Presentation on theme: "TREATMENT OF PEPTIC ULCERS & CONTROL OF GASTRIC ACIDITY"— Presentation transcript:
1TREATMENT OF PEPTIC ULCERS & CONTROL OF GASTRIC ACIDITY Prof. Riad Agbaria
2Microscopic Anatomy of the Stomach Four secretory epithelial cells:1- Mucous cells: secrete an alkaline mucus that protects the epithelium against shear stress and acid 2- Parietal cells: secrete hydrochloric acid! 3- Chief cells: secrete pepsin, a proteolytic enzyme 4- G cells: secrete the hormone gastrin5-Entrochromaffin-Like Cells (ECL)- HISTAMINE
3Physiological and pharmacological regulation of gastric secretions: the basis for therapy of peptic ulcer disease.
4Physiological stimulants of gastric acid secretion:
5Physiological stimulants of gastric acid secretion: Major physiologic stimulus: food intake -- three phases:cephalic phasegastric acid secretion responds to anticipation of food, sight, smell, tastegastric phasestimulation of mechanical and chemical gastric wall receptors by luminal contents.intestinal phasegastrin release (small amount); release of other peptides that stimulate gastric acid secretion
6Food constituents:Coffee (both caffeine containing and caffeine free) stimulates gastric acid secretion by stimulating gastric releaseBeer and wine: stimulation of gastric acid secretion
7Physiologic inhibition- gastric acid release: Factors that inhibit gastric acid secretion include:hyperglycemiahypertonic fluidsduodenal fatduodenal acidintragastric pH = 3; partial inhibitionintragastric pH < or = 1.5; complete blockade of gastrin release
10Pathogenic Factors: Peptic ulcer disease Peptic ulcer disease: an imbalance between aggressive factors (gastric acid and pepsin) and protective factors (gastric mucus, bicarbonate, prostaglandins)
11Role of pepsin in peptic ulcer disease: Secreted gastric acid plus effects of pepsin promote tissue injuryGastric acid promotes cleavage of pepsinogen (inactive) to proteolytically-active pepsinsPepsinogen classification:Direct correlation between pepsinogen I serum concentrations and maximal gastric acid secretion
13Pharmacological Management of Ulcer Disease OverviewPeptic ulcer: stomach or duodenal mucosal lesion -- acid and pepsin: major pathogenic rolesClassification of peptic ulcer:Duodenal (DU)Gastric (GU)Major causative factor: bacterium Helicobacter pylori Helicobacter pylori: risk factor for:gastric cancercertain types of gastric lymphoma
14Gastric Physiology Gastric mucosa: acid secretion Oxidative phosphorylation dependent secretion by parietal cells.Parietal cells: found in mucosal glandsof the body and fundus of the stomach.
15Regulation of gastric acid secretion Many factors: chemical, neural, hormonalstimulation:Gastrin-most potent stimulant Activation of postganglionic vagal fibers (muscarinic cholinergic parietal cells receptor activation)
161: Proton Pump Inhibitors: The most effective suppressors of gastric acid secretion
17Physiological and pharmacological regulation of gastric secretions: the basis for therapy of peptic ulcer disease.
18Proton PumpParietal cells H+ ion secretion depends on a H+,K+-ATPase pump-- promoting H K exchangeH+,K+-ATPase located in apical membraneto and tubulovesicular apparatus of parietal cellsLuminal surface of the membrane enzyme: exposed to gastric luminal acid
19Proton Pump Inhibitors: Omeprazole (Prilosec), 20mgLansoprazole (Prevacid), 30mgRapeprazole 20mgAll given daily before breakfast
20Proton Pump Inhibitors: Mechanism of Action Omeprazole (Prilosec) and lansoprazole (Prevacid) inhibit the proton pump, effectively irreversibly -- requiring synthesis of new enzyme proteinOmeprazole and lansoprazole approved for treatment of:Duodenal ulcer may be used in conjunction with triple therapyErosive esophagitisGastric acid hypersecretory states, including Zollinger-Ellison syndrome (Gastrinomas that cause secretion of large amounts of acids)
21Proton Pump Inhibitors: Side effects Long acting (irreversible)Hypergastrinemia: because no acids, Bacteria may enter to the bodyIn rats: omeprazole cause tumors in GI.
22Inhibitory effect of omeprazole on secretion of gastric acid.
27H2 receptor antagonists Cimetidine (Tagamet)Ranitidine (Zantac)Famotidine (Pepcid)Nizatidine (Axid)Inhibit:basal acid secretionsecretion in response to feeding, gastrin, histamine, hypoglycemia, or vagal stimulation
28H2 Receptor Antagonists Effective inhibitor of stimulated and NON-stimulated gastric acid secretionCimetidine (Tagamet) -- reduces acid secretion responses to: histamine, caffeine, hypoglycemia, gastrinHealing rates: similar between antacids and H2 receptor antagonists (compliance better with receptor blockers)
29H2 Antagonist: Cimetidine (Tagamet) Side effects;interaction with cytochrome P450 drug metabolizing systemtender gynecomastia: the two-week antiandrogenic effects (seen typically in Zollinger-Ellison disease patients following prolonged space or treatment with large doses. Due to pinding to androgen receptors and inhibition of P450 which catalyze hydroxylation of estradiol.Reduction of sperm count is reversible
30H2 Antagonist: Ranitidine (Zantac) Ranitidine (Zantac)-- six times as potent as cimetadine in inhibiting gastric acid secretionNO antiandrogenic propertiesSide effect:Smaller inhibitory effect on cytochrome P450 system than cimetidine (Tagamet)
31H2 Antagonist: Famotidine (Pepcid) Famotidine (Pepcid) and nizatidine (Axid): potent H2 receptor blockersSide effects: rare blood dyscrasias and rare hepatotoxicity (similarto that seen with cimetadine and ranitidine)
32Side effects antiandrogenic blood dyscrasias blood dyscrasias (Tagament)(Zantac)(Pepcid)(Axid)Side effectsantiandrogenicSAMALLINHIBITIONOF p450blood dyscrasiasblood dyscrasiasReduction of spermInhibition of P450
33Effect of cimetidine on betazole-stimulated secretion of acid (upper panel) and of pepsin (lower panel) in human beings.
34H2 antagonist therapeutic use Promoting healing if Gastric & Duodenal UlcerProphylaxis of stress ulcersGastroesophagal reflux Disease (GERD)
37Physiological and pharmacological regulation of gastric secretions: the basis for therapy of peptic ulcer disease.
38Muscarinic cholinergic antagonists can reduce basal secretion of gastric acid by 40% to 50%; stimulated secretion is inhibited to a lesser extent.
39Anticholinergic drugs: Atropine: not as effective as H2 receptor blockersSide effects:dryness of mouthblurred visionurinary retentioncardiac arrhythmias
40Pirenzepine& telenzepine pirenzepine is equivalent to cimetidine in preventing the recurrence of ulcers.Both are hydrophilic and poorly penetrate the blood-brain barrier.Dose:Pirenzepine, oral, 50 mg 2-3Xdaily.Telenzepine, oral, 3 mg/day.
41Pirenzepine & telenzepine: Side effects dry mouthblurred visionConstipation,may limit the utility of these drugs.
43What is Helicobacter pylori? H. pylori IS a bacterium causes chronic inflammation (gastritis) of the inner lining of the stomach in humans.the most common cause of ulcers worldwide.H. pylori infection is most likely acquired by ingesting contaminated food and water and through person to person contact.In the United States, 30% of the adult population is infected. (50% of infected persons are infected by the age of 60.)The infection is more common in crowded living conditions with poor sanitation.In countries with poor sanitation, 90% of the adult population can be infected.Infected individuals usually carry the infection indefinitely unless they are treated with medications to eradicate the bacterium.One out of every six patients with H. pylori infection will develop ulcers of the duodenum or stomach.H. pylori also is associated with stomach cancer and a rare type of lymphocytic tumor of the stomach called MALT lymphoma.
44Helicobacter pylori:Helicobacter pylori: a principal role in peptic ulcer pathogenesisH. pylori:causes active, chronic gastritisBacterial protein products appear damagingProteases and phospholipases produced by H. pylori degrade glycoprotein-lipid mucus layer complex
45Management of H. pylori infection Management of H. pylori infection: clinical consequences15% relapse rate for duodenal ulcer following H. pylori eradication75% relapse rate for duodenal ulcer following treatment with H2 receptor blockers only
46Drug Treatment for H. pylori Patients with documented duodenal ulcers (upper GI contrast radiography or endoscopy) -- treat for H. pylori Drugs include:bismuth compoundsamoxicillintetracycline (Achromycin)clarithromycin (Biaxin)metronidazole (Flagyl)omeprazole (Prilosec), lansoprazole (Prevacid)H2 antagonists
47Bismuth compounds: Mechanism of Action cytoprotective effectscompounds bind to the ulcer base, stimulating mucus and prostaglandin productionantibacterial effect: inhibition of proteolytic, lipolytic, and urease activities In monotherapy: bismuth compounds eradicate H. pylori in about 20% of patientsBismuth compounds in combination with antibiotics eradicate H. pylori in up to 95% of patients.
48Most successful protocol: triple therapy bismuth compounds metronidazole (Flagyl)amoxicillin or tetracycline (Achromycin)Triple therapy (two weeks) plus H2 blocker therapy (six weeks) is also a recommended protocolFurther increase in the rate of H. pylori eradication may be accomplished by the addition of omeprazole (Prilosec) to the regimen.
55Coating Agents: Sucralfate (Carafate) Sucralfate (Carafate)-complex polyaluminum hydroxide salt of sucrose sulfatehighly polar antacid pH: binds to ulcer bed (granulation tissue, not to gastric or duodenal mucosa)decreases proton diffusion to the ulcer basemay increase endogenous tissue prostaglandins and may bind epidermal growth factors and other growth factors-- improving mucosal defense
56Coating Agents: Colloidal bismuth Colloidal bismuth: -- bismuth-protein coagulantmay protect also from pepsin and acid digestionmay inhibit pepsin activityprevents proton diffusion into the ulcerStimulates gastric mucosal secretion of protective agents:Colloidal bismuth only class of antiulcer drugs that can eradicate H. pylori and cure associated gastritis
58Physiological and pharmacological regulation of gastric secretions: the basis for therapy of peptic ulcer disease.
59Prostaglandins: Mechanism of action reduction in basal and stimulated gastric acid secretion; enhanced mucosa resistance to injury (PGE1/PGE2).
60Misoprostol (CYTOTEC), misoprostol is moderately effective in treating duodenal and gastric ulcers.inhibits gastric acid secretion and is higher than the dose needed to produce cytoprotective effects (enhanced secretion of mucus and HCO3-).Dose: 200 mg, four times daily with food
61Misoprostol: therapeutic use Although prostaglandin analogs remain second-line agents in the treatment of peptic ulcer, they are valuable as cytoprotective agents in patients who require NSAIDS agents.Misoprostol is used for the prevention of gastric ulcer disease induced by NSAIDS in patients who must take aspirin-like drugs for the treatment of arthritis or other diseases and who are at high risk for complicated gastric ulcer disease.
62Misoprostol: Side Effects Diarrhea in up to 30% of patients at therapeutic doses, a side effect that may limit its use somewhat.Some abdominal cramping also may occur.These compounds are potential abortifacients and should NOT be used in women who are pregnant or in whom conception is a possibility.