1. Drugs for Peptic Ulcer Course: Pharmacology I Course Code: PHR 213
Course Instructor: Sarah zaheen
Lecturer
Department of Pharmacy
BRAC University

2. What is Peptic Ulcer?
 Peptic /stomach ulcer is the condition which results due to imbalance of aggressive factor and defensive factors.
 Aggressive factor : Gastric acid, gastrin, pepsin, H. pylori.
 Defensive factor : Prostaglandin, mucosa, bicarbonate secretions, nitric oxide.

4. REGULATION OF GASTRIC ACID SECRETION
Fig: Secretion of HCl by gastric parietal cell and its regulation.
C.Ase-Carbonic anhydrase; Hist.-Histamine; Ach- Acetlycholine; G-Gastrin/cholecystokinin (CCK2) receptor; M-Muscarinic receptor; N-Nicotinic receptor; H2- Histamine H2 receptor; EP3- Prostaglandin receptor; +-Stimulation; - Inhibition. Probable, but unconfirmed actions are shown by broken lines.

5. Classification Of Antiulcer Agent
Reduction of gastric acid secretion
 H2 antihistamines: Cimetidine, ranitidine, famotidine, roxaatidine, loxatidine
 PPI’s : Omeprazole, lansoprazole, pantoprazole, rabeprazole, esomeprazole
 Anticholinergics: Pirenzepine, propantheline, oxyphenonium
 Prostaglandine analogues:- Misoprostol, enprostil, rioprostil
2) Neutralization of gastric acid (Antacids)
 Systemic : Sodium bicarbonate, sod.citrate
 Nonsystemic (Local) : Mg hydroxide, Mg trisilicate, Al hydroxide gel, calcium carbonate
3) Ulcer protectives: Sucralfate, CBS ( Colloidal Bismuth Subcitrate)
4) Ulcer healing drugs: Carbenoxolone sodium
5) Anti-H. pyloric drugs: Amoxicillin, clarithromycin, metronidazole, tinidazole, tetracycline

6. Fig: Effects of acetylcholine, histamine, prostaglandin E2, and gastrin on gastric acid secretion by the parietal cells of stomach. Gs and Gi are membrane proteins that mediate the stimulatory or inhibitory effect of receptor coupling to adenylyl cyclase

7. Histamine: H2 Receptor Antagonist
 Histamine receptor on parietal cells
Autonomic system:
food stimulates gastrin release, gastrin stimulates histamine release, histamine stimulates parietal cells secretion of HCl.
MECHANISM OF ACTION
 The H2 receptor antagonists inhibit acid production by reversibly competing with histamine for binding to H2 receptors on the basolateral membrane of parietal cells.
 Block histamine from stimulating the acid-secreting parietal cells of the stomach.
 H2 antagonist mainly basal, psychic, neurogenic, gastric secretion is suppressed and other stimuli Ach, gastrin, alcohol, food also inhibited.
Act selectively on H2 receptors in stomach, blood vessels, and other sites, but they have no effect on H1-receptor.
They completely inhibit gastric acid secretion induced by histamine or gastrin. However, they only partially inhibit gastric acid secretion induced by acetylcholine.

8. Histamine: H2 Receptor Antagonist
 Reversible competitive inhibitors of H2 receptor.
 Highly selective for H2 receptors.
 Very effective in inhibiting nocturnal acid secretion ( as it depends largely on Histamine ).
 Modest impact on meal stimulated acid secretion (As it depends on gastrin, acetylcholine and histamine).
Pharmacokinetics
Absorbed rapidly and completely except for famotidine;
food and antacids may reduce absorption;
distributed widely throughout the body;
metabolized by the liver;
excreted primarily in the urine.

9. Topics
Cimetidine
Ranitidine
Bioavailability 80 50
Relative Potency 1
5-10
Half life (Hrs)
Duration of Action (Hrs) 6 8
Dose (BD) mg
400
150

10. Therapeutic Use and Adverse Effects
Therapeutic Uses
Used therapeutically to:
Promote healing of duodenal and gastric ulcers.
Provide long-term treatment of pathological GI hypersecretory conditions.
Reduce gastric acid production and prevent stress ulcers
Low dose of H2-antagonist appear to be effective for prevention and treatment of GERD (Gastroesophageal reflux disorder).
Adverse effect
 Headache
 Dizziness
 Bowel upset
 Cimetidine causes gynecomastia, galactorrhea(as it is antiandrogenic & increases prolactin level)

11. Proton Pump Inhibitors (PPI)
 Disrupt chemical binding in stomach cells to reduce acid production, lessening irritation and allowing peptic ulcers to heal.
 These drugs include:
 Omeprazole
 Rabeprazole
 Pantoprazole
 Iansoprazole
 Esomaprazole
MECHANISM OF ACTION OF PPIs.
Block the last step in the secretion of gastric acid by combining with hydrogen, potassium, and adenosine triphosphate in the parietal cells of the stomach.

12. Mechanism of Action (PPI)
 Most effective drugs in antiulcer therapy.
 Irreversible inhibitor of H+ K+ ATPase to apical membrane of the parietal cell.
 Prodrugs requiring activation in acid environment.
 Inactivate at neutral pH, at pH<5 rearranges to 2 charged cationic form- sulphenic acid & sulphenamide.
 React covalently with cysteine residue of the H+ K+ ATPase enzyme.
 Weakly basic drugs & so accumulate in canaliculi of parietal cell.
 Activated in canaliculi & binds covalently to extracellular domain of H+ K+ ATPase.
 Acid secretion resumes only after synthesis of new molecules. It takes approx 18hrs for the enzymes to be resynthesized.

13. PPI Pharmacokinetic  Adverse effect
Bioavailability : ~50% (instability at acidic pH)
Metabolism : In Liver (CYP2C19 and CYP3A4).
Excretion : Metabolites excreted through urine and faeces
Onset action : ½-1 hour
Duration of action : 24 hours
 Adverse effect
 Hepatic dysfunction Dizziness Nausea Headache
 Interaction
 Inhibits oxidation of certain drugs : diazepam, phenytoin, warfarin

14. Antacid
Antacids are weak bases that react with gastric acid to form water and a salt, thereby diminishing gastric acidity. Because pepsin is inactive at a pH greater than 4, antacids also reduce peptic activity. They may have other actions as well, such as reduction of H.pylori colonization and stimulation of prostaglandin synthesis.
The potency of antacid is generally expressed as ANC (acid neutralizing capacity)
Systemic antacid :
 Sodium bicarbonate, sodium citrate: water soluble, acts instantaneously, but duration of action is short.
 Potent neutralizer, pH may rises above 7.
 Produces CO2 in stomach leads to distention, discomfort, belching, risk of ulcer perforation.
 Increases sodium load leads to worsen CHF & edema; contraindicated in hypertension & cardiac disease
 Large dose produces alkalosis.

15. Antacid Non-systemic antacid:
These are insoluble and poorly absorbed basic compound.
React in stomach with acid to form respective chloride salts.
This again reacts with bicarbonate is not spared for absorption, hence no acid –base disturbance.
Aluminium hydroxide gel
The Al+³ ions relaxes smooth muscle leads to delay in gastric emptying.
Mucosal astringent reaction also leads to constipation.
Acts as a demulcent; claim to coat and protect the ulcer crater.
It binds with the phosphate in the intestine and prevents its absorption-hypophosphatemia occurs on regular use. This may a) cause osteomalacia
b) Be used therapeutically in hyperphosphatemia and phosphate stones.
Small amount of Al3+ that is absorbed is excreted by kidney which is not possible in renal failure-Aluminium toxicity (encephalopathy, osteoporosis) can occur.
Antacid combination

16. Ulcer Protectives Sucralfate
Sucralfate consists of the octasulfate of sucrose to which Al(OH)3 has been added.
 In an acid environment(pH <4), sucralfate undergoes extensive cross-linking to produce a viscous, sticky polymer that adheres to epithelial cells and ulcer craters for up to 6 hours after a single dose.
In addition to inhibiting hydrolysis of mucosal proteins by pepsin, sucralfate may have additional cytoprotective effects, including stimulation of local production of prostaglandins and epidermal growth factor.

17. Ulcer Protectives
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.
The usual dose of sucralfate is 1 g four times daily (for active duodenal ulcer) or 1 g twice daily (for maintenance therapy).
Colloidal Bismuth
Effectively heal peptic ulcers.
In addition to their antimicrobial actions,
they inhibit the activity of pepsin,
increase secretion of mucus,
interact with glycoproteins in necrotic mucosal tissue to coat and protect the ulcer crater.

18. Anti-H. pylori Agents
 H pylori: Spiral-shaped, pH-sensitive, gram –ve bacteria.
It attaches to the surface epithelium beneath the mucus.
Has high urease activity- produces ammonia which maintains a neutral microenvironment around the bacteria and promotes back diffusion of H+ ions
Antimicrobials found clinically effective against H.pylori : Amoxicillin, tetracycline, clarithromycin, metronidazole.
Single drugs rapidly develops resistance (metronidazole).

19. Anti-H. pylori Agents Diagnosis: Endoscopic biopsy (invasive)
Serologic tests (non-invasive)
Breath test for urea (non-invasive)
Treatment:
Eradication of H.pylori results in rapid healing of active peptic ulcers and low recurrence rates (less than 15% compared with % per year for patients with initial ulcer healed by traditional antisecretory therapy)
Successful eradication (80%-90%) of H.pylori is possible with combination therapy
Triple therapy
PPI + Metronidazole/amoxicillin + clarithromycin
Quadruple therapy
Bismuth subsalicylate + metronidazole + Tetracycline + H-2 antagonist (cimetidine,ranitidine,famotidine,nizatidine).
GERD is not associated with H.pylori infection and doesn’t respond to treatment with antibiotics.