Pharmacology 3: Peptic Ulcer Drugs

Pharmacology 3: Peptic Ulcer Drugs

• Peptic ulcer diseases include dyspepsia, gastroesophageal reflux, peptic ulcer (gastric and duodenal), and stress-related mucosal injury.
• Mucosal erosions or ulcerations arise when the caustic effects of aggressive factors (acid, pepsin, bile) overwhelm the defensive factors of the gastrointestinal mucosa (mucus, bicarbonate secretion, prostaglandins, blood flow, processes of restitution and regeneration).
• Over 90% of peptic ulcers are caused by infection with Helicobacter pylori or use of nonsteroidal anti-inflammatory drugs (NSAIDs).
• Drugs used in the treatment of acid-peptic disorders are divided into two classes: agents that reduce intragastric acidity and agents that promote mucosal defense.
• The parietal cell contains receptors for gastrin (CCK-B), histamine (H2), and acetylcholine (muscarinic, M3).
• Acetylcholine comes from vagal postganglionic nerves. Gastrin is released from antral G cells in the stomach and duodenum. These trigger an increase in cytosolic calcium, stimulating protein kinases which further stimulate acid secretion from a H+/K+-ATPase (proton pump) on the canalicular surface of the parietal cells.
• ECL cells are nearby gut endocrine cells that release histamine.
• Histamine binds to H2 receptors on the parietal cells, activating adenylyl cyclase, increasing intracellular cyclic adenosine monophosphate (cAMP), and activating protein kinases that stimulate acid secretion by the H+/K+-ATPase.
• Antacids have been used for centuries in the treatment of dyspepsia and acid-peptic disorders. They remain a common over-the-counter remedy for intermittent heartburn and dyspepsia. Antacids are weak bases that neutralize gastric acid. Antacid effectiveness varies depending on dissolution rate, water solubility, rate of reaction with acid, and rate of gastric emptying.
• Sodium Bicarbonate rapidly reacts with hydrochloric acid (HCl) to produce carbon dioxide and sodium chloride, resulting in gastric distension and belching. Unreacted alkali can cause metabolic alkalosis, especially when given in high doses to patients with renal insufficiency. Sodium chloride absorption may exacerbate fluid retention in patients with heart failure, hypertension, and renal insufficiency.
• Symptoms of alkalosis can include confusion, hand tremor, lightheadedness, muscle twitching, nausea, vomiting, and numbness or tingling in the face, hands, or feet. This can lead to prolonged muscle spasms(tetany).
• Calcium Carbonate is less soluble, reacts more slowly, and forms carbon dioxide and calcium chloride. Excessive doses can cause hypercalcemia, renal insufficiency, and metabolic alkalosis (milk-alkali syndrome) when combined with dairy products.
• Formulations containing magnesium hydroxide and aluminum hydroxide react slowly to form magnesium or aluminum chloride and water. These formulations do not cause belching. However, unabsorbed magnesium salts can cause osmotic diarrhea, while aluminum salts can cause constipation.
• Antacids should not be given within 2 hours of tetracyclines, fluoroquinolones, itraconazole, and iron doses, due to potential absorption interference from the binding or changes in pH.
• H2 receptor antagonists (cimetidine, ranitidine, famotidine, and nizatidine) are absorbed rapidly from the intestine. Cimetidine, ranitidine, and famotidine undergo first-pass hepatic metabolism, causing ~50% bioavailability. They exhibit competitive inhibition at the parietal cell H2 receptor, suppressing acid secretion in a linear, dose-dependent manner. Highly selective for H2 and do not affect H1 or H3 receptors. They reduce the volume of gastric secretion and concentration of pepsin.
• H2 antagonists are particularly effective in inhibiting nocturnal acid secretion (which depends largely on histamine). However, they have a less pronounced impact on meal-stimulated acid secretion, which is controlled by gastrin and acetylcholine along with histamine.
• When given in standard doses, H2 antagonists inhibit 60-70% of total 24-hour acid secretion. However, at OTC levels, acid inhibition duration is less than 6 hours. Gastric pH is raised to 4-5 in the nocturnal and fasting states.
• H2 antagonists are frequently used for infrequent heartburn or dyspepsia (less than 3 times per week) In cases with erosive esophagitis (~50% of GERD cases), proton pump inhibitors are generally preferred due to their superior acid inhibition properties.
• Proton pump inhibitors (PPIs) have largely replaced H2 antagonists in acute peptic ulcer disease. They, however, are still at times used for nocturnal acid suppression helping with ulcer healing. All are administered once daily at bedtime and result in 80-90% ulcer healing within 6-8 weeks.
• For ulcers caused by aspirin or other NSAIDs, the NSAID must be discontinued. If the NSAID cannot be discontinued, proton pump inhibitors (PPIs) must be used instead. For ulcers caused by H. pylori, H2 antagonists are not effective and H. pylori must be treated with a 10-14 day course of antibiotics and proton pump inhibitors.
• For patients in whom H.pylori eradication is not possible, H2 antagonists may be administered daily at bedtime in half of the normal ulcer therapeutic dose to help prevent recurrence.
• H2 antagonists are often used for non-ulcer dyspepsia as over-the-counter agents.
• Adverse effects of H2 antagonists are minor and usually include diarrhea, headache, fatigue, myalgia, and constipation. More serious mental status changes (confusion, hallucinations, agitation) may occur with intravenous H2 antagonists, particularly in elderly patients or those with renal or hepatic dysfunction. The drug cimetidine can be associated with gynecomastia, impotence, or galactorrhea.
• Cimetidine interferes with several important hepatic cytochrome P450 drug metabolism pathways, including those catalyzed by CYP1A2, CYP2C9, CYP2D6, and CYP3A4.
• Proton pump inhibitors (PPIs) are widely prescribed globally due to their efficacy and safety. Six types of PPIs are available: Omeprazole, Lansoprazole, Dexlansoprazole, Rabeprazole, Pantoprazole, and Esomeprazole. All are substituted benzi-midazoles that resemble H2 antagonists in structure, but have a completely different mechanism of action. Available in oral formulations.
• PPIs are administered as inactive prodrugs to prevent destruction in the acidic gastric lumen. They are instead formulated for delayed release using acid-resistant, enteric-coated capsules or tablets, which disintegrate once they reach the alkaline intestinal lumen. These are often given an hour before meals to coincide with maximum proton pump activity. They have a short serum half-life ( ~1.5 hours), but the acid inhibition lasts for around 24 hours due to irreversible inactivation of the proton pump.
• For children or patients with dysphagia or enteral feeding tubes, the capsule formulations may be opened and the microgranules mixed with apple or orange juice, or mixed with soft food.
• Omeprazole is available as a powder formulation that assists with the protection of the naked (non-enteric-coated) drug from acid degradation. When administered on an empty stomach, omeprazole absorption is rapid.
• The prodrug quickly becomes protonated, then undergoes a molecular conversion into the active form of a reactive thiophilic sulfenamide cation, creating a covalent disulfide bond with the H+/K+-ATPase to irreversibly inactivate the enzyme. At least 18 hours are necessary to generate new H+/K+-ATPase pump molecules. Daily medication can take up to 3-4 days to fully inhibit acid production. Similarly, it will take roughly 3-4 days for full acid secretion return after stopping PPI use.
• PPIs undergo rapid first-pass and systemic hepatic metabolism, and have negligible renal clearance meaning no dosage reduction is typically needed in patients with renal insufficiency or mild-moderate hepatic disease. However, PPIs should be administered with caution in patients with severe liver impairment.
• Pharmacokinetic properties of PPIs make them ideal drugs which have a short serum half-life, concentrated and activated near the site of action, and lasting long durations of action.
• PPIs inhibit both fasting and meal-stimulated acid secretion due to blocking the final common pathway for acid secretion, the proton pump. In standard doses, 90-98% of 24-hour acid secretion can be inhibited.
• The most effective clinical uses of PPIs include gastroesophageal reflux disease (GERD), peptic ulcers from both H. pylori or NSAIDs. GERD symptoms and/or complications can recur within 6 months of PPI discontinuation; therefore, in those with erosive esophagitis or other complications, long-term daily maintenance therapy and a full dose, or half-dose, PPI is usually required. Many patients however can be successfully treated with intermittent courses taken "on demand" with symptomatic occurrence.
• In current clinical practice, symptomatic GERD is treated empirically with PPIs, often without prior endoscopy and without knowing the presence of erosive or nonerosive reflux disease. Empirical treatment with an appropriate PPI can provide symptom relief in 70-80% of patients, compared with approximately 50-60% relief for those receiving H2 antagonists. Cost reductions lead to increased use.
• PPIs, compared with H2 antagonists, are more effective in rapidly providing symptom relief, faster ulcer healing for duodenal ulcers, and gastric ulcers to a lesser extent. More than 90% of duodenal ulcers heal within 4 weeks, and also a similar percentage for gastric ulcer healing within 6-8 weeks.
• In cases with H. pylori-associated ulcers, the two therapeutic goals are ulcer healing and eradication of the organism. The most effective regimens utilize a combination of proton pump inhibitors and two antibiotics. Alternatively sequential treatment is a 10-day therapy using a PPI, amoxicillin or metronidazole, with the addition of clarithromycin for the final 5 days. This sequential alternative offers an effective and viable treatment regimen.
• NSAID-associated ulcers benefit from either a H2 or PPI if NSAID administration can be interrupted. A once or twice daily PPI is more reliable in healing the associated ulcer versus H2 antagonists in cases with NSAID-induced ulceration who are still requiring continuous NSAID therapy.
• Asymptomatic peptic ulceration develops in 10-20% of people taking frequent NSAIDs, and ulcer-related complications may occur in 1-2% of persons per year. PPIs taken once daily effectively reduce the incidence of ulcers, complication, in patients taking aspirin or other NSAIDs.
• For patients with acute gastrointestinal bleeding due to a peptic ulcer with visual vessel or adherent clot, re-bleeding can be reduced with 3-5 day administration of a high-dose PPI orally, or through a continuous intravenous infusion. An intragastric pH of >6 can enhance coagulation and platelet aggregation. It is not known what the optimal dose of intravenous PPI is needed to achieve near-complete acid inhibition but administration of an initial bolus of esomeprazole or pantoprazole (80 mg), followed by a continuous infusion of 8 mg/hr, is common.
• PPIs have a slightly beneficial efficacy in treatment of non-ulcer dyspepsia, benefiting approximately 10-20% more patients than placebo. However, their demonstrated superiority compared to H2 antagonists, or placebo, is not conclusive.
• PPIs are generally considered to be safe. Adverse affects include diarrhea, headache, abdominal pain. However, acute interstitial nephritis, has been slightly increased but still rare, and is unrelated to placebo.
• PPIs are not associated with teratogenicity and are safe in animal models for pregnancy; however, safety during human pregnancy conditions remain to be established.
• A minor reduction in oral cyanocobalamin absorption is possible during PPI administration, which could lead to subnormal B12 levels, particularly with prolonged treatment.

Mucosal Protectives

• Sucralfate is a salt of sucrose complexed to sulfated aluminum hydroxide.
• In water or acidic solutions, sucralfate forms a viscous paste that binds selectively to ulcers or erosions for up to 6 hours.
• Sucralfate has limited solubility, breaking down into sucrose sulfate and an aluminum salt. Only a minimal amount less than 3% of drug and aluminum is absorbed.
• Prostaglandin analogs, such as misoprostol (a methyl analog of PGE1), are rapidly absorbed and metabolized to a metabolically active free acid following oral administration. A serum half life is less than 30 minutes. Given 3-4 times daily.
• Misoprostol has acid inhibitory and mucosal protective properties by stimulating mucus and bicarbonate secretion, enhances mucosal blood flow, directly binds to the prostaglandin receptor on parietal cells, thus reducing histamine-stimulated cAMP production and moderately inhibiting acid secretion. Prostaglandins have many functions including stimulation of intestinal electrolyte and fluid secretions, motility, and uterine contractions.
• Misoprostol reduces the occurrence of NSAID-induced ulcers to less than 3% and ulcer complications by 50%. It is approved for the prevention of NSAID-induced ulcers in high-risk patients. However, it's not used widely because of its profile of significant adverse effects and for the need for multiple daily doses.
• Adverse effects from misoprostol include diarrhea and cramping abdominal pain in 10-20% of patients. Administration should be avoided during pregnancy or in women of childbearing potential unless they have a negative pregnancy test and effective contraception. No other significant drug interactions are reported.

Explore the pharmacological treatments for peptic ulcer diseases, including mechanisms of action, classification of drugs, and the role of Helicobacter pylori. This quiz reviews important concepts related to reducing acid and promoting mucosal defense in the gastrointestinal tract.