Peptic Ulcer Drugs - Pharmacology 3 - PDF

Pharmacology 3 Peptic Ulcer drugs Dr. Lina Tamimi  Background Acid-peptic diseases include: dyspepsia gastroesophageal reflux peptic ulcer (gastric and duodenal) stress-related mucosal injury  Etiology Mucosal...

Pharmacology 3 Peptic Ulcer drugs Dr. Lina Tamimi  Background Acid-peptic diseases include: dyspepsia gastroesophageal reflux peptic ulcer (gastric and duodenal) stress-related mucosal injury  Etiology Mucosal erosions or ulceration 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 after cellular injury  1. Peptic Ulcer Over 90% of peptic ulcers are caused by: infection with the bacterium Helicobacter pylori Or use of nonsteroidal anti-inflammatory drugs (NSAIDs).  Classification Drugs used in the treatment of acid-peptic disorders may be divided into two classes: 1.Agents that reduce intragastric acidity 2.Agents that promote mucosal defense.  Physiology of acid secretion The parietal cell contains receptors for: 1. gastrin (CCK-B) 2. histamine (H2 ) 3. acetylcholine (muscarinic, M3 ). acetylcholine (from vagal postganglionic nerves) gastrin (released from antral G cells in the stomach and duodenum that secretes gastrin into the blood)  When ACH or gastrin: 1- bind to the parietal cell receptors, they cause an increase in cytosolic calcium. This stimulates protein kinases ……….. that stimulate acid secretion from a H + / K + -ATPase (the proton pump) on the canalicular surface. In close proximity to the parietal cells are gut endocrine cells called enterochromaffin-like (ECL) cells.  2- ECL cells also have receptors for gastrin and acetylcholine, which stimulate histamine release. Histamine binds to the H 2 receptor on the parietal cell, resulting in activation of adenylyl cyclase which increases intracellular cyclic adenosine monophosphate (cAMP) and activates protein kinases that stimulate acid secretion by the H + /K + - ATPase. Treatment  1. ANTACIDS Antacids have been used for centuries in the treatment of patients with: dyspepsia and acid-peptic disorders. They were the mainstay of treatment for acid- peptic disorders until the advent of: H 2− receptor antagonists and proton pump inhibitors.  Continue to be used commonly by patients as nonprescription remedies for the treatment of intermittent heartburn and dyspepsia.  MOA Antacids are weak bases weak bases + gastric HCl acid = salt +water Their principal mechanism of action is reduction of intra-gastric acidity.  A single dose of 156 mEq of antacid given 1 hour after a meal effectively neutralizes gastric acid for up to 2 hours. However, the acid-neutralization capacity among different proprietary formulations of antacids is highly variable, depending on: 1. rate of dissolution (tablet versus liquid) 2. water solubility 3. rate of reaction with acid 4. rate of gastric emptying.  1.1. Sodium Bicarbonate reacts rapidly with hydrochloric acid (HCL) to produce= carbon dioxide + sodium chloride. 1- Formation of carbon dioxide results in gastric distention and belching. 2- Unreacted alkali is readily absorbed, potentially causing metabolic alkalosis when given in high doses or to patients with renal insufficiency. 3- Sodium chloride absorption may exacerbate fluid retention in patients with heart failure, hypertension, and renal insufficiency.  Symptoms of alkalosis can include any of the following: Confusion (can progress to stupor or coma) Hand tremor. Lightheadedness. Muscle twitching. Nausea, vomiting. Numbness or tingling in the face, hands, or feet. Prolonged muscle spasms (tetany).  1.2. Calcium Carbonate less soluble and reacts more slowly than sodium bicarbonate with HCl to form= carbon dioxide + calcium chloride (CaCl2). Like sodium bicarbonate, calcium carbonate may cause belching or metabolic alkalosis. Excessive doses of calcium carbonate with calcium-containing dairy products can lead to : Hypercalcemia renal insufficiency metabolic alkalosis (milk-alkali syndrome). 1.3. Formulations containing: Magnesium Hydroxide Aluminum Hydroxide  React slowly with HCl to form magnesium chloride or aluminum chloride and water. no gas is generated belching does not occur. Metabolic alkalosis is also uncommon because of the efficiency of the neutralization reaction. unabsorbed magnesium salts these agents cause an osmotic diarrhea are aluminum salts commonly cause constipation administered together  Interactions All antacids may affect the absorption of other medications by : 1. binding the drug (reducing its absorption) 2. increasing intragastric pH so that the drug’s dissolution or solubility (especially weakly basic or acidic drugs) is altered. Therefore, antacids should not be given within 2 hours of doses of : tetracyclines, fluoroquinolones, itraconazole, and iron.  2. H 2 -RECEPTOR ANTAGONISTS Four H 2 antagonists are in clinical use: cimetidine, ranitidine, famotidine and nizatidine. All four agents are rapidly absorbed from the intestine. Cimetidine, ranitidine, and famotidine undergo first- pass hepatic metabolism resulting in a bioavailability of approximately 50%.  MOA The H 2 antagonists exhibit competitive : 1- inhibition at the parietal cell H 2 receptor and suppress acid secretion in a linear, dose- dependent manner. They are highly selective and do not affect H 1 or H 3 receptors. 2- The volume of gastric secretion and the concentration of pepsin are also reduced.  When given in usual prescription doses however, all inhibit 60–70% of total 24-hour acid secretion. especially effective at inhibiting nocturnal acid secretion (which depends largely on histamine) but they have a modest impact on meal-stimulated acid secretion (which is stimulated by gastrin and acetylcholine as well as histamine).  Nocturnal and fasting intragastric pH is raised to 4–5 but the impact on the daytime, meal-stimulated pH profile is less. Recommended prescription doses maintain greater than 50% acid inhibition for 10 hours; hence, these drugs are commonly given twice daily. At doses available in over-the-counter formulations, the duration of acid inhibition is less than 6 hours.  Gastroesophageal Reflux Disease (GERD) Patients with infrequent heartburn or dyspepsia (fewer than 3 times per week) may take either : antacids or intermittent H 2 antagonists. In patients with erosive esophagitis (approximately 50% of patients with GERD), H 2 antagonists afford healing in less than 50% of patients; hence proton pump inhibitors are preferred because of their superior acid inhibition.  Heartburn the effect of antacids is short-lived (1–2 hours) rapid acid neutralization H 2 antagonists long lived (6–10 hours). Slower action prophylactically : before meals Frequent heartburn is better treated with : twice-daily H 2 antagonists or PPIs.  Peptic Ulcer Disease Proton pump inhibitors have largely replaced H 2 antagonists in the treatment of acute peptic ulcer disease. Nevertheless, H 2 antagonists are still sometimes used. Nocturnal acid suppression by H 2 antagonists affords effective ulcer healing in most patients with uncomplicated gastric and duodenal ulcers.  All the agents may be administered once daily at bedtime, resulting in ulcer healing rates of more than 80–90% after 6– 8 weeks of therapy. For patients with ulcers caused by aspirin or other NSAIDs, the NSAID should be discontinued. If the NSAID must be continued for clinical reasons despite active ulceration, a proton pump inhibitor should be given instead of an H 2 antagonist to more reliably promote ulcer healing.  For patients with acute peptic ulcers caused by H pylori, H 2 antagonists no longer play a significant therapeutic role. H pylori should be treated with a 10- to 14-day course of therapy including: a proton pump inhibitor and two antibiotics.  For the minority of patients in whom H pylori cannot be successfully eradicated: H 2 antagonists may be given daily at bedtime in half of the usual ulcer therapeutic dose to prevent ulcer recurrence (eg, ranitidine, 150 mg; famotidine, 20 mg).  Non-ulcer Dyspepsia: -H 2 antagonists are commonly used as over-the- counter agents Intermittent Non-ulcer Dyspepsia: prescription agents  Adverse effects H2 antagonists are extremely safe drugs. Adverse effects occur in less than 3% of patients and include: diarrhea Headache Fatigue Myalgias constipation. Mental statuts changes : (confusion, hallucinations, agitation) may occur with administration of intravenous H 2 antagonists, especially in patients in: the intensive care unit who are elderly who have renal or hepatic dysfunction. These events may be more common with cimetidine. Mental status changes rarely occur in ambulatory patients.  Cimetidine: 1. inhibits binding of dihydrotestosterone to androgen receptors 2. inhibits metabolism of estradiol 3. increases serum prolactin levels. When used long-term or in high doses, it may cause: gynecomastia or impotence in men galactorrhea ( a milky nipple discharge unrelated to the normal milk production of breast-feeding) in women.  Drug Interactions Cimetidine interferes with several important hepatic cytochrome P450 drug metabolism pathways including those catalyzed by: CYP1A2 CYP2C9 CYP2D6 CYP3A4.  3. Proton pump inhibitors PPI (PPIs) are now among the most widely prescribed drugs worldwide due to : their outstanding efficacy safety.  Six proton pump inhibitors are available for clinical use: Omeprazole Lansoprazole Dexlansoprazole Rabeprazole Pantoprazole Esomeprazole All are substituted benzi-midazoles that resemble H2 antagonists in structure but have a completely different mechanism of action.  Formulation All are available in oral formulations. Esomeprazole and pantoprazole are also available in intravenous formulations.  Why PPI are protected from stomach acid? Proton pump inhibitors are administered as: inactive prodrugs To protect the acid-labile prodrug from rapid destruction within the gastric lumen: oral products are formulated for delayed release as: acid-resistant, enteric-coated capsules or tablets. After passing through the stomach into the alkaline intestinal lumen, the enteric coatings dissolve and the prodrug is absorbed. For children or patients with dysphagia or enteral feeding tubes: capsule formulations (but not tablets) may be opened and the micro granules mixed with apple or orange juice or mixed with soft food.  Omeprazole with sodium bicarbonate Omeprazole is also available as a powder formulation (capsule or packet) that contains sodium bicarbonate (1100–1680 mg NaHCO 3 ; 304–460 mg of sodium): to protect the naked (non-enteric- coated) drug from acid degradation. HOWWWW ??? When administered on an empty stomach by mouth or enteral tube, this “immediate-release” suspension results in rapid omeprazole absorption (T max < 30 minutes) and onset of acid inhibition. MOA The prodrug rapidly becomes protonated , then it rapidly undergoes a molecular conversion to the active form: a reactive thiophilic sulfenamide cation, which forms a covalent disulfide bond with the H + /K + -ATPase irreversibly inactivating the enzyme.  In a fasting state: only 10% of proton pumps are actively secreting acid and susceptible to inhibition. Proton pump inhibitors should be administered approximately 1 hour before a meal (usually breakfast)??? so that the peak serum concentration coincides with the maximal activity of proton pump secretion. The drugs have a short serum half-life of about 1.5 hours, but acid inhibition lasts up to 24 hours owing to the irreversible inactivation of the proton pump.  At least 18 hours are required for synthesis of new H + /K + -ATPase pump molecules. up to 3–4 days of daily medication are required before the full acid inhibiting potential is reached Because not all proton pumps are inactivated with the first dose of medication Similarly: after stopping the drug, it takes 3–4 days for full acid secretion to return.  PK Proton pump inhibitors undergo: 1. rapid first-pass 2. systemic hepatic metabolism have negligible renal clearance……… Dose reduction is not needed for patients with: 1. renal insufficiency 2. mild to moderate liver disease but should be considered in patients with severe liver impairment. Although other proton pumps exist in the body, the H + /K + -ATPase appears to exist only in the parietal cell and is distinct structurally and functionally from other H + - transporting enzymes.  Ideal drugs… why? From a pharmacokinetic perspective, proton pump inhibitors are ideal drugs: 1. they have a short serum half-life 2. they are concentrated and activated near their site of action 3. they have a long duration of action.  Comparison of PPI to H2 antagonists In contrast to H 2 antagonists, proton pump inhibitors inhibit both fasting and meal-stimulated secretion because they block the final common pathway of acid secretion, the proton pump. In standard doses, proton pump inhibitors inhibit 90– 98% of 24-hour acid secretion.  Clinical uses of PPI 1- Gastroesophageal Reflux Disease (GERD) -Most effective agents for the treatment of : 1. non erosive and erosive reflux disease 2. esophageal complications of reflux disease (peptic stricture or Barrett’s esophagus) 3. extraesophageal manifestations of reflux disease. Once-daily dosing provides effective symptom relief and up to 15% of patients require tissue healing in 85–90% of twice-daily dosing. patients -GERD symptoms recur in over 80% of patients within 6 months after discontinuation of a proton pump inhibitor. -For patients with erosive esophagitis or esophageal complications, long-term daily maintenance therapy with a full-dose or half-dose proton pump inhibitor is usually needed. -Many patients with non erosive GERD may be treated successfully with intermittent courses of proton pump inhibitors or H 2 antagonists taken as needed (“on demand”) for recurrent symptoms. In current clinical practice, many patients with symptomatic GERD are treated empirically with medications without prior endoscopy, ie, without knowledge of whether the patient has erosive or nonerosive reflux disease. -Empiric treatment with proton pump inhibitors provides sustained symptomatic relief in 70–80% of patients, compared with 50–60% with H 2 antagonists. -Because of recent cost reductions, proton pump inhibitors are being used increasingly as first-line therapy for patients with symptomatic GERD. 2- Peptic Ulcer Disease: Compared with H 2 antagonists, proton pump inhibitors afford more : 1. rapid symptom relief 2. faster ulcer healing for duodenal ulcers 3. a lesser extent, gastric ulcers. All the pump inhibitors heal: more than 90% of duodenal ulcers within 4 weeks a similar percentage (90%) of gastric ulcers within 6–8 weeks. 3- For H pylori -associated ulcers: -there are two therapeutic goals: to heal the ulcer to eradicate the organism. The most effective regimens for H pylori eradication are combinations of : two antibiotics a proton pump inhibitor.  Proton pump inhibitors promote eradication of H pylori through several mechanisms: 1. direct antimicrobial properties (minor) 2. raising intragastric pH 3. lowering the minimal inhibitory concentrations of antibiotics against H pylori.  The best treatment regimen consists of a 14-day regimen of “triple therapy”: 1. a proton pump inhibitor twice daily 2. clarithromycin, 500 mg twice daily 3. either amoxicillin, 1 g twice daily, or metronidazole, 500 mg twice daily. After completion of triple therapy, the proton pump inhibitor should be continued once daily for a total of 4–6 weeks to ensure complete ulcer healing.  Alternatively: 10 days of “sequential treatment” consisting on: days 1–5 of a PPI twice daily plus amoxicillin, 1 g twice daily followed on days 6–10 by five additional days of a proton PPI twice daily, plus clarithromycin, 500 mg twice daily, and tinidazole, 500 mg twice daily has been shown to be a highly effective treatment regimen. 4- NSAID-associated ulcers For patients with ulcers caused by aspirin or other NSAIDs, either H 2 antagonists or proton pump inhibitors provide rapid ulcer healing so long as the NSAID is discontinued however continued use of the NSAID impairs ulcer healing. In patients with NSAID-induced ulcers who require continued NSAID therapy, treatment with a once- or twice-daily proton pump inhibitor more reliably promotes ulcer healing.  Asymptomatic peptic ulceration develops in 10–20% of people taking frequent NSAIDs, and ulcer-related complications (bleeding, perforation) develop in 1–2% of persons per year. PPIs taken once daily are effective in reducing the incidence of ulcers and ulcer complications in patients taking aspirin or other NSAIDs. 5- Prevention of rebleeding from peptic ulcers In patients with acute gastrointestinal bleeding due to peptic ulcers, the risk of re-bleeding from ulcers that have a visible vessel or adherent clot is increased. Re-bleeding of this subset of high-risk ulcers is reduced significantly with proton pump inhibitors administered for 3–5 days either as: 1. high-dose oral therapy (eg, omeprazole, 40 mg orally twice daily) 2. or as a continuous intravenous infusion.  It is believed that an intragastric pH higher than 6 may enhance coagulation and platelet aggregation. The optimal dose of intravenous proton pump inhibitor needed to achieve and maintain this level of near complete acid inhibition is unknown -- initial bolus administration of esomeprazole or pantoprazole (80 mg) followed by -- constant infusion (8 mg/h) is commonly recommended. 6- Non-ulcer Dyspepsia Proton pump inhibitors have modest efficacy for treatment of non-ulcer dyspepsia, benefiting 10–20% more patients than placebo. Despite their use for this indication, superiority to H 2 antagonists (or even placebo) has not been conclusively demonstrated.  Adverse Effects Proton pump inhibitors are extremely safe. (reported in 1–5% of patients): 1. Diarrhea 2. Headache 3. abdominal pain Although the frequency of these events is only slightly increased compared with placebo. Increasing cases of acute interstitial nephritis have been reported. Proton pump inhibitors do not have teratogenicity in animal models; however, safety during pregnancy has not been established.  Acid is important in : 1- releasing vitamin B 12 from food. A minor reduction in oral cyanocobalamin absorption occurs during proton pump inhibition, potentially leading to subnormal B 12 levels with prolonged therapy. 2- promotes absorption of food bound minerals (non-heme iron, insoluble calcium salts, magnesium). Although a causal relationship is unproven, proton pump inhibitors may reduce calcium absorption or inhibit osteoclast function 4. Mucosal protectives 1- SUCRALFATE Sucralfate is a salt of sucrose complexed to sulfated aluminum hydroxide. In water or acidic solutions it 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 (strongly negatively charged) and an aluminum salt. Less than 3% of intact drug and aluminum is absorbed from the intestinal tract; the remainder is excreted in the feces. 2- PROSTAGLANDIN ANALOGS The human gastrointestinal mucosa synthesizes a number of prostaglandins the primary ones are prostaglandins E and F. Misoprostol: a methyl analog of PGE 1 , has been approved for gastrointestinal conditions. After oral administration, it is rapidly absorbed and metabolized to a metabolically active free acid. The serum half-life is less than 30 minutes; hence, it must be administered 3–4 times daily. It is excreted in the urine; however, dose reduction is not needed in patients with renal insufficiency  Misoprostol has both acid inhibitory and mucosal protective properties. It is believed to: 1. stimulate mucus and bicarbonate secretion 2. enhance mucosal blood flow. 3. it binds to a prostaglandin receptor on parietal cells, reducing histamine-stimulated cAMP production and causing modest acid inhibition. Prostaglandins have a variety of other actions including: stimulation of intestinal electrolyte and fluid secretion intestinal motility, and uterine contractions.  Misoprostol reduces the incidence of NSAID-induced ulcers to less than 3% and the incidence of ulcer complications by 50%. It is approved for prevention of NSAID-induced ulcers in high-risk patients; however, misoprostol has never achieved widespread use owing to : its high adverse-effect profile need for multiple daily dosing. As discussed, proton pump inhibitors may be as effective as and better tolerated than misoprostol for this indication. Cyclooxygenase-2-selective NSAIDs, which may have less gastrointestinal toxicity offer another option for patients at high risk for NSAID-induced complications.  Adverse Effects & Drug Interactions Diarrhea and cramping abdominal pain occur in 10–20% of patients. Because misoprostol stimulates uterine contractions: it should not be used during pregnancy or in women of childbearing potential unless they have a negative serum pregnancy test and are compliant with effective contraceptive measures. No significant drug interactions are reported.