y Reduce 80-95%, needs 3-4 days to return

Proton‐pump inhibitors
Pharmacokinetic: absorbed in intestinal lumen (available in enteric coated) y An acid-labile lipophylic prodrug: need acid environment to be activated Æ easily diffuse into acidified compartment (PC canaliculi) y To be administered 1 hour before meal y Highly protein bound y Undergo 1st pass & hepatic metabolism y T1/2: 1,5 hr but acid inhibition last up to 24 hr y No renal elimination

Proton‐pump inhibitors
Safety: ƒ Extremely safe ƒ SE: due to highly reduction acid • Reduction in cyanocobalamin absorption • Food-bound minerals (?) • Increase risk of enteric infections ƒ Drug interaction • Alter absorption of certain drugs

Proton‐pump inhibitors

Mucosal protective agents
Sucralfate: A complex of sucrose salt + sulfated AlOH Æ
forms a paste that selectively cover ulcers/erosions Pharmacokinetic: y Almost unabsorbed y Breaking down into sucrose sulfate & Al salt Pharmacodynamic: y Forming physical barrier so that prevent further caustic damage Æ stimulate mucosal PG & HCO3 secretion y Enhancing mucosal repair Drug interaction: y Inhibit absorption of digoxin, phenytoin, cimetidine, fluoroquinolone y Some Al can be absorbed

Mucosal defense enhancing agents
Bismuth compounds
Pharmacodynamic: = sucralfate ƒ Stimulate PG, mucus, bicarbonat secretion

Prostaglandin analog: misoprostol
A methyl analog of PGE1 Pharmacokinetic: y T1/2: 30 mnts Æ 3-4 times daily Pharmacodynamic: stimulates mucus and bicarbonat secretion SE: diarrhea, abdominal cramp (10-20%), stimulate uterine contraction

Mechanism of action of drug used in acid peptic disease

PROKINETIC AGENTS
Agents that enhance coordinated GI motility and transits material in the GI tract • Cholinomimetic – Bethanechol – Neostigmin methylsulfate • Dopamine receptor antagonist – Metoclopramide – domperidon • Serotonin (5-HT4) receptor agonist – Cisapride, prucalopride • Motilin agonist – Macrolides: erythromycin

PROKINETIC AGENTS
Side effects: • Metoclopramide – Extrapyramidal effect – Elevated prolactin level Ægalactorrhea, gynaecomastia, menstrual disorder – methaemoglobinemia • Domperidone – No extrapyramidal effect • Cisaprid – Fatal cardiac arrythmia (occasionally) – torsades de pointes due to induced EAD

PROKINETIC AGENTS
Therapeutic use: • GERD • Impaired gastric emptying – Postvagotomy – Diabetic gastroparesis – NGT-ed patients • Dyspepsia syndrome (non-ulcers) • Antiemetic • Persistent hiccup (metoclopramide)

LAXATIVES (cathartics)
1. Stimulant laxatives: y Castor oil y Diphenylmethane derivatives: bisacodyl y Anthraquinone derivatives: Aloe, senna, cascara 2. Bulk forming laxatives: y Natural plant: bran, psyllium, methylcellulose y Synthetic fibers: calcium polycarbophil 3. Stool softener: y docusate y mineral oil y glycerin supp 4. Osmotic laxatives: y saline laxatives: magnesium citrate, sodium phosphate y unabsorbable sugars: sorbitol, lactulose

Mechanism of action of laxatives

ANTIEMETIC
1. Serotonin (5-HT3) receptors antagonist ƒ Ondansetron, granisetron, ramosetron, palanosetron, dolasetron 2. Dopamine antagonist: Metoklopramide, domperidon 3. H1-antagonist : Cyclizine, Promethazine, prochlorperazine, CPZ 4. Antikolinergics: Scopolamine 5. Cannabioid antagonist: Dronabinol

ANTIDIARRHEA
1. Opioid agonist 2. Colloidal bismuth compound 3. Kaolin (hydrated Mg-Al silicate) & pectin (indigestible KH) 4. Bile salt-binding resin 5. Octreotide

Pharmacodynamic Opioid (Loperamide, Diphenoxylate)

ƒ Inhibit presynaptic cholinergic nerve, reduce peristaltic activity ƒ Increase transit time ƒ Decrease mass colonic  movements

antidiare

Side effects ƒ constipation, cramps, drowsiness,  paralytic ileus, abdominal bloating. ƒ Diphenoxylate, but not loperamide,  produce euphoria dan respiratory  depression ƒ Dark stools, black staining of the  tounge

Colloidal bismuth  compound Kaolin & pectin

ƒ direct antimicrobial effects and  binds enterotoxins

ƒ Have no significant adverse effect  ƒ adsorbents of bacterial toxins  except constipation. and fluid, thereby decreasing stool  liquidity and number. ƒ Should not be taken within 2 hours  of other medication ƒ binds bile salts  and increases  fecal excretion of bile acids ƒ Bloating, flatulence, constipation ƒ Fat malabsorption ƒ Should not be taken within 2 hours  of other medication

Bile salt‐binding resin (Cholestiramine, Colestipol, colesevalam)  Somatostatin‐like  (Octreotide)

ƒ reduces intestinal fluid secretion  ƒ Steatorrhea, nausea, bloating & pancreatic secretion ƒ Fat‐soluble vitamin deficiency ƒ slows GI motility, inhibit  ƒ Gallstone formation,  gallbladder contraction hypo/hyperglycemia

ANTIPASMODIC
1. Anticholinergic • Hyoscyamine, Dicyclomine 2. Serotonin (5-HT3) receptor antagonist • Alosetron Indication: ƒ to prevent the pain and fecal urgency in patient with IBS ƒ treatment of diarrhea-predominant IBS

Drug used for miscellaneous GI disorder
1. Pancreatic enzymes: pancreatin, pancrelipase ¾ Chronic pancreatitis ¾ Malabsorption 2. Bile acids: ursodeoxycholic ¾ Gallstone dissolution 3. Antiflatulance: simethicone, herbal prep. (antifoaming agent)

References 
• McQuaid KR. Drugs used in the treatment of Gastrointestinal diseases. In:  Katzung BG, Masters SB, and Trevor AJ. Basic and clinical pharmacology.  11th ed. Singapure. McGraw Hill; 2009. p.1067‐98. Wallace JL, Sharkey KA. Pharmacotherapy of gastric acidity, peptic ulcers,  and gastroesophageal reflux disease. In: Goodman & Gilman’s the  pharmacological basis of therapeutics. 12th ed. New York: McGraw Hill;  2011. p. 1309‐21. Wallace JL, Sharkey KA. Treatment of disorders of bowel motility and  water flux; antiemetics; agents used in biliary and pancreatic disease. In:  Goodman & Gilman’s the pharmacological basis of therapeutics. 12th ed.  New York: McGraw Hill; 2011. p. 1323‐49. Page C, Curtis M, Walker M, Hoffman B. Integrated pharmacology. 3rd ed.  Spain. Elsevier Mosby; 2006.p.475‐507