1. Drugs used in the treatment of peptic ulcer

2. Gastric Defenses Against Acid
1- Esophageal defense: the lower esophageal sphincter, which prevents reflux of acidic gastric contents into the esophagus.
2- Stomach defense: (require adequate mucosal blood flow because of the high metabolic activity and oxygen requirements of the gastric mucosa)
a) Secretion of a mucus layer that protects gastric epithelial cells. Mucus production is stimulated by prostaglandins E2 and I2, which also directly inhibit gastric acid secretion by parietal cells. Drugs that inhibit prostaglandin formation (are alcohol and NSAIDs) decrease mucus secretion and predispose to the development of acid-peptic disease.
b) Secretion of bicarbonate ions by superficial gastric epithelial cells. Bicarbonate neutralizes HCl.

3. Types of gastric HCl secretion
1- Nocturnal (basal) acid secretion: depend on histamine
2- Meal stimulated acid secretion: stimulated by:
Gastrin
Acetylcholine
Histamine

4. Phases of gastric secretion
1) Cephalic Phase 2) Gastric Phase 3) Intestinal Phase

5. Phases of gastric secretion
Stimuli
Pathway
Cephalic (stimulate)
Sight, smell, taste or thought of food
Vagus (M3 receptors)
Histamine (H2 receptor)
Gastrin
Gastric (stimulate)
Food in the stomach
Stretch: local reflex (M3 receptors)
Chemical substances in food (gastrin)
Increase pH: Inhibition of somatostatin release
Intestinal (inhibit)
Chyme in the duodenum

6. Regulatory molecules that stimulate acid secretion
Acetylcholine
Produced from nerve endings and stimulate M3 receptor on:
Parietal cells (produce HCl)
Enterochromaffin cells and Mast cells (produce histamine)
G cells (produce gastrin)
Histamine
Produced by enterochromaffin cells and Mast cells in response to stimulation of M3 receptors (by acetylcholine) and CCK3 receptors by gastrin. It stimulates parietal cells to produce HCL
Gastrin
Produced by G cells in response to stimulation of M3 receptors by acetylcholine and stretch and by chemical substances in food

7. Mechanism of HCl secretion

8. Steps of gastric acid secretion by parietal cells
* Chloride (Cl¯) and hydrogen ions are secreted actively from the cytoplasm of parietal cells into the lumen of the canaliculus where and they combine into HCl then secreted into the lumen of the stomach
* Hydrogen ions are produced in the parietal cells by the action of the enzyme carbonic anhydrase which catalyses the reaction between carbon dioxide and water, in which carbonic acid is produced. This acid immediately dissociates into hydrogen ions and carbonate ions.
Hydrogen ions leave the cell by the aid of H+/K+ ATPase pump.
* Chloride ions are transported across the basolateral membrane of the parietal cells into the parietal cells in exchange with bicarbonates

10. Ca++ Ca++ Protein Kinase
ACh
PGE1
Gastrin
Histamine
PGE
receptor _ H2 M3
Adenyl cyclase +
Gastrin receptor + +
Ca++
ATP
cAMP
Ca++ + + +
Protein Kinase
(Activated) K+ + H+
Parietal cell
Proton pump
Lumen of stomach
Gastric acid

11. Ca++ Ca++ Protein Kinase
ACh
PGE1
Gastrin
Histamine _ H2 M3
Adenyl cyclase +
Gastrin receptor
PGE
receptor + +
Ca++
ATP
cAMP
Ca++ + + +
Protein Kinase
(Activated) K+ H+ + K
Parietal cell
Proton pump
Lumen of stomach
Gastric acid

12. I- Agents that reduce gastric acidity
Proton pump inhibitors
H2 receptor antagonists
Muscarine receptor antagonists
Antacids
II- Mucosal protective agents
Sucralfate
Prostaglandin (PGE1) agonists (misoprostol)
Colloidal bismuth compounds
Carbenoxolone

13. I- Agents that reduce gastric acidity
Proton pump inhibitors
H2 receptor antagonists
Muscarine receptor antagonists
Antacids

14. I- Agents that reduce increased gastric acidity 1- Proton pump inhibitors
Proton pump inhibitors are the most potent suppressors of gastric acid secretion
Omeprazole
Esomeprazole
Lansoprazole
Rabeprazole
Pantoprazole
Action: Inhibit both fasting (basal) and meal-stimulated HCl secretion by irreversible inactivation of the proton pump in the wall of parietal cells

15. Proton pump inhibitors Pharmacokinetics:
Proton pump inhibitors are prodrugs that require activation in an acid environment
1- Oral forms are prepared as acid resistant formulations that release the drug in the intestine (because they are degraded in acid media)
2- After absorption, they are distributed by blood to parietal cells
3-They irreversibly inactivate the proton pump molecule (providing 24- to 48-hour suppression of acid secretion, despite the much shorter plasma half-lives of the parent compounds).

16. Proton pump inhibitors Pharmacokinetics
4- they should be given on an empty stomach because food affects absorption
5- They should be given 30 minutes to 1 hour before food intake because an acidic pH in the parietal cell acid canaliculi is required for drug activation, and food stimulates acid production (Concomitant use of other drugs that inhibit acid secretion, such as H2-receptor antagonists, might be predicted to lessen the effectiveness of the proton pump inhibitors )

17. Proton pump inhibitors Pharmacokinetics
6- Maximal effect is reached after 3 to 4 days of administration (the time required to fully inactivate the proton pumps)
7- Their effects persists for 3 to 4 days after stopping the drug (the time required for full recovery of the proton pumps)
8- Metabolized by the liver (dose reduction is necessary in severe liver impairment)
9- Minimal excretion by the kidney ( no dose reduction is necessary in renal impairment)

18. Proton pump inhibitors Adverse effects
Few 1- The most common are GIT troubles in the form of nausea, abdominal pain, constipation, flatulence, and diarrhea 2- Subacute myopathy, arthralgias, headaches, and skin rashes 3- Prolonged use leads to vitamin B12 deficiency (because HCl is important for releasing vitamin B12 from food). 4-Hypergastrinemia which may predispose to rebound hypersecretion of gastric acid upon discontinuation of therapy and may promote the growth of gastrointestinal tumors (carcinoid tumors )

19. Proton pump inhibitors Drug interactions
Metabolized by cytochrome P450 enzymes and may interfere with the metabolism of drugs metabolized with cytochrome P45o such as warfarin, diazepam and cyclosporine increasing their levels and producing toxicity

20. Proton pump inhibitors Therapeutic uses
Gastroesophageal reflux disease (GERD)
Gastric and duodenal ulcers
Prevention of recurrence of nonsteroidal antiinflammatory drug (NSAID)-associated gastric ulcers in patients who continue NSAID use.
Reducing the risk of duodenal ulcer recurrence associated with H. pylori infections.

21. H2 receptor antagonists-
Ranitidine
Famotidine
Nizatidine
Elimination
Small amounts are metabolized by the liver (liver disease is not an indication for adjusting dose)
Drug and metabolites are excreted by the kidney (dose should be reduced in kidney disease)
Mechanism of action
Suppression of HCl by competitive inhibition of H2 receptors in parietal cells.
less potent than proton pump inhibitors
They suppress basal gastric acid secretion more than meal stimulated secretion
Uses
1- Gastroeophageal reflux disease (uncomplicated)
2- Gastric and duodenal ulcers
3- Prevention of occurrence of stress ulcers
Adverse effects
Few
1- GIT: diarrhea and constipation.
2- Headache, dizziness and fatigue and muscle pain
3- Hypergastrinemia
Drug interactions
Agents that decrease gastric acidity alter the rate of absorption and subsequent bioavailability of H2-receptor antagonists

22. Muscarine receptor antagonists
Pirenzepine
Telenzepine
Mechanism of action:
reduce meal stimulated HCl secretion by reversible blockade of muscarinic (M1) receptors on the cell bodies of the intramural cholinergic ganglia ( receptors on parietal cells are M3).
Adverse effects:
They produce anticholinergic side effects at doses that block HCl secretion
Because of poor efficacy, side effects and delay of gastric emptying, they are not used in treating acid peptic disease

23. I- Agents that reduce increased gastric acidity
4- Antacids
Mechanism of action:
1- Reduction of intragastric acidity by reacting with gastric HCl to form salt and water
2- Stimulate mucosal PG production
Types:
NaHCO Sodium bicarbonate
CaCO Calcium carbonate
3- Al hydroxide Al(OH)3
Mg(OH)2 4- Magnesium hydroxide
frt

24. Chemical reactions of antacids with HCl in the stomach

25. Effects of antacids
1- Neutralize excess HCl in the stomach (by the reacted part)
2- Effect of the unreacted part
3- Effects of the products of the reaction
Raising gastric pH from 1.3 to 1.6 neutralizes 50% of gastric acid.
Raising gastric pH point from 1.3 to 2.3 neutralizes 90% of the gastric acid.

26. Effects of antacids 1- Sodium bicarbonate
1- Effect of the reacted part: rapid neutralization of the gastric HCL 2- Unreacted sodium bicarbonate could be absorbed causing metabolic alkalosis if given in high doses or in patients with impaired renal function. 3- NaCl produced by the reaction could be absorbed causing fluid retention and aggrevating hypertension 4- CO2 produced causes gastric distention and increased production of gastrin which causes rebound acidity 5- High doses given with dairy products can lead to hypercalcemia and renal insufficiency (milk-alkali syndrome)

27. Effects of antacids 2- Calcium carbonate
1- Effect of the reacted part: less rapid neutralization of the gastric HCL 2- CO2 produced causes gastric distention and increased production of gastrin which causes rebound acidity 3- High doses given with dairy products can lead to hypercalcemia and renal insufficiency (milk-alkali syndrome)

28. Effects of antacids 3- Aluminum hydroxide
1- Effect of the reacted part: slow neutralization of the gastric HCL 2- No metabolic alkalosis 3- Unabsorbed aluminum salts may cause constipation

29. Effects of antacids 4- Magnesium hydroxide
1- Effect of the reacted part: slow neutralization of the gastric HCL 2- No metabolic alkalosis 3- Unabsorbed magnesium salts may cause osmotic diarrhea 4- Magnesium could be absorbed and excreted by the kidney and therefore should not be given to patients with renal insufficiency for a long tine

30. Sodium bicarbonate
Calcium carbonate
Mg hydroxide
Aluminum hydroxide
Reaction with HCl
Reacts rapidly
Reacts slowly
Products of the reaction
NaCl and CO2 which produces gastric distension and aggrevate hypertension
CaCl2 and CO2 which produces gastric distension
MgCl2 and H2O
AlCl2 and H2O
Effect of unreacted antacids
absorbed causing alkalosis if given in high doses or in patients with renal insufficiency
Unabsorbed causing osmotic diarrhoea
Unabsorbed causing
constipation
Precautions
Affect absorption of other drugs therefore should not be given within 2 hours of tetracycline or iron

31. Mucosal protective agents 1- Sucralfate
Sucralfate = complex aluminum hydroxide + sulfate + sucrose
Mechanism of action:
1- in acidic environment of the stomach, it forms a viscous paste that binds to ulcers or erosions for 6 hours forming a physical barrier against hydrolysis of mucosal proteins by pepsin.
2- stimulates mucosal prostaglandins and bicarbonate production
3- Sucralfate binds bile salts (used to treat individuals with biliary gastritis

32. Mucosal protective agents 1- Sucralfate
Therapeutic uses:
Prophylaxis of stress ulcers in critically ill patients (increased pH of the stomach increases the possibility of nosocomial infections.
Conditions associated with mucosal ulceration not due to acid production as aphthous ulcers and by rectal enema solitary rectal ulcers.

33. Mucosal protective agents 1- Sucralfate
Administration:
Since it is activated by acid, sucralfate should be taken on an empty stomach 1 hour before meals. The use of antacids within 30 minutes of a dose of sucralfate should be avoided.

34. Mucosal protective agents 1- Sucralfate
Adverse Effects:
Constipation
Precautions:
should be avoided in patients with renal failure (because some aluminium is absorbed).
Should be taken at least 2 hours after the administration of other drugs as phenytoin and digoxin (forms a viscous layer in the stomach that may inhibit absorption of drugs)

35. Mechanism of gastric protection
Mucosal protective agents 2- Prostaglandin Analogs: (Misoprostol = Synthetic analog of prostaglandin E1)
Prostaglandins produced by the gastric mucosa
Prostaglandin
Mechanism of gastric protection
PGE1
Inhibit histamine-stimulated gastric acid secretion
Stimulation of mucin and bicarbonate secretion
Increase mucosal blood flow
PGI2 (prostacyclin)

36. Mucosal protective agents 2-Misoprostol
Actions:
Inhibit histamine-stimulated gastric acid secretion
Stimulation of mucin and bicarbonate secretion
Increase mucosal blood flow
Therapeutic uses:
Prevent ion of NSAID-induced mucosal injury (rarely used because it needs frequent administration – 4 times daily)

37. Mucosal protective agents 2-Misoprostol
Adverse Effects:
Diarrhea, with or without abdominal pain and
Exacerbations of inflammatory bowel disease and should be avoided in patients with this disorder.
Contraindications:
Inflammatory bowel disease
Pregnancy (may cause abortion)

38. Mucosal protective agents 3- Colloidal bismuth compounds (Bismuth subsalicylate)
Pharmacological actions: 1- Undergoes rapid dissolution in the stomach into bismuth and salicylates. 2- Salicylates are absorbed 3- Bismuth coats ulcers and erosions protecting them from acid and pepsin and increases prostaglandin and bicarbonate production Uses: -Treatment of dyspepsia and acute diarrhoea

39. Specific acid dyspeptic disorders and therapeutic strategies
Gastro-esophageal reflux disease
1- Mild: H2 receptor antagonists (twice daily)
2- Sevre: Proton pump inhibitors once daily (for 8 weeks)
3- Antacids are recommended only for the patient with mild, infrequent episodes of heartburn.
4- Severe with nocturnal acid breakthrough: proton pump inhibitors twice daily. If symptome persist, H2 receptor antagonist is added at night
Helicobacter pylori infection (H. pylori)
Triple therapy for 14 days:
[Proton pump inhibitor + clarithromycin 500 mg + (metronidazole 500 mg or amoxicillin 1 g)] twice a day.
NSAID-related Ulcers
1- Proton pump inhibitors (best)
2- H2 receptor antagonist
3- Misoprostil
Peptic ulcer
Proton pump inhibitors