Give an account of the different pharmacological approaches in the treatment of peptic ulcer disease.

Outline:

·        Pathogenesis of peptic ulcer disease.

·        Anti-secretory: H₂-receptor antagonist, proton pump inhibitor.

·        Acid neutralizing: antacids.

·        Cytoprotective: sucralfate, bismuth, misoprostol.

·        Antibacterial: metronidazole, amoxycillin, clarithromycin, tetracycline, bismuth.

·        Overall management.

Suggested Answer:

Peptic ulcer kills few patients but troubles many. Ulcers may be transient, recurrent or chronic, and drug therapy is valuable for the relief of symptoms, to aid healing and to prevent relapse.

Defensive mechanisms are present in the gastric and intestinal mucosa to protect it from the corrosive effects of gastric acid.

The protective mucosal defense mechanisms are:

·        Ability to secrete mucous and bicarbonate ion.

·        Mucosal barrier to protons.

·        Mucosal blood flow.

·        Replacement of damaged epithelial cells.

Endogenous prostaglandins are probably involved in all these mechanisms. Use of NSAIDs, cigarette smoking, the presence of Helicobacter pylori in the stomach and hereditary (male sex, blood group O) influence that equilibrium unfavorably and are associated with increased incidence of peptic ulcer.

Numerous factors influence acid secretion by the stomach, including food, psychological conditioning and drugs. Their effects are mediated at the parietal cells by histamine, gastrin and acetylcholine which, through a common path involving cAMP and calcium ions, interact with the gastric proton pump. Histamine appears to be necessary for the action of gastric and acetylcholine and H₂-receptor antagonists inhibit acid secretion induced by these agents also. The H₂-receptor antagonists are cimetidine, ranitidine, famotidine and nizatidine.

Cimetidine is a histamine H₂-receptor antagonist. Cimetidine contains an imidazole ring and is structurally similar to histamine. Cimetidine competitively inhibits the action of histamine on the H₂ receptors of parietal cells, reducing gastric acid output and concentration under basal conditions and also when stimulated by food, insulin, betazole, histamine, pentagastrin, and caffeine. Although the concentration of pepsin is not reduced, the total amount secreted falls because the volume of gastric juice is less. Cimetidine does not affect gastric emptying.

Cimetidine is readily absorbed from the upper small intestine. The half-life is 2h and 60% of an oral dose is recovered as unchanged drug in the urine, the remainder appearing as metabolites. Cimetidine is widely distributed throughout the body and is 15-20% bound to plasma proteins.

Cimetidine is used for conditions in which reduction of gastric acid secretion is beneficial. These are duodenal ulcer, benign gastric ulcer and reflux esophagitis. When treating a gastric ulcer, it is desirable to confirm that it is benign by endoscopy and biopsy every 6-8 weeks until it is healed, for the symptoms of gastric carcinoma can be relieved by cimetidine so that apparently successful treatment may fatally delay the correct diagnosis. Cimetidine is also used for the prophylaxis of gastrointestinal bleeding due to gastric erosions complicating the stress of burns, fulminant hepatic failure, renal failure or trauma. Cimetidine is given before anaesthesia for emergency surgery and before labor to lessen the risk of pulmonary aspiration of gastric acid; it is also used to prevent peptic ulcer induced by NSAIDs in high-risk patients, e.g. elderly women and those with a previous history of ulceration.

Cimetidine 400 mg  x 2/day, with breakfast and at bedtime is usually satisfactory for peptic ulcer. Most patients become symptom-free in about 8 days but treatment should continue for 6-8 weeks, after which 85-90% of duodenal and 60% of gastric ulcers can be expected to heal.

Adverse effects and interactions are few in short-term use. Minor complaints include headache, dizziness, constipation, diarrhea, tiredness and muscular pain. Bradycardia and cardiac conduction defects may also occur. Cimetidine is a weak anti-androgen and may cause gynaecomastia and sexual dysfunction in males. In the elderly particularly, it may cause CNS disturbances including lethargy, confusion and hallucinations. Cimetidine is an inhibitor of hepatic drug-oxidizing enzymes; raised plasma concentrations with enhanced activity of warfarin, phenytoin, lignocaine, propranolol and theophylline result when these drugs are administered with it.

Omeprazole produces a profound, long-lasting and probably irreversible enzyme inhibition of both basic and stimulated acid secretion. It is a pro-drug. In the secretory canaliculi of the parietal cell, omeprazole is activated into its active form sulphenamide which then binds to the H⁺/K⁺ ATPase, irreversibly inhibiting this enzyme which is involved in the final step of gastric acid secretion. Omeprazole must be given in enteric-coated granules for it is degraded at low pH; it is absorbed in the small intestine with a half-life of one hour.

Omeprazole is highly effective for ulcerative reflux esophagitis and is the drug of choice for Zollinger-Ellison syndrome. It heals peptic ulcers as well as H but the latter are generally drugs of the first choice because of persisting uncertainty about the safety of long-term suppression of acid secretion.

Adverse effects are nausea, headache, diarrhoea, constipation and rash. Omeprazole inhibits the oxidative metabolism of warfarin and phenytoin, enhancing the action of these drugs.

Pirenzepine is a relatively selective M₁ muscarinic receptor blocker. It inhibits the M₁ receptor on the paracrine cells resulting in decreased histamine release and subsequently, decreased acid secretion from the parietal cells. Pirenzepine is excreted mainly unchanged both in urine and bile. At slightly higher doses, patients may suffer from typical anti-cholinergic symptoms such as dry mouth, nose and throat, blurred vision and urinary retention. Its use is contraindicated in patients with esophageal reflux disease because it decreases gastric emptying.

Antacids are weak bases which can neutralize gastric acid from pH 1 –2 to pH 4 – 5, relieve gastric pain and promote ulcer healing. They are used intermittently when symptoms occur usually as an adjunct to H₂-receptor antagonists.

Magnesium hydroxide causes diarrhea whereas aluminium hydroxide and calcium carbonate are associated with constipation. Sufficient aluminium may be absorbed from the intestine to create a risk of encephalopathy in patients with chronic renal failure. Hypophosphataemia may result from binding phosphate so that it is not absorbed from the gut. Sodium bicarbonate is absorbed and causes alkalosis which can be a serious matter in patients with renal insufficiency. Sodium bicarbonate can release carbon dioxide in the stomach to cause discomfort and belching. Calcium containing antacids may cause rebound acid hypersecretion and with prolonged used, hypercalcaemia and alkalosis.

Magnesium trisillicate and aluminium hydroxide strongly bind iron, phenothiazines, tetracyclines, propranolol, phenytoin, isoniazid, ranitidine, indomethacin and sulfadiazine to decrease their bioavailability. Aluminium hydroxide delays gastric emptying and slows the rate of absorption of indomethacin, dicumarol, isoniazid and some benzodiazepines. Increased urinary pH delays the elimination of amines such as quinidine and lignocaine and increases the elimination of salicylates and phenobarbitone.

Drugs can increase mucosal resistance by protecting the base of a peptic ulcer, eradicating H. pylori and ‘cytoprotection’.

Sucralfate is a complex salt of sucrose sulphate and aluminium hydroxide. At pH < 4, it increases prostaglandin synthesis, inhibits pepsin activity, adsorbs bile acid and forms a viscid gel which has a high affinity for the base of an ulcer crater. Sucralfate is used for benign gastric and duodenal ulcer and for chronic gastritis. Its efficacy is equal to that of H₂-receptor antagonists but may be better at prolonging remission after healing has occurred. Maintenance treatment is effective at preventing relapse.

Sucralfate is effective only in acid conditions, an antacid should not be taken 30 min before or after a dose of sucralfate. Sucralfate interferes with absorption of ciprofloxacin, theophylline, digoxin, phenytoin and amitriptyline.

Endogenous prostaglandins particularly of the E and I group inhibit the secretion of acid and stimulate the secretion of mucus and bicarbonate, as well as increase mucosal blood flow. Misoprostol is an analogue of prostaglandin E1 methyl ester, which is taken as a prophylactic therapy to prevent gastric ulcers in patients who use large doses of NSAIDs. Diarrhoea, spotting dysmenorrhoea and abdominal cramps are common side effects. As it is a potential abortifacient, its use in contraindicated during pregnancy.

Bismuth chelate acts by selectively chelating with protein material in the ulcer base, so forming a coating that protects it from the adverse influences of acid, pepsin and bile. It is also active against Helicobacter pylori. Bismuth chelate is used for benign gastric and duodenal ulcers and has a therapeutic efficacy equivalent to H₂-receptor antagonists. It darkens the tongue, teeth and stool and may cause encephalopathy in renal impaired patients.

Duodenal and gastric ulcers are often associated with an active chronic inflammation of the duodenum and of the gastric antrum. A causal role for Helicobacter pylori in gastroduodenal disease is accepted because the organism is found in 90% of cases of duodenal ulcer and 70% of cases of gastric ulcer. Infection may be confirmed by mucosal histology, a radio-labelled breath test or by the detection of IgG antibodies to Helicobacter pylori.

Helicobacter pylori is sensitive to metronidazole, amoxycillin, clarithromycin, tetracycline and bismuth salts. Effective regimens will comprise one or two weeks of antimicrobial therapy combined with suppression of acid secretion with omeprazole. Eradication of infection usually results in long-term remission of the ulcer.

Before pharmacological treatment is instituted, general advice should be given to stop smoking, to avoid NSAID use and alcohol. Healing of peptic ulcer can be accelerated by a H₂-receptor antagonist (generally preferred due to safety and ease of administration), bismuth chelate and sucralfate (equally effective but the need for multiple dosing may limit compliance) and antacids (now limited to providing supplementary symptomatic relief). Ulcers that are difficult to heal may respond to double the normal dose of a H₂-receptor antagonist or to omeprazole. For duodenal ulcers, evidence of infection with Helicobacter pylori should be sought and, if found, one of the regimens to eradicate the organism should be used. Most ulcers induced by NSAIDs occur in the stomach and duodenum. The first step should be to review the necessity for using the NSAID. Misoprostol may prevent peptic ulceration in those at high risk, e.g. the elderly. Prevention of relapse, in those individuals who are prone to it, may be achieved with a H₂-blocker taken as a single dose at night, on a long-term basis.