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Chapter: Modern Medical Toxicology: Miscellaneous Drugs and Poisons: Gastrointestinal and Endocrinal Drugs

Antacids and Anti-ulcer Drugs

One of the commonest ailments plaguing mankind throughout history has been indigestion or dyspepsia, the causes for which are many: hepatic, gastric, cardiac, alco-holic, and even hysterical.


Antacids and Anti-ulcer Drugs


One of the commonest ailments plaguing mankind throughout history has been indigestion or dyspepsia, the causes for which are many: hepatic, gastric, cardiac, alco-holic, and even hysterical. By far the most prevalent form appears to be gastric (or more properly gastrointestinal), resulting from dysfunction of stomach and intestines, and the vast majority of such cases are related to excessive acidity— acid dyspepsia. It is no wonder then that a plethora of drugs exist for the prevention or treatment of this “ubiquitous” condition, never mind the fact that many a case may merely be the result of over-eating. For centuries, acid dyspepsia has been tackled by countering the acidity in the stomach with antacids, a classic example of therapeutic neutralisation.

Classification of Antacids

1. Aluminium

·              Aluminium carbonate

·              Aluminium hydroxide

·              Aluminium phosphate

·              Dihydroxyaluminium aminoacetate.


·              Calcium carbonate.


·              Magnesium carbonate

·              Magnesium hydroxide

·              Magnesium oxide

·              Magnesium trisilicate.

4.Combination preparations

·              Dihydroxyaluminium sodium carbonate

·              Magaldrate.


■■  Chewing gums

■■  Liquids

■■  Lozenges

■■  Powders

■■  Tablets.


■■  Peptic ulcer

■■  Acute gastritis and stress ulceration

■■  Non-ulcer dyspepsia

■■  Zollinger-Ellison syndrome

■■  Gastroesophageal reflux

■■  Gastrointestinal bleeding

■■  Oesophagitis

■■  Magnesium oxide: Hypomagnesaemia resulting from malnutrition, restricted diet, alcoholism, or magnesium-depleting drugs.


Antacids are generally poorly soluble and are cleared from the empty stomach in 15 to 30 minutes. Except for aluminium phos-phate, aluminium- containing antacids combine with dietary phosphate to form insoluble, nonabsorbable aluminium phos-phate. Calcium chloride formed in the reaction of hydrochloric acid and calcium carbonate is converted to insoluble calcium salts and soaps in the small intestine where absorption rate in therapeutic doses ranged from 9 to 37%. Magnesium chloride formed after neutralisation of hydrochloric acid is partly (15 to 30%) absorbed. Sodium citrate is completely absorbed.

While in most cases, almost all the ingested antacid is eliminated in the faeces, some cations (especially aluminium and magnesium) may be absorbed to a lesser or greater extent from the intestine. Small amounts of the cations from the insoluble aluminium and calcium- containing antacids and 97% of the magnesium-containing antacids are eliminated as soaps, phosphates, and sundry other insoluble compounds such as magnesium chloride. While this usually poses no problems, renal insufficiency can cause absorbed aluminium to predispose to osteoporosis, encephalopathy, and proximal myopathy. Calcium salts can produce hypercalcaemia. Overingestion of bismuth salts can raise the plasma bismuth level significantly.

Calcium reacts with carbonate in the intestines to form calcium carbonate which is excreted primarily in the faeces. Aluminium may be excreted as carbonates and hydroxides. Biliary excretion is an important route of elimination of orally absorbed aluminium thus requiring close monitoring of long-term antacid therapy in patients with liver disease.

Simethicone is included in many antacid preparations, and acts as a surfactant to decrease foaming.

Mode of Action

·              The primary action of antacid is to neutralise gastric acid (90% at gastric pH of 1.3 to 2.3 and 99% at pH of 3.3), thereby increasing the pH in the stomach and duodenal bulb. Antacids react with hydrochloric acid to form chlo- rides, water, and carbon dioxide. Acidity is thereby neutral- ised. Elevation of the pH in the gastric antrum increases the secretion of gastrin and causes a compensatory secretion of acid and pepsin. This rebound secretion is brief and of a low degree with aluminium hydroxide, magnesium hydroxide, or sodium bicarbonate, but is prolonged and intense with calcium carbonate.

·              The anti-pepsin effect of antacids has been attributed to the following mechanisms:

o     An increase in the pH to above 4 resulting in inhibition of pepsinogen conversion to pepsin.

o     Absorption of pepsin by the antacid.

o     Possible stimulation of endorphin release or prosta- glandin formation.

Adverse Effects and Clinical (Toxic) Features

·            Acute ingestion of antacids rarely leads to toxicity. Magnesium and aluminium hydroxide are of low-order toxicity, while calcium carbonate and sodium bicarbonate must be used with extreme caution because of their potential for systemic toxicity.

·            With prolonged administration and/or excessively large doses, arrhythmias, hypo- and hypertension, encepha-lopathy, renal failure, diarrhoea, constipation, gastroin-testinal obstruction and/or perforation, alkalosis, fluid, electrolyte, and mineral derangements, and myopathies and osteodystrophies have been reported.

·            Alkalosis (especially with unneutralised sodium bicar-bonate).

·              Milk-alkali syndrome: Common in the past when largedoses of sodium bicarbonate or calcium carbonate were advocated along with milk for the treatment of peptic ulcer. Problems associated with such a regimen include hypercalcaemia (with nausea, vomiting, anorexia, weak-ness, headache, dizziness, and change in mental status), reduced parathormone secretion, phosphate retention, precipitation of calcium salts in the kidney, metabolic alkalosis and renal insufficiency.

·            Nephrolithiasis: has been reported with long-term use of calcium- and magnesium-containing antacids.

·            Side effects: Belching, abdominal distension, nausea,flatulence. Bismuth salts can cause blackish discoloura-tion of oral mcosa (and stools). Constipation is the main side effect of aluminium antacids.

·            Bismuth salts in excess can cause ataxia, encephalopathy, and osteodystrophy.

·            Prophylactic antacid therapy in paediatric intensive care units (to prevent stress ulcers) can cause hypotonia, diffi-culty in arousing, hypermagnesaemia, hypercalcaemia, and aluminium hydroxide bezoar formaton.

·            Dialysis encephalopathy syndrome, characterised by dysarthria, apraxia, asterixis, myoclonus, dementia, focal seizures, and vitamin D-resistant osteomalacia, has been reported in patients with elevated aluminium levels in bone, brain and muscle.

·            Phosphate depletion syndrome—hypophosphataemia may occur as early as the second week of therapy with aluminium hydroxide given in doses of 30 ml three times a day. Manifestations include anorexia, bone pain, muscle weakness, paraesthesias and seizures.

·            Alzheimer’s disease and its possible association with antacids has been inferred in a few inconclusive case-control studies.

Drug Interactions

Antacids alter the rate of dissolution, absorption, and elimina-tion of several drugs, especially theophylline, iron, tetracycline, quinolones, isoniazid, ketoconazole, ethambutol, benzodi-azepines, phenothiazines, ranitidine, phenytoin, prednisone, procainamide, etc., where bioavailability is decreased, and sulfonamides, levodopa, and valproate, where bioavailability is increased.


·      Supportive and symptomatic measures. Decontamination with activated charcoal is not necessary because of the poor absorption from the gastrointestinal tract and lack of systemic toxicity after overdose.

·      Monitor electrolytes, pH, serum aluminium, calcium, and/or magnesium levels, EKG, and renal function tests in patients with renal impairment, especially if symptomatic.

·      Normal serum aluminium levels are less than 15 mg/L.

·      Normal total serum calcium levels are 9 to 10.4 mg/dL (4.5 to 5.2 mEq/L).

·      Normal serum magnesium levels range from 1.3 to 2.6 mEq/L.

·      Excessive aluminium tissue deposits can be mobilised with desferrioxamine prior to haemodialysis.

·              Symptomatic hypercalcaemia in chronic ingestion may require fluids and diuretic therapy. Mithramycin is indicated in severe hypercalcaemia unresponsive to 12 to 24 hours of saline diuresis.

·      Haemodialysis and peritoneal dialysis can reduce serum aluminium, calcium, and magnesium levels but are rarely necessary after acute ingestion.

Anti-ulcer Drugs

·      H2 receptor antagonists

·      Inhibitors of H+, K+-ATPase

·      Agents effective against Helicobacter pylori.

H2 Receptor Antagonists

Examples include burimamide, cimetidine, famotidine, nizati-dine, ranitidine, roxatidine, zolentidine. These drugs are used in the treatment of duodenal ulcer, gastric ulcer, Zollinger-Ellison syndrome, gastroesophageal reflux disease, stress ulcers and hypersecretory states.

H2 receptor antagonists are well absorbed after oral admin-istration and peak plasma concentrations are attained in 1 to 2 hours. Although subject to hepatic metabolism, these drugs are excreted unmetabolised in large part in the urine.

H2 receptor antagonists competitively inhibit the interac-tion of histamine with H2 receptors, which results in inhibi-tion of gastric acid secretion. The output of pepsin also falls correspondingly. It is postulated that by blocking H2 recep-tors on the parietal cell, the ability of histamine, gastrin, and acetylcholine to stimulate acid secretion is blocked. However, there is no effect on rate of gastric emptying, pressure of lower oesophageal sphincter, and pancreatic secretion. Ranitidine is 5 to 12 times better than cimetidine, and famotidine is 30 to 60 times better than cimetidine on a molar basis in controlling gastric acid hypersecretion.

Adverse effects include somnolence, confusion, slurred speech, restlessness, hallucinations, and seizures. Rarely there may be facial twitching, Parkinsonism, chorea, and dystonia. There have been reports of gynaecomastia. Cardiovascular effects include bradycardia, hypotension, AV block, and cardiac arrest. They are more common with intravenous use. Famotidine and ranitidine can cause thrombocytopenia. The following have also been reported: agranulocytosis, pancyto-penia, and aplastic anaemia. Hepatic hypersensitivity reactions are more common with ranitidine. Hyperprolactinaemia occurs with the use of all H2 receptor antagonists. Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported. Cimetidine, ranitidine, and famotidine have been associated with drug-induced fever, which typically resolves within 48 to 72 hours after discontinuation of the drug. The mechanism is thought to be CNS histamine receptor blockade. Cardiac arrest has occurred following therapeutic IV administration of cimetidine.

CNS disturbances may occur with therapeutic or overdoses of all the H2 receptor antagonists, but is reported to a greater degree with cimetidine, which crosses the blood-brain barrier more readily than the other drugs in this class. The most common symptom reported has been confusion. The most consistent adverse reaction reported with famotidine is a severe, throbbing headache, with an incidence of up to 4.7%. This has also been reported for ranitidine.

Liver enzyme elevation is the most frequently reported hepatic effect of H2 receptor antagonists. The LFT’s typically normalise following discontinuation of the drug, and may be due to a hypersensitivity reaction. Acute interstitial nephritis has also been reported. Gynaecomastia and increased prolactin levels may be seen following therapeutic doses of cimetidine.

Cimetidine has an imidazole ring and therefore inhibits the cytochrome P450 mixed-function oxidase involved in the hepatic metabolism of several drugs. It also reduces hepatic blood flow and impedes the elimination of drugs like propran-olol which are metabolised in the liver. Absorption of cimeti-dine is significantly reduced by antacids, and hence there is need for adequate spacing between the two (of at least 1 hour). Cimetidine potentiates the effect of anticoagulants, phenytoin, theophylline, benzodiazepines, beta blockers, metronidazole, lignocaine, procainamide, verapamil, and quinidine. Potentially lethal interactions have been reported with morphine. There is also potentiation of effects of ethyl alcohol. Ranitidine has a furan ring instead of an imidazole ring, and does not inhibit the cytochrome P450 mixed-function oxidase enzyme system. However it may interact adversely with warfarin, benzodiaz-pines, metoprolol, nifedipine and paracetamol.

Overdose is associated with dry mouth, mild drowsiness, epigastric discomfort with diarrhoea, muscle pain, elevated liver or kidney function tests, leukopenia, thrombocytopenia, vertigo, slurred speech, mydriasis, confusion, drowsiness, headache, delirium, psychosis, mild bradycardia, hypotension, and other CVS effects (vide supra). Fatalities are rare.

Treatment: In significant overdoses it may be advisableto monitor cardiac function, liver function and renal function tests, as well as endocrine and CNS effects. Stomach wash may be done (within 4 hours). Convulsions constitute an abso-lute contraindication. Activated charcoal may be beneficial. Benzodiazepines can be given for convulsions. If seizures persist or recur, administer phenobarbitone. Cimetidine-induced agitation and delirium have been reversed by physostigmine in several reported cases. However, the use of physostigmine for this purpose is still very questionable. Doses used in adults were 1 mg IV, repeated once if needed. Patients demonstrating cardiac abnormalities should have continuous ECG monitoring. Arrhythmias must be managed in the usual way, e.g. atro-pine for bradycardia, lignocaine for ventricular arrhythmias. Haemodialysis may be effective.

Inhibitors of H+, K+-ATPase (Proton Pump Inhibitors)

The proton pump inhibitors act by inhibiting the H+,K+-ATPase system which acts as the ultimate mediator of acid secretion, and is located in the apical membrane of the gastric parietal cell. Examples include esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole. They are used in the treatment of patients with ulcers in the stomach, duodenum, or oesophagus, when there is inadequate response to H2 receptor antagonists (especially in Zollinger-Ellison syndrome). They are also beneficial in the treatment of gastroesophageal reflux disease (GERD). In addition, they are used in combination with amoxycillin and clarithromycin in the treatment of H. pylori infection and duodenal ulcer disease (active or past history within 5 years).

Because it is acid-labile, omeprazole is marketed in capsules containing enteric-coated granules. The absolute oral bioavailability is approximately 30 to 60% at doses of 20 to 40 mg which may be due in part to presystemic metabolism. Omeprazole is extensively metabolised in the liver. About 80% of a dose is eliminated in the urine as at least six metabolites, predominantly hydroxyomeprazole and its corresponding carboxylic acid. The remainder is excreted in the bile.

Chronic use of proton pump inhibitors can cause headache, nausea, abdominal pain, diarrhoea, peripheral neuropathy, gynaecomastia, haemolytic anaemia, subacute myopathy, hepatic failure, and gastric polyposis. Hyperhydrosis can be a troublesome recurrent feature. Diarrhoea is frequently reported with therapeutic use of proton pump inhibitors. Ocular damage has been associated with the use of proton pump inhibitors. In several case reports, individuals reported the following after therapeutic use of omeprazole or pantoprazole: papillary oedema and papillitis which progressed to anterior ischaemic optic neuropathy with persistent visual field defects, ocular pain and irreversible visual impairment. Acute interstitial nephritis has been reported in a few cases. Isolated cases of neutropenia and agranulocytosis have been reported following therapeutic use of omeprazole. There are indications that tendency to carci-nogenicity may be enhanced during long-term use.

Proton pump inhibitors can interfere with the absorption of some drugs (e.g. ketoconazole, iron salts, and digoxin) by inhibiting gastric acid secretion. Omeprazole inhibits cytochrome P450, and may interfere with metabolic clearance of concomi-tantly administered drugs. Elimination of the following drugs may be prolonged: diazepam, warfarin, phenytoin and aminophylline.

Overdose results in mild tachycardia, vasodilation, confu-sion, abdominal pain, nausea, vomiting, drowsiness, sweating, headache, dry mouth, and blurred vision. Individuals have survived doses ranging from 320 mg to 900 mg (16 to 45 times the usual therapeutic dose). Treatment consists of supportive and symptomatic measures. Stomach wash may be beneficial if done within 4 hours of ingestion. Activated charcoal can be administered. Haemodialysis was shown to be effective.

Agents Effective Against Helicobacter pylori

Helicobacter pylori is a gram-negative bacillus which can colo-nise the gastric epithelium and cause an inflammatory gastritis leading to peptic ulceration, gastric lymphoma, and adeno-carcinoma. 70 to 90% of patients with gastric and duodenal ulcers have H.pylori that can be identified in antral samples. Eradication of H.pylori correlates well with amelioration of peptic ulcer disease.

The usual method recommended today is triple therapy involving metronidazole, a bismuth compound, and either tetracycline or amoxycillin. Adverse effects include vertigo, nausea, vomiting, and diarrhoea. Alternatively, omeprazole is used in combination with amoxycillin and tinidazole. The incidence of adverse effects is less with this regimen.

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