Summary
Drugs commonly used for symptom relief or healing of peptic ulcers can be divided into 4 main groups: antacids (including bismuth for convenience), anticholinergics, H2-receptor antagonists and liquorice derivatives. For all such drugs the safety margin during normal clinical use must be great, as they are widely used in otherwise healthy subjects.
Side effects of the widely used insoluble antacids usually take the form of bowel upset: constipation and diarrhoea from aluminium- and magnesium-containing preparations, respectively. Accumulation of individual ions is uncommon, but aluminium encephalopathy may occur in the presence of severe uraemia. Although bismuth may be absorbed from some preparations, encephalopathy has not been reported with the popular form tripotassium-dicitrato-bis-muthate. Experimental single dose studies have shown altered disposition of many drugs when taken with antacids; clinically important interactions during long term therapy seem to be rare.
Anticholinergic drugs taken in doses which reduce gastric acid secretion produce the expected side effects of dry mouth, constipation and urinary retention. Although interference with the accommodation reflex can be troublesome, the danger of precipitating acute glaucoma has probably been overstated. The development of selective muscarinic antagonists should provide antisecretory agents with minimal side effects.
The H2-receptor antagonist cimetidine has been in widespread clinical use for 5 years, and serious adverse reactions seem rare. The unwanted effects most commonly seen are gynaecomastia when used alone in high doses, confusion in the elderly or those with impaired excretory mechanisms, and modest inhibition of the oxidative metabolism of other drugs. Overall the drug has proved remarkably safe.
In practice the only significant adverse effect encountered with carbenoxolone is salt retention and hypokalaemia. Although identified quite frequently, this is seldom severe enough to warrant cessation of therapy. The elderly and those with pre-existing abnormalities of salt and water handling are at greater risk, and the drug should be avoided in these patients.
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References
Alfrey, A.C.; Le Gendre, G.R. and Kaehny, W.D.: The dialysis encephalopathy syndrome: Possible aluminium intoxication. New England Journal of Medicine 294: 184–188 (1976).
Ambre, J.J. and Fischer, L.J.: Effect of co-administration of aluminium and magnesium hydroxides on absorption of anticoagulants in man. Clinical Pharmacology and Therapeutics 14: 231–237 (1973).
Atherton, S.T. and White, D.J.: Stomach as a source of bacteria colonising respiratory tract during artificial ventilation. Lancet 2: 968–969(1978).
Avella, J.; Madsen, J.E.; Binder, H.J. and Askenase, P.W.: Effect of histamine H2-receptor antagonists on delayed hypersensitivity. Lancet 1: 624–626 (1978).
Barber, S.G.: Male sexual dysfunction and cimetidine. Lancet 1: 1147 (1979).
Barry, R.E. and Ford, J.: Sodium content and neutralising capacity of some commonly used antacids. British Medical Journal 1: 413(1978).
Beerman, B.; Hellstrom, K. and Rosen, A.: Gastrointestinal absorption of certain anticholinergic drugs. European Journal of Clinical Pharmacology 5: 87–92 (1972).
Blain, P.G.: Unwanted effects of cimetidine. Adverse Reaction Bulletin No. 83, p.302 (1980).
Bleumink, A.: H2-receptor antagonists; in Dukes (Ed) Side Effects of Drugs, Annual 4, p. 111 (Excerpta Medica, Amsterdam 1980).
Bodemar, G.; Norlander, B. and Walan, A.: Diminished absorption of cimetidine caused by antacids. Lancet 1: 445–446 (1979).
Brodie, M.J.; Ganguli, P.C.; Fine, A. and Thomson, T.J.: Effects of oral calcium gluconate on gastric acid secretion and serum gastrin concentration in man. Gut 18: 111–114 (1977).
Brown, D.D. and Junl, R.P.: Decreased bioavailability of digoxin due to antacids and Kaolin-pectin. New England Journal of Medicine 295: 1034–1037 (1976).
Buge, A.; Rancurel, G. and Dechy, H.: Encéphalopathies bismuthiques: données étiologiques et pharmacologiques. Nouvelle Presse Médicale 7: 3531–3534 (1978).
Burland, W.L; Gleadle, R.I.; Lee, R.M. and Rowley-Jones, D.: Cimetidine and serum prolactin. Lancet 1: 717 (1978).
Burland, W.L; Mills, J.G.; Sharpe, P.C.; Horton, M.A. and Mollin, D.L.: The effect of cimetidine on intrinsic factor secretion; in Burland and Simkins (Eds) Cimetidine: Proceedings of the Second International Symposium on Histamine H2-receptor antagonists. p.177 (Excerpta Medica, Amsterdam 1977).
Burns, R.; Thomas, D.W. and Baron, V.J.: Reversible encephalopathy possibly associated with bismuth subgallate ingestion. British Medical Journal 1: 220–223 (1974).
Byron, J.W.: Cimetidine and bone marrow toxicity. Lancet 2: 555–556(1977).
Carlson, H.E. and Ippoliti, A.F.: Cimetidine, an H2 antihistamine stimulates prolactin secretion. Journal of Clinical Endocrinology and Metabolism 45: 367 (1977).
Clemens, J.D. and Feinstein, A.R.: Calcium carbonate and constipation: A historical review of medical mythopoeia. Gastroenterology 72: 957–961 (1977).
Cocking, J.B. and MacCaig, J.N.: Effect of low dosage of carbenoxolone sodium on gastric ulcer healing and acid secretion. Gut 10: 219–225(1969).
Cohen, J.; Weetman, A.P.; Dargie, H.J. and Krikler, D.M.: Life-threatening arrhythmias and intravenous cimetidine. British Medical Journal 2: 768(1979).
Cole, J.J.; Charles, B.G. and Ravenscroft, P.J.: Interaction of cimetidine with tetracycline absorption. Lancet 2: 536 (1980).
Cooke, J. and Smith, J.A.: Absence of interaction of digoxin with antacids under clinical conditions. British Medical Journal 2: 1166–1167 (1978).
Cooke, N.; Teitelbaum, S. and Avioli, L.V.: Antacid-induced osteomalacia and nephrolithiasis. Archives of Internal Medicine 138: 1007–1009 (1978).
Craven, E.R. and Whittington, J.M.: Agranulocytosis four months after cimetidine. Lancet 2: 294 (1977).
Crean, G.P.; Daniel, D.; Leslie, G.B. and Bates, C: The effects of prolonged administration of large doses of cimetidine on the gastric mucosa of rats; in Wastell and Lance (Eds) Cimetidine. The Westminster Hospital Symposium, p.191 (Churchill Livingstone, London 1978).
Dawes, P. and Atherton, ST.: Cimetidine in the critically ill: A cautionary note. Lancet 1: 1137 (1980).
Delaney, J.C. and Ravey, M.: Cimetidine and mental confusion. Lancet 2: 512 (1977).
Delitala, G.; Stubbs, W.A.; Yeo, T.; Jones, A. and Besser, G.M.: Failure of cimetidine to antagonise dopamine induced suppression of prolactin in vitro. British Journal of Clinical Pharmacology 7: 117–118(1979).
Doll, R.; Langman, M.J.S. and Shawdon, H.H.: Treatment of gastric ulcer with carbenoxolone: Antagonistic effect of spironolactone. Gut 9: 42–45 (1968).
Dronfield, M.W.; Batchelor, A.J.; Larkworthy, W. and Langman, M.J.S.: Controlled trial of maintenance cimetidine treatment in healed duodenal ulcer: Short and long-term effects. Gut 20: 526–530(1979).
Dubb, J.W.; Stote, R.M.; Familiar, R.G.; Lee, K. and Alexander, F.: Effect of cimetidine on renal function in normal man. Clinical Pharmacology and Therapeutics 24: 76–83 (1978).
Edmonds, C.J.: Carbenoxolone and electrolyte metabolism in peptic ulcer healing; in Jones, Langman and Mann (Eds) Peptic Ulcer Healing: Recent Studies on Carbenoxolone, p.21 (MTP Press, Lancaster 1978).
Elder, J.B.; Ganguli, P.C. and Gillespie, I.E.: Cimetidine and gastric cancer. Lancet 1: 1005–1006 (1979a).
Elder, J.B.; Ganguli, P.C. and Gillespie, I.E.: Gastric cancer in patients who have taken cimetidine. Lancet 2: 245 (1979b).
Engel, T.R. and Luck, J.C.: Histamine2-receptor antagonism by cimetidine and sinus node function. New England Journal of Medicine 301: 591–592(1979).
Field, R. and Meyer, G.W.: Diarrhoea from cimetidine. New England Journal of Medicine 299: 262 (1978).
Fink, M. and Irwin, P.: EEG and behavioural effects of pirenzapine in normal volunteers. Scandinavian Journal of Gastroenterology 15(Suppl. 66): 39–46 (1980).
Flind, A.C.: Cimetidine and oral anticoagulants. British Medical Journal 2: 1367 (1978).
Fraser, P.; Chilvers, C; Beral, V. and Hill, M.J.: Nitrate and human cancer: A review of the evidence. International Journal of Epidemiology 9: 3–11 (1980).
Garty, M. and Hurwitz, A.: Effect of cimetidine and antacids on gastrointestinal absorption of tetracyclines. Clinical Pharmacology and Therapeutics 28: 203–207 (1980).
Geismar, P.; Mosbech, J. and Myren, J.: A double-blind study of the effect of carbenoxolone sodium in the treatment of gastric ulcer. Scandinavian Journal of Gastroenterology 8: 251–256 (1973).
Gilbert, J.A.L.: Multi-centre Canadian double-blind study of carbenoxolone (Biogastrone®) in the treatment of gastric ulcer; in Beck (Ed) North American Symposium on Carbenoxolone, pp.85–92 (Excerpta Medica, Amsterdam 1976).
Greenblatt, D.J.; Allen, M.D.; MacLaughlin, D.S.; Harmatz, J.S. and Shader, R.I.: Diazepam absorption: Effect of antacids and food. Clinical Pharmacology and Therapeutics 24: 600–609 (1978).
Greenblatt, D.J.; Shader, R.I.; Harmatz, J.S.; Franke, K. and Koch-Weser, J.: Influence of magnesium and aluminium hydroxide mixture on chlordiazepoxide absorption. Clinical Pharmacology and Therapeutics 19: 234–239 (1976).
Grimson, T.A.: Reactions to cimetidine. Lancet 1: 858 (1977).
Gudmand-Høyer, E.; Jensen, K.B.; Krag, A.; Rask-Madsen, J.; Rahbek, I.; Rune, S.J. and Wulff, H.R.: Prophylactic effect of cimetidine in duodenal ulcer disease. British Medical Journal 1: 1095–1097(1978).
Gugler, R. and Somogyi, A.: Reduced cimetidine clearance with age. New England Journal of Medicine 301: 435 (1979).
Hawker, P.C.; Muscroft, T.J. and Keighley, M.R.B.: Gastric cancer after cimetidine in a patient with two negative pre-treatment biopsies. Lancet 1: 709–710 (1980).
Hayes, M.J.; Sprackling, M.E. and Langman, M.J.S.: Changes in the plasma clearance and protein binding of carbenoxolone with age, and their possible relationship to adverse drug effects. Gut 18: 1054–1058 (1977).
Henry, D.A.; Macdonald, I.A.; Kitchingman, G.; Bell, G.D. and Langman, M.J.S.: Cimetidine and ranitidine: Comparison of effects on hepatic drug metabolism. British Medical Journal 281: 775 (1980).
Hiatt, R.L.; Fuller, I.B.; Smith, L.; Swartz, L. and Risser, C: Systemically administered anticholinergic drugs and intraocular pressure. Archives of Ophthalmology 84: 735–740 (1970).
Horwich, L. and Galloway, R.: Treatment of gastric ulcer with carbenoxolone sodium. Clinical and radiological evaluation. British Medical Journal 2: 1272–1277 (1965).
Hurwitz, A.: Antacid therapy and drug kinetics. Clinical Pharmacokinetics 2: 269–280 (1977).
Jefferys, D.B. and Vale, J.A.: Cimetidine and bradycardia. Lancet 1: 828(1978).
Johnson, N.; Black, A.E.; Hughes, A.S.B. and Clarke, S.W.: Leucopenia with cimetidine. Lancet 2: 1226 (1977).
Kaehny, W.D.; Hegg, A.P. and Alfrey, A.C.: Gastrointestinal absorption of aluminium from aluminium-containing antacids. New England Journal of Medicine 296: 1389–1390 (1977).
Khoury, W.; Geraci, K.; Askari, M. and Johnson, M.: The effect of cimetidine on aspirin absorption. Gastroenterology 76: 1169(1979).
Kimelblatt, B.J.; Cerra, FB.; Calleri, G., Berg, M.J.; McMillen, M.A. and Schentag, J.J.: Dose and serum concentration relationships in cimetidine associated mental confusion. Gastroenterology 78: 791–795 (1980).
Klotz, U. and Reimann, I.: Delayed clearance of diazepam due to cimetidine. New England Journal of Medicine 302: 1012–1015(1980).
Langman, M.J.S.: Gastrointestinal drugs; in Meyler and Herxheimer (Eds) Side Effects of Drugs Vol. 7, pp.501–506 (Excerpta Medica, Amsterdam 1972).
Langman, M.J.S.: Carbenoxolone in the treatment of chronic gastric ulcer; in Jones, Langman and Mann (Eds) Peptic Ulcer Healing: Recent Studies on Carbenoxolone. (MTP Press, Lancaster 1978).
Leslie, G.B. and Walker, T.F.: A toxicological profile of cimetidine; in Burland and Simkins (Eds) Cimetidine, Proceedings of the Second International Symposium on Histamine H2-receptor antagonists, p.24 (Excerpta Medica, Amsterdam 1977).
Ligumsky, M.; Skochina, M. and Rachmilewitz, D.: Cimetidine and arrhythmia suppression. Annals of Internal Medicine 89: 1008–1009 (1978).
Loiseau, P.; Henry, P.; Jallon, P. and Leroux, M.: Encéphalopathies myocloniques iatrogènes aux sels de bismuth. Journal of Neurological Sciences 27: 133–143 (1976).
Lorber, S.H.: U.S. Trial of Carbenoxolone (Biogastrone®) in gastric ulcer, in Beck (Ed) North American Symposium on Carbenoxolone, p.93–97 (Excerpta Medica, Amsterdam 1976).
Lotz, M.; Zisman, E. and Bartter, F.C.: Evidence for a phosphorus-depletion syndrome in man. New England Journal of Medicine 278: 409–415 (1968).
McDaniel, J.L. and Stein, J.J.: Thrombocytopenia with cimetidine therapy. New England Journal of Medicine 300: 864 (1979).
McElnay, J.C; Harron, D.W.G.; D’Arcy, P.F. and Collier, P.S.: Interaction of warfarin with antacid constituents. British Medical Journal 2: 1166 (1978).
McGregor, C.J.A.; Cochran, A.J.; Ogg, L.J.; Gray, G.R.; Smith, I.S.; Gillespie, G. and Forrester, J.: Immunological and other laboratory studies of patients receiving short-term cimetidine therapy. Lancet 1: 122–123 (1977).
Mignon, M.; Vallot, T.K.; Mayeur, S. and Bonfils, S.: Ranitidine and cimetidine in Zollinger-Ellison syndrome. British Journal of Clinical Pharmacology 10: 173–174 (1980).
Morrison, P.J.; Rogers, H.J.; Bradbrook, I.D. and Parsons, C: Concurrent administration of cimetidine and enteric coated prednisolone: Effect on plasma levels of prednisolone. British Journal of Clinical Pharmacology 10: 87–89 (1980).
Nicholls, P.E. and Henry, K.: Gastritis and cimetidine: A possible explanation. Lancet 1: 1095 (1978).
Nistico, G.; Rotitoti, D.; De Savro, A. and Naecari, F.: Mechanisms of cimetidine-induced fever. Lancet 2: 265–266 (1978).
Patwardhan, R.V., Yarborough, G.W.; Desmond, P.V.; Johnson, R.F.; Schenker, S. and Speeg, K.V.: Cimetidine spares the glucuronidation of lorazepam and oxazepam. Gastroenterology 79: 912–916 (1980).
Pelkonen, O. and Puurunen, J.: The effect of cimetidine on in vitro and in vivo microsomal drug metabolism in the rat. Biochemical Pharmacology 29: 3075–3080 (1980).
Porter, G.A.; Rhodes, C. and Sacra, P.: Comparative studies on the minerallo-corticoid action of aldosterone and carbenoxolone sodium in the adrenalectomized rat. Pharmacology 12: 224–229(1974).
Puurunen, J.; Sotaniemi, E. and Pelkonen, O.: Effect of cimetidine on microsomal drug metabolism in man. European Journal of Clinical Pharmacology 18: 185–187(1980).
Reed, P.I.; Cassell, P.G. and Walters, C.L.: Gastric cancer in patients who have taken cimetidine. Lancet 1: 1234 (1979).
Reed, P.I.; Lewis, S.I., Vincent Brown, A.; Holdstock, D.J.; Gribble, R.J.N.; Murgatroyd, R.E. and Baron, J.H.: The influence of amiloride on the therapeutic and metabolic effects of carbenoxolone in patients with gastric ulcer. Scandinavian Journal of Gastroenterology 15(Suppl. 65): 51–55 (1980).
Rendic, S.; Sunjic, V.; Toso, R.; Kajfez, F. and Ruf, H.: Interaction of cimetidine with liver enzymes. Xenobiotica 9: 555–564 (1979).
Rivera-Calimlim, L.; Dujovne, C.A.; Morgan, J.O.; Lasagna, L. and Bianchine, J.R.: Absorption and metabolism of L-dopa by the human stomach. European Journal of Clinical Investigation 1: 313–320(1971).
Rogers, H.J.; James, C.A.; Morrison, P.J. and Bradbrook, I.D.: Effect of cimetidine on oral absorption of ampicillin and cotrimoxazole. Journal of Antimicrobial Chemotherapy 6: 297–300(1980).
Rotoli, B.; Formisano, S. and Alfinito, F.: Autoimmune haemolytic anaemia associated with cimetidine. Lancet 2: 583 (1979).
Ruddell, W.S.J.; Axon, A.T.R.; Findlay, J.M.; Bartholomew, B.A. and Hill, M.J.. Effect of cimetidine on the gastric bacterial flora. Lancet 1: 672 (1980).
Schentag, J.J.; Cerra, F.B.; Calleri, G.; De Glopper, E.; Rose, J.Q. and Bernhard, H.: Pharmacokinetic and clinical studies in patients with cimetidine associated mental confusion. Lancet 1: 177–181 (1979).
Schmahl, D.: The role of nitrosamines in carcinogenesis — an overview; in Safey Evaluation of Nitrosatable Drugs and Chemicals. Symposium held in London (January, 1980).
Searles, R.P.; Bankhurst, A.D.; Ahlin, T.D. and Messner, R.P.: Antacid-induced hypophosphatemia: An unusual cause of ‘pseudo-myopathy’. Journal of Rheumatology 4: 176 (1977).
Serlin, M.J.; Mossman, S.; Sibeon, R.G.; Breckenridge, A.M.; Williams, J.R.B.; Atwood, J.L. and Willoughby, J.M.T.: Cimetidine: Interactions with oral anticoagulants in man. Lancet 2: 317–319 (1979).
Shader, R.I.; Georgotas, A.; Greenblatt, D.J.; Harmatz, J.S. and Allen, M.D.: Impaired absorption of desmethyldiazepam from clorazepate by magnesium aluminium hydroxide. Clinical Pharmacology and Therapeutics 24: 308–315 (1978).
Sharpe, P.C. and Hawkins, B.W.: Efficacy and safety of cimetidine; Long term treatment with cimetidine; in Burland and Simkins (Eds) Cimetidine. Proceedings of the Second International Symposium on Histamine H2-Receptor Antagonists (Excerpta Medica, Amsterdam 1977).
Sternberg, W.; King, C. and Toskes, P.: Cimetidine inhibits the absorption of protein bound vitamin B12 but not crystalline vitamin B12. Gastroenterology 74: 1099 (1978).
Ufberg, M.H.; Brooks, CM.; Bosanac, P.R. and Kintzel, J.E.: Transient neutropenia in a patient receiving cimetidine. Gastroenterology 73: 635–638 (1977).
Van Thiel, D.H.; Gavaler, J.S.; Smith, W.I. and Paul, G.: Hypothalamic-pituitary-gonadal dysfunction in man using cimetidine. New England Journal of Medicine 300: 1012–1015(1979).
Verbeeck, R.; Tjandramaga, T.B.; Mallis, A.; Verbesselt, R. and de Schepper, P.J.: Effect of aluminium hydroxide on diflunisal absorption. British Journal of Clinical Pharmacology 7: 519–522 (1979).
Villeneuve, J.P. and Warner, H.A.: Cimetidine hepatitis. Gastroenterology 77: 143–144(1979).
Waisbren, B.A. and Hueckel, J.S.: Reduced absorption of aureomycin caused by aluminium hydroxide gel (amphogel). Proceedings of the Society for Experimental Biology and Medicine 73: 73–74 (1950).
Wallace, W.A.; Orr, C.M.E. and Beam, A.R.: Perforation of chronic peptic ulcers after cimetidine. British Medical Journal 2: 865–866 (1977).
Walls, T.J.; Pearce, S.J. and Venables, G.S.: Motor neuropathy associated with cimetidine. British Medical Journal 281: 974 (1980).
Webster, J.: Male sexual dysfunction and cimetidine. British Medical Journal 1: 889 (1979).
White, M.C.; Gare, M. and Jewell, D.P.: Endocrine function after cimetidine. New England Journal of Medicine 301: 502 (1979).
Wilson, J.A.C.: A comparison of carbenoxolone sodium and deglycyrrhizinated liquorice in the treatment of gastric ulcer in the ambulant patient. British Journal of Clinical Practice 26: 563–566 (1972).
Winters, S.J.; Banks, J.L. and Loriaux, D.L.: Cimetidine is an antiandrogen in the rat. Gastroenterology 76: 504–508 (1979).
Yokel, R.A.: Sodium and potassium levels in antacids. American Journal of Hospital Pharmacy 34: 200–202 (1977).
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Henry, D.A., Langman, M.J.S. Adverse Effects of Anti-ulcer Drugs. Drugs 21, 444–459 (1981). https://doi.org/10.2165/00003495-198121060-00004
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DOI: https://doi.org/10.2165/00003495-198121060-00004