COURSE: PHARMACOLOGY I COURSE CODE: PHR 213 COURSE INSTRUCTOR: MD. SAMIUL ALAM RAJIB SENIOR LECTURER DEPARTMENT OF PHARMACY BRAC UNIVERSITY Drugs for Peptic Ulcer

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.

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. REGULATION OF GASTRIC ACID SECRETION

Classification Of Antiulcer Agent 1)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

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

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.

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.

TopicsCimetidineRanitidine Bioavailability8050 Relative Potency15-10 Half life (Hrs) Duration of Action (Hrs) 68 Dose (BD) mg400150

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. Adverse effect Headache Dizziness Bowel upset Cimetidine causes gynecomastia, galactorrhea(as it is antiandrogenic & increases prolactin level)

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 Lansoprazole 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.

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 –SH groups 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.

PPI Pharmacokinetic Bioavailability : ~50% (instability at acidic pH) Metabolism : In Liver (CYP2C19 and CYP3A4). Excretion : Metabolites excreted through renally 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

Antacid These are the basic substances which neutralize gastric acidity. Acid neutralizing capacity: no.of mEq of 1N HCl that brought to pH 3.5 in 15 min. by a unit dose of the antacid preparation. Systemic antacid :  Sodium bicarbonate, water soluble, acts i.v. duration of action is short.  Potent neutralizer, pH may rises above 7.  Produces CO2 in stomach leads to distention, discomfort.  Increases sodium load leads to worsen in CHF with edema.  Large dose produces alkalosis.

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.  This causes constipation.  Mucosal astringent reaction also leads to constipation.

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.

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).

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.  Promotes back diffusion of H+  Antimicrobials found clinically effective against H.pylori : Amoxicillin, clarithromycin, metronidazole.  Single drugs rapidly develops resistance (metronidazole).