Peptic Ulcer Drugs Introduction: In peptic ulcer (gastric and duodenal), mucosal ulceration arises when the caustic

effects of aggressive factors (acid, pepsin, bile) overwhelm the defensive factors of the
gastrointestinal mucosa (mucus and bicarbonate secretion, prostaglandins, blood flow, and the processes of restitution and regeneration after cellular injury). Over 90% of peptic ulcers are caused by infection with the bacterium Helicobacter pylori or by use of nonsteroidal anti-inflammatory drugs (NSAIDs). Drugs used in the treatment of acidpeptic disorders may be divided into two classes: agents that reduce intragastric acidity and agents that promote mucosal defense.

I. Agents that Reduce Intragastric Acidity: Physiology of Acid Secretion: The parietal cell contains receptors for gastrin (CCK-B), histamine (H2), and acetylcholine (muscarinic, M3). When acetylcholine (from vagal postganglionic nerves) or gastrin (released from antral G cells into the blood) bind to the parietal cell receptors, they cause an increase in cytosolic calcium, which in turn stimulates protein

kinases that stimulate acid secretion from a H+,K+ ATPase (the proton pump) on the canalicular surface. Histamine binding causes activation of adenylyl cyclase. Gastrin stimulates acid secretion indirectly by inducing the release of histamine by ECL cells.

1- Proton Pump Inhibitors (PPIs): (e.g. omeprazole, lansoprazole) Pharmacokinetics:

These agents are prodrugs with an acid-resistant enteric coating to protect them from
premature degradation by gastric acid. The coating is removed in the alkaline duodenum, and the prodrug, a weak base, is absorbed and transported to the parietal cell canaliculus. There, it is converted to the active form, which forms a covalent disulfide bond with the H+,K+ ATPase, irreversibly inactivating the enzyme. It takes about 18 hours for the enzyme to be resynthesized. The bioavailability of all agents is decreased approximately 50% by food; hence, the drugs should be administered on

an empty stomach. Because not all proton pumps are inactivated with the first dose of
medication, up to 34 days of daily medication are required before the full acidinhibiting potential is reached.

Pharmacodynamics: In contrast to H2 antagonists, PPIs inhibit both fasting and meal-stimulated secretion

because they block the final common pathway of acid secretion, the proton pump. In
standard doses, PPIs inhibit 9098% of 24-hour acid secretion.

Clinical Uses: 1- Gastroesophageal Reflux Disease (GERD). 2- Peptic Ulcer Disease: a. H. pylori-Associated Ulcers

There are two therapeutic goals: to heal the ulcer and to eradicate the organism.
Treatment regimen is 10 days of "sequential treatment" consisting on days 15 of a PPI twice daily plus amoxicillin, 1 g twice daily, and followed on days 610 by five additional days of a PPI twice daily, plus clarithromycin, 500 mg twice daily, and tinidazole, 500 mg twice daily. b. NSAID-Associated Ulcers

c. Prevention of Rebleeding from Peptic Ulcers 3- Prevention of Stress-Related Mucosal Bleeding. 4- Gastrinoma: Zollinger-Ellison syndrome, in which a gastrin-producing tumor causes hypersecretion of HCl.

Adverse effects: The PPIs are generally well tolerated, but concerns about long-term safety have been raised due to the increased secretion of gastrin. In animal studies, the incidence of gastric carcinoid tumors increased, possibly related to the effects of prolonged hypochlorhydria and secondary hypergastrinemia. However, this has not been found in humans. Increased concentrations of viable bacteria in the stomach have been

reported with continued use of these drugs. Omeprazole inhibits the metabolism of
warfarin, phenytoin, diazepam, and cyclosporine. However, drug interactions are not a problem with the other PPIs. Prolonged therapy with agents that suppress gastric acid, such as the PPIs and H2 antagonists, may result in low vitamin B12, because acid is required for its absorption.

Another problem with prolonged elevation of gastric pH is that calcium carbonate products require low gastric pH to be absorbed in the upper intestine. An effective option would be to use calcium citrate as a source of calcium by patients taking prolonged acid-suppressing medications. The absorption of the citrate salt is not affected by gastric pH. There are increased reports of diarrhea and Clostridium difficile

colitis in community patients receiving PPIs.

2- H2-Receptor Antagonists: (e.g. cimetidine, ranitidine, and famotidine) Pharmacokinetics: All H2 antagonists are rapidly absorbed from the intestine. Cimetidine, ranitidine, and famotidine undergo first-pass hepatic metabolism resulting in a bioavailability of approximately 50%. H2 antagonists are cleared by a combination of hepatic

metabolism, glomerular filtration, and renal tubular secretion. Dose reduction is

required in patients with moderate to severe renal (and possibly severe hepatic) insufficiency.

Pharmacodynamics: The H2 antagonists exhibit competitive inhibition at the parietal cell H2 receptor and principally inhibit basal acid secretion, which accounts for their efficacy in suppressing nocturnal acid secretion. They are highly selective (do not affect H1 or H3 receptors).

The volume of gastric secretion and the concentration of pepsin are also reduced.

H2 antagonists reduce acid secretion stimulated by histamine as well as by gastrin and cholinomimetic agents through two mechanisms. First, histamine released from enterochromaffin-like (ECL) cells by gastrin or vagal stimulation is blocked from binding to the parietal cell H2 receptor. Second, direct stimulation of the parietal cell by gastrin or acetylcholine has a diminished effect on acid secretion in the presence of

H2-receptor blockade.
H2-receptor antagonists inhibit 6070% of total 24-hour acid secretion. H2 antagonists are 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).

Clinical Uses: H2-receptor antagonists continue to be prescribed but PPIs are steadily replacing H2 antagonists for most clinical indications (e.g. GERD and peptic ulcer disease). However, the over-the-counter preparations are heavily used by the public.

Adverse effects:
They occur in less than 3% of patients and include headache, dizziness, diarrhea, and muscular pain. Mental status changes (confusion, hallucinations) occur primarily in elderly patients or after intravenous administration. These events may be more common with cimetidine. Cimetidine inhibits binding of dihydrotestosterone to androgen receptors, inhibits metabolism of estradiol, and increases serum prolactin levels. When used long-term or in high doses, it may cause gynecomastia or impotence in men and galactorrhea in women. These effects are specific to cimetidine and do not occur with the other H2 antagonists. Cimetidine inhibits cytochrome P450 and can slow metabolism (and, thus, potentiate the action) of several drugs (e.g., warfarin, diazepam, phenytoin, and theophylline).

3- Antacids: Antacids are weak bases that react with gastric acid to form water and a salt, thereby

diminishing gastric acidity. Because pepsin is inactive at a pH greater than 4, antacids

also reduce pepsin activity. Therapeutic uses: Aluminum- and magnesium-containing antacids are used for symptomatic relief of peptic ulcer disease and GERD; they may promote healing of duodenal ulcers, but the evidence for efficacy in the treatment of acute gastric ulcers is less compelling; therefore, these agents are used as last-line therapy.

Sodium bicarbonate reacts rapidly with HCl to produce carbon dioxide and sodium
chloride. Formation of carbon dioxide results in gastric distention and belching. Unreacted alkali is readily absorbed, potentially causing metabolic alkalosis when given in high doses or to patients with renal insufficiency. Sodium chloride absorption may exacerbate fluid retention in patients with heart failure, hypertension, and renal insufficiency. Calcium carbonate like sodium bicarbonate, may cause belching or metabolic alkalosis. Excessive doses of either sodium bicarbonate or calcium carbonate

with calcium-containing dairy products can lead to hypercalcemia, renal insufficiency, and metabolic alkalosis (milk-alkali syndrome).

Formulations containing magnesium hydroxide or aluminum hydroxide react slowly

with HCl to form magnesium chloride or aluminum chloride and water. Because no gas is generated, belching does not occur. Metabolic alkalosis is also uncommon because of the efficiency of the neutralization reaction. Because unabsorbed magnesium salts may cause an osmotic diarrhea and aluminum salts may cause constipation, these agents are commonly administered together to minimize the impact on bowel function. Both magnesium and aluminum are absorbed and excreted by the kidneys. Hence,

patients with renal insufficiency should not take these agents long-term. The binding of
phosphate by aluminum-containing antacids can lead to hypophosphatemia.

All antacids may affect the absorption of other medications by binding the drug (reducing its absorption) or by 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, and iron.

II. Mucosal Protective Agents:

1- Sucralfate Pharmacokinetics: 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 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. Because it
requires an acidic pH for activation, sucralfate should not be administered with H2 antagonists or antacids.

Pharmacodynamics: It is believed that the negatively charged sucrose sulfate binds to positively charged proteins in the base of ulcers or erosion, forming a physical barrier that restricts further

caustic damage and stimulates mucosal prostaglandin and bicarbonate secretion.

Clinical Uses: Sucralfate is administered in a dosage of 1 g four times daily on an empty stomach (at least 1 hour before meals). At present, its clinical uses are limited. Sucralfate is still used by many clinicians for prevention of stress-related bleeding because of concerns that acid inhibitory therapies (antacids, H2 antagonists, and

PPIs) may increase the risk of nosocomial pneumonia.

Adverse Effects: Because it is not absorbed, sucralfate is virtually devoid of systemic adverse effects. Constipation occurs in 2% of patients due to the aluminum salt. Because a small amount of aluminum is absorbed, it should not be used for prolonged periods in patients with renal insufficiency. Sucralfate may bind to other medications, impairing their absorption.

2- Prostaglandin Analogs Pharmacokinetics: Misoprostol, a methyl analog of PGE1, is rapidly absorbed after oral administration and metabolized to a metabolically active free acid.

Pharmacodynamics: Misoprostol has both acid inhibitory and mucosal protective properties. It is believed to stimulate mucus and bicarbonate secretion and enhance mucosal blood flow. In addition, it binds to a prostaglandin receptor on parietal cells, reducing histaminestimulated cAMP production and causing modest acid inhibition.

Clinical Uses: Peptic ulcers develop in approximately 1020% of patients who receive long-term NSAID therapy. Misoprostol reduces the incidence of NSAID-induced ulcers to less than 3% and the incidence of ulcer complications by 50%. However, misoprostol has never achieved widespread use owing to its high adverse-effect profile and need for multiple daily dosing.

Adverse Effects: Diarrhea and cramping abdominal pain occur in 1020% of patients. Because misoprostol stimulates uterine contractions, it should not be used during pregnancy.