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Case: Agents for upper GI disorders. Class

Drugs used to treat acid-peptic diseases (Table Medications for peptic ulcers) either reduce gastric acidity (antacids, histamine H2-receptor antagonists, and PPIs) or promote the defense of the GI mucosa (sucralfate, bismuth subsalicylate, and the prostaglandin analog, misoprostol).

Table: Medications for peptic ulcers

ANTACIDS ADVERSE EFFECTS
Sodium bicarbonate Bloating, belching, metabolic acidosis as a result of absorbed unreacted alkali at high doses, and fluid retention caused by absorption of sodium chloride that may compromise patients with heart failure and hypertension. Hypercalcemia at high doses when administered with dairy products containing calcium.
Calcium carbonate Bloating, belching, metabolic acidosis, hypercalcemia.
Magnesium hydroxide Osmotic diarrhea from unabsorbed magnesium.
Aluminum hydroxide Constipation from unabsorbed aluminum.
HISTAMINE H2-RECEPTOR ANTAGONIST ADVERSE EFFECTS
Cimetidine (prototype)

Ranitidine

Famotidine

Nizatidine

Mild diarrhea or constipation, headache, myalgia. Confusion, hallucinations, and excitement, particularly cimetidine, when administered IV to elderly or patients with renal or liver disease.
PROTON PUMP INHIBITORS ADVERSE EFFECTS
Omeprazole (prototype)

Esomeprazole

Lansoprazole

Pantoprazole

Rabeprazole

Small increase in incidence of diarrhea and headache. Otherwise, no significant adverse effects documented in humans, although there are theoretical concerns with long-term therapy regarding the development of certain cancers and enteric infections.
GI PROTECTIVE AGENTS ADVERSE EFFECTS
Sucralfate Constipation as a consequence of the aluminum salt. It may bind other drugs to limit their absorption (phenytoin, quinoline antibodies).
Bismuth subsalicylate Black stools and darkening of the tongue.
Misoprostol Diarrhea and abdominal discomfort. Contraindicated in women unless proved negative for pregnancy.

Available antacid preparations are used primarily to treat heartburn and dyspepsia. When given concomitantly with other drugs, antacids may reduce their absorption through direct binding or, as a result of an increase in gastric pH, by altering their dissolution or solubility.

Available histamine H2-receptor antagonists are used to treat dyspepsia, GERD, peptic ulcer disease, and stress-induced gastritis.

PPIs are generally considered the first-line drugs for treating acid-peptic disease as a result of their superior efficacy and safety profile. Available proton pump inhibitors (PPIs) are also used to treat dyspepsia, GERD, peptic ulcer disease, and stress-induced gastritis, as well as gastrinomas. For treating peptic ulcer disease caused by H. pylori, PPIs are used in a multidrug regimen that includes the antibiotics clarithromycin and amoxicillin and/or metronidazole.

Sucralfate use has, for the most part, been supplanted by other agents for the treatment of upper gastrointestinal disorders. It is still used clinically to treat stress-related gastritis.

Misoprostol is used rarely, to treat nonsteroidal anti-inflammatory drug (NSAID)-induced peptic ulcer disease.

Bismuth subsalicylate (Pepto-Bismol) is available as a nonprescription agent and is used to treat dyspepsia, acute diarrhea, and, as a second-line agent in a multidrug combination, H. pylori infection where it is thought to inhibit growth of the organism.

Structure

PPIs are substituted benzimidazoles. They resemble histamine H2-receptor antagonists but have a different mechanism of action. Sucralfate is a complex salt of sucrose sulfate and aluminum hydroxide. Misoprostol is a prostaglandin analog of prostaglandin E1 (PGE1). Bismuth subsahcylate is a combination of bismuth and salicylate.

Mechanism of Action

Antacids are weak bases that directly neutralize gastric hydrochloric acid to form a salt and water and to reduce pepsin activity. They may also stimulate the production of prostaglandins and thus increase the defense of the gastrointestinal mucosa.

Histamine H2-receptor antagonists are highly specific and selective competitive antagonists of histamine binding to gastric parietal cell histamine H2 receptors. Thus they prevent activation of adenylyl cyclase and accumulation of cAMP, which mediate acid release into the gastric lumen. Parietal cell acid secretion induced by the secretagogues gastrin and acetylcholine, which act synergistically with histamine, is also inhibited by histamine H2-receptor antagonists, albeit indirectly. PPIs irreversibly inhibit the H+, K+-ATPase proton pump in parietal cells, thus reducing transport of acid from the cell into the lumen of the stomach.

Sucralfate in its viscous form may bind to positively charged proteins to coat epithelial cells and to form a physical barrier in the GI tract that protects the luminal surface and any already formed ulcers from the deleterious effects of gastric acid and pepsin.

Misoprostol, a PGE1 analog, stimulates bicarbonate and mucus secretion and mucosal blood flow, resulting in enhanced neutralization and action of secreted acid. It also binds to parietal cell prostaglandin receptors to modestly inhibit secretagogue-induced acid secretion.

Bismuth subsahcylate, like sucralfate, coats epithelial cells to form a physical barrier in the gastrointestinal tract and protect it from the deleterious effects of gastric acid and pepsin. It may also stimulate bicarbonate and PGE2 secretion.

Administration

All antacids, histamine H2-receptor antagonists, proton pump inhibitors, sucralfate, misoprostol, and bismuth subsahcylate can be given orally. The PPIs pantoprazole and the histamine H2-receptor antagonists (cimetidine, famotidine, and ranitidine) are available for parenteral use.

As over-the-counter preparations, magnesium hydroxide, which can cause diarrhea, and aluminum hydroxide, which can cause constipation, are usually administered in combination to balance their effects on the GI tract.

PPIs are inactive, acid-labile, prodrugs that are administered in acid-resistant, enteric-coated preparations to protect them from destruction in the stomach. In the acidic environment of the stomach, sucralfate forms a viscous gel.

Pharmacokinetics

The acid-neutralizing capacity of available antacid preparations varies considerably, being highly influenced by their rate of dissolution, their solubility in water, and the rate of gastric emptying among other factors. Sodium bicarbonate and calcium carbonate react more rapidly with HCl to produce C02 and water than do magnesium or aluminum hydroxide and, therefore, may cause bloating and belching.

Histamine H2-receptor antagonists are absorbed rapidly; however, cimeti-dine, ranitidine, and famotidine have a bioavailability of only 50 percent. Their clearances can be reduced in the elderly and by renal and hepatic dysfunction. Cimetidine inhibits the activity of several hepatic cytochrome P450 enzymes that can prolong the duration of action of a number of other drugs.

PPI bioavailability is decreased significantly by food. Because maximal inhibition of H+, K+-ATPase occurs when proton pumps are actively secreting acid, PPIs are best administered within an hour or so of meals. After dissolution of the enteric-coated PPI capsule in the intestine, the lipophilic prodrug diffuses into the acidic environment of the parietal cell, where it becomes protonated and highly concentrated, and where it is then converted to a reactive sulfonamide cation that irreversibly binds to and inactivates parietal cell H+, K+-ATPase through a covalent disulfide linkage. Although their serum half-life is short, PPI inhibition of the proton pump lasts up to 24 hours while synthesis of new H+, K+-ATPase occurs. PPIs are metabolized by hepatic P450 microsomal enzymes; however, no clinically significant drug-drug interactions have been documented.

Sucralfate is very insoluble, and therefore it acts locally with little systemic absorption from the gastrointestinal tract.

Misoprostol is absorbed rapidly and is metabolized to an active agent that has a very short serum half-life and short duration of action and therefore must be administered three to four times daily.

Bismuth subsalicylate is rapidly dissociated in the stomach into bismuth, which is eliminated in the stool, and salicylate, which is absorbed systemically.

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