Peptic ulcer: A peptic ulcer, also known as PUD or peptic ulcer disease is an ulcer (defined as mucosal erosions equal

l to or greater than 0.5 cm) of an area of the gastrointestinal tract that is usually acidic and thus extremely painful. As much as 80% of ulcers are associated with Helicobacter pylori, a spiral-shaped bacterium that lives in the acidic environment of the stomach, however only 20% of those cases go to a doctor. Ulcers can also be caused or worsened by drugs such as Aspirin and other NSAIDs. Contrary to general belief, more peptic ulcers arise in the duodenum (first part of the small intestine, just after the stomach) than in the stomach. About 4% of stomach ulcers are caused by a malignant tumor, so multiple biopsies are needed to make sure. Duodenal ulcers are generally benign. Classification: A peptic ulcer may arise at various locations. 1) Stomach (called gastric ulcer) 2) Duodenum (called duodenal ulcer) 3) Esophagus (called esophageal ulcer) Treatment strategies: Treatment goals comprise: - To relieve pain - To heal the ulcer - To prevent complications Therapeutic interventions inlcude: - Drugs that neutralize gastric acid e.g. antacids - Drugs that inhibit acid secretion such as H2-antagonists, proton pum inhibitors, prostaglandins analogs and M1 antagonists - Drugs that do not directly inhibit gastric acid secretion e.g. bismuth chelates and sucralfate - Drugs combinations to eradicate H Pylori.

Antacids: Antacids are weak alkalis that perform a neutralization reaction, i.e. they buffer gastric acid, raising the pH to reduce acidity in the stomach. When gastric hydrochloric acid reaches the nerves in the gastrointestinal mucosa, they signal pain to the central nervous system. This happens when these nerves are exposed, as in peptic ulcers. The gastric acid may also reach ulcers in the esophagus or the duodenum. Many factors, including palatability, determine the effectiveness and choice of antacid. Although sodium bicarbonate effectively neutralizes acid, it is very water-soluble and rapidly absorbed from the stomach, and the alkali and sodium loads may pose a risk for patients with cardiac or renal failure. Depending on particle size and crystal structure, CaCO3 rapidly and effectively neutralizes gastric H+, but the release of CO2 from bicarbonate- and carbonate-containing antacids can cause belching, nausea, abdominal distention, and flatulence. Calcium also may induce rebound acid secretion, necessitating more frequent administration. Combinations of Mg2+ (rapidly reacting) and Al3+ (slowly reacting) hydroxides provide a relatively balanced and sustained neutralizing capacity and are preferred by most experts. In general, antacids should be administered in suspension form, as this probably has a greater neutralizing capacity than do powder or tablet dosage forms. If tablets are used, they should be thoroughly chewed for maximum effect. Antacids are cleared from the empty stomach in about 30 minutes. However, the presence of food is sufficient to elevate gastric pH to about 5 for approximately 1 hour and to prolong the neutralizing effects of antacids for about 2 to 3 hours. Antacids vary in the extent to which they are absorbed, and hence in their systemic effects. In general, most antacids can elevate urinary pH by about one pH unit. Antacids that contain Al3+, Ca2+, or Mg2+ are absorbed less completely than are those that contain NaHCO3. With normal renal function, the modest accumulations of Al3+ and Mg2+ do not pose a problem; with renal insufficiency, however, absorbed Al3+ can contribute to osteoporosis, encephalopathy, and proximal myopathy.

H2-antagonists: The H2 antagonists are competitive inhibitors of histamine at the parietal cell H2 receptor. They suppress the normal secretion of acid by parietal cells and the meal-stimulated secretion of acid. They accomplish this by two mechanisms: histamine released by enterochromaffin-like cells in the stomach is blocked from binding on parietal cell H2 receptors which stimulate acid secretion, and other substances that promote acid secretion (such as gastrin and acetylcholine) have a reduced effect on parietal cells when the H2 receptors are blocked. This group includes cimetidine (1970s ), ranitidine, famotidine, nizatidine (1980s) structurally all share homology with histamine. They competitively antagonise H2 receptors on gastric parietal cells, thus inhibiting the formation of cAMP and thus acid secretion. Suppression of acid secretion is less than with proton pump inhibitors because only the histamine component is inhibited. All are effective orally and mostly eliminated via kidney and liver with relatively short half-life. Cimetidine is a strong enzyme inducer of CYPP450 (beware warfarin, theophylline, phenytoin). Pharmacokinetic disposition of H2 blockers
Bioavailability (%) 60-70 50 40-50 95 Halflife (h) 1-3 2-3 3-4 2-3

Drug Cimetidine Ranitidine Famotidine Nizatidine Ranitidine bismuth citrate

Elimination Renal Renal/hepatic Renal/biliary Renal

Comment Inhibits P-450 enzymes No effect on P450 enzymes No effect on P450 enzymes No effect on P450 enzymes Dissociates in gastric fluid to ranitidine and bismuth; bismuth has negligible absorption and slow renal excretion

50

Renal/hepatic

2-3

 The drugs are well tolerated but headache, dizziness, reversible confusion, constipation and diarrhoea may occur. In addition, urticaria, sweating and somnolence are reported with nizatidine. The drugs do not inhibit hepatic microsomal enzymes and do not block androgen receptors. The anti-androgenic side effects of cimetidine in male and female made its use almost obsolete. People that suffer from heartburn due to peptic ulcer, GERD, or dyspepsia infrequently may take either antacids or H2-receptor antagonists for treatment. H2-antagonists offer several advantages over antacids including longer duration of action (6 10 hours vs 12 hours for antacids), greater efficacy, and ability to be used prophylactically before meals to reduce the chance of heartburn occurring. Proton pump inhibitors (PPIs): PPIs are a group of drugs whose main action is pronounced and longlasting reduction of gastric acid production. They are the most potent inhibitors of acid secretion available today. The group followed and has largely superseded H2-receptor antagonists. Proton pump inhibitors act by irreversibly blocking the hydrogen/potassium adenosine triphosphatase enzyme system (the H+/K+ ATPase, or more commonly just gastric proton pump) of the gastric parietal cell. The proton pump is the terminal stage in gastric acid secretion, being directly responsible for secreting H+ ions into the gastric lumen, making it an ideal target for inhibiting acid secretion. Targeting the terminal-step in acid production, as well as the irreversible nature of the inhibition, result in a class of drugs that are significantly more effective than H2 antagonists and reduce gastric acid secretion by up to 99%. PPIs are prodrugs that show covalent binding and hence irreversible inactivation of the H+/K+ ATPase (proton pump). They are given as enterically coated and slow-release formulations to prevent the degradation into the stomach. PPIs have longer duration of action (due to the irreversible inhibition of the pump) than H2 antagonists and are given once daily. Onset of action is rapid with maximum effect at 2-6 h and lasts 72-96 h. Takes 2-5 days for acid to return to normal after discontinuation. Pumps needs to be activated for maximum efficacy therefore drugs are given before meals.

Pharmacokinetic disposition of PPIs

Drug Omeprazole Lansoprazole Pantoprazole Rabeprazole Esomeprazole Bioavailability (%) 45 85 77 52 64-90 Elimination Hepatic Hepatic Hepatic Hepatic Hepatic Half-life (h) 0.5-1 <2 1 1-2 1.5

Pantoprazole does not inhibit P-450, but other PPIs do to a variable extent. PPIs are metabolized partly by P-450. Therefore, the AUC of all drugs increases in liver diseases but dosage adjustment is not necessary. Duration of action of PPIs far outlasts their half-lives but rabeprazole has a shorter duration of action as its action on the proton pump is partially reversible. More effective than H2 blockers in healing peptic ulcers. Differences between PPIs are small but higher healing rates were reported follwoing esomeprazole. When gastrointestinal erosions result from NSAIDs consumption, PPIs are effective in preventing erosion formation and appear to be more effective than H2 blockers. Omeprazole is the drug of choice for Gastrointestinal Reflux Disease (GERD). Symptoms are relieved in days and healing of esophagitis in 4-8 weeks. Esomeprazole is the first to be licensed for on -demand treatment of GERD where patients will take it as necessary to control symptoms. All PPIs have some ability to inhibit Heliobacter Pylori. M1 antagonists: The M1 muscarinic receptor antagonists pirenzepine can reduce basal acid production by 40% to 50% and long have been used to treat patients with peptic ulcer. The ACh receptor on the parietal cell itself is of the M3 subtype, and these drugs are believed to suppress neural stimulation of acid production via actions on M1 receptors of intramural ganglia. Because of their relatively poor efficacy, significant and undesirable anticholinergic side effects, and risk of blood disorders (pirenzepine), they rarely are used today. In the hope of providing more rapid onset of action and sustained acid suppression, reversible inhibitors of the gastric H+,K+-ATPase (e.g.,

the pyrrolopyridazine derivative AKU517) are being developed for clinical use. Antagonists of the CCK2 gastrin receptor on parietal cells also are under study. The precise role that these agents will play in the therapy of acid-peptic disorders in the future is yet to be determined. Prostaglandins analogs: PGE2 and PGI2 are the major prostaglandins synthesized by the gastric mucosa. They bind to the EP3 receptor on parietal cells and stimulate the Gi pathway, thereby decreasing intracellular cyclic AMP and gastric acid secretion. PGE2 also can prevent gastric injury by cytoprotective effects that include stimulation of mucin and bicarbonate secretion and increased mucosal blood flow. Since NSAIDs diminish prostaglandin formation by inhibiting cyclooxygenase, synthetic prostaglandin analogs offer a logical approach to reducing NSAID-induced mucosal damage (see below). Misoprostol (15-deoxy-16-hydroxy-16-methyl-PGE1) is a synthetic analog of PGE1. The degree of inhibition of gastric acid secretion by misoprostol is directly related to dose; oral doses of 100200 g significantly inhibit basal acid secretion (up to 95% inhibition) or food-stimulated acid secretion (up to 85% inhibition). The usual recommended dose for ulcer prophylaxis is 200 g four times a day Misoprostol is rapidly absorbed after oral administration and then is rapidly and extensively de-esterified to form misoprostol acid, the principal and active metabolite of the drug. A single dose inhibits acid production within 30 minutes; the therapeutic effect peaks at 6090 minutes and lasts for up to 3 hours. Food and antacids decrease the rate of misoprostol absorption, resulting in delayed and decreased peak plasma concentrations of the active metabolite. Misoprostol can prevent NSAID-induced mucosal injury. However, adverse effects and the inconvenience of four-timesdaily dosing limit its use.