THE MAGNESIUM REPORT
CLINICAL, RESEARCH, AND LABORATORY NEWS FOR CARDIOLOGISTS
Second Quarter 2000
TIMOTHY J. MAHER, PHD
The importance of adequate magnesium intake is documented by scientific and clinical data that justify the consumption of magnesium-rich foods and the use of oral magnesium supplements for good health. When intake or retention of magnesium is inadequate, magnesium deficiency can take either of 2 forms—clinical hypomagnesemia or chronic latent magnesium deficiency. Clinical hypomagnesemia is easier to recognize because it is associated with specific clinical manifestations (Table 1), but chronic latent magnesium deficiency is more common.
The consequences of chronic latent magnesium deficiency are extremely prevalent, and some are potentially very serious (please see The Magnesium Report, First Quarter 2000, in which Drs. Ronald J. Elin and Robert K. Rude discuss chronic latent magnesium deficiency and the role of magnesium in preventive medicine). Chronic latent magnesium deficiency increases the risk for cardiac arrhythmias, coronary artery disease, diabetes mellitus, hypertension, migraine, osteoporosis, and premenstrual syndrome (Table 2).
There are clinically significant interactions between magnesium and a number of medications that may alter magnesium status and affect medication efficacy (Table 3). Some commonly used medications, including certain antibiotics, loop and thiazide diuretics, cisplatin, and cyclosporine can lead to decreased absorption or increased elimination of magnesium, as can ethanol consumption. In addition, antacids that contain magnesium can decrease the bioavailability of some medications by interfering with intestinal absorption.
Magnesium, the second most common intracellular cation in the body, is a crucial cofactor for more than 300 enzymatic reactions involved in normal physiologic processes. These include pathways in metabolism of carbohydrates, fats, and proteins. Magnesium is required in every enzymatic reaction of ATP and in many of the steps involved in the synthesis of DNA and RNA, and it stabilizes these macromolecules as well.
The gut and kidney control the magnesium content of the body. Magnesium absorption occurs primarily in the small intestine, and may be impaired by gastrointestinal infections, inflammatory bowel disease, radiation-induced gastroenteritis, steatorrheic states, severe diarrhea, and familial malabsorption syndromes. Of more significance in the gut, however, may be the effect of magnesium on the absorption or availability of medications.
Normal kidney function is essential to the body’s ability to retain magnesium. As part of the normal filtration-reabsorption process, most calcium, magnesium, and sodium in plasma are filtered through the glomerular membrane. Unlike calcium and sodium, which are largely reabsorbed in the proximal convoluted tubule, most magnesium reabsorption takes place in the loop of Henle—specifically, in the thick ascending limb of the cortical segment. Some reabsorption also occurs in the distal. tubule.
Use of diuretics is the most frequent reason for hypomagnesemia. Magnesium reabsorption in the thick ascending limb of the loop of Henle is decreased significantly by loop diuretics, and in the distal tubule by thiazide diuretics. In addition, patients taking diuretics are at increased risk when gut absorption of magnesium is compromised by inflammatory bowel disease, a bout of severe diarrhea, or during an episode of “stomach flu.” The magnesium-wasting effect of diuretics is especially important in patients who have cardiac arrhythmias or risk factors for arrhythmias.
Hypokalemia, which also occurs with use of loop or thiazide diuretics, may lead to renal magnesium wasting. Cellular potassium depletion is associated with diminished magnesium reabsorption within the loop of Henle and the distal tubule and may lead to increased magnesium excretion. Long-term use of loop or thiazide diuretics may deplete potassium and promote renal magnesium wasting.
Most patients who take loop diuretics such as furosemide or bumetamide or a thiazide diuretic such as chlorothiazide will become hypomagnesemic unless they augment their magnesium intake with oral supplements or magnesium-rich foods (Table 4). For these patients, it is reasonable to emphasize the need for the recommended daily intake of magnesium—that is, 420 mg/d for adult men or 320 mg/d for non-pregnant women. A single 400 mg tablet of magnesium oxide contains 241.3 mg of elemental magnesium, so 1 or 2 tablets daily is appropriate.
Cancer patients undergoing chemotherapy with regimens containing cisplatin are at significant risk for hypomagnesemia. Cisplatin impairs renal reabsorption of magnesium because it is directly toxic to the ascending limb of the loop of Henle and the distal tubule. Approximately 90% of patients who receive this nephrotoxic antineoplastic drug will become hypomagnesemic unless corrective pretreatment measures are initiated. Adequate dietary magnesium intake before chemotherapy will not prevent cisplatin-associated magnesium deficiency.
While there is general agreement that oral or intravenous (IV) supplementation of magnesium is appropriate with cisplatin therapy, there is no consensus on the ideal dosage or mode of administration. In 4 randomized trials and 2 nonrandomized studies, a statistically significant benefit for oral or IV magnesium supplementation has been found. Evans and colleagues randomized 28 patients receiving cisplatin, 5-fluorouracil, and epirubicin for upper gastrointestinal cancers to either scheduled or “as needed” IV magnesium supplementation, with oral supplementation given if necessary. They found that IV supplementation alone was not fully protective against hypomagnesemia during cisplatin chemotherapy but concluded that patients should receive 1V supplementation with each cycle of chemotherapy.
Martin and associates found that both oral and IV supplementation significantly reduced the decline in serum magnesium levels after the first two or three courses of chemotherapy. Patients with tumors of the head and neck, ovary, and bladder were randomized to receive 7.15 mmol of magnesium (as magnesium pidolate) orally q8h on days 2 through 21 of each chemotherapy cycle, 12 mmol of magnesium (as magnesium sulfate) IV in the prehydration fluid given before each cycle, or no magnesium supplementation (control group). Compared to the control group, statistically significant differences in serum magnesium levels were seen after the second cycle in patients receiving oral supplementation and after the third cycle in patients receiving IV supplementation.
Persons with alcoholism represent the second largest group of people with hypomagnesemia. This is due in part to the inherent effects of alcohol on magnesium homeostasis and in part to the consequences of the poor diet typical of alcohol abusers. Acutely, alcohol increases urinary magnesium excretion by as much as 260% above baseline values; this occurs within minutes of ingestion or parenteral administration.
With chronic alcohol intake, body stores of magnesium become depleted. Reasons include inadequate intake, starvation ketosis, vomiting and diarrhea, and urinary excretion. In advanced alcoholism, however, urinary magnesium excretion may decline in response to reduced intake and depleted stores. Among the effects of chronic alcoholism are a negative magnesium balance, decreased plasma levels of magnesium, decreased magnesium concentration in cerebrospinal fluid and in muscle biopsies, and the development of a magnesium-responsive hypocalcemia.
The increased cancer risk associated with alcoholism may be partly explained by alcohol-induced magnesium deficiency. According to Richard Rivlin, MD, of New York’s Memorial Sloan-Kettering Cancer Center, there are several lines of evidence suggesting that abnormalities in magnesium metabolism are associated with cancer development. Among them are the observations that magnesium inhibits carcinogenesis and may affect oncogene amplification, and that magnesium deficiency favors tumor formation by leading to impaired immune surveillance and enhanced susceptibility of cell membranes to oxidant injury.
Magnesium repletion by mouth is recommended for patients known to be heavy drinkers. It is also appropriate to give magnesium parenterally during alcohol withdrawal. Many of the manifestations of advanced or chronic alcoholism, such as personality changes, neuromuscular irritability, seizures, and delirium tremens, are probably aggravated by magnesium deficiency. The recalcitrant hypocalcemia frequently seen in patients with alcoholism usually becomes amenable to treatment when magnesium is given.
A number of antacids contain magnesium, including AmphojelTM, MaaloxTM, MylantaTM, and RiopanTM. The liquid formulation of bismuth subsalicylate, used in the treatment of Helicobacter pylori infections, also contains magnesium (in the form of magnesium aluminum silicate, an inactive excipient). These will not cause hypermagnesemia in the individual with normal renal function. In the face of renal impairment, however, there can be significant accumulations of magnesium.
Magnesium, as a divalent cation, can bind with certain drugs, decreasing their bioavailability (Table 3). Such an effect has been shown for quinidine, quinolone antibiotics (especially the older ones such as ciprofloxacin and norfloxacin), tetracycline and related antibiotics, and certain nonsteroidal antiinflammatory drugs (specifically diclofenac, diflunisal, indomethacin, and naproxen). Moreover magnesium loading in the gut may cause diarrhea, which can adversely affect absorption of a number of drugs.
Hypomagnesemia, with concomitant hypocalcemia and hypokalemia, can develop after less than a week of gentamicin use. A number of instances of reversible hypomagnesemia secondary to gentamicin use have been reported. Although the mechanism is unknown, nephrotoxicity has been suggested, and several investigators have suggested that gentamicin contributes to renal magnesium and potassium wasting.
In 1 case report, a 68-year-old woman hospitalized for acute myelomonocytic leukemia (2 years after being treated with radiation and chemotherapy for ovarian carcinoma) was given gentamicin (80 mg q6h) IV when she became febrile. After 7 days of antibiotic therapy (including penicillin and cefazolin), she developed Chvostek’s sign and was found to be hypomagnesemic, hypocalcemic, and hypokalemic. IV administration of 10 g magnesium sulfate and 120 mmol potassium over 48 hours was associated with normalization of electrolyte levels and the disappearance of Chvostek's sign.
In another instance, a 65-year-old man with diabetes and peripheral vascular disease was given gentamicin (80 mg q8h) IV, along with clindamycin and metronidazole, after amputation of a gangrenous leg. After 6 days of gentamicin therapy he developed Chvostek’s sign and was hypomagnesemic, hypocalcemic, and hypokalemic. Gentamicin therapy was continued while the patient was given IV magnesium and potassium replacement. At the end of the 13-day course of gentamicin, his electrolyte levels were normal and Chvostek’s sign had disappeared.
Magnesium replacement may be appropriate in the treatment and prevention of hypertension associated with cyclosporine use. In a case-controlled study, June and colleagues observed that hypomagnesemia developed in a group of 32 bone marrow transplant recipients who developed hypertension after cyclosporine treatment but hypomagnesemia did not develop in 32 cyclosporine-treated controls matched for age, sex, and disease who remained normotensive. These investigators concluded that either hypomagnesemia and hypertension were coincident toxic effects of cyclosporine or that magnesium derangement contributed to hypertension. Using an animal model, Rob and associates found that oral magnesium reduced the toxicity of cyclosporine even when dietary intake of magnesium was normal.
The intestinal absorption of magnesium is decreased in persons taking oral zinc preparations. Zinc is a divalent cation found in certain cold medication lozenges arid is also taken by some men for prostate health. Spencer and colleagues studied magnesium absorption and magnesium and zinc metabolic balance in 142 men taking high, low, and intermediate levels of calcium. They found that high zinc intake caused a highly significant decrease in magnesium absorption and a negative magnesium balance regardless of calcium intake.
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The above article is from the "The Magnesium Report", Second Quarter 2000. Blaine Pharmaceuticals is the manufacturer of Mag-Ox 400 and Uro-Mag magnesium supplements.
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