Introduction Peptic /stomach ulcer is the condition in which imbalance of aggressive factor and defensive factors. From ancient time stomach ulcer has been recognized and also therapy established according to their knowledge. A Roman emperor Marcus Aurelius, whose death has been attributed by some to a perforated ulcer. More than 12 centuries ago, Paulus Aeginata who recognized that acid – neutralization was the effective treatment. Later in starting of 19 century the lot of research has been developed for the treatment of ulcer.
Continue…. After period of time it has been identified that bacteria can causes the ulcer. Mainly Helicobacter pylori found to be recurrence of stomach ulcer. The main goal of anti-ulcer drug is that to decreasing the level of gastric acidity or enhancing mucosal protection. For infectious agent new approaches was found in order to prevention of infection or removal of micro organism.
PHYSIOLOGY OF GASTRIC ACID SECERTION Gastric acid secretion is a complex, continuous process in which multiple central and peripheral factors contribute to a common endpoint: the secretion of H+ by parietal cells. Neuronal (acetylcholine, ACh), paracrine (histamine), and endocrine (gastrin) factors all regulate acid secretion . Their specific receptors (M3, H2, and CCK2 receptors, respectively) are on the basolateral membrane of parietal cells in the body and fundus of the stomach.
The H2 receptor is a GPCR that activates the Gs- adenylylcyclase-cyclic AMP-PKA pathway. ACh and gastrin signal through GPCRs that couple to the Gq-PLC-IP3-Ca2+ pathway in parietal cells. In parietal cells, the cyclic AMP and the Ca 2+-dependent pathways activate H+,K+-ATPase (the proton pump), which exchanges hydrogen and potassium ions across the parietal cell membrane.
What is Peptic Ulcer? Peptic /stomach ulcer is the condition in which imbalance of aggressive factor and defensive factors. Aggressive factor : Gastric acid, gastrin, pepsin Defensive factor : Prostaglandin, mucosa, bicarbonate
•Abdominal pain,classically epigastricwith severity relatingto mealtimes, afteraround 3 hours oftaking a meal.•Loss of appetite andweight loss.•Waterbrash (rush ofsaliva after an episodeof regurgitation todilute the acid inesophagus);•Nausea, and copiousvomiting
Complications Gastrointestinal bleeding is the most common complication. Sudden large bleeding can be life- threatening. It occurs when the ulcer erodes one of the blood vessels. Perforation (a hole in the wall) often leads to catastrophic consequences. Erosion of the gastro- intestinal wall by the ulcer leads to spillage of stomach or intestinal content into the abdominal cavity. Perforation at the anterior surface of the stomach leads to acute peritonitis, initially chemical and later bacterial peritonitis. The first sign is often sudden intense abdominal pain. Posterior wall perforation leads to pancreatitis; pain in this situation often radiates to the back. Penetration is when the ulcer continues into adjacent organs such as the liver and pancreas. Scarring and swelling due to ulcers causes narrowing in the duodenum and gastric outlet obstruction. Patient often presents with severe vomiting.
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.
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).
PharmacokineticsAbsorbed rapidly and completely except for famotidine; food and antiacids may reduce absorption; distributed widely throughout the body; metabolized by the liver; excreted primarily in the urine.
Cimetidine RanitidineBioavailability 80 50Relative Potency 1 5 -10Half life (hrs) 1.5 - 2.3 1.6 - 2.4Duration of 6 8action (hrs)Inhibition of 1 0.1CYP 450Dose mg(bd) 400 150
Therapeutic UsesUsed 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, Interaction, Contraindication Adverse effect Headache Dizziness Bowel upset Cimetidine causes gynecomastia, galactorrhea(as it is antiandrogenic & increases prolactin level) Interaction Inhibits CYP-450 leads to inhibits the metabolism of many drugs so that they accumulate to toxic level. e.g. theophylline,warfarin, phenytoin, quinidine Contraindication Renal impairment Hepatic failure
Proton Pump Inhibitors (PPIs) 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 EsomaprazoleMECHANISM 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.
Continued MOA…. 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.
o PharmacokineticBioavailability : ~50% (instability at acidic pH)Metabolism : In Liver (CYP2C19 and CYP3A4).Excretion : Metabolites excreted through renallyOnset action : ½-1 hourDuration of action : 24 hours Adverse effect Hepatic dysfunction Dizziness Nausea Headache Interaction Inhibits oxidation of certain drugs : diazepam, phenytoin, warfarin
AntacidThese 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.
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 - SucralfateSucralfate 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 cytoprotectiveeffects, including stimulation of local production of prostaglandins and epidermal growth factor.
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 drugs H pylori: Spiral-shaped,pH-sensitive, gram –ve bacteria.It attaches to the surface epithelium beneth the mucus.Has high urease activityProduces 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). CBS is active against H.pylori and resistance does not develop to it.
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