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In medicine (endocrinology), hypoaldosteronism refers to decreased levels of the hormone aldosterone. There are several causes for this condition, including primary adrenal insufficiency, congenital adrenal hyperplasia, and medications (certain diuretics, NSAIDs, and ACE inhibitors). This condition may result in hyperkalemia, which can be serious medical condition. It can also cause hyponatremia.

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Hyperkalemia due to drugs in diabetic patients
From American Family Physician, 1/1/89 by Allan B. Schwartz

Hyperkalemia Due to Drugs in Diabetic Patients Most clinicians are alert to the dangers of hypokalemia. In patients with diabetes mellitus, however, hyperkalemia is a more commonly encountered hazard. This is especially true if the diabetic patient is taking one or more of the frequently prescribed drugs that may raise serum potassium levels.(1)

Normally, two major mechanisms maintain homeostasis of blood potassium. First, a rise in blood potassium is antagonized by insulin, which drives potassium back into the intracellular space. (The greatest concentration of this ion is intracellular.) Second, aldosterone stimulates secretion of potassium in the renal distal tubules and collecting ducts.(2)

A person with diabetes mellitus suffers from deficient and impaired insulin effect, hyporeninemia and hypoaldosteronism. In addition, there is likely to be some degree of renal insufficiency as a result of diabetic nephropathy. Consequently, the diabetic patient is less able than others to compensate for an added potassium load, whether it is induced endogenously or exogenously.(3)

This article describes the mechanisms of potassium overload in diabetic patients, with an emphasis on prescription and over-the-counter drugs that may cause hyperkalemia in this population.

Hyperosmolality Due to Hyperglycemia

Hyperglycemia induces hyperkalemia, which may lead to cardiac arrhythmias. Diabetic patients with hyperosmolality due to hyperglycemia are at greatest risk, even in the absence of ketosis and acidosis.(3)

Hypertonic glucose infusion may cause potassium to efflux across cell membranes even in situations of normal cellular membrane integrity. The mechanism by which this occurs is somewhat unclear. The increase in serum potassium should produce an insulin-secretagogue effect, and the subsequent rise in insulin should drive the potassium back into the intracellular space.(4)

The same biochemical mechanisms are involved in sustained hyperosmolality due to hyperglycemia. However, the absence of adequate insulin response that occurs in insulin-deficient diabetics results in a more sustained hyperglycemia and hyperosmolality, and therefore produces a more profound hyperkalemia. The greater the concentration of hypertonic glucose and extracellular impermeable solute, the greater the transcellular movement of potassium with water. Hypertonic mannitol infusion and hypertonic saline infusion have also been shown to induce hyperkalemia in diabetic and nondiabetic individuals. Glucose-induced hyperkalemia has been noted in nondiabetic patients who have isolated aldosterone deficiency.

Hormonal stimulation of glycogenolysis may induce systemic release of large amounts of potassium previously sequestered in glycogen stores.(5) This hypothesis is based on the observation that diabetic patients may demonstrate a paradoxic rise in plasma glucagon concentration following hypertonic glucose administration.

In patients with hyperosmolality, the increment in serum potassium may range from 0.2 to 2.0 mEq per L (0.2 to 2.0 mmol per L) above baseline. The increment in serum potassium following an intravenous or oral dose of hypertonic glucose solution is reached within 30 to 60 minutes. In patients with diabetes mellitus, there is a strong positive correlation between serum concentrations of potassium and blood glucose.

Nonsteroidal Anti-Inflammatory Drugs

Hyperkalemia resulting from nonsteroidal anti-inflammatory drugs (NSAIDs) was documented as early as 1979.(6,7) NSAID inhibition of prostaglandin synthetase (cyclo-oxygenase) has been well established since 1971. Later, it was recognized that renal prostaglandins act as modulators of human juxtaglomerular cell function; therefore, prostaglandins are necessary for renin synthesis.

Hyperkalemia was noted in patients with normal and impaired renal function receiving NSAID therapy and was associated with a reduction in plasma and urinary aldosterone levels.(8,9) These cases appeared to resemble the syndrome of hyporeninemic hypoaldosteronism. NSAID-induced suppression of renin secretion was found to occur at the juxtaglomerular cell level.(10) Reduced renal prostaglandin synthesis provided the explanation for the decreased renin production and subsequent depression of the renin-angiotensin-aldosterone axis. This secondary hypoaldosteronism limits potassium secretion by the renal distal tubules and collecting ducts, which results in hyperkalemia.

Hyperkalemia induced by NSAIDs may develop in one to three days. In some cases, azotemia and acidosis have also been observed in patients with NSAID-induced hyperkalemia. Discontinuing the NSAID usually corrects the 1 to 2 mEq per L (1 to 2 mmol per L) increase in serum potassium. This may require several days to two weeks after the offending agent has been withdrawn.

ACE Inhibitors

Aldosterone reduction in both plasma and urine was observed early in the development of the angiotensin-converting enzyme (ACE) inhibitors and subsequently was linked to elevated serum potassium.(11,12) Reduction in both angiotensin II and aldosterone has been noted in association with a reciprocal increase in plasma renin activity due to ACE inhibitors. Patients with dissimilar glomerular filtration rates exhibit a decline in plasma aldosterone concentration following captopril (Capoten) therapy.

Hypoaldosteronism alone is not necessarily the cause of hyperkalemia in patients receiving ACE inhibitor therapy. Patients with azotemia appear to be extremely vulnerable to the hyperkalemic effect of ACE inhibitors. Thus, some additional derangement in renal potassium homeostasis may be implicated. Other studies have shown that the increase in absolute potassium value from baseline levels results in a new steady-state level during captopril therapy. This increase is inversely proportional to the glomerular filtration rate and somewhat independent of the absolute aldosterone concentration.(13)

Beta-Adrenergic Blockers

Reports of elevation in serum potassium after beta-adrenergic blocker therapy for essential hypertension were common in the mid-1970s. Serum potassium levels increased in 17 of 18 hypertensive patients treated with pindolol (Visken) and in 14 of 18 hypertensive patients treated with propranolol (Inderal).(14)

Since skeletal muscle beta2-adrenergic receptors are antagonized by beta-adrenergic blockers, cellular uptake of potassium is limited. This extrarenal mechanism is responsible for hyperkalemia induced by beta blockers. Several reports have confirmed that initiation of beta-adrenergic blockade before the administration of epinephrine abolishes epinephrine-induced hypokalemia.(15)

An increase in plasma potassium of 0.2 to 0.5 mEq per L (0.2 to 0.5 mmol per L) is commonly observed in patients taking beta-adrenergic blockers. In most cases, discontinuance of therapy corrects the hyperkalemia.

Potassium-Sparing Diuretics

Potassium-sparing diuretics act on the distal tubules and collecting ducts of the kidneys to promote sodium excretion while conserving potassium and hydrogen ions.(16,17) These diuretics have two mechanisms of action. Spironolactone (Alatone, Aldactone) is dependent on an aldosterone-blocking effect, while triamterene (Dyrenium) and amiloride (Midamor) have a potassium-retaining mechanism that is independent of aldosterone blockade.

The aldosterone antagonist, spironolactone, binds to cytoplasmic receptors in the distal tubule and collecting duct cells. This complex binding prevents nuclear uptake of aldosterone, thereby blocking mineralocorticoid activity.(18) Amiloride and triamterene also exert an effect on the distal tubule and collecting duct cells, but by a different mechanism.(16) Amiloride and, perhaps, triamterene block sodium conductive pathways along the luminal-apical cell membranes, impeding movement of sodium from the tubular lumen into the cells.

Serious and even fatal hyperkalemic complications have been associated with spironolactone, triamterene and amiloride therapy. Impaired tubular secretion of potassium is coupled with an impairment of tubular secretion of hydrogen ions during therapy with the potassium-sparing diuretics. In many patients, normalization of serum potassium may require up to ten days after discontinuance of these drugs. Severe hyperkalemia may be complicated by metabolic acidosis and paralysis. Obviously, potassium-sparing diuretics should be prescribed with extreme caution in diabetic patients who are already prone to hyperkalemia.

Neuromuscular Depolarizing Agents

The neuromuscular depolarizing agent succinylcholine chloride (Anectine, Quelicin, Sucostrin) is used to induce skeletal muscle relaxation during surgery and to facilitate endotracheal intubation. A brief rise in serum potassium of approximately 0.5 mEq per L (0.5 mmol per L) has been reported.(19) Depolarization at the myoneural junction causes (1) an increase in postjunctional membrane permeability for sodium and potassium ions and (2) the efflux of intracellular potassium with concurrent sodium influx. Cardiac arrest and hyperkalemia have been reported in patients given intravenous succinylcholine.

Patients at greatest risk of life-threatening hyperkalemia induced by succinylcholine administration are those with trauma, massive burns, central nervous system injury or disease, tetanus or severe abdominal infections.(20) Succinylcholine-induced hyperkalemia may have its onset within one minute of intravenous administration. The peak effect occurs in three to five minutes, and the duration is approximately ten minutes. Serum potassium increments may be 1 to 6 mEq per L (1 to 6 mmol per L) above baseline in patients at risk. Several hours may be required for serum potassium to return to the pretreatment levels.

Digitalis Glycosides

Fatal hyperkalemia has been reported following massive ingestion or intravenous administration of digoxin (Lanoxin).(21) In one fatal case, serum potassium concentration increased to 9.8 mEq per L (9.8 mmol per L) three hours after the ingestion of 23 mg of digoxin (serum digoxin: 42 ng per mL [53.8 nmol per L]). In another case, a 13.5 mEq per L (13.5 mmol per L) serum potassium level was noted in conjunction with a serum digoxin level of 152 ng per mL (194.7 nmol per L) four hours after intravenous administration of a digoxin dose of 200 mg.(22)

Digoxin-induced hyperkalemia is believed to develop secondary to poisoning of the membrane-bound sodium-potassium adenosinetriphosphatase transport system. This results in an increase in serum potassium that may continue for several hours if left uncorrected. A subsequent reduction in resting cell membrane potential occurs. In cardiac cells, the resulting decrease in automaticity can produce a slow idioventricular rhythm or cardiac arrest.

In diabetic patients, even standard doses of digitalis preparations may cause toxic increases in plasma potassium levels.

Immunosuppressant Therapy

In cases of kidney transplantation, hyperkalemia has occured in the absence of acute rejection in patients with adequate glomerular filtration rates and normal potassium excretion. Sustained hyperkalemia has been reported in renal allograft recipients.(23) Patients receiving cyclosporine (Sandimmune) and steroids have been found to have higher serum potassium levels than patients receiving azathioprine (Imuran) and steroids. Gross renal failure secondary to cyclosporine-induced nephrotoxicity was not thought to be the cause of the potassium imbalance in these patients.(24)

Some patients with cyclosporine-associated hyperkalemia have been characterized as having hyperkalemic renal tubular acidosis. These patients have hypoaldosteronism and moderage kidney damage, which results in impaired sodium-potassium exchange and sodium-hydrogen ion exchange in the distal tubules and collecting ducts.(25) Cyclosporine-induced hyperkalemia does not appear to be related either to dosage or to duration of therapy.

Acidifying Agents

Arginine hydrochloride in a 10 percent solution (R-Gene 10) is a potent acidifying agent that is administered intravenously. Hyperkalemia has been a well-known consequence of this form of therapy since the initial reports in the late 1960s.(26) Hyperkalemia has been noted after the use of arginine hydrochloride in patients with severe metabolic alkalosis.

Arginine hydrochloride, which is similar to other cationic amino acids, has been shown to displace intracellular potassium to the extracellular compartment. Intravenous administration of a 30- to 60-g dose of arginine hydrochloride has been associated with a rise in serum potassium of approximately 0.6 to 1.0 mEq per L (0.6 to 1.0 mmol per L) within 30 minutes after the infusion.(27) Patients at greatest risk are those with diabetes mellitus, moderate or end-stage renal disease, or hepatic insufficiency.

Potassium Supplements

Potassium supplements are available by prescription and over the counter. Prescribed potassium supplements are four to 50 times stronger in total mEq dosage than over-the-counter products. In our study of 35 patients with normal renal function taking potassium chloride 10 percent elixir for thiazide-induced hypokalemia,(28) hyperkalemia did not occur. The patients in this study continued to take hydrochlorothiazide, 50 mg twice daily, along with the potassium chloride supplement. Urinary potassium and chloride levels increased progressively and paralleled increases in the dosage of potassium chloride from 40 mEq per day to 60, 80 and 100 mEq per day.

Sustained hyperkalemia is rarely observed after potassium ingestion because renal compensatory mechanisms are prompt in patients with normal renal function. However, sudden large intravascular potassium loading may cause hyperkalemia in patients with abnormal renal function, including some patients with diabetes.


Some physicians may not be aware that the formulary product standard USP penicillin G contains 1.7 mEq potassium and 0.3 mEq sodium per million u of penicillin. This potassium-containing preparation may inadvertently be prescribed for rapid intravenous administration in patients at risk. Intravenous push doses and rapid intravenous infusion doses of 4 to 5 million u of penicillin G potassium for the treatment of endocarditis and sepsis have been associated with cardiac arrest.(29)

Penicillin-sensitive streptococcal endocarditis and sepsis in patients with moderate to severe kidney disease should be treated with the sodium form of penicillin, which contains 2 mEq sodium per million u of penicillin and no potassium. Hyperkalemia due to renal interstitial tubular toxicity has been noted with methicillin (Staphcillin) and other antibiotics.(30)

Salt Substitutes

Salt substitutes have been recommended for patients with congestive heart failure, hypertension, edema of pregnancy and other edematous states that may warrant low sodium intake. However, the product labels may not provide a cautionary note to patients on potassium-restricted diets or diabetics with kidney disease. Potassium content may or may not be indicated, and when stated, may be noted in milligrams per teaspoonful (5 g) or a fraction of a teaspoonful. This may not be an accurate reflection of the quantity of potassium chloride released from a simple shaking motion. Thus, a substantial amount of potassium chloride could be delivered with several shakes of a salt substitute.(31)

Labels on many over-the-counter potassium supplements do not warn consumers about excessive use. "Health foods" should be checked for their potassium content. Elderly patients, those with chronic renal disease, diabetic patients and others receiving potassium-sparing diuretics should be warned against the routine use of potassium-containing products.

Oral Nutrient Supplements

Dietary supplements may be an occult source of large quantities of potassium. In an effort to increase caloric intake in a debilitated or recuperating patient, the physician may inadvertently prescribe these potassium-containing products. Acute hyperkalemia has been reported in vulnerable individuals.(32) One patient received a potassium load of 121.5 mEq after ingesting 2.5 L of a standard high-protein, high-calorie supplement. The product contained 48.6 mEq of potassium per L. The result was acute hyperkalemia of 6.9 mEq per L (6.9 mmol per L) on the fourth day. Obviously, the serum potassium level should be monitored closely in any at-risk patient receiving nutritional supplementation, especially a patient with diabetes mellitus.

Final Comment

Severe hyperkalemia (7 mEq per L [7 mmol per L]) is rare, except in cases of advanced renal failure. However, milder degrees of hyperkalemia are common in patients with diabetes mellitus. Since such patients are especially vulnerable to drugs that tend to increase plasma potassium, they should have frequent monitoring of their potassium levels. In addition to prescribed drugs, the patient's diet, over-the-counter preparations and dietary supplements may also contribute to the tendency toward hyperkalemia. REFERENCES (1)Cannon-Babb ML, Schwartz AB. Drug-induced hyperkalemia. Hosp Pract [Off] 1986;21(9A):99-107, 111, 114-27. (2)Schwartz AB. Balance distribution and reference ranges of potassium throughout the body. In: Whelton PK, Whelton A, Walker WC. Potassium in cardiovascular and renal medicine. New York: Marcel Dekker, 1985:85-95. (3)Cahill GF, Arky RA, Perlman AJ. Diabetes mellitus. In: Rubenstein E, Federman DD, eds. Scientific American medicine. Vol 2. New York: Scientific American, 1988:VI, 4, 9. (4)Zerbe R, Vincor F, Robertson GL. Hypertonic glucose and saline have similar hyperkalemic effects in diabetes [Abstract]. Clin Res 1979;27:263. (5)Schwartz AB. Normal potassium balance. In: Schwartz AB, Lyons H, eds. Acid-base and electrolyte balance: normal regulation and clinical disorders. New York: Grune & Stratton, 1977: 203-12. (6)Dunn MJ, Zambraski EJ. Renal effects of drugs that inhibit prostaglandin synthesis. Kidney Int 1980;18:609-22. (7)Meier DE, Myers WM, Swenson R, Bennet WM. Indomethacin-associated hyperkalemia in the elderly. J Am Geriatr Soc 1983;31:371-3. (7)Tan SY, Shapiro R, Franco R, Stockard H, Mulrow PJ. Indomethacin-induced prostaglandin inhibition with hyperkalemia. A reversible cause of hyporeninemic hypoaldosteronism. Ann Intern Med 1979;90:783-5. (9)Goldszer RC, Coodley EL, Rosner MJ, Simons WM, Schwartz AB. Hyperkalemia associated with indomethacin. ARch Intern Med 1981;141:802-4. (10)Norby LH, Weidig J, Ramwell P, Slotkoff L, Flamenbaum W. Possible role for impaired renal prostaglandin production in pathogenesis of hyporeninaemic hypoaldosteronism. Lancet 1978;2(8100): 1118-22. (11)Warren SE, O'Connor DT. Hyperkalemia resulting from captopril administration. JAMA 1980;244: 2551-2. (12)Textor SC, Bravo EL, Fouad FM, Tarazi RC. Hyperkalemia in azotemic patients during angiotensin-convernting enzyme inhibition and aldosterone reduction with captopril. Am J Med 1982; 73:719-25. (13)Grossman A, Eckland D, Price P, Edwards CR. Captopril: reversible renal failure with severe hyperkalemia [Letter]. Lancet 1980;1(8170):712. (14)Brecht HM, Werner E, Schoeppe W. Increase of total body potassium and decrease of exchangeable sodium after long-term treatment with a beta-receptor-blocking agent (Pindolol) in essential hypertension. Clin Sci Mol Med 1976;51(Suppl 3):551s-4s. (15)Traub YM, Rabinov M, Rosenfeld JB, Treuherz S. Elevation of serum potassium during beta blockade: absence of relationship to the reninaldosterone system. Clin Pharmacol Ther 1980;28: 765-68. (16)Walker BR, Capuzzi DM, Alexander F, Familiar RG, Hoppe RC. Hyperkalemia after triamterene in diabetic patients. Clin Pharmacol Ther 1972;13:643-51. (17)Jaffey L, Martin A. Malignant hyperkalaemia after amiloride/hydrochlorothiazide treatment [Letter]. Lancet. 1981;1:(8232):1272. (18)Greenblatt DJ, Koch-Weser J. Adverse reactions to spironolactone. A report from the Boston Collaborative Drug Surveillance Program. JAMA 1973;225:40-3. (19)John DA, Tobey RE, Homer LD, Rice CL. Onset of succinylcholine-induced hyperkalemia following denervation. Anesthesiology 1976;45:294-9. (20)Kohlschutter B, Baur H, Roth F. Suxamethonium-induced hyperkalaemia in patients with severe intra-abdominal infections. Br J Anaesth 1976;48:557-62. (21)Smith TW, Willerson JT. Suicidal and accidental digoxin ingestion. Report of five cases with serum digoxin level correlations. Circulation 1971;44:29-36. (22)Reza MJ, Kovick RB, Shine KI, Pearce ML. Massive intravenous digoxin overdosage. N Engl J Med 1974;291:777-8. (23)Adu D, Turney J, Michael J, McMaster P. Hyperkalaemia in cyclosporin-treated renal allograft recipients. Lancet 1983;2(8346):370-2. (24)Cyclosporin A as sole immunosuppressive agent in recipients of kidney allografts from cadaver donors. Preliminary result of a European multicentre trial. Lancet 1982;2(8289):57-60. (25)Sebastian A, Morris RC. Renal tubular acidosis. In: Earley LE, Gottschalk CW, eds. Strauss and Welt's Diseases of the kidney. Boston: Little, Brown, 1979:1029-54. (26)Alberti KG, Johnston HH, Lauler DP. The effect of arginine and its derivatives on potassium metabolism in the dog [Abstract]. Clin Res 1967;15:476. (27)Merimee TJ, Rabinowitz D, Riggs L, Burgess JA, Rimoin DL, McKusick VA. Plasma growth hormone after arginine infusion. Clinical experiences. N Engl J Med 1967;276:434-9. (28)Schwartz AB, Swartz CD. Dosage of potassium chloride elixer to correct thiozide-induced hypokalemia. JAMA 1974;230:702-4. (29)Mercer CW, Logic JR. Cardiac arrest due to hyperkalemia following intravenous penicillin administration. Chest 1973;64:358-9. (30)Cogan MC, Arieff AI. Sodium wasting, acidosis and hyperkalemia induced by methicillin interstitial nephritis. Evidence for selective distal tubular dysfunction. Am J Med 1978;64:500-7. (31)Snyder EL, Dixon T, Bresnitz E. Abuse of salt "substitute" [Letter]. N Engl J Med 1975;292:320. (32)Nanji AA. High-calorie liquid nutrients and hyperkalemia. J Am Geriatr Soc 1983;31:626.

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