Pharmacology Notes

Rabeprazole increases serum levels and potentially increases the toxicity of benzodiazepines when taken concurrently.

Histamine H2-Receptor Antagonists
Th ere are two types of histamine receptors: histamine (H1) and histamine (H2). Th e second of these mediates the acid secretion from gastric parietal cells and is inhibited by the H2-receptor-blocking drugs. These drugs may be preferred to other antiulcer agents because of their convenience and lack of effect on GI motility. H2-receptor antagonists are listed in Table 15-2.

Mechanism of Action
Cimetidine was the fi rst H2-receptor antagonist approved for clinical use. It blocks the H2 receptor on the parietal cells of the stomach, thus decreasing gastric acid secretion.

Indications
H2-receptor antagonists are used to promote healing of gastric and duodenal ulcers, and hypersecretory states such as Zollinger-Ellison syndrome. Prototypes of H2-receptor antagonists include cimetidine, famotidine, nizatidine, and ranitidine. Th ey are a remarkably safe group of drugs.

• Cimetidine is available OTC for the treatment of acute gastric ulcer, duodenal ulcer, and gastroesophageal refux. It is also used in the treatment of Zollinger-Ellison syndrome. 

• Famotidine is the most potent H2-receptor antagonist. Aft er a 40-mg dose, mean nocturnal gastric acid secretion is reduced by 94 percent for up to 10 hours. It is recommended for the short-term treatment of mucosal ulcers of the GI tract. Famotidine is absorbed incompletely. It should be used in a lower dosage and at longer dosing intervals in patients with severe renal insuffi ciency. 

• The newest H2-receptor antagonist, nizatidine, may be used to treat and prevent recurrence of duodenal ulcers. It is also used for gastric ulcers, and gastroesophageal refl ux. More than 90 percent of an oral dose is excreted in the urine within 12 hours, and 60 percent as unchanged drug. Therefore, it should be used in reduced dosage in patients with severe renal insuffi ciency.

• Ranitidine is a more potent drug. It is fi ve to ten times more potent than cimetidine. Ranitidine requires a less frequent dosing schedule than cimetidine. It is an H2-receptor antagonist indicated for the short-term treatment of duodenal ulcers and the management of hypersecretory conditions such as Zollinger-Ellison syndrome. Th e pharmacokinetic profi le of ranitidine is similar to that of cimetidine.

Adverse Effects
The list of adverse reactions is long, but the incidence is low. Among the adverse eff ects associated with all four drugs are headache, dizziness, malaise, myalgia, nausea, diarrhea, constipation, rashes, pruritus, and impotence. Adverse effects, such as unusual bleeding, fever, sore throat, hallucinations, or skin rash should be reported promptly, and the therapy must be discontinued.

Contraindications and Precautions
Histamine H2 antagonists should be avoided in patients with a known hypersensitivity, and during lactation or pregnancy. Th ese agents are used cautiously in patients with hepatic or renal dysfunction. Cimetidine is used used cautiously in elderly patients because they may cause confusion, and a dosage reduction may be needed. Cimetidine, famotidine, and ranitidine are pregnancy category B drugs, while nizatidine is a pregnancy category C drug.

All of these drugs should be used cautiously during pregnancy and lactation.

Drug Interactions
Cimetidine increases the risk of decreased white blood cell counts with antimetabolites and alkylating agents. It also increases serum levels and risk of toxicity of warfarin-type anticoagulants, phenytoin, beta-adrenergic blocking agents, alcohol, quinidine, lidocaine, theophylline, chloroquine, and diazepam. Nizatidine increases serum salicylate levels with aspirin. Ranitidine also increases the eff ects of warfarin and toxicity of lidocaine. Ranitidine decreases the eff ectiveness of diazepam and its clearance.

Antacids
There are differences in the types of antacids, in terms of their contents, neutralizing capacity, duration of action, side eff ects, and cost. These must be considered when choosing an antacid for therapeutic use. Antacids are OTC drugs. The most widely used antacids are sodium bicarbonate, calcium carbonate, aluminum hydroxide, and magnesium hydroxide.

Mechanism of Action
Antacids neutralize hydrochloric acid and raise gastric pH, thus inhibiting pepsin (a gastric enzyme). Antacids reduce the concentration and total load of acid in the gastric contents. By increasing gastric pH, antacids also inhibit pepsin activity. In addition, they strengthen the gastric mucosal barrier.

Indications
These agents are used widely for the relief of heartburn, dyspepsia, and medical treatment of peptic ulcer. Th e primary role of antacids in the management of acid-peptic disorders is the relief of pain. Nonsystemic antacids (magnesium or aluminum substances) are preferred to systemic antacids such as sodium bicarbonate for intensive ulcer therapy because they avoid the risk of alkalosis. Liquid antacid forms have a greater buff ering capacity than tablets. However, tablets are more convenient to carry. Antacid mixtures such as aluminum hydroxide with magnesium hydroxide provide more even, sustained action than single-agent antacids, and permit a lower dosage of each compound.

Adverse Effects
Constipation can occur in patients using calcium carbonate and aluminum containing antacids. Diarrhea is a common adverse effect of magnesium- and sodium-containing antacids. If diarrhea occurs, the patient may alternate the antacid mixture with aluminum hydroxide. Hypophosphatemia and osteomalacia can occur with long-term use of aluminum hydroxide, but patients, such as alcoholics. Calcium carbonate usually is avoided because it causes acid rebound, hypercalcemia, vomiting, metabolic alkalosis, confusion, and renal calculi. It may also delay pain relief and ulcer healing.

Contraindications and Precautions
Antacids are contraindicated in patients with severe abdominal pain of unknown cause, and during lactation. Sodium bicarbonate is contraindicated in patients with hypertension, congestive heart failure (CHF), severe renal disease, and edema. It should not be used for ulcer therapy. All antacids should be used cautiously in elderly patients and renally impaired patients. Chronic administration of calcium carbonate-containing antacids should be avoided because of hypercalcemia. Calcium carbonate and magnesiumcontaining antacids should be used cautiously in patients with severe renal disease.

Drug Interactions
Because antacids alter gastric pH and affect absorption of ingested substances, they have a high potential for drug interactions. To ensure consistent absorption and therapeutic effi cacy, orally administered drugs should be given 30 to 60 minutes before antacids. Th ese agents bind with tetracycline and inhibit its absorption, reducing its therapeutic efficacy.
Antacids may destroy the coating of enteric-coated drugs, leading to premature drug dissolution in the stomach. Antacids may interfere with the absorption of many drugs, including cimetidine, ranitidine, digoxin, isoniazid, iron products, anticholinergics, and phenothiazines

Peptic ulcer refers to a lesion located in either the stomach (gastric ulcer) or in the duodenum (small intestine) . In general, ulcers occur whenever there is an increase in acid secretion or a decrease in mucosal resistance. Mucosal injury in the acid peptic diseases includes gastric ulcer, duodenal ulcer, and gastroesophageal refl ux disease, which are mediated by gastric acid. Hydrochloric acid is secreted by parietal cells in the body of the stomach. It is regulated by adjacent endocrines, such as gastrin, or by histamine, somatostatin, and prostaglandin E2. Gastrin is a relatively weak stimulant of the parietal cells. It acts primarily to cause the release of histamine, which is the most potent stimulus of acid secretion, and acts as the common mediator. Histamine antagonists inhibit acid secretion that is stimulated by gastrin and acetylcholine, as well as histamine. There are a number of causes of peptic ulcer, including:

• Family history

• Smoking tobacco

• Alcohol

• Coffee

• Stress

• Infection with Helicobacter pylori (H. pylori)

• Blood group O

• Anti-infl ammatory drugs (aspirin, NSAIDs, and glucocorticoids)

A wide variety of prescription and OTC medications are available for the treatment of peptic ulcer. These drugs include: antacids, H2-receptor antagonists, proton pump inhibitors, and antibiotics. Antibiotics treat peptic ulcers caused by Helicobacter pylori

The digestive system, sometimes called the gastrointestinal tract, alimentary tract, or gut, consists of a long hollow tubule. The digestive tract secretes substances used in the process of digestion into the canal. Th e growth of the body depends upon the consumption, absorption, and metabolism of food. Th is system also involves the elimination of waste. The digestive system is subject to many disorders, some of which are very common. Numerous drugs are used to treat these varying conditions.

• bisacodyl
• castor oil
• senna.

• bisacodyl
• castor oil
• senna.

• glycerin
• lactulose
• saline compounds (magnesium salts, sodium biphosphate, sodium phosphate, polyethylene glycol [PEG], and electrolytes).

• glycerin
• lactulose
• saline compounds (magnesium salts, sodium biphosphate, sodium phosphate, polyethylene glycol [PEG], and electrolytes).