Pharmacological Agents for the Symptoms of Abdominal Pain, Nausea, Vomiting, and Dysphagia

1. Pharmacological Agents for the Symptoms ofAbdominal Pain, Nausea, Vomiting, and Dysphagia

2. SOME MECHANISMS OF PAIN ORIGINATING IN THE ABDOMEN • Inflammation of the Parietal Peritoneum • Obstruction of Hollow Viscera • Vascular Disturbances • Abdominal Wall Pain

3. OTHER MECHANISMS OF PAIN IN THE ABDOMEN • Referred Pain • Metabolic Abdominal Crises • Neurogenic Causes

5. LONG-STANDING DICTUM: No acid, no ulcer. Protect the gastric mucosa from acid physiological prophylactic i.e., control factors that increase acid pharmacological

6. Protective Mechanisms of The Stomach: • Prostaglandin E:  inhibits gastric acid secretion  maintains mucosal blood flow  stimulates production of mucus and bicarbonate

7. Protective Mechanisms of The Stomach: 2. Gastric mucus – a viscus gel that:  lubricates the gastric mucosa  traps microorganisms  serves as barrier to back diffusion of H+ from the mucosa

8. Protective Mechanisms of The Stomach: 3. Bicarbonate – neutralizes H+ 4. Vascular capillaries 5. Continuous renewal of gastric cells

9. Mechanisms involved in the Pathogenesis of Ulcers: • Gastric acid hypersecretion • Decreased mucosal defenses due to PG inhibitors (NSAIDs - especially for gastric PUD)

10. Mechanisms involved in the Pathogenesis of Ulcers: 3. Helicobacter pylori  mostly found in gastric antrum inflammation  most common cause of antral gastritis  pathogenesis: a. production of cytotoxin b. breakdown of mucosal defenses (possibly aided by urease production)  90% of duodenal and 70% of gastric ulcers

11. Risk Factors in PUD: • Food: •  No scientific data presently supports • that diet imparts an increased risk for • PUD • - Caffeine, milk, alcohol, spices- • increase acid secretion • 2. Genetic predilection: duodenal ulcers • 3. Stress

12. Important Factors to the Development of PUD: 4. Bacterial GI infection 5. NSAIDs 6. Cigarette smoking

13. Cigarette smoking:  impairs healing  promotes ulcer recurrence  increases likelihood of complications

14. Goals of Treatment for PUD: • Relief of symptoms • Promote ulcer healing • Prevent ulcer recurrence and complications  Eradicate Helicobacter pylori 4. Provide cost-effective therapy

15. Agents for PUD

16. These drugs have secondary and tertiary mechanisms that may prove beneficial in the alleviation of pain and in the treatment of acid-peptic disorders.

17. Histamine released from mast cells binds H2 receptors & activates adenylase cyclase activates proton pump of pareital cells to secrete H+ against a concentration gradient in exchange for K+

18. Antisecretory: Proton Pump Inhibitors Omeprazole Efficacy: • MOA: inhibits H+K+ATPase (proton) pump found only in the parietal cell • relieve symptoms more quickly than H2 blockers • inhibit 90% of gastric acid secreted in 24 hours

19. Proton Pump Inhibitors: Efficacy: Kinetics: - unstable in acid medium > usual preparation: enteric coated granules - bioavailability: 50-80% - currently available PPIs are prodrugs: - active metabolites: > omeprazole = omeprazolesulfonamide > lansoprazole = lanzoprazolesulfone and hydroxy lanzoprazole - elimination: almost entirelyhepatic

20. Proton Pump Inhibitors Omeprazole Efficacy: • Indications: PUD Zollinger-Ellison syndrome gastroesophageal reflux

21. Proton Pump Inhibitors: • Suitability: Drug Interactions: • - all PPIs bind to the P450 oxidative • enzymes • >can potentially interfere with drug • metabolism

22. Proton Pump Inhibitors: Suitability: Drug Interactions: Omeprazole – affinity to CYP2C19 – decreased metabolism of: diazepam, phenytoin, warfarin, and tolbutamide

23. Proton Pump Inhibitors: Suitability: Drug Interactions: Sucralfate – decreases bioavailability of omeprazole, lansoprazole, and probably other PPIs

24. Histamine released from mast cells binds H2 receptors & activates adenylase cyclase activates proton pump of pareital cells to secrete H+ against a concentration gradient in exchange for K+

25. Antisecretory: H2 Receptor Blockers Cimetidine Mechanisms of action: 1. competitive antagonism for H2 receptor 2. decrease of mucosal blood flow 3. alteration of histamine metabolism

26. H2 Receptor Blockers Cimetidine Kinetics: > absorbed from the small intestine > 65-75% bioavailability; > peak serum levels attained in 90-120 min > metabolism: hepatic Duration of treatment: acute phase : 4-6 weeks maintenance: 6-12 weeks

27. H2 Receptor Blockers Cimetidine Other pharmacological actions and effects: 1. liver: a. inhibits activity hepatic microsomal enzymes b. hepatitis 2. endocrine – anti-androgenic a. gynecomastia b. loss of libido, impotence

28. H2 Receptor Blockers Cimetidine Other pharmacological actions and effects: 3. CNS a. mental confusion b. lethargy c. somnolence d. hallucinations 4. GIT – ??role in carcinogenesis??

29. H2 Receptor Blockers Cimetidine 5. CVS a. dysrrhythmias, bradycardia b. hypotension with rapid IV administration 6. hematologic – agranulocytosis 7. immune system – augments cell mediated response

30. H2 receptor blockers: Efficacy: • effective in acute healing of both duodenal & gastric PUD • commonly available antacids: famotidine – mostpotent nizatidine ranitidine cimetidine

31. H2 receptor blockers: Pharmacokinetics first pass metabolism exhibited by: cimetidine, famotidine, and ranitidine  elimination: > principally hepatic: cimetidine ranitidine > principally renal: famotidine nizatidine

32. H2 receptor blockers: Safety: remarkably safe: low frequency of adverse effects  patients with the greatest risk for ADRs: a. elderly b. those taking high doses of the drug c. patients with altered renal function

33. H2 receptor blockers Drug Interactions: a.Cimetidine - cyt P450 enzyme binding - inhibits biotransformation of several drugs - primarily affects oxidative drug metabolism - reduce clearance by 20-30% of the ff: phenytoin, warfarin, theophylline (clinically significant because of their narrow therapeutic range)

34. H2 receptor blockers Drug Interactions: b. Ranitidine - binds less intensely to cyt P450 system c. Famotidine and Nizatadine - do not bind appreciably to cyt P450

35. H2 receptor blockers Drug Interactions: • Weak inhibition of alcohol dehydrogenase enzyme: - cimetidine, ranitidine, and nizatadine enhance absorption of ethanol - famotidine – has little effect on this enzyme

36. Antacids General actions: a. acid neutralizing capacity b. antipeptic activity c. binds with bile acids

37. Antacids Other pharmacological actions: a. GIT: 1] gastric acid rebound 2] motor activity a] Magnesium-containing compounds – laxative activity b] Aluminum-containing compounds – constipating activity 3] CO2 liberation 4] expansion of pareital cell mass

38. Antacids • Other pharmacological actions: • metabolic acidosis • – especially in systemically-absorbed • antacids (ie, Na+ bicarbonate) • b. disordered mineral • metabolism

39. Antacids Other pharmacological actions: d. milkalkali syndrome e. effects secondary to cation absorption: 1] fluid retention 2] uremic encephalopathy syndrome 3] hypermagnesemia

40. Milk Alkali Syndrome • caused by hypercalcemia and metabolicalkalosis • calcium deposits in the kidneys and other • tissues may occur (i.e., hypercalcemic nephropathy with alkalosis) • rarely seen today, because of newer, better • medications available for PUD • often asymptomatic • > when symptoms occur, they are often • related to complications, like kidney • problems.

41. Antacids Other pharmacological actions: d. milkalkali syndrome e. effects secondary to cation absorption: 1] fluid retention 2] uremic encephalopathy syndrome 3] hypermagnesemia

42. Antacids Sodiumbicarbonate and Calcium salts – have systemic effects Other therapeutic uses of Na bicarbonate: a. for barbiturate poisoning b. for sulfonamide therapy c. in some cases of gout d. as component of antipruritics e. as component of mouthwashes, douches, enemas

43. Best given 1 hour after meals and every two hours thereafter • Liquid preparations are preferred

44. Antacids Calcium carbonate (Tums): - rapid, effective neutralization of acid - high dose (4-8 mg/day) may potentially: > stimulate gastric acid production > induce milk-alkali syndrome

45. Antacids Magnesium- and aluminum- containing antacids: - are slightly absorbed in the GIT - effectively excreted in patients with normal kidney function - the ions can accumulate in patients with renal failure

46. Antacids  Drug Interactions: a. affect drugs that require acid for dissolution and absorption: > decrease absorption: digoxin phenytoin isoniazid > decrease dissolution/absorption: ketoconazole

47. Antacids  Drug Interactions: b. bind to concomitantly administered drugs: > ciprofloxacin – decrease bioavailability > tetracycline – binds with multivalent cations

48. Cytoprotective: Prostaglandins Misoprostol Actions: 1. inhibits gastric acid secretion 2. stimulates production of protective mucus 3. increases mucosal blood flow 4. enhances endogenous bicarbonate secretion

49. Prostaglandins Misoprostol Indications: • for NSAID-induced gastropathy 2. powerful oxytocic

50. Prostaglandins Misoprostol Adverse effects: • may produce diarrhea at doses required to produce inhibition of gastric acid secretion 2. abortion