5. Anti-Peptic Ulcer Agents_ZS 06.04.21.pdf

Anti-Peptic Ulcer Agent ZULFAHMI SAID, (Ph.D) Faculty of Dentistry USIM 6th April 2021  Learning objectives: ❑ Identify the underlying causes of peptic ulcer. ❑Identify different groups of drugs used in peptic ulcer disease. ❑ Describe the mechanism o...

Anti-Peptic Ulcer Agent ZULFAHMI SAID, (Ph.D) Faculty of Dentistry USIM 6th April 2021  Learning objectives: ❑ Identify the underlying causes of peptic ulcer. ❑Identify different groups of drugs used in peptic ulcer disease. ❑ Describe the mechanism of action, clinical uses, and adverse effects of drugs used in peptic ulcer treatment.  Peptic Ulcer ❑ Peptic ulcer is erosion in the lining of the stomach or the first part of the small intestine (duodenum). ❑ Ulcers damage the mucosa of the alimentary tract which extends through the muscularis mucosa into the submucosa or deeper. ❑ There are two types of peptic ulcers: - Gastric ulcer: which forms in the lining of the stomach - Duodenal ulcer: which forms in the upper part of the small intestine.  Peptic Ulcer ❑ Peptic ulcer is the condition in which imbalance of aggressive factor and defensive factors. ❑ Aggressive factor: H. pylori, gastric acid, gastrin, NSAID. ❑ Defensive factor: prostaglandin, mucous, bicarbonate. Peptic Ulcer  Peptic Ulcer Causes: ❑Destruction of the gastric or intestinal mucosal lining of the stomach by hydrochloric acid (digestive juices of the stomach). ❑Infection with a bacterium called Helicobacter pylori. ❑Long-term use of Non-Steroidal Anti- Inflammatory Drugs (NSAIDs), such as ibuprofen, naproxen and aspirin. Causes of Peptic Ulcer Hydrochloric Acid (HCL) Production Mechanism of action of Gastrin and Mechanism of action of histamine: Acetylcholine: Physiology of Gastric Acid Secretion H. pylori Structures Helicobacter pylori Infection NSAID induces gastric ulcer NSAID induces gastric ulcer  Anti-Peptic Ulcer Agent Treatment approaches include: ❑ Eradicating the H. pylori infection. ❑Reducing secretion of gastric acid. ❑Providing agents that protect the gastric mucosa from damage.  Anti-Peptic Ulcer Agent Classification: ❑ Reduction of gastric acid secretion. - H2 antagonists - Cimetidine - Proton Pump Inhibitors (PPI) - Omeprazole - Anticholinergics - Dicyclomine - Prostaglandin analogues - Misoprostol ❑ Neutralization of gastric (Antacids) - Systemic – Sodium bicarbonate - Non-systemic (Local) – Magnesium hydroxide, aluminum hydroxide. ❑ Ulcer protective drugs - misoprostol and sucralfate ❑ Antimicrobial drugs - Amoxicillin, metronidazole, tetracycline  Antimicrobial Agents ❑ Eradication of H. pylori → results in rapid healing of peptic ulcers and low recurrence rates. ❑ Eradication of H. pylori with various combinations of antimicrobial drugs. e.g : (1) PPI + metronidazole/amoxicillin + clarithromycin (triple therapy). (2) PPI + bismuth subsalicylate + metronidazole + tetracycline (quadruple therapy). ❑ Administered for a 2-week course. ❑ Treatment with a single antimicrobial drug – is less effective & results in antimicrobial resistance.  H2 Antagonists ❑ Cimetidine – is the prototype histamine H2-receptor antagonist; however, its utility is limited by adverse effect profile and drug interactions. Mechanism of action: ❑ Antagonists of histamine H2 receptor – is clinical use to inhibit gastric acid secretion (particularly effective against nocturnal acid secretion). ❑ Competitively blocking the binding of histamine to H2 receptors in the stomach (but they have no effect on H1 receptors) → reduce the intracellular concentrations of cyclic adenosine monophosphate (cAMP) → thereby reduce secretion of gastric acid.  H2 Antagonists Therapeutic uses: (a) Peptic ulcers ❑ All agents – effective in promoting healing of duodenal and gastric ulcers. But recurrence is common after treatment is stopped. ❑ Patients with NSAID-induced ulcers should be treated with PPIs – these agents heal and prevent future ulcers better than H2 antagonists. (b) Acute stress ulcers ❑ Drugs are useful in managing acute stress ulcers associated with physical trauma in high-risk patients in ICU.  H2 Antagonists Therapeutic uses: (c) Gastroesophageal reflux disease (GERD) ❑ Low doses of H2 antagonists – effective for prevention and treatment of heartburn in only about 50% of patients. ❑ Antacids more quickly and efficiently – neutralize secreted acid already in the stomach but their action is only temporary.  H2 Antagonists Pharmacokinetics: (a) Cimetidine ❑ It is given orally. ❑ Distribute widely throughout the body (including into breast milk and across the placenta). ❑ Slowly inactivated in the liver (30%). ❑ Excreted – in the urine (70% unchanged). ❑ Short serum half-life & is increased in renal failure. ❑ Dosage must be decreased in patients with hepatic or renal failure. ❑ Cimetidine inhibits cytochrome P450 and can slow metabolism of several drugs – warfarin, diazepam, phenytoin and theophylline.  H2 Antagonists Adverse effects ❑ Most common side effects – headache, dizziness, diarrhea, and muscular pain. ❑ Central nervous system effects (confusion, hallucinations) – in elderly patients or after IV administration. ❑ Cimetidine have endocrine effects, because it acts as a nonsteroidal antiandrogen; including gynecomastia, galactorrhea (continuous release/discharge of milk) & reduced sperm count. ❑ Ketoconazole which depend on an acidic medium for gastric absorption – may not be efficiently absorbed if taken with these antagonists.  H2 Antagonists (b) Ranitidine Ranitidine is longer acting and is 5 – 10 fold more potent (compared to cimetidine). Has minimal side effects & does not produce the antiandrogenic or prolactin-stimulating effects of cimetidine. It does not inhibit the mixed-function oxygenase system in the liver → thus, does not affect the concentrations of other drugs. (c) Famotidine Is similar to ranitidine in its pharmacologic action, but 3 to 20 times more potent than ranitidine.  H2 Antagonists (d) Nizatidine Is similar to ranitidine in its pharmacologic action and potency. In contrast to cimetidine, ranitidine, and famotidine (metabolized by the liver) – nizatidine is eliminated principally by kidney. Little first-pass metabolism occurs → its bioavailability is nearly 100 percent.  Proton Pump Inhibitors (PPI) ❑ Omeprazole – is the first drugs that bind to the H+/K+- ATPase enzyme system (proton pump) of the parietal cell. ❑ They suppress secretion of hydrogen ions into the gastric lumen. ❑ The membrane-bound proton pump is the final step in the secretion of gastric acid. ❑ Additional PPIs are now available: dexlansoprazole, esomeprazole, Iansoprazole, pantoprazole and rabeprazole. ❑ Omeprazole and Iansoprazole are for short-term treatment of GERD.  Proton Pump Inhibitors (PPI) Actions: ❑ These agents are prodrugs with an acid-resistant enteric coating (protection against premature degradation by gastric acid). ❑ Coating is removed in the alkaline duodenum, and the prodrug is absorbed and transported to the parietal cell canaliculus. ❑ It is converted to the active form & reacts with a cysteine residue of the H+/K+-ATPase → forming stable covalent bond. ❑ PPIs inhibit basal and stimulated gastric acid secretion by more than 90%.  Proton Pump Inhibitors (PPI) Therapeutic uses: ❑ The PPI – superior over the H2 antagonists for suppressing acid production and healing peptic ulcers. ❑ Preferred drugs for stress ulcer treatment and prophylaxis, treating erosive esophagitis and active duodenal ulcer and for long-term treatment of pathologic hypersecretory condition (e.g. Zollinger- Ellison syndrome). ❑ Approved for treatment of GERD. ❑ PPIs reduce the risk of bleeding from an ulcer (caused by NSAIDs). ❑ Successfully used with the antimicrobial regimens to eradicate H.pylori.  Proton Pump Inhibitors (PPI) Therapeutic uses: ❑ Maximum effect: PPIs should be taken 30 minutes before breakfast or the largest meal of the day. ❑ If an H2-receptor antagonist is needed – it should be taken after the PPI. ❑ In patients with GERD – once-daily PPI is partially effective → increase dose to a twice-daily or keeping the PPI in the morning and H2 antagonist in the evening (may improve symptom control). Pharmacokinetics ❑ All agents are effective orally ❑ Available for IV injection. ❑ Metabolites – excreted in urine and feces  Proton Pump Inhibitors (PPI) Adverse effects: ❑ Increased risk of fractures of the hip, wrist and spine – one year or more (long-term use). ❑ Omeprazole inhibits the metabolism of warfarin, phenytoin, diazepam, and cyclosporine through competitive inhibition of CYP450 enzymes. ❑ Prolonged therapy with PPIs and H2 antagonists→ suppress gastric acid → result in low vitamin B12, because acid is required for its absorption. Another problem: incomplete absorption of calcium carbonate products (require acidic condition to be absorbed). ❑ Reports of diarrhea and Clostridium difficile colitis in receiving PPIs → discontinue PPI therapy  Prostaglandin analogues ❑ Prostaglandin E2 – inhibits secretion of HCl and stimulates secretion of mucus and bicarbonate (cytoprotective effect). ❑ Deficiency of prostaglandins – pathogenesis of peptic ulcers. ❑ Misoprostol – a stable analog of prostaglandin E1 : approved for prevention of gastric ulcers induced by NSAIDs. ❑ Less effective than H2 antagonists & PPIs for acute treatment of peptic ulcers. ❑ Clinically effective at higher doses (diminish gastric acid secretion).  Prostaglandin analogues ❑ Misoprostol produces uterine contractions – contraindicated during pregnancy. ❑ Common adverse effects – dose-related diarrhea & nausea.  Antimuscarinic Agents ❑Or Anti-cholinergic agents. ❑Muscarinic receptor stimulation – increases gastrointestinal motility and secretory activity. ❑Cholinergic antagonist, such as dicyclomine – can be used in management of peptic ulcer disease. ❑Many side effects - for example, cardiac arrhythmias, dry mouth, constipation, and urinary retention → limit its use  Antacids ❑ Antacids - are weak bases react with gastric acid to form water and a salt → thereby diminishing gastric acidity. ❑ Pepsin is inactive at a pH greater than 4 → thus antacids also reduce pepsin activity ❑ Commonly used antacids – are salts of aluminum and magnesium: aluminum hydroxide (Al(OH)3) ; magnesium hydroxide [Mg(OH)2]. ❑ Sodium bicarbonate [NaHCO3] - Systemic absorption can produce transient metabolic alkalosis → therefore, this antacid is not recommended for long-term use  Antacids Therapeutic uses: ❑ Aluminum- & magnesium-containing antacids – used for symptomatic relief of peptic ulcer disease and GERD (gastroesophageal reflux disease). ❑ May promote healing of duodenal ulcers.  Antacids Adverse effects: ❑ Aluminum hydroxide – constipation. ❑ Magnesium hydroxide – diarrhea. ❑ The binding of phosphate by aluminum-containing antacids – can lead to hypophosphatemia. ❑ Sodium bicarbonate liberates CO2, causing belching and flatulence - potential for systemic alkalosis. ❑ Adverse effects may occur in patients with renal impairment, caused by accumulation of magnesium, calcium, sodium. ❑ Sodium content – an important consideration in patients with hypertension or congestive heart failure.  Mucosal Protective Agents ❑ Known as cytoprotective compounds. ❑ Actions : mucosal protection – thereby preventing mucosal injury, reducing inflammation, and healing existing ulcers Sucralfate: ❑ Formation of complex gels with epithelial cells ; sucralfate → creates a physical barrier that impairs diffusion of HCl and prevents degradation of mucus by pepsin and acid. ❑ Also stimulates prostaglandin release, mucus and bicarbonate output & inhibits peptic digestion. ❑ Sucralfate effectively heals duodenal ulcers; long-term use prevent the recurrence.  Mucosal Protective Agents ❑ Requires an acidic pH for activation → sucralfate should not be administered with PPIs, H2 antagonists or antacids. ❑ Less drug is absorbed systemically. ❑ Can interfere with the absorption of other drugs by binding to them. Bismuth subsalicylate: ❑ Effectively heal peptic ulcers. ❑ Antimicrobial actions. ❑ Inhibit pepsin, increase secretion of mucus & interact with glycoproteins in necrotic mucosal tissue to coat and protect the ulcer crater.