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Diuretics
Loop Diuretics


Depletions
Calcium
Mechanism

Short-term treatment with furosemide (4 to 7 days) increased urinary calcium excretion and reduced serum ionized calcium levels in normal subjects (Fujita et al. 1985). However, along with marked calciuresis, furosemide (40 mg) elevated serum calcium levels in another study with five healthy male volunteers (Ogawa et al. 1984). Chronic treatment (25 days) with furosemide (40 mg/day) altered calcium levels in rats (Warshaw et al. 1980). The effects on calcium may be less pronounced with bumetanide; urinary calcium loss was initially elevated but was followed by retention at 24 hours in 16 healthy volunteers treated with the drug (0.25 to 1 mg po) (Davies et al. 1974). More studies are needed to clarify the clinical effects of loop diuretics on calcium metabolism and homeostasis.


Significance of Depletion

Osteoporosis is the primary disease associated with chronic calcium deficiency; it can result in pathologic fractures associated with bone pain, spinal deformity, and premature morbidity and mortality (Cashman and Flynn 1999; Covington 1999). Other signs and symptoms of depleted serum calcium levels include arrhythmias, neuromuscular irritability, and mental status changes such as depression and psychosis (Potts 1998).


Replacement Therapy

Calcium supplementation in the form of citrate, malate, gluconate, or carbonate salts may range from 1000 mg to 1500 mg or more daily (Adler and Rosen 1999; Covington 1999). Doses as high as 3000 mg/day with 10 to 50 mcg/day of 25-OH-D3 may be appropriate if plasma calcium and phosphate levels are stable and within normal range (DrŁeke 1999). In cases where calcium deficits are associated with vitamin D deficiency, up to 6000 mg/day of calcium (acetate or carbonate) may be warranted. These values should be adjusted on an individual basis depending upon the patient's age, gender, clinical presentation, serum calcium levels, dietary habits, and medication regimen. Calcium replacement should be part of a comprehensive approach to the evaluation and treatment of osteoporosis.


Magnesium
Mechanism

Loop diuretics inhibit passive magnesium absorption and promote urinary loss of this electrolyte that could lead to a deficiency (Abrams 1981; Davies et al. 1974; Leary et al. 1990; Quamme 1997; Ryan 1986).


Significance of Depletion

Magnesium deficiency can be a serious side effect of loop diuretic therapy; it is implicated in the development of cardiac arrhythmias and sudden death in certain patient populations, including those with congestive heart failure (Iseri et al. 1975; Schwinger and Erdmann 1992). Severely depleted levels of magnesium affect calcium and vitamin D metabolism and are associated with hypocalcemia (Cashman and Flynn 1999). Clinically, neuromuscular hyperexcitability may be the first symptom manifested in patients with hypomagnesemia (reflected in a serum concentration of 17 mg/L or less). Recent evidence supports a possible connection between chronically low magnesium levels and various illnesses such as cardiovascular disease, hypertension, diabetes, and osteoporosis.


Replacement Therapy

The current recommended dietary allowance (RDA) for magnesium ranges from 30 to 420 mg/day, depending upon age and gender (Cashman and Flynn 1999). For replacement therapy, doses should be tailored to the patient's clinical condition, taking into account serum magnesium levels, dietary habits, and medication regimen.


Phosphorus
Mechanism

The rate of phosphorus elimination doubled in healthy volunteers treated with bumetanide (2 mg/day) compared to furosemide or placebo (Carriere and Dandavino 1976). This effect was observed under conditions of normal diet and fluid intake as well as over-hydration. In contrast, furosemide produced no phosphaturic effect under the conditions studied.


Significance of Depletion

Although rare, suboptimal intake of phosphorus can lead to hypophosphatemia, which is associated with general debility characterized by muscle weakness, bone pain, paraesthesia, ataxia, acute respiratory failure, mental confusion, seizures, anorexia, anemia, increased susceptibility to infection, and even death (Cashman and Flynn 1999; Covington 1999). In chronic situations, patients with severely depleted phosphate levels below approximately 0.3 mmol/L may exhibit signs of rickets (children) or osteomalacia (adults) (Cashman and Flynn 1999).


Replacement Therapy

The recommended dietary allowance (RDA) for phosphorus ranges from 100 to 1250 mg/day depending on age (Cashman and Flynn 1999; Covington 1999). Doses for replacement therapy should be adjusted to reflect individual circumstances, including the patient's age, gender, clinical presentation, serum phosphate levels, dietary habits, and medication regimen.


Potassium
Mechanism

Loop diuretics increase potassium excretion (Rastogi et al. 1985). This may occur as a result of inhibition of renal reabsorption of cations at the proximal and distal tubules as well as at the Loop of Henle (Hines Burnham et al. 2000). Increased potassium excretion could lead to hypokalemia, which could be of particular concern in patients with hepatic cirrhosis, congestive heart failure, and ventricular arrhythmias.


Significance of Depletion

Potassium depletion as a consequence of prolonged drug therapy is usually associated with chloride deficiency and manifests as hypokalemic, hypochloremic metabolic acidosis (Covington 1999). Signs and symptoms of deficiency include anorexia, apprehension, drowsiness, listlessness, fatigue, nausea, muscle cramps and weakness, tetany, excessive thirst, altered mental status, and irrational behavior. Severe hypokalemia could also result in clinical manifestations of cardiac arrythmia, including primarily palpitations, cardiac arrest, and death. A loss from total body stores of approximately 100 to 200 mEq of potassium is usually required to cause a decrease in serum potassium levels of 1 mEq/L.


Replacement Therapy

The usual range of treatment is 20 to 100 mEq/day of potassium (PDR 2000). The appropriate doses for replacement therapy should be determined on an individual basis, considering the patient's age, gender, clinical presentation, serum potassium levels, dietary habits, and medication regimen. The chloride salt is appropriate treatment for cases of alkalosis (Covington 1999). In cases of acidosis, other potassium salts such as bicarbonate, citrate, acetate, or gluconate are preferred.


Vitamin B1 (Thiamine)
Mechanism

Low doses of furosemide (1, 3, and 10 mg IV over 6 hours) caused significant urinary losses of thiamine in healthy volunteers (Rieck et al. 1999). Long-term furosemide therapy can cause thiamine deficiency and impair cardiac performance in patients with CHF; poor dietary intake of thiamine increases this risk (Brady et al. 1995; Seligmann et al. 1991).


Significance of Depletion

Early nonspecific manifestations of depleted thiamine levels include weakness, fatigue, anorexia, constipation, nystagmus, and mental status changes such as memory loss, confusion, and depression (Covington 1999). Beriberi is the classic condition associated with thiamine deficiency. Symptoms include polyneuritis, cardiac disturbances (bradycardia, heart failure, hypertrophy), and possibly edema. Thiamine deficiency rarely occurs alone; it is usually accompanied by deficiencies in other B vitamins.


Replacement Therapy

Although the recommended dietary allowance (RDA) for this nutrient ranges from 1.1 to 1.5 mg for adults depending on gender, treatment of beriberi requires oral doses as high as 5 to 10 mg/day for one month to achieve tissue saturation and replenish body stores of thiamine (Covington 1999). Treatment of deficiency secondary to alcoholism may require up to 40 mg/day of thiamine orally; cardiovascular disease may warrant a total daily intake of 90 mg (Marcus and Coulston 1996). Replacement therapy should be tailored to the patient's needs depending on age, gender, clinical presentation, serum vitamin B1 levels, dietary habits, and medication regimen.


Vitamin B6 (Pyridoxine); Vitamin C (Ascorbic Acid)
Mechanism

Furosemide (20 mg IV) increased urinary excretion of vitamins B6 and C in patients with chronic renal failure; these patients should be monitored for deficiency of these vitamins if they are on chronic treatment with this drug (Mydlik et al. 1998).


Significance of Depletion

Vitamin B6: Usually, vitamin B6 deficiency is accompanied by depletions of other B vitamins (National Research Council 1989). Signs and symptoms of low levels of this vitamin include epileptiform convulsions with abnormal EEG findings, dermatitis, anemia, weakness, mental confusion, irritability, nervousness, insomnia, and abnormal tryptophan metabolism (Covington 1999; National Research Council 1989; Wilson 1998). Depleted levels may increase the risk of colon and prostate cancers, heart disease, brain dysfunction, and birth defects (Ames 2000).

Vitamin C: Patients with depleted levels of vitamin C may present with anemia, icterus, edema, lethargy, fatigue, fever, ecchymoses, hypotension, convulsions, gum disorders, tooth loss, emotional changes, and perifollicular hyperkeratotic papules (Carr and Frei 1999; Covington 1999; National Research Council 1989; Wilson 1998). In addition, they may exhibit signs of poor wound healing, increased susceptibility to infection, and markedly defective collagen synthesis. Severe deficiency results in scurvy, which is potentially fatal (Carr and Frei 1999; National Research Council 1989; Wilson 1998). Scurvy involves degenerative changes in capillaries, bone, and connective tissue, resulting in clinical symptoms that include weakness, joint tenderness and swelling, and spontaneous hemorrhages (Carr and Frei 1999; Covington 1999; National Research Council 1989; Wilson 1998). Patients with vitamin C deficiency may also be at increased risk of developing cataracts and heart disease (Ames 2000).


Replacement Therapy

Vitamin B6:Neuropathology resulting from vitamin B6 deficiency should be treated with doses of 50 to 200 mg/day (Covington 1999). Dietary deficiency usually responds to doses of 10 to 20 mg/day. Doses should be tailored to account for the patient's age, gender, clinical presentation, serum vitamin B6 levels, dietary habits, and medication regimen.

Vitamin C: Treatment of scurvy requires doses between 300 and 1000 mg/day for adults (Covington 1999). Other recommendations range from the recommended dietary allowance (RDA) of 60 mg to 2000 mg/day for adults (Carr and Frei 1999; Wilson 1998). One study proposes that no adult receive more than 1000 mg/day because higher doses could cause nausea and diarrhea (Ausman 1999). To minimize the possibility of gastric upset, buffered and sustained-release vitamin C preparations are recommended. Specific doses account for the patient's age, gender, overall health status, dietary habits, and medication regimen. Smokers must consume 2 to 3 times more vitamin C than non-smokers (Ames 2000).


Editorial Note

This information is intended to serve as a concise reference for healthcare professionals to identify substances that may be depleted by many commonly prescribed medications. Depletion of these substances depends upon a number of factors including medical history, lifestyle, dietary habits, and duration of treatment with a particular medication. The signs and symptoms associated with deficiency may be nonspecific and could be indicative of clinical conditions other than deficiency. The material presented in these monographs should not in any event be construed as specific instructions for individual patients.


References

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Adler RA, Rosen CJ. Glucocorticoids and osteoporosis. Endocrinol Metab Clin North Am. 1999;23:641-654.

Ames BN. Micronutrient deficiencies: A major cause of DNA damage. Ann NY Acad Sci. 2000;889:87-106.

Ausman LM. Criteria and recommendations for vitamin C intake. Nutr Review. 1999;57(7):222-229.

Brady JA, Rock CL, Horneffer MR. Thiamin status, diuretic medications, and the management of congestive heart failure. J Am Diet Assoc. 1995;95(5):541-544.

Carr AC, Frei B. Toward a new recommended dietary allowance for vitamin C based on antioxidant and health effects in humans. Am J Clin Nutr 1999;69:1086-1107.

Carriere S, Dandavino R. Bumetanide, a new loop diuretic. Clin Pharm Ther. 1976;20:424-438.

Cashman K, Flynn A. Optimal nutrition: calcium, magnesium and phosphorus. Proc Nutr Soc. 1999;58:477-487.

Covington T, ed. Nonprescription Drug Therapy Guiding Patient Self-Care. St Louis, MO: Facts and Comparisons; 1999:467-545.

Davies DL, Lant AF, Millard NR, Smith AJ, Ward JW, Wilson GM. Renal action, therapeutic use, and pharmacokinetics of the diuretic bumetanide. Clin Pharmacol Ther. 1974;15:141-155.

DrŁeke T. Medical management of secondary hyperparathyroidism in uremia. Am J Med Sci. 1999;317(6):383-389.

Fujita T, Delea CS, Bartter FC. The effects of oral furosemide on the response of urinary excretion of cyclic adenosine monophosphate and phosphate to parathyroid extract in normal subjects. Nephron. 1985;41(4):333-336.

Gabow PA, Hanson TJ, Popovtzer MM, Schrier RW. Furosemide-induced reduction in ionized calcium in hypoparathyroid patients. Ann Intern Med. 1977;86(5):579-581.

Hines Burnham T, et al, eds. Drug Facts and Comparisons. St. Louis, MO:Facts and Comparisons; 2000:624-626.

Iseri LT, Freed J, Bures AR. Magnesium deficiency and cardiac disorders. Am J Med. 1975;58(6):837-846.

Leary WP, Reyes AJ, Wynne RD, van der Byl K. Renal excretory actions of furosemide, of hydrocholorothiazide and of the vasodilator flosequinan in healthy subjects. J Int Med Res. 1990;18:120-141.

Marcus R, Coulston AM. Water-soluble vitamins. In: Hardman JG, Limbird LE, et al, eds. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill Health Professions Division; 1996:1557-1558.

Mydlik M, Derzslova K, Zemberova E, Rajnic A. [The effect of furosemide on urinary excretion of oxalic acid, vitamin C and vitamin B6 in chronic renal failure]. Vnitr Lek. 1998;44(3):127-131.

National Research Council. Recommended Dietary Allowances. 10th ed. Washington, DC: National Academy Press; 1989.

Ogawa K, Hatano T, Yammoto M, Matsui N. Influence of acute diuresis on calcium balance – a comparative study of furosemide and azosemide. Int J Clin Pharmacol, Ther, Toxicol. 1984;22(8):401-405.

Physicians' Desk Reference, PDR. 52nd ed. Montvale, NJ: Medical Economics Company; 1998.

Potts JT. Diseases of the parathyroid gland and other hyper- and hypocalcemic disorders. In: Fauci AS, Braunwald E, Isselbacher KJ, et al, eds. Harrison's Principles of Internal Medicine. 14th ed. New York: McGraw-Hill Companies Health Professional Division; 1998:2241.

Quamme GA. Renal magnesium handling: new insights in understanding old problems. Kidney Int. 1997;52(5):1180-1195.

Rastogi S, Bayliss JM, Nascimento L, Arruda JA. Hyperkalemic renal tubular acidosis: effect of furosemide in humans and in rats. Kidney Int. 1985;28(5):801-817.

Rieck J, Halkin H, Almog S, et al. Urinary loss of thiamine is increased by low doses of furosemide in healthy volunteers. J Lab Clin Med. 1999;134(3):238-243.

Ryan MP. Magnesium and potassium-sparing diuretics. Magnesium. 1986;5(5-6):282-292.

Schwinger RH, Erdmann E. Heart failure and electrolyte disturbances. Methods Find Exp Clin Pharmacol. 1992;14(4):315-325.

Seligmann H, Halkin H, Rauchfleisch S, et al. Thiamine deficiency in patients with congestive heart failure receiving long-term furosemide therapy: a pilot study. Am J Med. 1991;91(2):151-155.

Warshaw BL, Anand SK, Kerian A, Lieberman E. The effect of chronic furosemide administration on urinary calcium excretion and calcium balance in growing rats. Pediatr Res. 1980;14(10):1118-1121.

Wilson JD. Vitamin deficiency and excess. In: Fauci AS, Braunwald E, Isselbacher KJ, et al, eds. Harrison's Principles of Internal Medicine. 14th ed. New York: McGraw-Hill Companies Health Professional Division; 1998:483-485.


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