Indomethacin
Brand Names: Indocin, IndocidPlease read the disclaimer concerning the intent
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References
Akbarpour F, Afrasiabi A, Vaziri ND. Severe hyperkalemia caused by indomethacin and potassium supplementation.
South Med J 1985 Jun;78(6):756-757.
Abstract: Treatment with a combination of indomethacin and potassium chloride supplementation resulted in severe hyperkalemia in a patient with Bartter's syndrome. The clinical and electrocardiographic findings and hyperkalemia improved promptly with intravenous administration of sodium bicarbonate, glucose, and insulin, discontinuation of the potassium supplement, and reduction of the indomethacin dose. This case suggests that life-threatening hyperkalemia can occur when indomethacin and potassium supplementation are prescribed simultaneously in Bartter's syndrome.
Ganchev T, Negrev N, Mileva V. Effects of indomethacin on erythropoiesis and plasma iron in rats.
Acta Physiol Pharmacol Bulg 1989;15(2):53-57.
Abstract: The effect of indomethacin on erythropoiesis and plasma iron in rats is investigated after 3-day treatment. A more considerable decrease of erythrocytes, haemoglobin and plasma iron is observed, as well as an increase in reticulocytes and 59Fe incorporated in the newly-formed erythrocytes. The plasma bilirubin and lactate levels are also higher. Obviously, this suggests a regeneratory anaemia. It is concluded that prostaglandins are necessary for the normal iron metabolism and for erythropoiesis, but their absence does not prevent entirely the process of erythroid regeneration.
Goldszer RC, Coodley EL, Rosner MJ, Simons WM, Schwartz AB. Hyperkalemia associated with
indomethacin. Arch Intern Med 1981 May;141(6):802-804.
Abstract: Substantial hyperkalemia with ECG abnormalities developed in a patient. None of the common causes of hyperkalemia was found, eg, acidosis, hemolysis, rhabdomyolysis, renal failure, hypoadrenalism, leukocytosis, or thrombocytosis. The patient had been receiving indomethacin, a drug known to inhibit renin production, aldosterone excretion, and prostaglandin synthetase. The patient was rechallanged with indomethacin, and measurements of serum potassium and renin, urinary potassium, aldosterone, and creatinine levels were done. The study period clearly showed a hyporeninemic-hypoaldosterone states with diminished renal potassium excretion, leading to hyperkalemia associated with the indomethacin therapy. The development of hyperkalemia caused by indomethacin is probably unusual; however, we believe it is important to report this potentially serious pathophysiologic occurrence associated with a commonly used medication.
MacCarthy EP, Frost GW, Strokes GS. Indomethacin-induced hyperkalaemia. Med J Aust 1979 Jun 16;1(12):550.
Abstract: A patient with mild chronic renal failure developed significant hyperkalaemia while receiving indomethacin therapy. The hyperkalaemia, which was reversed by discontinuing indomethacin, is attributed to a drug-induced defect in the cellular uptake of potassium.
Mactier RA, Khanna R. Hyperkalemia induced by indomethacin and naproxen and reversed by
fludrocortisone. South Med J 1988 Jun;81(6):799-801.
Abstract: We have described a patient with severe rheumatoid arthritis and a history of mefenamic acid nephropathy in whom hyperkalemia and inappropriate hypoaldosteronism were caused by both indomethacin and naproxen, without major decline in renal function. It is likely that preexisting renal disease predisposed this patient to type IV renal tubular acidosis with prostaglandin synthetase inhibitors. Because he was unable to discontinue nonsteroidal anti-inflammatory drug therapy, fludrocortisone was added, correcting the hyperkalemia and allowing indomethacin therapy to be continued safely.
Mitjavila MT, Carbonell MT, Saiz MP, Muntane J, Sanchez J, Puig-Parellada P. Role of iron in carrageenan-induced granuloma: action of desferrioxamine and
indometacin. Pharmacology 1990;40(4):236-240.
Peterson DA, Gerrard JM, Rao GH, White JG. Inhibition of ferrous iron induced oxidation of arachidonic acid by
indomethacin. Prostaglandins Med 1979 Feb;2(2):97-108.
Abstract: The molecular mechanism by which indomethacin exerts its inhibitory effects on the prostaglandin endoperoxide synthetase enzyme is unknown. In the present study we have explored the possibility that indomethacin might interact with Fe++ in the enzyme to produce its inhibitory effect. For this study we made use of the recent discovery that Fe++ alone can oxidize arachidonic acid, and the interaction of this fatty acid with the metal can be detected by following reduction of nitroblue tetrazolium (NBT) or by conversion of the Fe++ to Fe+++. Indomethacin markedly inhibited NBT reduction in the presence of arachidonic acid and Fe++ when the indomethacin had been preincubated with the Fe++. Indomethacin also inhibited the conversion of Fe++ to Fe+++ by arachidonic acid. Results obtained by varying the concentrations of indomethacin and arachidonic acid and measuring inhibition of the conversion of Fe++ to Fe+++ by the indomethacin are consistent with a one to one complex forming between indomethacin and Fe++. The complex between indomethacin and Fe++ separates on prolonged incubation of the complex with arachidonic acid. The nature of the binding is suggested by a molecular model. Our results suggest that indomethacin may act to inhibit the prostaglandin endoperoxide synthetase enzyme by complexing Fe++ in the enzyme. Ibuprofen and tolmetin, two other prostaglandin synthetase inhibitors, also inhibit the interaction of Fe++ with arachidonic acid suggesting this may be a general mechanism for this type of drug.
Tan SY, Burton M. Hyporeninemic hypoaldosteronism. An overlooked cause of hyperkalemia.
Arch Intern Med 1981 Jan;141(1):30-33.
Abstract: To establish the frequency and clinical and biochemical characteristics of hyporeninemic hypoaldosteronism (HH), we reviewed 100 consecutive cases of hyperkalemia (potassium content > 5.3 mEq/L). The most common cause was end-stage renal failure (34%). Other causes included overzealous potassium replacement, spironolactone therapy, hemolysis, acute renal failure, acidosis, thrombocytosis, and Addison's disease. Ten of 19 patients with unexplained hyperkalemia showed suppressed renin (0.12 to 1.3 ng/mL/hr) and aldosterone (5.4 to 21.6 ng/dL) responses to furosemide-posture challenge. Cortisol reserve was normal in HH. Fludrocortisone acetate therapy corrected the hyperkalemia. Other features of HH include low serum bicarbonate content, mild renal insufficiency, diabetes, and advanced age. The use of indomethacin and ibuprofen was associated with one case of HH each. Results suggest that HH is an overlooked cause of hyperkalemia, especially in patients whose hyperkalemia is unexplained.
Taylor RT, Huskisson EC, Whitehouse GH, Hart FD, Trapnell DH. Gastric ulceration occurring during indomethacin therapy.
Br Med J 1968 Dec 21;4(633):734-737.
Vaananen PM, Meddings JB, Wallace JL. Role of oxygen-derived free radicals in indomethacin-induced gastric injury.
Am J Physiol 1991 Sep;261(3 Pt 1):G470-G475.
Abstract: The role of oxygen-derived free radicals in the pathogenesis of acute gastric ulceration induced by indomethacin (Indo) was investigated in rats. Gastric damage was assessed by blood-to-lumen leakage of 51Cr-EDTA, as well as by measuring the extent of macroscopically visible hemorrhagic lesions. The stomach was perfused with isotonic saline for 30 min, followed by Indo (10 mg/ml for 30 min) and HCl (100 mM for 60 min). Rats were given a continuous intravenous infusion of the antioxidant enzymes superoxide dismutase (SOD) or catalase or the iron-chelating agent deferoxamine. Additional rats received an intravenous infusion of the vehicle (control group) or were pretreated with prostaglandin E2 (100 micrograms/kg ip) or allopurinol (50 mg/kg po). Exposure of the stomach to Indo caused a fourfold increase in 51Cr-EDTA leakage compared with that observed in rats receiving only the vehicle for Indo. Subsequent exposure of the stomach to HCl resulted in a further twofold increase in 51Cr-EDTA leakage. Treatment with SOD, catalase, or deferoxamine significantly (P less than 0.05) reduced 51Cr-EDTA leakage during the intragastric perfusion with Indo and during the subsequent exposure to HCl. Pretreatment with PGE2 reduced 51Cr-EDTA leakage during perfusion with HCl only. Pretreatment with allopurinol did not significantly affect 51Cr-EDTA leakage at any time during the experiment. In addition to reducing the leakage of 51Cr-EDTA into the gastric lumen, SOD, catalase, and PGE2 significantly reduced the extent of macroscopically visible mucosal damage (P less than 0.05). These results support the hypothesis that oxygen-derived free radicals, probably derived from neutrophils, contribute to the pathogenesis of Indo-induced ulceration.