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Learning Objectives 1. Know the major classes of acid-suppressive drugs and their mechanisms of action 2. Know the common side effects of acid- suppressive.

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Presentation on theme: "Learning Objectives 1. Know the major classes of acid-suppressive drugs and their mechanisms of action 2. Know the common side effects of acid- suppressive."— Presentation transcript:

1 Learning Objectives 1. Know the major classes of acid-suppressive drugs and their mechanisms of action 2. Know the common side effects of acid- suppressive drugs 3. Know the specific treatment of acid-peptic disorders Gastrointestinal Pharmacology Prof. Sri Agus Sudjarwo.,Ph.D

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3 Peptic Ulcer Disease Factors that Increase Acidity Factors that Increase Acidity Factors that Protect Against Acidity Factors that Protect Against Acidity

4 Peptic Ulcer Disease Imbalance between defenses and aggressive factors Defensive factors: -Mucus: continually secreted, protective effect -Bicarbonate: secreted from endothelial cells -Blood flow: good blood flow maintains mucosal integrity -Prostaglandins: stimulate secretion of bicarbonate and mucus, promote blood flow, suppress secretion of gastric acid

5 Aggressive factors: -Helicobacter pylori: gram negative bacteria, can live in stomach and duodenum, may breakdown mucus layer => inflammatory response to presence of the bacteria also produces urease – forms CO2 and ammonia which are toxic to mucosa -Gastric Acid: needs to be present for ulcer to form => activates pepsin and injures mucosa -Decreased blood flow: causes decrease in mucus production and bicarbonate synthesis, promote gastric acid secretion -NSAIDS: inhibit the production of prostaglandins -Smoking: nicotine stimulates gastric acid production

6 Classes of Agents 1. Proton Pump Inhibitors 2. Histamine H 2 -Receptor Antagonists 3. Prostaglandin Analogs 4. Cytoprotectants 5. Antacids

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8 1. Proton Pump Inhibitors (PPI’s)

9 PPIs - Most potent suppressors of acid secretion hr effects on acid suppression - Irreversible inhibitor of proton pump; blocks 98% of acid secretion in all forms of ulcer and hypersecretory Zollinger-Ellison syndrome. -The drug is given in gelatin coated capsule to resist breakdown in stomach acid. It reaches the intestine, well absorbed, enters blood stream,reaches the parietal cell.

10 PPIs Irreversibly inhibit H + /K + ATPase function to: Irreversibly inhibit H + /K + ATPase function to: – Block gastric acid secretion – Decrease pepsin concentration – Increase gastric pH Secretion of acid only resumes when new proton pumps are deployed Secretion of acid only resumes when new proton pumps are deployed Steady-state inhibition (affecting 70% of pumps) may take 2-5 days Steady-state inhibition (affecting 70% of pumps) may take 2-5 days

11 PPI Pharmacology Activated only when pH decreases below 4 Activated only when pH decreases below 4 – Occurs only in parietal cell – Achieved only when parietal cell activation occurs (after meals) – Most effective after a prolonged fast when large amounts of active proton pumps are present (i.e. breakfast)

12 Available PPIs Esomeprazole (Nexium) Esomeprazole (Nexium) Lansoprazole (Prevacid) (iv) Lansoprazole (Prevacid) (iv) Omeprazole (Prilosec, generic, OTC) Omeprazole (Prilosec, generic, OTC) Pantoprazole (Protonix) (iv) Pantoprazole (Protonix) (iv) Rabeprazole (Aciphex) Rabeprazole (Aciphex)

13 PPI Metabolism Rapidly absorbed Rapidly absorbed Highly protein bound Highly protein bound Extensively metabolized in the liver by the P450 system (CYP2C19 and CYP3A4) Extensively metabolized in the liver by the P450 system (CYP2C19 and CYP3A4) Sulfated metabolites are excreted in the urine or feces Sulfated metabolites are excreted in the urine or feces Hepatic disease reduces the clearance of lansoprazole--reduce dose Hepatic disease reduces the clearance of lansoprazole--reduce dose

14 Common PPI Side Effects Headache ( %) vs.Placebo ( %) Headache ( %) vs.Placebo ( %) Diarrhea (3%) vs.Placebo (3.1%) Diarrhea (3%) vs.Placebo (3.1%) Abdominal pain ( %) vs.Placebo ( %) Abdominal pain ( %) vs.Placebo ( %) Constipation ( %)vs. Placebo (0-0.8%) Constipation ( %)vs. Placebo (0-0.8%)

15 Drug-Drug Interactions Ketoconazole and Digoxin absorption is decreased due to reduced acidity. Ketoconazole and Digoxin absorption is decreased due to reduced acidity. Omeprazole may inhibit coumadin, diazepam and phenytoin metabolism Omeprazole may inhibit coumadin, diazepam and phenytoin metabolism

16 2. Histamine H 2 -Receptor Antagonists (H 2 RAs)

17 H 2 RAs Reversibly compete with histamine for binding to H 2 receptors on the basolateral membrane of parietal cells Reversibly compete with histamine for binding to H 2 receptors on the basolateral membrane of parietal cells Less potent than PPIs but still suppress acid by 70% over 24 hrs Less potent than PPIs but still suppress acid by 70% over 24 hrs

18 Available H 2 RAs H2 receptor blockers: Cimetidine (Tagamet®) First H2-blocker available Inhibits P450 => Drug interaction Ranitidine (Zantac®) Does not inhibit P450 => fewer side effects Nizatidine (Axid®) Famotidine (Pepcid®)

19 Pharmacokinetics Rapidly absorbed after oral administration Rapidly absorbed after oral administration Serum concentrations peak in 1-3 hr Serum concentrations peak in 1-3 hr Therapeutic levels maintained up to 12 hrs Therapeutic levels maintained up to 12 hrs Small percentage is protein bound Small percentage is protein bound 10% to 35 % metabolized by the liver 10% to 35 % metabolized by the liver Drugs and metabolites primarily excreted by kidneys (**reduce doses in renal disease) Drugs and metabolites primarily excreted by kidneys (**reduce doses in renal disease)

20 -inhibit 90% acid secretion in basal state as well as food-induced and nocturnal acid production. -they are helpful in healing gastric and duodenal ulcers and prevent their recurrence. Have benefits in preventing increased gastric acid secretion in Zollinger-Ellison syndrome. -Cimetidine Has several side effects, not a choice now - Under Prescription.

21 Common H 2 RA Side Effects All less than 3% All less than 3% – Diarrhea – Headache – Drowsiness – Fatigue – Muscular pain – Constipation Much less common Much less common – Confusion, delirium in the elderly – Associated with thrombocytopenia – Cimetidine anti-androgen effects

22 Drug-Drug Interactions -Inhibits CyP450: Inhibits the metabolism of various drugs that are concomitantly taken: phenytoin, warfarin, theophylinne, BZD. -These adverse effects are relatively least with ranitidine and famotidine

23 3. Prostaglandin Analogs: Misoprostol

24 Protective Effects of Prostaglandins PGE 2 and PGI 2 synthesized by gastric mucosa PGE 2 and PGI 2 synthesized by gastric mucosa Acid-reducing effects Acid-reducing effects – Bind to EP 3 receptors on parietal cells – Decrease acid production Cytoprotective effects Cytoprotective effects – Stimulation of mucin and bicarbonate – Increase mucosal blood flow Contrast with NSAIDS which diminish prostaglandin formation by inhibition of cycloxygenase and lead to Contrast with NSAIDS which diminish prostaglandin formation by inhibition of cycloxygenase and lead to ulcer formation ulcer formation

25 Misoprostol: Cytotec Synthetic analog of PGE 1 Synthetic analog of PGE 1 – Enhanced potency – Increased oral bioavailability Inhibit basal acid secretion (85-95%) Inhibit basal acid secretion (85-95%) Inhibit stimulated acid secretion (75- 85%) Inhibit stimulated acid secretion (75- 85%)

26 Pharmacokinetics Rapidly absorbed Rapidly absorbed Rapidly de-esterfied to misoprostol acid-- the active metabolite Rapidly de-esterfied to misoprostol acid-- the active metabolite Therapeutic effect peaks at minutes Therapeutic effect peaks at minutes Lasts 3 hours (qid dose required) Lasts 3 hours (qid dose required)

27 Side Effects Diarrhea ± abdominal cramps as high as 30% Diarrhea ± abdominal cramps as high as 30% Begins within 2 weeks and often resolves spontaneously in 1 week Begins within 2 weeks and often resolves spontaneously in 1 week Can exacerbate inflammatory bowel disease Can exacerbate inflammatory bowel disease Contraindicated during pregnancy Contraindicated during pregnancy

28 4. Sucralfate: Carafate

29 Sucralfate Sulfated polysaccharide Sulfated polysaccharide Acid activated Acid activated Administered on an empty stomach 1 hr before meals Administered on an empty stomach 1 hr before meals Stimulates local prostaglandin synthesis, adsorbs pepsin Stimulates local prostaglandin synthesis, adsorbs pepsin Binds bile acids Binds bile acids Not absorbed => essentially free of side effects

30 Common Side Effects Constipation (2%) Constipation (2%) Avoid in renal failure Avoid in renal failure May impair absorption of other drugs May impair absorption of other drugs

31 5. Antacids

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33 Antacids Sodium bicarbonate Sodium bicarbonate CaCO3 CaCO3 Mg 2+ hydroxides Mg 2+ hydroxides Al 3+ hydroxide Al 3+ hydroxide

34 Antacids Given orally 1-3 hrs after meals and bedtime Given orally 1-3 hrs after meals and bedtime Mg +2 based preparations increase motility Mg +2 based preparations increase motility – Diarrhea Al +3 based preparations relax smooth muscle Al +3 based preparations relax smooth muscle – Constipation Ca +2 based preparations release CO2 Ca +2 based preparations release CO2 – Belching, nausea, distension, and flatulence.

35 Common Side Effects Aluminum toxicity with renal disease Aluminum toxicity with renal disease – Osteoporosis, enchephalopathy, myopathy Hypercalcemia Hypercalcemia – Phosphate retention – Calcium precipitation in the kidney Impair absorption of some drugs Impair absorption of some drugs – Take 2 hrs before or after other drugs

36 Antibiotic ulcer therapy : Combinations must be used: -Bismuth (PeptoBismol®) – disrupts cell wall of H. pylori -Clarithromycin – inhibits protein synthesis -Amoxicillin – disrupts cell wall -Tetracyclin – inhibits protein synthesis -Metronidazole – used often due to bacterial resistance to amoxicillin and tetracyclin, or due to intolerance by the patient Standard treatment regimen for peptic ulcer: Omeprazole + amoxicillin + metronidazole

37 Laxatives

38 Constipation Abnormally infrequent and difficult passage of feces through the lower GI tract Abnormally infrequent and difficult passage of feces through the lower GI tract Symptom, not a disease Symptom, not a disease Disorder of movement through the colon and/or rectum Disorder of movement through the colon and/or rectum Can be caused by a variety of diseases or drugs Can be caused by a variety of diseases or drugs

39 Laxatives : Bulk forming Bulk forming Emollient Emollient Hyperosmotic Hyperosmotic Saline Saline Stimulant Stimulant

40 Laxatives: Mechanism of Action Bulk forming High fiber High fiber Absorbs water to increase bulk Absorbs water to increase bulk Distends bowel to initiate reflex bowel activity Distends bowel to initiate reflex bowel activity Examples: Examples: – psyllium (Metamucil) – methylcellulose (Citrucel) – polycarbophil

41 Laxatives: Mechanism of Action Emollient Stool softeners and lubricants Stool softeners and lubricants Promote more water and fat in the stools Promote more water and fat in the stools Lubricate the fecal material and intestinal walls Lubricate the fecal material and intestinal walls Examples: Examples: – Stool softeners: docusate salts (Colace, Surfak) – Lubricants: mineral oil

42 Laxatives: Mechanism of Action Hyperosmotic Increase fecal water content Increase fecal water content Result: bowel distention, increased peristalsis, and evacuation Result: bowel distention, increased peristalsis, and evacuation Examples: Examples: – polyethylene glycol (GoLYTELY) – sorbitol – glycerin – lactulose (Chronulac)

43 Laxatives: Mechanism of Action Saline Increase osmotic pressure within the intestinal tract, causing more water to enter the intestines Increase osmotic pressure within the intestinal tract, causing more water to enter the intestines Result: bowel distention, increased peristalsis, and evacuation Result: bowel distention, increased peristalsis, and evacuation

44 Saline laxative examples: Saline laxative examples: – magnesium sulfate (Epsom salts) – magnesium hydroxide (MOM) – magnesium citrate – sodium phosphate (Fleet Phospho- Soda, Fleet enema)

45 Laxatives: Mechanism of Action Stimulant Increases peristalsis via intestinal nerve stimulation Increases peristalsis via intestinal nerve stimulation Examples: Examples: – castor oil – senna – cascara – bisacodyl

46 Laxatives: Side Effects Bulk forming Bulk forming – Impaction – Fluid overload Emollient Emollient – Skin rashes – Decreased absorption of vitamins Hyperosmotic Hyperosmotic – Abdominal bloating – Rectal irritation

47 Laxatives: Side Effects Saline Saline – Magnesium toxicity (with renal insufficiency) – Cramping – Diarrhea – Increased thirst Stimulant Stimulant – Nutrient malabsorption – Skin rashes – Gastric irritation – Rectal irritation

48 Antidiarrheals

49 Causes of Diarrhea Acute Diarrhea BacterialViral Drug induced NutritionalProtozoal Chronic Diarrhea TumorsDiabetes Addison’s disease Hyperthyroidism Irritable bowel syndrome

50 Antidiarrheals – Drugs that decrease peristalsis, thereby allowing fluid absorption from the intestinal contents – Examples: Anticholinergics Anticholinergics Protectants/adsorbents Protectants/adsorbents Opiate-related agents Opiate-related agents Probiotics Probiotics Metronidazole Metronidazole

51 Antidiarrheals Antidiarrheals – Anticholinergics are used to treat tenemus and vomiting – Examples: Atropine Atropine Aminopentamide Aminopentamide Isopropamide Isopropamide Propantheline Propantheline Methscopolamine Methscopolamine – Side effects include dry mucous membranes, urine retention, tachycardia, and constipation

52 Antidiarrheals Antidiarrheals – Protectants/adsorbents coat inflamed intestinal mucosa with a protective layer (protectants) or bind bacteria and/or digestive enzymes and/or toxins to protect intestinal mucosa from damaging effects (adsorbents) – Examples: Bismuth subsalicylate (bismuth + aspirin-like product) Bismuth subsalicylate (bismuth + aspirin-like product) Kaolin/pectin Kaolin/pectin Activated charcoal Activated charcoal – Side effects include constipation

53 Antidiarrheals Antidiarrheals – Opiate-related agents control diarrhea by decreasing both intestinal secretions and the flow of feces and increasing segmental contractions – Examples: Diphenoxylate Diphenoxylate Loperamide Loperamide Paregoric Paregoric – Side effects include CNS depression, ileus, urine retention, bloat, and constipation

54 Antidiarrheals Antidiarrheals – Probiotics seed the GI tract with beneficial bacteria; use is based on the theory that some forms of diarrhea are caused by disruption of the normal bacterial flora of the GI tract – Must be refrigerated to maintain the viability of the bacteria – Examples: Plain yogurt with active cultures Plain yogurt with active cultures Variety of trade-name products Variety of trade-name products

55 Antidiarrheals Antidiarrheals – A theory regarding the development of diarrhea is that anaerobic bacteria may increase due to disruption of normal GI flora – One way to treat this is to use an antibiotic effective against anaerobic bacteria – Metronidazole is an example of an antibiotic used to treat diarrhea


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