Potassium

Potassium

Common Names: Potassium aspartate, Potassium bicarbonate, Potassium chloride, Potassium citrate

Clinical Name: Potassium

Summary

Potassium

chemical name: K

forms: Potassium aspartate, Potassium bicarbonate, Potassium chloride, Potassium citrate

overview of interactions:
• nutrient affected by drug: ACE Inhibitors

• nutrient affected by drug: Acetylsalicylic Acid

• nutrient affected by drug: Amiloride

• nutrient affected by drug: Aminoglycosides

• nutrient affected by drug: Antacids

• nutrient affected by drug: Captopril

• nutrient affected by drug: Cisplatin

• nutrient affected by drug: Colchicine

• nutrient affected by drug: Corticosteroids including Prednisone

• nutrient affected by combination drug: Cotrimoxazole (Sulfamethoxazole and Trimethoprim)

• nutrient affected by drug: Digoxin

• nutrient affected by drug: Loop Diuretics and Thiazide Diuretics

• nutrient affected by drug: Enalapril

• nutrient affected by drug: Gentamicin

• nutrient affected by drug: Glucocorticoids

• nutrient affected by drug: Haloperidol

• nutrient affected by drug: Heparin

• nutrient affected by drug: Indomethacin

• nutrient affected by drug: Mineral Oil

• nutrient affected by drug: Spironolactone (Aldactone®)

• nutrient affecting drug performance: Tetracyclines

• nutrient affected by drug: Triamterene

chemistry:
• Both potassium and sodium are actively transported into and out of the cells of the body. They are both cations. They are very water soluble and, hence, tend to dissolve easily in cooking water. Foods cooked this way tend to be much lower in nutritional value.

metabolism:
• 90-98% is absorbed. Aldosterone increases the excretion of potassium. Many anti-diuretics also increase excretion of potassium along with other minerals.

function:
• Acid base balance: Both potassium and sodium are intimately involved with acid base balance and if there is an imbalance, the heart may beat irregularly.
• Electrical activity for nerve cells and muscle cell function including the heart: Both a deficiency and an excess of potassium can cause electrical disturbances in the heart which can lead to arrhythmias and other problems.
• Potassium deficiency in muscles can cause cramping and spasms in the muscles. Since potassium is essential for the storage of glycogen in muscles, a deficiency can cause muscles to become fatigued and weak.
• Water balance: Sodium is pumped out of cells while potassium is pumped into cells. Without this active pumping of sodium out of cells, swelling of the cells occurs.

dietary sources:
• All vegetables, especially green leafy vegetables; oranges, whole grains, sunflower seeds, mint leaves, oranges, nuts, milk, potatoes, and bananas.
• Currently, the average American consumes only 2 g per day of potassium compared with 3-7 g of sodium per day.

causes of potassium deficiency:
• Diarrhea and/or vomiting: Gastrointestinal disturbances caused by disease, parasites or food reactions can deplete potassium significantly.
• Diuretics: Medications, especially those for hypertension, can deplete large amounts of potassium.
• COPD and diabetes mellitus: Acidosis: Excess loss of glucose will cause solute loss, especially in the form of potassium. The body, in attempt to buffer the hyperacidity, will lose potassium.
• Glucocorticoids: Many medications, including adrenal steroid hormones, can disturb potassium levels in the body.
• Perspiration: Up to 3 g of potassium can be lost in one day due to perspiration. More may be lost in extreme cases; e.g. extreme athletic events.

symptoms of potassium deficiency:
• A potassium deficiency leads to muscle weakness, fatigue, mental confusion, irritability, heart disturbances, muscle cramps, abdominal bloating and nerve conduction abnormalities.
• Minimum requirements for adults: 2000 mg per day; this is not optimal.
• Apart from drug-induced depletion, replacement is usually only required after extreme perspiration.

Note: The average intake of potassium is about 1-3 g per day. This intake is only about 25% of what hunter-gatherers took in thousands of years ago. This means that the average ratio of sodium to potassium is 5 to 2. Ideally, this should be reversed to a 5 or even 10 to 1 ratio of potassium to sodium. People might benefit from consuming a much higher amount of potassium in their diets.
(Marz R. 1977.)

known or potential therapeutic uses: Allergies, arrhythmias, atherosclerosis, cancer, diarrhea in infants, glaucoma, hypertension, diabetes mellitus (mild).

maintenance dose:
• Supplementation with potassium is not normally necessary in the presence of a balanced diet.
• RDA: 1.9 - 5.6 g per day
• Optimal Daily Intake: 6-9 g per day from food sources.
• Supplemental potassium is only available at a maximum dose of 99 mg.

therapeutic dose: 300 mg - 5 g per day, under medical supervision at higher dosage levels.

side effects: Potassium salts taken orally can cause symptoms of nausea, vomiting, diarrhea, and ulcers can occur. Dietary potassium does not seem to cause the same side effects.

toxicity:
• Nausea, vomiting, and diarrhea with ulcers have been reported with high doses of supplemental potassium. This does not seem to occur when even very high levels are consumed through dietary means.
• Arrhythmia. Arrhythmias may also occur.
• Magnesium increases excretion of potassium via stools if too much is taken. It also maintains the sodium/potassium ATP pump and maintains intracellular potassium.

contraindications: None known to date.

Interactions

nutrient affected by drug: ACE Inhibitors

• mechanism: ACE inhibitors enhance potassium levels in the blood.

• nutritional concerns: Potassium supplements and even high-potassium foods, such as fruit, can lead to problematic interactions and should be avoided. A patient using ACE Inhibitors is advised to discuss these issues with their prescribing doctor, a pharmacist, or both.

nutrient affected by drug: Acetylsalicylic Acid

• mechanism: High doses of aspirin can result in hypokalemia.
(Smith MJH, Smith PK, eds. 1966.)

nutrient affected by drug: Amiloride

• mechanism: Amiloride intentionally reduces urinary excretion of potassium. As a result of its role as a potassium-sparing diuretic, amiloride can produce a state of inappropriately elevated potassium levels.

• nutritional concerns: Individuals using potassium-sparing diuretics such as amiloride should limit their dietary intake of potassium to avoid excessive levels. Potassium supplements and potassium-containing salt substitutes, such as Lite Salt®, Morton's Salt Substitute and No Salt®, are designed for individuals suffering from potassium depletion due to other types of diuretics and should be avoided when taking potassium-sparing diuretics such as amiloride. For some individuals, foods with high potassium content may need to be limited. Several pieces of fruit per day may provide adequate potassium to elevate serum levels. Individuals taking amiloride should work with their prescribing physician to monitor potassium levels and modify their diet accordingly to avoid elevated potassium levels and associated problems.
(Stepan VM, et al. Eur J Gastroenterol Hepatol 1997 Oct;9(10):1001-1004.)

nutrient affected by drug: Aminoglycosides

• reports: Animal studies and case reports indicate that renal tubular damage due to aminoglycosides, such as gentamicin, can lead to hypokalemia combined with hypocalcemia, hypomagnesemia and alkalosis.
(Mazze RI, Cousins MJ. Br J Anaesth. 1973 Apr;45(4):394-398; Valdivieso A, et al. Rev Med Chil. 1992 Aug;120(8):914-919; Kes P, et al. Magnes Trace Elem. 1990;9(1):54-60. Parsons PP, et al. Br J Pharmacol 1997 Oct;122(3):570-576.)

• nutritional support: Individuals using aminoglycosides, especially on a repeated or chronic basis, should consult with their prescribing physician and/or a nutritionally oriented healthcare professional about nutritional support to restore normal levels of potassium and these other important minerals. Patients undergoing extended treatment with aminoglycosides may need to have their doctor regularly monitor their kidney function along with magnesium and potassium status. Serum creatinine, BUN and creatinine clearance should be measured prior to initiating therapy and should be monitored throughout treatment. Only after such assessment should supplementation with potassium be undertaken and then only under close supervision by the prescribing physician.

Slow-K® and Micro-K® are typical examples of the potassium supplementation suggested by most physicians. Potassium levels can be further enhanced by eating several pieces of fruit each day. However, increasing potassium intake by any means is usually contraindicated and often dangerous in patients with reduced kidney function, especially those on dialysis. It is also important to note that magnesium is needed to maintain intracellular potassium.

nutrient affected by drug: Antacids

• mechanism: Antacids may cause low blood levels of potassium when used excessively.
(Lotz M, et al. N Eng J Med. 1968; 278:409.)

nutrient affected by drug: Captopril

• mechanism: In general, ACE inhibitors enhance potassium levels in the blood.
(Lavin F, et al. Cardiology 1993;82(6):405-408; O'Keeffe S, et al. Cardiology 1992;80(2):100-105; Good CB, et al. JAMA 1995 Aug 16;274(7):538.)

• nutritional concerns: Potassium supplements and even high-potassium foods, such as fruit, can lead to problematic interactions and should be avoided. A patient using an ACE inhibitor, such as captopril, is advised to discuss these issues with their prescribing doctor, a pharmacist, or both.

nutrient affected by drug: Cisplatin

• nutritional concerns: Individuals being treated with cisplatin often experience a decline in potassium levels that is unresponsive to potassium supplementation unless accompanied by supplemental magnesium. Magnesium is needed to maintain intracellular potassium. (Rodriguez M, et al. Arch Intern Med 1989;149:2592-2594; Bianchetti MG, et al. Pediatr Nephrol 1990 May;4(3):219-222.)

• nutrient adverse effects due to drug: It is important to avoid supplementation, especially of potassium, if kidney failure is present. Supplementation of magnesium and potassium can pose a significant risk for an individual on cisplatin due to the kidney damage which frequently results from the drug and impairs the urinary excretion of both minerals.

• testing and nutritional support: Patients undergoing treatment with cisplatin need to have their doctor regularly monitor their kidney function along with magnesium and potassium status. Serum creatinine, BUN and creatinine clearance should be measured prior to initiating therapy and should be monitored throughout treatment. In this regard, many nutritionally-oriented practitioners find that a testing magnesium levels in red blood cells in far more reliable than testing serum magnesium. Only after such assessment should supplementation with magnesium or potassium be undertaken and then only under close supervision by the prescribing physician.

• nutritional concerns: Avoid supplementation, especially of Potassium, if kidney failure is present.

• nutrient affected by drug: Colchicine

• mechanism: Colchicine has been linked to impaired absorption of Potassium.
(Roe DA. 1985, 159-160.)

• nutritional support: Individuals taking colchicine would most likely benefit from taking a high-potency multivitamin/mineral supplement to compensate for these interactions.

nutrient affected by drug: Corticosteroids including Prednisone

• mechanism: Steroidal anti-inflammatory drugs cause increased loss of potassium through the urine. Though widely observed, it remains unclear as to whether this is clinically significant. However, it is known that the mineralocorticoid action of cortisol causes a drop in serum potassium and an increase in serum sodium concentration which might lead to water retention, weight gain, and increased risk of hypertension.
(Threlkeld DS, ed. Apr 1991; Pronsky Z. 1991, 60.)

• nutritional support: Supplemental potassium may be necessary in some patients. However, increasing the daily consumption of fruit can be the most effective way to obtain the potassium supplementation needed to make up for depletion due to steroidal anti-inflammatory drugs. In fact, the levels of potassium available through fruit will usually exceed those found in most potassium supplements since they cannot legally exceed 99 mg each.

nutrient affected by combination drug: Cotrimoxazole (Sulfamethoxazole and Trimethoprim)

• research:, alone or in combination, cause increased blood levels of potassium, along with increased levels of BUN and creatinine in the blood. Trimethoprim is thought to act by inhibiting amiloride sensitive sodium channels in the distal nephron and impairing renal potassium secretion in a dose dependent manner. This is of particular concern to individuals with impaired kidney function; in such cases, close monitoring and treatment by a physician is necessary in the event that such abnormalities develop.
(Alappan R, et al. Ann Intern Med 1996;124:316-320; Perazella MA. Conn Med. 1997 Aug;61(8):451-458 ; Marinella MA. Gerontology. 1999 Jul;45(4):209-212; Alappan R, et al. Am J Nephrol. 1999 May;19(3):389-394; Perazella MA, et al. Clin Nephrol. 1996 Sep;46(3):187-192; Perlmutter EP, et al. Am J Med Sci. 1996 Feb;311(2):84-85; Reiser IW, et al. Kidney Int. 1996 Dec;50(6):2063-2069; Witt JM, et al. Ann Pharmacother. 1996 Apr;30(4):347-350.)

• nutritional concerns:
Individuals using sulfamethoxazole and/or trimethoprim should consult with their prescribing physician or pharmacist before taking any potassium supplements or potassium-containing products such as No Salt®, Morton Salt Substitute®, or Lite Salt®.

nutrient affected by drug: Digoxin

• mechanism: Potassium deficiency induced by concommitant diuretic use are very common in individuals using digoxin, often being secondary to hypomagnesia. Hypokalemia may predispose to digitalis toxicity.

• nutritional support: Individuals taking digoxin will often benefit from increasing their intake of potassium. Many physicians who prescribe digoxin monitor for potassium depletion and prescribe potassium supplements when measurable deficiencies are found. However direct supplementation of potassium may not be appropriate since potassium pills are limited to dosages of 99 mg each and taking several at a time may cause digestive irritation. Adequate dietary potassium can easily be obtained by eating several pieces of fruit each day; for example, one banana typically provides 500 mg. Other research, including that by Schmidt et al, indicates that the impairment of extrarenal potassium homeostasis by heart failure and digoxin treatment may be counterbalanced by exercise. Anyone taking digoxin should consult the prescribing physician and/or a nutritionally-oriented healthcare professional regarding the issue of potassium supplementation.
(Schmidt TA, et al. Cardiovasc Res 1995 Apr;29(4):506-511.)

nutrient affected by drug: Loop Diuretics and Thiazide Diuretics

• mechanism: By definition potassium-depleting diuretics increase potassium excretion and, in practice, they also usually deplete blood levels of magnesium. In turn, the drug-induced magnesium deficiency can contribute to further potassium depletion. Ultimately the relationship between these two patterns of depletion can be difficult to determine.
(Kroenke K, et al. Arch Intern Med 1987;147:1553-1556; Martin BJ, et al. Arch Intern Med 1987 Oct;147(10):1768-1771)

• adverse drug effects: A lack of magnesium interferes with healthy cardiac muscle function. This is especially important for patients on both diuretics and digitalis as they are more likely to develop arrythmias if not adequately supplemented with magnesium.

• nutritional support: In practice, it is generally advisable for individuals taking any potassium-depleting diuretic, other than those with kidney failure, to supplement with both potassium and magnesium.

Slow-K® and Micro-K® are typical examples of the potassium supplementation suggested by most physicians. Potassium levels can be further enhanced by increasing the amount of fruit in the diet. However, increasing potassium intake by any means is usually contraindicated and often dangerous in patients with reduced kidney function, especially those on dialysis.

All Nutrients, especially Potassium, affected by drug: Dulcolax

• mechanism: Dulcolax has a known tendency to cause potassium depletion due to its mechanism of action. Research indicates that stimulation of mucus secretion and synthesis contributes to the laxative action of dulcolax and that part of the potassium secretion is due to mucus release. However, all laxatives carry the potential for decreased nutrient absorption and eventual depletion.
(Farack UM, et al. Eur J Pharmacol 1985 Nov 5;117(2):215-222; Fleming BJ, et al. Ann Intern Med 1975 Jul;83(1):60-62; Ritsema GH, Eilers G. Clin Radiol 1994 Dec;49(12):874-876; Ewe K, Holker B. Klin Wochenschr. 1974 Sep 1;52(17):827-833.]

• nutritional concerns: The best means for preventing nutrient deficiencies, in this regard, is to avoid overuse of laxatives. In the event that constipation is a chronic or stubborn problem, consult a nutritionally-oriented physician or other qualified healthcare provider who can help determine and address the underlying cause(s).

nutrient affected by drug: Enalapril

• mechanism: ACE inhibitors enhance potassium levels in the blood. Ohya et al have demonstrated enalapril ability to significantly inhibit plasma aldosterone concentration and urinary aldosterone excretion.
(Ohya Y, et al. Int J Clin Pharmacol Ther 1994 Dec;32(12):655-659.)

• nutritional concerns: Potassium supplements and even high-potassium foods, such as fruit, can lead to problematic interactions and should be avoided. Individuals using ACE Inhibitors are advised to discuss these issues with their prescribing physician, a pharmacist, or both.

nutrient affected by drug: Gentamicin

• mechanism: Research indicates that gentamicin can cause increased urinary potassium loss.

• report: Animal studies and case reports indicate that renal tubular damage due to aminoglycosides, such as gentamicin, can lead to hypokalemia combined with hypocalcemia, hypomagnesemia and alkalosis.
(Mazze RI, Cousins MJ. Br J Anaesth. 1973 Apr;45(4):394-398; Valdivieso A, et al. Rev Med Chil. 1992 Aug;120(8):914-919.)

nutrient affected by drug: Glucocorticoids

• mechanism: Hypokalemia may occur during prolonged, high-dosage corticosteroid therapy. Steroidal anti-inflammatory drugs cause increased loss of potassium through the urine. Though widely observed, it remains unclear as to whether this is clinically significant.
(Thorn GW. N Engl J Med. 1966 274:775; Threlkeld DS, ed. Apr 1991; Pronsky, Z. 1991, 60.)

• nutritional support: Supplemental potassium may be necessary in some patients. However, increasing the daily consumption of fruit can be the most effective way to obtain the potassium supplementation needed to make up for depletion due to glucocorticoid drugs. In fact, the levels of potassium available through fruit will usually exceed those found in most potassium supplements since they cannot legally exceed 99 mg each.

nutrient affected by drug: Haloperidol

• research: Haloperidol has variously been observed to induce both hyperkalemia and hypokalemia, i.e., high and low blood levels of potassium, respectively.
(Aunsholt NA. Acta Psychiatr Scand. 1989 Apr;79(4):411-412; Mathe V, et al. Int Pharmacopsychiatry. 1971;6(2):111-130.)

• nutritional concerns: The clinical significance of changes in potassium levels due to haloperidol remains unclear. Individuals concerned about this aspect of haloperidol intoxication's side effects should consult their prescribing physician and/or pharmacist. Serum potassium levels are commonly measured as part of standard lab tests.

nutrient affected by drug: Heparin

• mechanism: Heparin therapy has been associated with hyperkalemia, i.e., abnormally high potassium levels.

• nutritional concerns: The clinical significance of changes in potassium levels due to heparin remains unclear. Individuals concerned about this side effect of heparin should consult their prescribing physician and/or pharmacist. Serum potassium levels are commonly measured as part of standard lab tests.

nutrient affected by drug: Indomethacin

• mechanism: Indomethacin inhibits prostaglandins, which reduces renin and aldosterone, and, in turn, reduces potassium excretion and causes hyperkalemia.

• nutritional concerns: Individuals taking indomethacin should be cautious in using KCl (such as "No Salt®"). Serum potassium levels need to be monitored.

nutrient affected by drug: Mineral Oil

• mechanism: Mineral oil, as a lipid solvent, may absorb many substances and/or interfere with normal absorption of potassium and other nutrients.

• research: While there is some disagreement, most research has found that mineral oil interferes with the absorption of many nutrients, including beta-carotene, calcium, phosphorus, potassium, and vitamins A, D, K, and E.

• nutritional concerns: If using mineral oil for any extended period of time, regular use of a multivitamin-mineral supplement would be beneficial. Malabsorption of fat-soluble vitamins due to ingestion of mineral oil can be minimized by administering mineral oil on an empty stomach or consuming vitamin or mineral supplements at least two hours before or after the mineral oil. In general it is advisable to limit the internal use of mineral oil to periods of less than one week.

nutrient affected by drug: Spironolactone (Aldactone®)

• mechanism: Spironolactone intentionally reduces urinary excretion of potassium. As a result of its role as a potassium-sparing diuretic, spironolactone can produce a state of inappropriately elevated potassium levels. On the other hand, concern has been raised that this potassium-sparing diuretic may cause hypokalemia by blocking distal tubular sodium-potassium exchange.
(Herman E, Rado J. Arch Neurol 1966 Jul;15(1):74-77.)

• nutritional concerns: Individuals using potassium-sparing such as spironolactone should limit their dietary intake of potassium to avoid excessive levels. Potassium supplements and potassium-containing salt substitutes, such as Lite Salt®, Morton's Salt Substitute and No Salt®, are designed for individuals suffering from potassium depletion due to other types of diuretics and should be avoided when taking potassium-sparing diuretics such as spironolactone. For some individuals, foods with high potassium content may need to be limited. Several pieces of fruit per day may provide adequate potassium to elevate serum levels. Individuals taking spironolactone should work with their prescribing physician to monitor potassium levels and modify their diet accordingly to avoid elevated potassium levels and associated problems.
(Herman E, Rado J. Arch Neurol 1966 Jul;15(1):74-77; Herman E, Rado J. Orv Hetil 1967 Jan 8;108(2):74-76; Stepan VM, et al. Eur J Gastroenterol Hepatol 1997 Oct;9(10):1001-1004.)

nutrient affecting drug performance: Tetracyclines

• research: Tetracycline may interfere with the activity of potassium.
(Holt GA. 1998, 256-58.)

There have been case reports of self-limiting esophagitis associated with tetracycline, particularly in combination with potassium.
(Teplick JG, et al. Radiology 1980 Jan;134(1):23-25; Kobler E, et al. Schweiz Med Wochenschr 1979 Aug 25;109(32):1180-1182; Eng J, Sabanathan S. Am J Gastroenterol 1991 Sep;86(9):1127-1133.)

Other researchers have also expressed concern that tetracycline may cause hypokalemia due to its nephrotoxic side effects.
(Mavromatis F. JAMA 1965 193:191.)

• nutritional support: Depletion of potassium may not have clinical significance with short-term use of tetracycline. Individuals using the drug for periods longer than two weeks may want to ask their prescribing physician and/or a nutritionally trained healthcare professional about possible benefits from increasing potassium intake. Several pieces of fruit per day may provide adequate potassium to elevate serum levels. Tetracycline is best taken on an empty stomach, with a full glass of water, one hour before or two hours after ingestion of any supplements, food, or other drugs.

nutrient affected by drug: Triamterene

• mechanism: Triamterene intentionally reduces urinary excretion of potassium. As a result of its role as a potassium-sparing diuretic, triamterene can produce a state of hyperkalemia, i.e., inappropriately elevated potassium levels. When used in combination with a thiazide diuretic, hyperkalemia (>5.4 mEq/L) has been reported ranging from 4% in patients less than 60 years of age to 12% in patients 60 years and older, with an overall incidence of less than 8%. Hyperkalemia has been reported to be associated with cardiac irregularities. On the other hand, concern has been raised about potential risks of hypokalemia among some patients using triamterene even though hypokalemia is a less common occurrence with the use of triamterene than with non-potassium sparing diuretics.
(Dorph S, Oigaard A. Nord Med 1968 Apr 18;79(16):516-518; Stepan VM, et al. Eur J Gastroenterol Hepatol. 1997 Oct;9(10):1001-1004; Schnaper HW, et al. Arch Intern Med 1989 Dec;149(12):2677-2681; Sawyer N, Gabriel R. Postgrad Med J 1988 Jun;64(752):434-437.)

• nutritional concerns: Individuals using potassium-sparing such as triamterene should limit their dietary intake of potassium to avoid excessive levels. Potassium supplements and potassium-containing salt substitutes, such as Lite Salt®, Morton's Salt Substitute and No Salt®, are designed for individuals suffering from potassium depletion due to other types of diuretics and should be avoided when taking potassium-sparing diuretics such as triamterene. For some individuals, foods with high potassium content may need to be limited. Several pieces of fruit per day may provide adequate potassium to elevate serum levels. Individuals taking triamterene should work with their prescribing physician to monitor serum potassium determinations regularly during the course of therapy and modify their diet accordingly to avoid elevated potassium levels and associated problems. This is particularly important in the treatment of patients with suspected or confirmed renal insufficiency such as elderly or diabetic patients.

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Do not rely solely on the information in this article.

The information presented in Interactions is for informational and educational purposes only. It is based on scientific studies (human, animal, or in vitro), clinical experience, case reports, and/or traditional usage with sources as cited in each topic. The results reported may not necessarily occur in all individuals and different individuals with the same medical conditions with the same symptoms will often require differing treatments. For many of the conditions discussed, treatment with conventional medical therapies, including prescription drugs or over-the-counter medications, is also available. Consult your physician, an appropriately trained healthcare practitioner, and/or pharmacist for any health concern or medical problem before using any herbal products or nutritional supplements or before making any changes in prescribed medications and/or before attempting to independently treat a medical condition using supplements, herbs, remedies, or other forms of self-care.

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.

Alappan, R, Perazella, MA, Buller, GK. Hyperkalemia in hospitalized patients treated with trimethoprim-sulfamethoxazole. Ann Intern Med 1996;124:316-320.

Alappan R, et al. Trimethoprim-Sulfamethoxazole Therapy in Outpatients: Is Hyperkalemia a Significant Problem? Am J Nephrol. 1999 May;19(3):389-394.

Aunsholt NA. Prolonged Q-T interval and hypokalemia caused by haloperidol. Acta Psychiatr Scand. 1989 Apr;79(4):411-412.
Abstract: A patient is described who developed hypokalemia and cardiac arrhythmia after acute intoxication with haloperidol.

Bianchetti MG, Kanaka C, Ridolfi-Luthy A, Wagner HP, Hirt A, Paunier L, Peheim E, Oetliker OH. Chronic renal magnesium loss, hypocalciuria and mild hypokalaemic metabolic alkalosis after cisplatin. Pediatr Nephrol 1990 May;4(3):219-222.
Abstract: Renotubular handling of sodium, potassium (K) calcium (Ca), phosphate, hydrogen ions and glucose, and urinary concentrating ability were studied in three children (aged 8, 8.5, 11 years) with renal magnesium (Mg) loss, persisting for more than 2 years after discontinuation of cisplatin treatment for neuroblastoma. A group of healthy children served as controls. Besides renal Mg wasting, a clear-cut tendency towards reduced calciuria associated with normal or slightly elevated plasma Ca was observed. Plasma K tended to be low (3.4-3.7 mmol/l), and plasma chloride was normal. Plasma bicarbonate (HCO3) ranged from 24.9 to 27.8 mmol/l, and urinary pH was always less than 6.0, indicating a renal HCO3 threshold exceeding 24 mmol/l. Plasma creatinine levels, glucosuria and phosphaturia, and urinary concentrating capacity were adequate. Comparable features were found in three children (aged 4.5, 9, 13 years) with primary renotubular hypomagnesaemia-hypokalaemia and hypocalciuria. This study complements the picture of chronic cisplatin tubulopathy in childhood demonstrating that, apart from Mg wasting, a reduced Ca excretion, and a tendency to hypokalaemia and metabolic alkalosis exist. Thus cisplatin may induce renal functional damage identical to that found in primary renotubular hypomagnesaemia--hypokalaemia with hypocalciuria.

Bugge JF. Severe hyperkalaemia induced by trimethoprim in combination with an angiotensin-converting enzyme inhibitor in a patient with transplanted lungs. J Intern Med. 1996 Oct;240(4):249-251.

Buist RA. Drug-nutrient interactions - an overview. Intl Clin Nutr Rev 1984;4(3):114. (Review)

Cohen L. Potassium replacement associated with the development of tetany in a patient with hypomagnesaemia. Magnes Res 1993 Mar;6(1):43-45.
Abstract: A case of hypomagnesaemia secondary to cisplatin therapy and diarrhoea had concomitant hypokalaemia. Increasing the serum potassium level from 2.8 to 3.4 mmol/litre by potassium supplementation induced tetany. Hypokalaemia in the face of hypomagnesaemia may have a membrane-stabilizing effect and preserve excitability.

Dorph S, Oigaard A. [Effect of triamterene on serum potassium and serum creatinine in long-term treatment with thiazides]. Nord Med 1968 Apr 18;79(16):516-518. [Article in Danish]

Elisaf M, Milionis H, Siamopoulos KC. Hypomagnesemic hypokalemia and hypocalcemia: clinical and laboratory characteristics. Miner Electrolyte Metab 1997;23(2):105-112

Eng J, Sabanathan S. Drug-induced esophagitis. Am J Gastroenterol 1991 Sep;86(9):1127-1133.

Ewe K. Influence of diphenolic laxatives on water and electrolyte permeation in man. pp. 420-426. Monograph. 1977 Aug 12.

Ewe K, Holker B. [The effect of a diphenolic laxative (Bisacodyl) on water- and electrolyte transport in the human colon]. Klin Wochenschr. 1974 Sep 1;52(17):827-833. [Article in German]

Farack UM, Gruber E, Loeschke K. The influence of bisacodyl and deacetylbisacodyl on mucus secretion, mucus synthesis and electrolyte movements in the rat colon in vivo. Eur J Pharmacol 1985 Nov 5;117(2):215-222.
Abstract: The effect of the diphenolic laxatives bisacodyl and deacetylbisacodyl on mucus secretion and fluid, sodium and potassium net transport was studied in rat colon perfused in vivo. Mucus output in the effluent was determined as total protein-bound hexose. Deacetylbisacodyl was more potent than the parent compound and was used to investigate dose-response relationships. At a low concentration (0.1 mg/dl), mucus and potassium secretion were stimulated whereas sodium and fluid absorption were inhibited, or converted to secretion, only at higher concentrations (0.5-3.0 mg/dl). All effects were dose-dependent and reversible within 1 h. With longer lasting perfusion of deacetylbisacodyl, mucus appeared in two peaks, one initial peak and another after 4 h. The late peak contained newly synthetized glycoproteins as indicated by the incorporation of intravenously injected [14C]galactose. It is concluded that stimulation of mucus secretion and synthesis contributes to the laxative action of bisacodyl. The effects of low versus high concentrations suggests that part of the potassium secretion is due to mucus release.

Fleming BJ, Genuth SM, Gould AB, Kamionkowski MD. Laxative-induced hypokalemia, sodium depletion and hyperreninemia. Effects of potassium and sodium replacement on the renin-angiotensin-aldosterone system. Ann Intern Med 1975 Jul;83(1):60-62.
Abstract: A patients with marked chronic hypokalemia (potassium, 1.7 to 2;3 meg/litre) and sodium depletion secondary to laxative abuse and dietary inadequacy was studied with respect to the renin-aldosterone system during sequential potassium and potassium-plus-sodium replacement. Extreme hyperreninemia of 20 Goldblatt units X 10-minus 4 was reduced to 0.9 with potassium replacement alone. Aldosteron excretion (15.8 mug/24 h) was initially low for a sodium-deprived state and high for a potassium-deprived state; it increased with potassium administration, but this rise was opposed by decreases in renin secretion induced by potassium and sodium administration. The results provide clinical confirmation of a dual effect of potassium on aldosterone secretion, with renin as a mediator.

Garland HO, Phipps DJ, Harpur ES. Gentamicin-induced hypercalciuria in the rat: assessment of nephron site involved. J Pharmacol Exp Ther. 1992 Oct;263(1):293-297.
Abstract: Two independent techniques were used in anesthetized rats in an attempt to locate the nephron site of the reduced tubular calcium reabsorption accompanying acute gentamicin infusion. The first technique was that of lithium clearance used to assess proximal sodium (and secondarily calcium) handling. Observations that lithium clearance was comparable in control and gentamicin-treated animals (1.83 +/- 0.39 vs. 1.46 +/- 0.14 ml.min-1 for first experimental period) suggests a lack of proximal effect of the drug. The second technique was that of tracer microinjection whereby superficial nephrons were injected with 45Ca and tubule calcium transport was assessed from the recovery of radioactivity in the final urine. 45Ca recovery values from distal microinjections were comparable in control and gentamicin-treated groups (81.1 +/- 2.0 vs. 77.7 +/- 4.6%). However, 45Ca recovery values from proximal microinjections were significantly higher in the gentamicin group (9.4 +/- 1.0 vs. 3.5 +/- 0.8%; P < .001). These data suggest that the effects of gentamicin on renal calcium handling are mediated at a nephron site proximal to the distal tubule (i.e., loop of Henle or proximal tubule itself). Closer examination of individual proximal micropuncture data may point to an effect occurring predominantly in the pars recta of the proximal tubule or loop of Henle. Taken together, the results of both parts of the present study suggest that the early physiological effects of gentamicin on the kidney occur in a different nephron segment from any subsequent nephrotoxicity.

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.

Good, CB, McDermott, L, McCloskey, B. Diet and serum potassium in patients on ACE inhibitors. JAMA 1995 Aug 16;274(7):538. (Letter)

Herman E, Rado J. Fatal hyperkalemic paralysis associated with spironalactone. Observation on a patient with severe renal disease and refractory edema. Arch Neurol 1966 Jul;15(1):74-77.

Herman E, Rado J. [Hyperkalemia with fatal paralysis in a diabetic patient treated with aldactone]. Orv Hetil 1967 Jan 8;108(2):74-76. [Article in Hungarian]

Holt GA. Food and Drug Interactions. Chicago: Precept Press, 1998.

Kes P, Reiner Z. Symptomatic hypomagnesemia associated with gentamicin therapy. Magnes Trace Elem. 1990;9(1):54-60.
Abstract: Seven patients (3 females, 4 males) developed symptomatic hypomagnesemia, hypocalcemia, and hypokalemia following gentamicin therapy. The excessive and inappropriate urinary excretion of magnesium and potassium in the presence of subnormal serum concentrations was noted. A significant correlation was found between the total cumulative dose of gentamicin and serum Mg concentration (r = 0.76, p less than 0.05), as well as between the renal wasting of Mg and the total cumulative dose of gentamicin administered (r = 0.89, p less than 0.01). The gentamicin-induced Mg depletion is a very rare but important complication which is most likely to occur when the drug is given to older patients in large doses over extended periods of time.

Kobler E, Nuesch HJ, Buhler H, Jenny S, Deyhle P. [Drug-induced esophageal ulcers]. Schweiz Med Wochenschr 1979 Aug 25;109(32):1180-1182. [Article in German]

Kosek JC, Mazze RI, Cousins MJ. Nephrotoxicity of gentamicin. Lab Invest. 1974 Jan;30(1):48-57.

Kroenke K, Wood DR, Hanley JF. The value of serum magnesium determination in hypertensive patients receiving diuretics. Arch Intern Med 1987;147:1553-1556.

Lavin F, O'Keeffe S, Grimes H, Finn J, Mannion A, Daly K. Effect of prolonged nifedipine or captopril therapy on lymphocyte magnesium and potassium levels in hypertension. Cardiology 1993;82(6):405-408.
Abstract: The effect of prolonged treatment with calcium channel blockers on potassium and magnesium stores is uncertain. We measured lymphocyte and serum magnesium and potassium in 28 patients treated for hypertension for 6 months with nifedipine or captopril. There was no difference in serum or lymphocyte concentrations in the two groups compared to 45 healthy, normotensive controls. These results suggest that intracellular cation levels are maintained with prolonged therapy with calcium channel blockers.

Lotz M, Zisman E, Bartter FC. Evidence for a phosphorus-depletion syndrome in man. N Eng J Med. 1968; 278:409.

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.

Marinella MA. Trimethoprim-Induced Hyperkalemia: An Analysis of Reported Cases. Gerontology. 1999 Jul;45(4):209-212.
Abstract: Background: Trimethoprim has been recently implicated in the development of hyperkalemia when administered at standard doses to immunocompetent patients. However, many clinicians are unaware of this potentially dangerous adverse effect. Objective: To review reported cases of trimethoprim-induced hyperkalemia in immunocompetent patients and identify predisposing factors, treatment, and outcome. Methods: A MEDLINE literature search was performed using the key words 'trimethoprim' and 'hyperkalemia'. All English-language case reports and bibliographies of immunocompetent patients with trimethoprim-induced hyperkalemia were reviewed. Results: Nine cases were identified. The mean patient age was 77.6 years, and the mean duration of therapy was 10.2 days. Seven patients received standard oral dosages of trimethoprim-sulfamethoxazole for common infections, and 2 patients were concurrently receiving angiotensin-converting enzyme inhibitors. The mean pretreatment levels of creatinine and potassium were 1.01 mg/dl and 4.55 mmol/l, respectively. The mean peak serum potassium level was 7.0 mmol/l. No deaths attributable to hyperkalemia occurred. Conclusions: Hyperkalemia due to trimethoprim typically affects elderly patients administered standard oral dosages, even in the presence of a normal serum creatinine level. Concurrent angiotensin-converting enzyme inhibitor therapy may increase the risk of hyperkalemia. The prognosis is favorable with standard therapy for hyperkalemia and withdrawal of trimethoprim.

Martin BJ, Milligan K. Diuretic-associated hypomagnesemia in the elderly. Arch Intern Med 1987 Oct;147(10):1768-1771.
Abstract: Serum magnesium concentration was measured in 320 consecutive elderly patients (mean age, 81 years) receiving diuretic therapy at the time of hospital admission. When compared with serum concentrations of 250 elderly patients who were not taking diuretics at the time of hospital admission, only the group taking thiazide diuretics had a significantly reduced mean serum level. The 24-hour urine sampling from representative subgroups demonstrated impaired magnesium-conserving ability in hypomagnesemic subjects receiving loop and thiazide diuretic therapy. Patients taking therapy that included a potassium-sparing diuretic had no significant evidence of reduced magnesium-conserving ability. Dietary assessments of the study population revealed suboptimal magnesium intake in the diet.

Marz R. Medical Nutrition From Marz. Second Edition. Portland, OR. 1997.

Mathe V, Kassay G, Tuske M. [Results of glucose tolerance tests and changes in inorganic serum phosphate and potassium levels in schizophrenic patients responding to treatment with psychotropic drugs]. Int Pharmacopsychiatry. 1971;6(2):111-130. [Article in German]

Mavromatis F. Tetracycline nephropathy. Case reports with renal biopsy. JAMA 1965 193:191.

Mazze RI, Cousins MJ. Combined nephrotoxicity of gentamicin and methoxyflurane anaesthesia in man. A case report. Br J Anaesth. 1973 Apr;45(4):394-398.

McLean, R. Magnesium and its therapeutic uses: A review. Am J Med 1994 Jan;96(1):63-76. (Review)

Montie T, Patamasucon P. Aminoglycosides: the complex problem of antibiotic mechanisms and clinical applications. Eur J Clin Microbiol Infect Dis 1995;14:85-87. (Editorial)

Nielsen H, Landbo K. [Hypokalemia, myopathy with myoglobinuria after prolonged ingestion of licorice]. Ugeskr Laeger 1970 Sep 17;132(38):1778-1780. [Article in Danish]

Ohya Y, Ueno M, Takata Y, Tominaga M, Ohmori S, Kobayashi K, Abe I, Fujishima M. Crossover comparison of the effects of enalapril and captopril on potassium homeostasis in patients with mild hypertension. Int J Clin Pharmacol Ther 1994 Dec;32(12):655-659.
Abstract: The effects of two types of angiotensin converting enzyme (ACE) inhibitors, enalapril (long-acting) and captopril (short-acting), on serum electrolytes and circadian rhythm of urinary electrolyte excretions were compared in relation to aldosterone status in patients with essential hypertension and normal renal function. Enalapril (5 mg once daily) and captopril (12.5 mg t.i.d.) were administered to 11 patients for 1 week each in a crossover fashion. Blood sampling in the early morning and 4-hour split urinary sampling for 24 hours were performed on the last day of control and each treatment periods. Enalapril and captopril significantly reduced blood pressure to similar levels. Enalapril but not captopril significantly inhibited plasma aldosterone concentration and urinary aldosterone excretion. Neither drug apparently altered serum or urinary Na levels. Both drugs significantly decreased urinary K excretion (p < 0.05, control: 44 +/- 4 mEq/day, captopril: 39 +/- 2 mEq/day, enalapril: 39 +/- 2 mEq/day; mean +/- SEM), but did not significantly alter serum K level (control: 4.1 +/- 0.1 mEq/l, captopril 4.2 +/- 0.2 mEq/l, enalapril 4.3 +/- 0.1 mEq/l). The circadian rhythm (acrophase) of urinary K excretion was not affected by either drug, while the amplitude was decreased by both, as assessed by the cosinor method. In summary, although enalapril caused more sustained inhibition of aldosterone secretion compared with captopril, both drugs showed similar effects on the K homeostasis in patients with mild essential hypertension.

O'Keeffe S, Grimes H, Finn J, McMurrough P, Daly K. Effect of captopril therapy on lymphocyte potassium and magnesium concentrations in patients with congestive heart failure. Cardiology 1992;80(2):100-105.
Abstract: Lymphocyte potassium and magnesium were measured before and 3 months after the introduction of captopril in 18 patients taking diuretics for congestive heart failure. Compared to 32 healthy controls, 9 patients who had been on potassium supplements plus frusemide had decreased baseline lymphocyte magnesium and potassium concentrations (p less than 0.01), in spite of similar plasma electrolyte levels. There was a significant (p less than 0.01) increase in both lymphocyte potassium and magnesium levels after 3 months' treatment with captopril and frusemide in these patients. Nine patients who had been taking a potassium-sparing combination diuretic also had an increase in lymphocyte magnesium (p less than 0.05) following the introduction of captopril. Increased intracellular potassium and magnesium may be one mechanism whereby angiotensin-converting enzyme inhibitors reduced arrhythmias and improve survival in patients with congestive heart failure.

Parsons PP, Garland HO, Harpur ES, Old S. Acute gentamicin-induced hypercalciuria and hypermagnesiuria in the rat: dose-response relationship and role of renal tubular injury. Br J Pharmacol 1997 Oct;122(3):570-576.
Abstract: 1. Standard renal clearance techniques were used to assess the dose-response relationship between acute gentamicin infusion and the magnitude of hypercalciuria and hypermagnesiuria in the anaesthetized Sprague-Dawley rat. Also investigated were whether these effects occurred independently of renal tubular cell injury. 2. Acute gentamicin infusion was associated with a significant hypercalciuria and hypermagnesiuria evident within 30 min of drug infusion. The magnitude of these responses was related to the dose of drug infused (0.14-1.12 mg kg(-1) min[-1]). Increased urinary electrolyte losses resulted from a decreased tubular reabsorption of calcium and magnesium. 3. A rapid dose-related increase in urinary N-acetyl-beta-D-glucosaminidase (NAG) excretion was also observed in response to gentamicin infusion. However, there was no evidence of renal tubular cell injury and no myeloid bodies were observed within the lysosomes of the proximal tubular cells. Gentamicin may thus interfere with the mechanisms for cellular uptake and intracellular processing of NAG causing increased NAG release into the tubular lumen. 4. The absence of changes in renal cellular morphology indicates that the excessive renal losses of calcium and magnesium were an effect of gentamicin per se and not the result of underlying renal tubular injury. The renal effects described in this paper were apparent after administration of relatively low total drug doses, and with plasma concentrations calculated to be within the clinical range. These findings suggest that disturbances of plasma electrolyte homeostasis could occur in the absence of overt renal injury in patients receiving aminoglycoside antibiotics.

Patki PS, Singh J, Gokhale SV, Bulakh PM, Shrotri DS, Patwardhan B. Efficacy of potassium and magnesium in essential hypertension: a double-blind, placebo controlled, crossover study. BMJ. 1990 Sep 15;301(6751):521-523.
Abstract: OBJECTIVE--To evaluate the antihypertensive activity of potassium given alone or in combination with magnesium in patients with mild hypertension. DESIGN--A double blind, randomised, placebo controlled, crossover trial of 32 weeks' duration. SETTINGS--Cardiology outpatient department, Sassoon General Hospitals, Pune, India. PATIENTS--37 Adults with mild hypertension (diastolic blood pressure less than 110 mm Hg). INTERVENTION--Patients received either placebo or potassium 60 mmol/day alone or in combination with magnesium 20 mmol/day in a crossover design. No other drug treatment was allowed. MEASUREMENTS--Blood pressure and heart rate assessed at weekly intervals and biochemical parameters at monthly intervals. RESULTS--Potassium alone or in combination with magnesium produced a significant reduction in systolic and diastolic blood pressures (p less than 0.001) and a significant reduction in serum cholesterol concentration (p less than 0.05); other biochemical variables did not change. Magnesium did not have an additional effect. Urinary potassium excretion increased significantly in the groups who received potassium alone or in combination with magnesium. The drug was well tolerated and compliance was satisfactory. CONCLUSION--Potassium 60 mmol/day lowers arterial blood pressure in patients with mild hypertension. Giving magnesium as well has no added advantage.

Perazella MA. Hyperkalemia and trimethoprim-sulfamethoxazole: a new problem emerges 25 years later. Conn Med. 1997 Aug;61(8):451-458. (Review)
Abstract: Trimethoprim-sulfamethoxazole is a frequently prescribed antibiotic with a wide spectrum of antimicrobial activity. A previously unreported and potentially lethal adverse reaction associated with "high dose" trimethoprim-sulfamethoxazole therapy, hyperkalemia, was described. Subsequent to the descriptions of hyperkalemia with "high dose" trimethoprim-sulfamethoxazole, a handful of cases noted the development of hyperkalemia with "standard dose" trimethoprim-sulfamethoxazole in elderly patients without evidence of an obvious defect in potassium homeostasis. A surveillance study of patients treated with "standard dose" trimethoprim-sulfamethoxazole as compared to similar controls treated with other antibiotics confirmed the rise in potassium associated with trimethoprim-sulfamethoxazole therapy. Recognition of this potassium disorder led to investigation and description of the mechanism by which trimethoprim-sulfamethoxazole-induced hyperkalemia. Trimethoprim was found to act like the potassium-sparing diuretic amiloride and reduce renal potassium excretion. Hence, trimethoprim-sulfamethoxazole therapy was found to be associated with a new adverse reaction, hyperkalemia, nearly 25 years after its introduction into clinical practice as an antimicrobial agent.

Perazella MA, et al. Trimethoprim-sulfamethoxazole: hyperkalemia is an important complication regardless of dose. Clin Nephrol. 1996 Sep;46(3):187-192. (Review)

Perlmutter EP, Sweeney D, Herskovits G, Kleiner M. Case report: severe hyperkalemia in a geriatric patient receiving standard doses of trimethoprim-sulfamethoxazole. Am J Med Sci. 1996 Feb;311(2):84-85.

Pronsky Z. Powers and Moore's Food-Medications Interactions. Ninth Edition. Food-Medication Interactions. Pottstown, PA, 1991.

Reiser IW, Chou SY, Brown MI, Porush JG. Reversal of trimethoprim-induced antikaliuresis. Kidney Int. 1996 Dec;50(6):2063-2069.
Abstract: High-dose trimethoprim-sulfamethoxazole (TMP-SMX) causes hyperkalemia, thought to result from TMP-induced blockade of amiloride-sensitive Na(+)-channels in the distal nephron. The present study was performed in anesthetized dogs to determine if increasing distal sodium delivery affects this antikaliuretic effect. In Group 1, intrarenal infusion of vehicle did not alter renal function. In Group 2, i.v. infusion of amiloride led to diuresis, natriuresis and antikaliuresis associated with a reduction of the transtubular potassium gradient (TTKG) in both kidneys. Intrarenal infusion of TMP (0.2 mg/kg/min) into the left kidney did not further alter these parameters. In groups 3 and 4, intrarenal infusion of TMP caused an ipsilateral diuresis, natriuresis, antikaliuresis and a reduction in (TTKG) without affecting the contralateral kidney. The TMP infusion was followed by furosemide (20 mg i.v.) in group 3 and acute saline loading in group 4. Despite continuous TMP infusion, both furosemide and saline loading reversed the antikaliuretic effect of TMP in the ipsilateral kidney and was associated with a similar kaliuresis, diuresis, natriuresis and decrease in urine osmolality in both kidneys. The TTKG following furosemide or saline loading increased in the ipsilateral kidney and decreased in the contralateral kidney. In all groups the systemic and renal hemodynamics remained unchanged. These results suggest that acute administration of TMP inhibits the amiloride-sensitive Na(+)-channel and K+ secretion in the distal nephron. Maneuvers that increase distal Na+ delivery can abrogate TMP's antikaliuretic effect due, in part, to an increase of the low TTKG observed with TMP.

Ritsema GH, Eilers G. Potassium supplements prevent serious hypokalaemia in colon cleansing. Clin Radiol 1994 Dec;49(12):874-876.
Abstract: The association between colonic cleansing and hypokalaemia was studied prospectively by monitoring the serum potassium levels in four groups of patients: groups 1 (55 patients), 2 (72 patients), and 3 (97 patients) received the same 2-day preparation of 15 g magnesium sulphate and 10 mg bisacodyl twice daily; group 4 (96 patients) received a 1-day preparation of 2.4 mg sennoside per kg of bodyweight. Groups 1 and 2 were on diuretics, but only group 2 received potassium supplementation. Serum potassium levels were measured before and after bowel preparation. Hypokalaemia was present prior to cleansing in six (11%), and after cleansing in 20 (36%) of the 55 patients in the group 1 patients on diuretics but without potassium supplements. There was, after cleansing, no significant fall in serum potassium in the group 2 patients on diuretics who received potassium supplements. No hyperkalaemia resulted from supplementation. A significant fall of the mean level of serum potassium occurred in patients in both group 3 (2-day-preparation) and group 4 (1-day-preparation). We conclude that both 1 day and 2 days of cleansing with cathartics may result in a significant fall in serum potassium, which can be prevented by oral potassium supplements. Potassium supplements (three times a day 15 ml of potassium chloride with 0.9 mmol K per ml during the preparation) in patients on diuretics may be prudent to avoid the risk of cardiac arrhythmia.

Rodriguez M, Solanki DL, Whang R. Refractory potassium repletion due to cisplatin-induced magnesium depletion. Arch Intern Med 1989 Nov;149(11):2592-2594.
Abstract: Cisplatin is a common cause of hypomagnesemia and hypokalemia due to renal magnesium (Mg) and potassium (K) losses. Magnesium plays an important role in the maintenance of intracellular K. An unrecognized and untreated Mg depletion can lead to a refractory K repletion. We describe two patients with hypomagnesemia-associated refractory hypokalemia following cisplatin following cisplatin therapy. Potassium supplementation failed to replace the K deficit. Profound hypokalemia persisted until hypomagnesemia was recognized and corrected. In neither patient was the concurrent hypomagnesemia recognized until the 11th and 9th hospital days. These two cases demonstrated the association of a refractory K repletion and an Mg deficiency. Thus, both serum K ion and Mg levels should routinely be assessed in patients who require cisplatin therapy.

Robinson C, Weigly E. Basic Nutrition and Diet Therapy. New York: MacMillan, 1984.

Roe DA. Diet and Drug Interactions. New York: Van Nostrand Reinhold, 1989.

Roe DA. Drug-induced Nutritional Deficiencies. 2nd ed. Westport, CT: Avi Publishing, 1985.

Roe DA. Risk factors in drug-induced nutritional deficiencies. In: Roe DA, Campbell T, eds. Drugs and Nutrients: The Interactive Effects. New York: Marcel Decker, 1984: 505-523.

Ryan MP. Interrelationships of magnesium and potassium homeostasis. Miner Electrolyte Metab 1993;19(4-5):290-295.
Abstract: The interrelationships of magnesium (Mg) and potassium (K) homeostasis are reviewed. Evidence from clinical and experimental studies including whole animal and cell culture experiments indicate that (1) homeostasis of Mg and K are closely related in the whole organism, (2) deficiencies of Mg and K frequently co-exist with gastrointestinal and especially renal losses from diuretic and nephrotoxic drug treatment being mainly responsible, and (3) Mg is required for maintenance of normal cellular K. Evidence from many laboratories indicate that Mg has direct effects at a cellular level on K transport. These include effects on Na-K-ATPase, Na-K-Cl cotransport, K channels, charge screening and permeability effects on membranes. New data on positive correlations between Mg and K in cardiac tissue, skeletal muscle and lymphocytes from patients undergoing cardiopulmonary bypass are presented. Interrelationships in Mg and K in cardiac tissue have probably the greatest clinical significance in terms of arrhythmias, digoxin toxicity, and myocardial infarction. Future studies will be aimed at elucidating mechanisms of Mg-K interrelationships at a cellular level using new techniques with the ability to detect concentrations and modulations of free intracellular Mg.

Sawyer N, Gabriel R. Progressive hypokalaemia in elderly patients taking three thiazide potassium-sparing diuretic combinations for thirty-six months. Postgrad Med J 1988 Jun;64(752):434-437.
Abstract: Three different thiazide potassium-sparing diuretic combinations were given to elderly patients for heart failure. Eighty patients received their allocated combinations for 3 years and had 6-monthly measurements of plasma potassium. A further 84 were recruited for study but 29 died within 6 months and 55 had to be withdrawn from the trial. The triamterene-containing preparation was discontinued most frequently (6/44) because of hypokalaemia (plasma potassium less than 3.0 mmol/l); amiloride (5/44) and spironolactone (1/47). The median fall in plasma potassium over 3 years in those patients not withdrawn because of hypokalaemia was similar in each case (P greater than 0.05) and possibly failed to reach significance because of the withdrawal rate (9%). The trend was for a greater fall in those patients taking triamterene. The spironolactone-containing preparation may be the least unsatisfactory of the three.

Schmidt TA, Bundgaard H, Olesen HL, Secher NH, Kjeldsen K. Digoxin affects potassium homeostasis during exercise in patients with heart failure. Cardiovasc Res 1995 Apr;29(4):506-511.
Abstract: OBJECTIVE: The aim was to evaluate whether digitalisation of heart failure patients affects extrarenal potassium handling during and following exercise, and to assess digoxin receptor occupancy in human skeletal muscle in vivo. METHODS: In a paired study of before versus after digitalisation, 10 patients with congestive heart failure underwent identical exercise sessions consisting of three bouts of increasing work rates, 41-93 W, on a cycle ergometer. The final bouts were followed by exercise to exhaustion. The femoral vessels and brachial artery were catheterised. Arterial blood pressure, heart rate, leg blood flow, cardiac output, plasma potassium, haemoglobin, pH, and skeletal muscle receptor occupancy with digoxin in biopsies were determined. RESULTS: Occupancy of skeletal muscle Na/K-ATPase with digoxin was 9% (P < 0.05). Following digitalisation femoral venous plasma potassium increased by 0.2-0.3 mmol.litre-1 (P < 0.05) at work rates of 69 W, 93 W, and at exhaustion, as well as during the first 3 min of recovery. Following digitalisation the femoral venoarterial difference in plasma potassium increased by 50-100% (P < 0.05) during exercise, and decreased by 66-75% (P < 0.05) during early recovery. Total loss of potassium from the leg increased by 138%. The effects of digitalisation on plasma potassium were not the outcome of changes in haemodynamics, because cardiac output and leg blood flow increased by up to 13% and 19% (P < 0.05), nor was it the outcome of changes in haemoconcentration or pH. CONCLUSIONS: Extrarenal potassium handling is altered as a result of digoxin treatment. This is likely to reflect a reduced capacity of skeletal muscle Na/K-ATPase for active potassium uptake because of inhibition by digoxin, adding to the reduction of skeletal muscle Na/K-ATPase concentration induced by heart failure per se. In heart failure patients, improved haemodynamics induced by digoxin may, however, increase the capacity for physical conditioning. Thus the impairment of extrarenal potassium homeostasis by heart failure and digoxin treatment may be counterbalanced by training.

Schnaper HW, Freis ED, Friedman RG, Garland WT, Hall WD, Hollifield J, Jain AK, Jenkins P, Marks A, McMahon FG, et al. Potassium restoration in hypertensive patients made hypokalemic by hydrochlorothiazide. Arch Intern Med 1989 Dec;149(12):2677-2681.
Abstract: Among 447 hypertensive patients, most with a history of diuretic-induced hypokalemia, 252 developed diuretic-induced hypokalemia while receiving hydrochlorothiazide, 50 mg/d. In a randomized study we evaluated the efficacy of three drug regimens in restoring potassium levels while maintaining blood pressure control: hydrochlorothiazide (50 mg/d) plus potassium supplement (20 mmol/d); hydrochlorothiazide (50 mg/d) plus potassium supplement (40 mmol/d); or hydrochlorothiazide (50 mg/d) with triamterene (75 mg/d) in one combination tablet. In all groups, mean serum levels of potassium rose within 1 week and showed no further change thereafter. However, the hydrochlorothiazide/triamterene and hydrochlorothiazide plus 40 mmol of potassium regimens were significantly more effective in restoring serum potassium levels than was the hydrochlorothiazide plus 20 mmol of potassium regimen. A significant increase in magnesium levels was observed only in the group treated with the hydrochlorothiazide/triamterene combination. Each regimen provided continued control of mild to moderate hypertension.

Smith MJH, Smith PK, eds. The Salicylates: A Critical Bibliographic Review. New York: Interscience, 1966.

Stepan VM, Hammer HF, Krejs GJ. Hyperkalaemia and diarrhoea in a patient with surreptitious ingestion of potassium sparing diuretics. Eur J Gastroenterol Hepatol 1997 Oct;9(10):1001-1004.
Abstract: We report a patient who presented with the unusual combination of chronic diarrhoea and hyperkalaemia. The patient was admitted to our hospital after repeated negative evaluations elsewhere including exploratory laparotomy. The patient had a long history of diarrhoea with hypokalaemia which was documented on several occasions in the past. Several months before admission to our hospital for evaluation of diarrhoea the patient developed hyperkalaemia. Her daily stool output reached 1200 g and her serum potassium was as high as 6.0 mmol/l. Extensive evaluation revealed surreptitious ingestion of the diuretics triamterene, hydrochlorothiazide and spironolactone as the cause of hyperkalaemia and diarrhoea. In addition, she had melanosis coli which was interpreted to be the consequence of surreptitious ingestion of anthraquinone-containing laxatives in the past although no current laxative intake could be proven. We postulate that diarrhoea in our patient was mainly due to the decreased sodium absorption in the small intestine and colon caused by diuretics. Serum aldosterone levels were more than eight times the upper limit of normal. Increased aldosterone levels presumably arose secondary to volume contraction and sodium chloride depletion, but presumably were not able to affect renal and colonic electrolyte transport because of blockage of mineralocorticoid receptors by spironolactone. Thus, the unusual combination of diarrhoea and hyperkalaemia resulted.

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.

Teplick JG, Teplick SK, Ominsky SH, Haskin ME. Esophagitis caused by oral medication. Radiology 1980 Jan;134(1):23-25.

Thorn GW. Clinical considerations in the use of corticosteroids. N Engl J Med. 1966 274:775.

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Toffaletti J. Electrolytes, divalent cations, and blood gases (magnesium). Analyt Chem 1991 63(12):192R-194R.

Trovato A, Nuhlicek DN, Midtling JE. Drug-nutrient interactions. Am Fam Physician 1991 Nov;44(5):1651-1658.(Review)

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Valdivieso A, Mardones JM, Loyola MS, Cubillos AM. [Hypomagnesemia associated with hypokalemia, hyponatremia and metabolic alkalosis. Possible complication of gentamycin therapy]. Rev Med Chil. 1992 Aug;120(8):914-919. [Article in Spanish]
Abstract: Hypomagnesemia is a serious abnormality with different causes and usually associated to other disorders of electrolyte metabolism. We report a female patient developing hypomagnesemia after administration of gentamycin. This was associated to severe hypokalemia, hyponatremia and metabolic alkalosis. Possible pathogenetic mechanisms and therapeutic measures are discussed.

Werbach MR. Foundations of Nutritional Medicine. Tarzana, CA: Third Line Press, 1997. (Review).

Whang R, Oei TO, Watanabe A. Frequency of hypomagnesemia in hospitalized patients receiving digitalis. Arch Intern Med 1985 Apr;145(4):655-656.
Abstract: We examined the frequency of hypokalemia and hypomagnesemia in patients receiving digitalis. Serum sodium, magnesium, and potassium levels were determined in 136 serum samples sent to the laboratory for digoxin assay. Hyponatremia (less than or equal to 130 mEq/L) occurred most frequently (21%), followed by hypomagnesemia (less than or equal to 1.25 mEq/L) in 19%, hypokalemia (less than or equal to 3.5 mEq/L) in 9%, and hypermagnesemia (greater than or equal to 2.25 mEq/L) in 7%. The twofold frequency of hypomagnesemia (19%) contrasted with hypokalemia (9%) indicates that clinicians are more attuned to avoiding hypokalemia than hypomagnesemia in patients receiving digitalis. Because hypokalemia and/or hypomagnesemia may contribute to the toxic effects of digitalis, ourobservation suggests that hypomagnesemia may be a more frequent contributor than hypokalemia to induction of toxic reactions to digitalis. Routine serum magnesium determination in patients receiving digitalis, who often are also receiving potent diuretics, may assist in identifying additional patients at risk for the toxic effects of digitalis.

Whang R, Whang DD, Ryan MP. Refractory potassium repletion-a consequence of magnesium deficiency. Arch Intern Med 1992;152:40-45.
Abstract: Experimental and clinical observations support the view that uncorrected magnesium (Mg) deficiency impairs repletion of cellular potassium (K). This is consistent with the observed close association between K and Mg depletion. Concomitant Mg deficiency in K-depleted patients ranges from 38% to 42%. Refractory K repletion due to unrecognized concurrent Mg deficiency can be clinically perplexing. Refractory K repletion as a consequence of Mg deficiency may be operative in patients with congestive failure, digitalis toxicity, cisplatin therapy, and in patients receiving potent loop diuretics. Therefore, we recommend that: (1) serum Mg be routinely assessed in any patients in whom serum electrolytes are necessary for clinical management and (2) until serum Mg is routinely performed consideration should be given to treating hypokalemic patients with both Mg as well as K to avoid the problem of refractory K repletion due to coexisting Mg deficiency.

Witt JM, Koo JM, Danielson BD. Effect of standard-dose trimethoprim/sulfamethoxazole on the serum potassium concentration in elderly men. Ann Pharmacother. 1996 Apr;30(4):347-350.
Abstract: OBJECTIVE: To determine the effect of standard-dose trimethoprim/sulfamethoxazole (TMP/SMX) (TMP 160 mg and SMX 800 mg q12h) on the serum potassium concentration. DESIGN: Retrospective and concurrent study. SETTING: A Veterans Affairs Medical Center. PATIENTS: Fifty-three men hospitalized at the Fargo Veterans Affairs Medical Center. Thirty-three patients who received standard-dose TMP/SMX for 3 or more days comprised the study group. Twenty patients who received oral cephradine or amoxicillin for 3 or more days comprised the control group. Patients who received potassium supplements, potassium-sparing diuretics, angiotensin-converting enzyme inhibitors, nonsteroidal antiinflammatory drugs, beta-blockers, heparin, known nephrotoxic agents, patients with a serum creatinine concentration of more than 177 mumol/L, and patients with baseline hyperkalemia (serum potassium concentration > 5.1 mmol/L) were excluded. RESULTS: The serum potassium concentration in the study group was 4.22 +/- 0.40 mmol/L and increased by 0.31 +/- 0.38 mmol/L at the end of therapy (p < 0.001). Twenty-six patients in the study group (78.8%) had an increase in the serum potassium concentration during TMP/SMX therapy. Fourteen of these patients had follow-up serum potassium concentrations obtained after completion of therapy. The serum potassium concentration returned to baseline in 10 of these patients. The serum creatinine concentration also increased during therapy. However, the correlation between the increase in the serum potassium concentration and the increase in the serum creatinine concentration was weak (Pearson r = 0.29). The serum potassium in the control group was 4.34 mmol/L and remained essentially unchanged during therapy. CONCLUSIONS: Therapy with standard-dose TMP/SMX is associated with a slight increase in the serum potassium concentration. Routine monitoring of the serum potassium concentration in patients who are treated with standard-dose TMP/SMX therapy is unnecessary. However, TMP/SMX should be considered as a possible cause of unexplained hyperkalemia in elderly patients receiving TMP/SMX therapy.

Wright LF, DuVal JW Jr. Renal injury associated with laxative abuse. South Med J 1987 Oct;80(10):1304-1306.
Abstract: Surreptitious laxative abuse is a common cause of unexplained diarrhea, but has not been considered an important cause of irreversible electrolyte and renal functional abnormalities. We have described five patients with the laxative abuse syndrome associated with significant renal injury and electrolyte disorders. We conclude that laxative abuse, like analgesic abuse, is a cause of interstitial renal disease that is more common than generally recognized.

Yeh JK, Aloia JF, Semla HM. Interrelation of cortisone and 1,25 dihydroxycholecalciferol on intestinal calcium and phosphate absorption. Calcif Tissue Int 1984 Sep;36(5):608-614.
Abstract: The interrelation of glucocorticoids and 1,25 dihydroxycholecalciferol (1,25(OH)2D3) on intestinal calcium and phosphate absorption was investigated. The active and passive transport of calcium and phosphate was evaluated by the in situ intestinal loop technique. Administration of cortisone resulted in a decrease of the luminal fluid and an increase of the luminal calcium and phosphate concentration. Under active transport conditions, administration of cortisone resulted in a decrease of net calcium absorption through two mechanisms: (1) depressed vitamin D-dependent calcium absorption, (2) increased vitamin D-independent calcium backflux. The enhancement of bidirectional phosphate flux by cortisone was independent of 1,25(OH)2D3. An enhancement of water movement by cortisone resulted in an increase of luminal calcium and phosphate concentration which favors the passive diffusion of these ions. Enhanced calcium diffusion by cortisone compensates for the inhibitory effect of cortisone on vitamin D-dependent calcium transport. However, enhanced phosphate diffusion by cortisone is additive to the effect of 1,25(OH)2D3.

Young IS, Goh EM, McKillop UH, Stanford CF, Nicholls DP, Trimble ER. Magnesium status and digoxin toxicity. Br J Clin Pharmacol. 1991 Dec;32(6):717-721.
Abstract: 1. Eighty-one hospital patients receiving digoxin were separated into groups with and without digoxin toxicity using clinical criteria. Serum digoxin, sodium, potassium, calcium, creatinine, magnesium and monocyte magnesium concentrations were compared. 2. Subjects with digoxin toxicity had impaired colour vision (P less than 0.0001, Farnsworth-Munsell 100 hue test) and increased digoxin levels (1.89 (1.56-2.21) vs 1.34 (1.20-1.47) nmol l-1, P less than 0.01) (mean (95% confidence limits], though there was considerable overlap between two groups. 3. Subjects with digoxin toxicity had lower levels of serum magnesium (0.80 (0.76-0.84) vs 0.88 (0.85-0.91) mmol l-1, P less than 0.01) and monocyte magnesium (6.40 (5.65-7.16) vs 8.76 (7.81-9.71) mg g-1 DNA, P less than 0.01), but there were no significant differences in other biochemical parameters. A greater proportion of toxic subjects were receiving concomitant diuretic therapy (20/21 vs 37/60, P less than 0.05). 4. Magnesium deficiency was the most frequently identified significant electrolyte disturbance in relation to digoxin toxicity. In the presence of magnesium deficiency digoxin toxicity developed at relatively low serum digoxin concentrations.