Gastric ulcers are due to a combination of etiologies, including diet, stress, and lifestyle associated with the following risk factors:
1) Helicobacter pylori
2) Non-steroidal anti-inflammatory drugs
3) Malignancy

Normal Physiology of Acid Release

Target areas for the treatment of gastric/duodenal ulcers include the effector mechanisms illustrated above.

H₂ Antagonists -- Cimetidine, Ranitidine, Famotidine, Nizatidine
These agents are all selective inhibitors of the H₂ receptor.  Their primary differences are pharmacokinetic.  Famotidine exhibits the longest half-life (up to four hours), but the least bioavailability.  Nizatidine is the most bioavailable, but has the shortest half-life (approximately one and one-half hours).  Additionally, cimetidine has the greatest incidence of side effects as described below.

All these agents produce a dose-dependent decrease in gastric acid secretion.  This decrease is coincidental with decreases in the secretion of pepsin and intrinsic factor, though in most cases these are not clinically relevant.

Adverse Effects: The incidence of side effects in this class of drugs is relatively minor.  Cimetidine exhibits the greatest incidence, still at 3% of the population or less (consistent with placebo).  Reported side effects include changes in lactation, headache, dizziness, nausea, myalgia, rash, and itching.  Somnolence and confusion are more common in elderly patients.   The lack of significant side effects is due in part to the specificity of these agents for the H₂ receptor and the relative predominance of H₁ over H₂ effects elsewhere in the body.

Potentially serious blood dyscrasias, including aplastic anæmias, have been reported for cimetidine, but not the others in the class.  Other adverse reactions particular to cimetidine include the following (most often seen with chronic and/or high dose therapy):  Decreased libido, impotence, and gynecomastia in males and hirsutism and galactorrhœa secondary to increase prolactin release in females.  These are due to two additional mechanistic actions of cimetidine.  Cimetidine weakly binds to androgen receptors and exerts mild anti-androgenic effects.  It also inhibits microsomal hydroxylation of œstradiol, thereby increasing circulating levels of the hormone.

The inhibition of this hepatic enzyme also gives rise to potential drug interactions with cimetidine.  Increases in circulating levels (due again to decreased metabolism) of phenytoin, theophylline, phenobarbitone, and numerous other drugs may occur if given concomitantly with cimetidine.  Clinical significance may require a decrease in the dosage of these drugs.  Other drugs in the class do not appear to inhibit hepatic metabolism (ranitidine has very slight inhibitory activity that is not clinically relevant).

The H₂ blockers are used in the treatment of:
Gastric & duodenal ulcers -- By decreasing the secretion of gastric acid, further mucosal damage is prevented, and healing of the ulcerated areas may proceed.

Gastro-œsophageal reflux disease (GERD) -- decreases in stomach acid content decrease damage and pain to the œsophagus.  Note that these agents do not prevent the reflux, but merely reduce the potential damage.

Zollinger-Ellison Syndrome -- this disease state results from a malignancy of non-beta cell tumors in the islets of the pancreas.  This tumor causes an overproduction of gastrin with subsequent hypersecretion of gastric acid.  The drug of choice for Zollinger-Ellison Syndrome is omeprazole (see below).
 

PROTON PUMP INHIBITORS -- Omeprazole, Lansoprazole, Rabeprazole

These agents are prodrugs.  They must first be bioactivated in the acidic environment of the stomach.  The active metabolite covalently binds (irreversibly) to the ATPase enzyme that drives the proton pump.  NOTE that two molecules of drug must bind with each ATPase to achieve 100% inhibition of the activity of that pump.  New pump (ATPase) protein must be synthesised to restore acid secretory ability following inhibition with omeprazole.  NOTE that lansoprazole inhibition MAY be reversed by a glutathione-dependent mechanism.  This may account for the shorter duration for recovery observed with lansoprazole.  Omeprazole, administered at 20 mg daily for one week, will result in a 95% reduction in acid secretion.  Rabeprazole has a slightly faster onset of action with 88% maximal response observed within 24 hr of initial dosing.  If discontinued, recovery time to pre-treatment levels of acid production ranges from 4 to 5 days -- the time required for synthesis of new proton pumps.  Due to the effectiveness of these agents, they are the drug of choice in hypersecretory conditions such as Zollinger-Ellinson Syndrome.

Side Effects -- These agents also typically have few side effects that limit their use.  Typical incidence is less than 3% and generally includes GI disturbances (possibly related to decrease food breakdown in the absence of gastric acid), headache, dizziness, and drowsiness.  The potential for overgrowth of H. pylori (again, in the absence of acid) has not proven clinically significant thus far.  The relative lack of side effects is due, at least in part, to the specificity of the proton pump in the stomach, the necessity of bioactivation in an acidic environment, and in the rapid degradation of the drug following systemic absorption.

Drug Interactions -- These drugs may decrease the metabolism of phenytoin, diazepam, and warfarin, among other drugs.

CLINICAL NOTE -- Capsules of these drugs MUST be taken whole.  If the capsules are compromised, or if the contents are administered in the absence of the protective capsule, the drug becomes inactivated before it reaches the site of action.

ADDITIONAL TREATMENT OF GASTRIC/DUODENAL ULCERS

ANTIBIOTICS -- Since the discovery that Helicobacter pylori plays a role in gastric ulceration in some patients, appropriate antibiotic therapy has proven successful in shortening the time required for ulceration healing.  Metronidazole, amoxicillin, tetracycline, clarithromycin, and bismuth are currently used as anti-bacterial treatments in gastric ulcer disease.

ANTACIDS -- These agents, probably the oldest pharmacologic intervention in ulcerative diseases, are valuable in the acute treatment of excess acid in the stomach.  While not preventative, they are effective in neutralising existing acid.

SUCRALFATE -- This drug is a complex of sucrose octasulphate and aluminium hydroxide.  In acidic conditions (pH < 4), the complex polymerises to a "sticky, viscid, yellow-white gel" that binds to and covers ulcerated craters.  The binding affinity of this polymer is greater for eroded areas than for intact mucosa.  (Additionally, the binding is greater on duodenal ulcers than gastric ulcers.)  This covering then acts as a "bandage" on the ulceration, preventing further exposure to gastric acid and, thus, further erosion and damage to the mucosa.  Side effects to sucralfate include constipation (<2%, probably due to liberated aluminium) and a feeling of dry mouth (<1%).  Sucralfate will diminish the absorption of digoxin, tetracycline, phenytoin, fluoroquinolone antibiotics, and ketoconazole.

PROSTAGLANDIN ANALOGUES -- Misoprostol is an analogue of prostaglandin E₁.  Although it is an analogue of  PGE₁, It exerts action at both the PGE₂ receptor on the parietal cell, decreasing acid secretion, and at the PGI₂ receptor on the superficial epithelial cell, increasing bicarbonate and mucous secretion.  Both of these actions have a beneficial effect in the treatment of gastric ulcers.  The former prophylactic effect occurs at higher doses while the latter cytoprotective effect occurs at lower doses.  This agent is especially useful in NSAID-induced gastric ulcers, when NSAID-mediated decreases in prostaglandins prevent these beneficial effects.  Approximately 30% of patients taking misoprostol experience diarrhœa, which may limit their taking the drug.  Additionally, misoprostol is a powerful ABORTIFACIENT.  Pregnant women, or those who may become pregnant, should not take, nor handle if possible, misoprostol.

PENTAGASTRIN is a gastrin analogue that is used as a diagnostic aid.  Its' administration will elicit acid secretion without the adverse effects associated with histamine administration.

ANTICHOLINERGICS -- These agents are pharmacologically effective in reducing acid secretion.  However the high incidence of side effects precludes their use.  Two agents (pirenzepine and telenzepine) are being investigated for potential use in gastric ulcer disease.

CARBENOXOLONE -- This agent is found in glycyrrhizia (licorice root) and is used in Europe in the treatment of gastric ulcers.  Its mechanism of action is similar to that of sucralfate.  However, its' strong mineralocorticoid effects (aldosterone-like actions) have prevented its' approval in the United States of America.  It may be present in some herbal preparations that are available in this country.

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