Beneficial or Supportive Interaction, with Professional Management

Emerging

Effect and Mechanism of Action

Magnesium can enhance the therapeutic efficacy of albuterol, and potentially other adrenergic bronchodilators, as a delivery vehicle, as a concomitant therapy, or simply as nutrient support in the treatment of individuals with asthma. Both agents exercise a bronchodilatory effect that can be amplified by coadministration. Albuterol therapy is associated with significant hypokalemia but apparently does not directly deplete magnesium levels.

Research

Magnesium deficiency is associated with the occurrence and severity of asthma, particularly airway hyperreactivity, wheeze, and impairment of lung function. Hypomagnesemia is common in chronic asthmatic individuals, and those with low serum magnesium tend to have more hospitalizations than chronic asthmatic persons with normal magnesium; hypomagnesemia is also associated with more severe asthma. ¹⁷

Human studies indicate that coadministration of albuterol and magnesium can invoke synergistic effects in the treatment of asthma, but concerns have been raised that adrenergic bronchodilators may adversely affect magnesium (and potassium) levels. Magnesium sulfate is considered an effective bronchodilator in the treatment of acute, moderate to severe asthma when administered intravenously, and it can be safely administered to patients with stable asthma by inhalation. ^18-20 However, Lipworth et al. ²¹ found that inhaled albuterol caused no significant change in magnesium level, but it did produce hypokalemic and hyperglycemic effects of probable clinical significance, especially during acute exacerbations of airflow obstruction.

The therapeutic effects of and supportive interactions between albuterol and magnesium have been researched in various permutations. In vitro experimental data show that magnesium increases beta-receptor affinity to agonists. Clinical research comparing inhaled magnesium sulfate and albuterol (salbutamol sulfate) in the treatment of patients with acute asthma has found that both agents produced significant bronchodilatory effects, but that the duration from the albuterol was longer than that of the magnesium (e.g., 6 hours vs. 1 hour). ^22,23 In a randomized, double-blind, controlled trial involving 35 patients with acute asthma, Nannini et al. ²⁴ found that isotonic magnesium sulfate, as a vehicle for nebulized albuterol, increased the peak flow response to treatment compared with salbutamol plus normal saline. In a small, double-blind, placebo-controlled trial involving six patients with asthma, Rolla et al. ²⁵ observed that a mild sustained increase in serum magnesium level, using IV magnesium infusion, increases the bronchodilating effect of low doses of albuterol, possibly through an increased beta-receptor affinity. They found, however, no effect on the maximum bronchodilating effect of albuterol. Subsequently, in a double-blind placebo-controlled trial involving 52 emergency care patients, Hughes et al. ²⁶ demonstrated an enhanced bronchodilator response using isotonic magnesium as an adjuvant to nebulized albuterol in the treatment of severe asthma. The clinical relevance of these findings remains contentious, particularly whether the use of isotonic magnesium confers any additional improvement to optimized nebulized bronchodilator therapy with albuterol and ipratropium, standard first-line therapies for the treatment of acute severe asthma. No clinical trials have yet been published exploring any potential differential clinical response to acute albuterol therapy in individuals regularly supplementing with pharmacologically efficacious doses of magnesium compared with those not taking magnesium regularly for asthma (or other comorbid conditions); clinical trials into such integrative options are warranted.

In 2005 the Cochrane Reviewpublished a meta-analysis examining the evidence regarding the use of inhaled magnesium sulfate in conjunction with inhaled beta-2 agonists. They concluded that there was good evidence that nebulized magnesium sulfate was safe and effective and that it should be considered as a combined therapy with beta-2 agonists. The authors noted that magnesium sulfate was most useful in situations where the asthmatic exacerbations were severe. ²⁷

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Magnesium can provide an efficacious adjuvant to conventional care for patients with asthma, including coadministration of magnesium sulfate with albuterol in emergency care settings. Concomitant use, especially in acute care and through IV infusion, will inherently be appropriate only under qualified medical care informed by an integrative approach to, and necessary training in, such synergistic therapeutic options. Close monitoring of potassium and magnesium levels, and possible coadministration of either or both, is appropriate when administering beta-2-adrenoceptor agonists, such as albuterol/salbutamol, levalbuterol, and rimiterol, as inhalant bronchodilators or especially as IV infusions. Within conventional practice, bronchodilators are almost never used alone (except for pure exercise-induced bronchospasm), and some treatment directed at airway inflammation, predominantly inhaled corticosteroids, is considered a necessary part of asthma management.

	Drug-Induced Nutrient Depletion, Supplementation Therapeutic, with Professional Management
	Prevention or Reduction of Drug Adverse Effect

Consensus

Effect and Mechanism of Action

Aminoglycoside antibiotics can induce magnesium depletion and deficiency-related symptoms by several mechanisms. Neomycin impairs absorption of oral magnesium. ^28,29 Aminoglycosides can inhibit hormone-stimulated Mg ⁺⁺ uptake in distal convoluted tubule cells. ³⁰ Gentamicin can cause increased urinary magnesium loss. ^31,32 Renal tubular damage and nonoliguric renal insufficiency are well-known nephrotoxic adverse effects resulting from aminoglycosides, particularly gentamicin and tobramycin, and can lead to hypomagnesemia, usually combined with hypocalcemia, hypokalemia, and alkalosis. ^31,33-35 Such tubular damage may occasionally be reversible in the absence of any change in the renal function. ³⁶

Research

Numerous animal studies have demonstrated hypomagnesemia, as well as hypocalcemia, hypokalemia, and alkalosis, as a result of aminoglycoside-induced renal tubular damage. ^30,35,37,38

Keating et al. ³⁹ reported that 17 oncology patients developed a complex metabolic syndrome of 2 to 8 weeks’ duration, characterized by hypocalcemia, hypomagnesemia, and hypokalemia, after administration of several aminoglycoside antibiotics, including tobramycin, gentamicin, amikacin, and sisomicin. The authors attributed these adverse outcomes to the nephrotoxic effects of the aminoglycoside and noted the possible potentiating action of chemotherapeutic agents, particularly doxorubicin. Twelve patients died before recovering from the metabolic stress, and five patients developed progressive renal impairment. Kes and Reiner ³¹ described renal wasting of magnesium and symptomatic hypomagnesemia, hypocalcemia, and hypokalemia in seven patients after gentamicin therapy. They noted a pattern of “excessive and inappropriate urinary excretion of magnesium and potassium in the presence of subnormal serum concentrations” and suggested that adverse effects were most likely in older patients given large doses of gentamicin over extended periods. Aminoglycosides and platinum together are particularly responsible for tubular damage.

Akbar et al. ⁴⁰ have noted that hypomagnesemia may be especially common among children with cystic fibrosis who have a history of repeated use of aminoglycosides.

Reports

Kelnar et al. ⁴¹ reported the case of a 12-year-old boy who developed renal wasting of magnesium, calcium, and potassium, with secondary hypomagnesemia, hypocalcemia, and hypokalemia (without hyperaldosteronism) after treatment with high-dose gentamicin over 4 months. They recommended that prolonged courses of gentamicin not be administered if less toxic antibiotics are suitable, and that, when it is given, plasma magnesium, calcium, and potassium levels be monitored during and after treatment.

Slayton et al. ⁴² reported a case of tetany in a child with acquired immunodeficiency syndrome (AIDS) who developed magnesium, calcium, and potassium depletion, requiring prolonged replacement therapy, subsequent to a 3-week course of IV tobramycin. Adams et al. ⁴³ reported hypomagnesemic tetany associated with repeated courses of IV tobramycin in a patient with cystic fibrosis.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians prescribing aminoglycosides, particularly on a repeated or chronic basis, should regularly monitor kidney function along with magnesium and potassium status, especially in individuals in high-risk groups, such as children and the elderly. Nutritional support may restore normal levels of magnesium, as well as potassium or other related minerals; prophylactic administration may be appropriate in susceptible populations. Individuals taking neomycin are generally at less risk of adverse effects as a result of magnesium depletion. Clinically significant drug-induced magnesium depletion is an uncommon but important complication of gentamicin therapy. However, in patients receiving IV tobramycin, close monitoring of calcium, magnesium, and potassium levels and the consideration of mineral replacement are especially warranted. Serum creatinine, blood urea nitrogen (BUN), and creatinine clearance should be measured before initiating therapy and monitored throughout treatment. In this regard, many nutritionally oriented practitioners find that testing magnesium levels in RBCs is much more reliable than testing serum magnesium, even though low serum levels virtually always reflect serious intracellular compartment deficits. In individuals with a low threshold for osmotic diarrhea, parenteral magnesium replacement may be the only effective way to replenish the intracellular compartment. Careful assessment should precede administration of magnesium or potassium and then preferably within the context of integrative care involving health care professionals trained and experienced in both conventional pharmacology and nutritional therapeutics.

Magnesium supplementation is often medically appropriate to prevent or correct depletion patterns associated with the various aminoglycosides. Even though conclusive evidence demonstrating the unqualified need for therapeutic supplementation is lacking, 250 to 400 mg daily would generally provide a safe, protective dose of magnesium for individuals receiving neomycin for more than 2 to 3 days. Administration of magnesium in the dosage range of 300 to 500 mg daily is usually appropriate for individuals prescribed more potent aminoglycosides but requires evaluation of renal function testing and other individual characteristics. Magnesium augmentation can be risky in patients with compromised renal function and is usually contraindicated in such cases. It is also important to note that magnesium is needed to maintain intracellular potassium, as well as calcium homeostasis, becasue PTH production is magnesium dependent.

Beneficial or Supportive Interaction, with Professional Management

Emerging

Effect and Mechanism of Action

Magnesium may favorably alter the kinetics of mixed amphetamines and thereby enhance their retention and bioavailability. Medications in this class appear to elevate plasma magnesium levels and favorably shift the calcium/magnesium ratio. Further, the independent therapeutic effects of both agents on various forms of hyperactivity may result in an additive or synergistic effect, pharmacological and/or functional.

Research

Magnesium salts, specifically magnesium hydroxide in the context of antacids, alter the pharmacokinetics of amphetamines so as to enhance retention of such medications, thereby increasing their activity. ⁴⁴ Conversely, in a double-blind placebo-controlled study of methylphenidate and dextroamphetamine in hyperactive boys, Schmidt et al. ⁴⁵ found that plasma magnesium levels were significantly higher and calcium/magnesium ratio was significantly lower after 3 weeks of dextroamphetamine treatment, compared with the baseline or placebo condition. These authors cited other research suggesting that concomitant magnesium may enhance learning and the therapeutic response to stimulants. In particular, they proposed that the lowering of the calcium/magnesium ratio may play a significant role in the therapeutic action of stimulants such as dextroamphetamine.

The significant association observed between magnesium deficiency and hyperactivity has led to promising research into the role of magnesium as a component of an integrative approach to the treatment of this cluster of conditions. ⁴⁶ Starobrat-Hermelin and Kozielec ⁴⁷ assessed magnesium levels (in blood serum, RBCs, and hair) in 116 children with recognized attention deficit–hyperactivity disorder (ADHD) and determined that 95% demonstrated some form of magnesium deficiency, most frequently in hair (77.6%), RBCs (58.6%), and blood serum (33.6%). Subsequently, this same research team conducted a clinical trial in which they administered 200 mg/day magnesium to 50 of these children, who had been diagnosed with both ADHD and magnesium deficiency, but not to 25 similarly diagnosed controls. They concluded that the children treated with magnesium, independently of other mental disorders coexisting with hyperactivity, demonstrated an increase in magnesium contents in hair and a significant decrease of hyperactivity, compared with their clinical state before magnesium administration and with the control group. ⁴⁸ These findings suggest that coadministration of magnesium and mixed amphetamines might produce beneficial clinical outcomes, and that controlled clinical trials into such integrative options is warranted.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians prescribing mixed amphetamines can reasonably suggest the option of concomitant magnesium. Given the potential effect on pharmacokinetics, close supervision and regular monitoring are advised, and reduction of the medication dosage may be appropriate if magnesium enhances bioavailability. Coordinated treatment involving health care professionals trained and experienced in both conventional pharmacology and nutritional therapeutics may serve to ensure safety and enhance clinical outcomes. A dosage of magnesium in the range of 200 to 400 mg per day, depending on age, weight, diet, and comorbid conditions, would typically be appropriate.

	Drug-Induced Nutrient Depletion, Supplementation Therapeutic, Not Requiring Professional Management
	Prevention or Reduction of Drug Adverse Effect

Consensus

Effect and Mechanism of Action

Renal toxicity is a common and serious adverse effect of conventional amphotericin B. Renal impairment manifests as a decrease in glomerular filtration and damage to tubular function. ⁴⁹ Hypomagnesemia due to renal magnesium wasting can result from cumulative dosages of amphotericin B, most likely from a tubular defect in magnesium reabsorption. ⁵⁰ Hydration and administration of depleted nutrients, particularly magnesium and potassium, may prevent or reduce such adverse effects.

Research

Barton et al. ⁵⁰ documented the effect of amphotericin B on magnesium metabolism in 10 adults being treated for systemic fungal infections. After relatively small cumulative dosages of amphotericin B, renal magnesium wasting (as evidenced by fractional magnesium excretion and serum magnesium level) and mild to moderate hypomagnesemia appeared to manifest by the second week of therapy, peak by the fourth week, and then plateau. Follow-up data in three subjects, from 1 year after discontinuation of amphotericin B therapy, showed that serum magnesium level and fractional magnesium excretion were restored to pretreatment levels and indicate that the magnesium wasting was reversible.

Mayer et al. ⁴⁹ tested the hypothesis that administration of potassium and magnesium corresponding to the amounts lost by the kidneys, as well as sufficient hydration, are necessary to prevent renal function damage. In subsequent clinical trials, they found that the nephrotoxicity of amphotericin B therapy can be significantly reduced through minimal nephroprotective measures, including hydration and administration of magnesium and other ionic minerals susceptible to depletion. ^51,52

Because of the toxicity of amphotericin B, a modified lipid complex variant of the drug was introduced. The liposomal amphotericin B formulation appears to be well tolerated and effective in treating systemic fungal infections, without the high occurrence of severe adverse effects associated with conventional amphotericin B therapy. ^53-55

Reports

Clinicians have published case reports of tetany and other adverse effects of hypomagnesemia and hypokalemia caused by IV administration of amphotericin B. ^56-58

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians prescribing extended courses of amphotericin B may find it prudent to recommend magnesium administration (e.g., IV or 300 mg/day orally). Monitoring of magnesium levels and compensatory administration may be especially appropriate in patients with cardiovascular conditions or pathophysiological dysfunction in whom magnesium depletion might have clinically significant impact. Vigorous hydration and IV administration of magnesium, potassium, and sodium, as described by Mayer and Doubek, in the context of close monitoring of renal function and magnesium and other ionic levels, are appropriate for inpatient or oncological care settings where IV amphotericin B is being administered for systemic fungal infections. Use of the liposomal form of amphotericin B may reduce risk of adverse effects and complications.

	Impaired Drug Absorption and Bioavailability, Precautions Appropriate
	Adverse Drug Effect on Nutritional Therapeutics, Strategic Concern

Consensus

Effect and Mechanism of Action

Some oral magnesium compounds may interfere with the absorption and bioavailability of the various bisphosphonate derivatives. Magnesium salts may interfere with absorption of tiludronate. This pharmacokinetic interaction typically is immediate in onset but of moderate severity. According to manufacturers, simultaneous ingestion of divalent cations will interfere with absorption of the various bisphosphonates by forming insoluble (nonabsorbable) chelates; specifically, the bioavailability of tiludronate is reduced 60% by supplements or antacids containing magnesium (or aluminum) and 80% by calcium.

The occurrence of insoluble chelates will also reduce the bioavailability of the magnesium and interfere with its therapeutic efficacy.

Research

The apparently unpublished research cited by the manufacturers of these agents and secondary references primarily focuses on magnesium in the context of antacids. However, the various extrapolations underlying the cautions are reasonable and consistent with generally accepted pharmacological research and principles regarding chelation properties of orally administered minerals.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

In patients undergoing therapy with bisphosphonates, concurrent but segregated administration of magnesium (and calcium) enables an integrative approach to therapeutics. Oral magnesium, as well as other mineral supplements or related antacids, should be taken at least 2 hours before or 30 minutes after oral administration of bisphosphonate derivatives to minimize interference with the drug's absorption. Conversely, patients taking magnesium for therapeutic purposes will derive greater benefit from the nutrient by avoiding its binding with the bisphosphonate agent.

	Bimodal or Variable Interaction, with Professional Management
	Potentially Harmful or Serious Adverse Interaction—Avoid
	Minimal to Mild Adverse Interaction—Vigilance Necessary
	Drug-Induced Nutrient Depletion, Supplementation Therapeutic, with Professional Management

Emerging

Effect and Mechanism of Action

Both calcium channel blockers and magnesium can reduce the amount of ionic calcium available to muscle cells. Their concomitant use can result in an additive effect, thereby enhancing their hypotensive effect and decreasing cardiac function. Felodipine therapy is also associated with increased magnesium excretion.

Research

Magnesium's central role in regulating calcium metabolism contributes to its ability to lower blood pressure ⁵⁹ and may account for its reputed efficacy in the treatment of glaucoma. ⁶⁰ Both calcium channel blockers and magnesium are used to treat a range of cardiovascular conditions, especially arrhythmias and angina, and individuals with such conditions (e.g., variant angina) ⁶¹ often demonstrate magnesium deficiency. In a rodent study, Mervaala et al. ⁶² found that the cardiovascular effects of low-dose felodipine and ramipril could be enhanced by regular administration of a magnesium-enriched salt, in place of sodium. However, Davis et al. ⁶³ reported that the synergistic effect from combining magnesium sulfate and calcium channel blockers may decrease cardiac function and increase the risk of cardiac toxicity in pregnant women.

Reports

Two published case reports have described the development of muscular weakness and subsequent paralysis in pregnant women who were being treated for preeclampsia with concomitant oral nifedipine and IV magnesium sulfate. ^64,65 In one case, cessation of the magnesium resulted in the resolution of the adverse symptoms within 25 minutes. In the other case, the paralytic state reversed after IV administration of calcium gluconate. Waisman et al. ⁶⁶ reported a potentiation effect in two pregnant patients who were receiving methyldopa and IV magnesium and developed transient hypotension within 1 hour after administration of oral nifedipine.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

The concomitant use of calcium channel blockers and magnesium can produce an additive effect that has the potential to be detrimental or beneficial, depending on patient characteristics, pathophysiological processes, and clinical management. Initial evaluation and regular monitoring of magnesium (and potassium) levels are necessary when the patient's history and cardiac risk factors indicate that magnesium might be clinically appropriate as part of the therapeutic strategy, as well as to counter drug-induced magnesium depletion. In particular, both magnesium and calcium channel blockers may have roles to play in the prevention and treatment of hypertension during pregnancy, especially preeclampsia, but their concomitant use should be discouraged except under close supervision and regular monitoring. The coordinated use of a calcium channel blocker and oral magnesium may provide greater efficacy while allowing reduced dosage of the drug and reducing the risk of adverse effects. However, collaboration by health care professionals trained and experienced in both conventional pharmacology and nutritional therapeutics is essential given the potential synergy of these combined agents and attendant risks. In most cases the typical therapeutic dosages of magnesium for adults are in the range of 250 to 350 mg per day.

	Drug-Induced Nutrient Depletion, Supplementation Therapeutic, Not Requiring Professional Management
	Adverse Drug Effect on Nutritional Therapeutics, Strategic Concern

Consensus

Effect and Mechanism of Action

Cisplatin can induce clinically significant hypomagnesemia by increasing urinary excretion of magnesium, through its toxic effects on the kidneys, and possibly by a direct injury to mechanisms of magnesium reabsorption in the ascending limb of Henle's loop as well as the distal tubule. ^67-70 This drug-induced impairment of the renal tubules’ ability to conserve magnesium may persist for months, or possibly years, after discontinuing the drug. ⁷¹ Cisplatin may also cause excessive excretion of potassium that will amplify the adverse effects of magnesium depletion, and vice versa. ^72,73

Research

Numerous animal and human studies, as previously cited, have documented the occurrence, mechanisms, and sequelae of cisplatin's nephrotoxic effects on magnesium (and potassium) status. One British study found higher serum magnesium concentration levels in children given IV magnesium before and after administration of cisplatin than in those give magnesium only after the cisplatin. ⁷⁴ These researchers concluded that magnesium supplements should be given to patients receiving cisplatin during the precisplatin hydration period to prevent hypomagnesemia. An unrecognized and untreated magnesium deficiency can lead to refractory potassium depletion. Rodriguez et al. ⁷⁵ and Whang et al. ⁷³ documented cases of refractory hypokalemia following cisplatin therapy that failed to respond to potassium administration until hypomagnesemia was recognized and corrected.

Reports

Van de Loosdrecht et al. ⁷⁶ reported the case of seizures in a male patient with disseminated testicular cancer caused by cisplatin-induced hypomagnesemia.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians prescribing or administering cisplatin are advised to evaluate magnesium and potassium status, as well as renal function, before initiating therapy and throughout its course; some clinicians would recommend continuing such monitoring through posttherapy follow-up examinations. The research cited suggests that coadministration of magnesium be initiated before beginning chemotherapy and that supplemental potassium be added if indicated. A collaborative approach based on principles of integrative care and involving health care professionals trained and experienced in both conventional pharmacology and nutritional therapeutics is recommended to enhance safety and efficacy.

Drug-Induced Nutrient Depletion, Supplementation Therapeutic, Not Requiring Professional Management

Inadequate

Effect and Mechanism of Action

Colchicine has been linked to impaired absorption of magnesium. ⁷⁷

Research

Published research has documented colchicine-induced depletion of calcium, potassium, and other nutrients and reported that such absorption-related depletion patterns resolved subsequent to cessation of colchicine therapy. Clinical trials investigating and confirming specific effects by colchicine on magnesium are lacking.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Individuals prescribed colchicine would most likely benefit from daily supplementation with a high-potency multivitamin/mineral formulation to compensate for these interactions. Separate oral intake by at least 2 hours.

	Drug-Induced Nutrient Depletion, Supplementation Therapeutic, Not Requiring Professional Management
	Adverse Drug Effect on Nutritional Therapeutics, Strategic Concern

Emerging

Effect and Mechanism of Action

Long-term use of corticosteroids is associated with depletion of magnesium and decrease in serum and bone levels. ^22,78,79 Magnesium deficiency adversely influences calcium and vitamin D metabolism and is primarily associated with hypocalcemia ⁸⁰ ; bone loss is a significant adverse effect of long-term steroid therapy.

Magnesium trisilicate has been reported to interfere with GI absorption of dexamethasone in healthy male volunteers, as indicated by the increased urinary excretion of 11-hydroxycorticosteroids. ⁸¹ However, magnesium trisilicate is a poorly absorbable form of magnesium never used as a nutrient source, although sometimes used in laxative preparations.

Research

Using adult male rats, Simeckova et al. ⁷⁸ found that prednisolone caused a significant decrease in bone magnesium content. In a clinical trial involving 95 patients with chronic airway obstruction, Rolla et al. ²² found a significant negative correlation between serum magnesium and the length of oral steroid therapy; diuretics were also associated with a significantly lower serum magnesium level. Atkinson et al. ⁷⁹ conducted a clinical trial involving 56 children with acute lymphoblastic leukemia (ALL) to investigate abnormalities in mineral homeostasis and bone mass. They found that more than 70% of children had abnormally low plasma 1,25-dihydroxyvitamin D, 73% had low osteocalcin (a reflection of vitamin K status), and 64% had hypercalciuria, at diagnosis, indicating an effect of the leukemic process on vitamin D metabolism and bone turnover. During remission induction, treatment with high-dose steroid (prednisone or dexamethasone) resulted in further reduction in plasma osteocalcin and elevated PTH levels. Despite normal dietary intake and absorption of magnesium, 84% of children developed hypomagnesemia (of whom 52% were hypermagnesuric) by 6 months; plasma 1,25-dihydroxyvitamin D remained abnormally low in 70%. The authors attributed the altered magnesium status to renal wasting of magnesium after cyclical prednisone therapy and treatment with aminoglycoside antibiotics. Magnesium coadministration for up to 16 to 20 weeks normalized plasma magnesium in only half the children treated for hypomagnesemia.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Magnesium can provide an important therapeutic component within integrative care for many pathological and dysfunctional conditions, such as asthma and irritable bowel syndrome, which are often treated with corticosteroids. Physicians prescribing oral corticosteroids for longer than 2 weeks should discuss with their patient the potential benefit of concomitant magnesium to counter the depleting effects of the drug(s). A typical dose in such situations would be 300 to 400 mg of magnesium daily. A multimineral formulation would add support against parallel depletions of other vulnerable minerals; however, clinically effective levels of potassium require a prescription. Any such mineral preparations should be taken at least 2 hours before or 30 minutes after oral corticosteroids to minimize risk of interference with absorption of the medication.

	Drug-Induced Nutrient Depletion, Supplementation Therapeutic, Not Requiring Professional Management
	Prevention or Reduction of Drug Adverse Effect
	Adverse Drug Effect on Nutritional Therapeutics, Strategic Concern

Emerging

Effect and Mechanism of Action

Cyclosporin A (cyclosporine) is a highly potent immunosuppressive agent for solid-organ transplantation, but its use carries significant risk of varied adverse effects. In addition to magnesium depletion and its sequelae, cyclosporine's adverse effects include nephrotoxicity, hepatotoxicity, hypertension, neurotoxicity, and gum hyperplasia. ⁸² Magnesium may reduce the severity of some of the drug's toxic effects, especially its nephrotoxicity.

Severe hypomagnesemia and renal magnesium wasting are associated with the use of cyclosporine and many of its toxic effects. In particular, systemic depletion of magnesium appears to play a significant role in the pathogenesis of cyclosporine-induced neurotoxicity and produces a high risk of seizures. ^82-94

Research

Pere et al. ⁹⁵ reported beneficial effects of dietary magnesium and potassium on cardiac and renal morphological features in cyclosporin A–induced damage in spontaneously hypertensive rats. In a series of rodent studies, Asai et al. ⁹⁶ showed that correction of cyclosporine-induced hypomagnesemia by magnesium coadministration ameliorates chronic cyclosporin A (CsA) nephropathy by inhibiting gene expression of fibrogenic molecules. Subsequently, they demonstrated that CsA induced a decline in glomerular filtration with characteristic striped fibrosis, but that magnesium abolished precedent interstitial inflammation, possibly through inhibition of chemoattractant expression and consequently, attenuated tubulointerstitial fibrosis. ⁹⁷

Thompson and June and colleagues documented association between cyclosporine neurotoxicity and hypomagnesemia ⁸³ and the correlation of hypomagnesemia with the onset of cyclosporine-associated hypertension ⁸⁵ in marrow transplant patients. These researchers concluded that their findings suggested that such adverse effects may be prevented with or treated by magnesium replacement.

Vannini et al. ⁹⁰ investigated kidney function and magnesium status in 109 renal transplant patients receiving cyclosporine, with allografts functioning stably for more than 6 months and plasma creatinine levels of less than 200 μmol/L, as well as 15 renal transplant patients not receiving cyclosporine and 21 healthy volunteers. They found that the cyclosporine patients showed significantly lower total and ionized circulating magnesium values than the two control groups, and that these deficiencies appeared to be permanent. They also noted that plasma total and ionized magnesium levels were significantly lower among cyclosporine patients treated concurrently with insulin or oral hypoglycemic agents.

Low total serum magnesium concentration has been reported in transplant recipients on cyclosporine therapy, and this is a risk factor for hypertension and cardiac death, especially after renal transplant. In a study involving 31 post–renal transplant patients, Thakur et al. ⁹⁴ found that mean total serum magnesium in posttransplant patients was significantly lower than in 16 chronic renal failure patients who had not yet received a transplant as controls, and that an inverse correlation existed between total serum magnesium and blood CsA concentration. Systolic and diastolic blood pressures were also higher in the cyclosporine-treated patients.

Reports

Numerous published case reports have described aspects of cyclosporine-associated neurotoxicity in recipients of solid-organ and bone marrow transplants, especially in relation to magnesium wasting. Ozkaya et al. ⁹⁸ reported a case of a 16-year-old renal transplant patient who developed tremor, tinnitus, and peripheral facial paralysis during oral CsA treatment; her serum magnesium level was below the normal range. Al-Rasheed et al. ⁹⁹ reported on a girl who had idiopathic renal magnesium wasting secondary to suspected Gitelman's syndrome and CsA neurotoxicity after a heart transplant. The child had acute progressive encephalopathy, intractable seizures, quadriparesis, and extensive bilateral cortical involvement on neuroimaging. Many of these symptoms improved dramatically 2 days after discontinuing CsA, and she was fully ambulatory after 6 weeks. This drug-induced neurotoxicity was exacerbated by hypomagnesemia. The authors emphasized that caution was especially important in administering cyclosporine to transplant patients with Gitelman's syndrome or other acquired magnesium homeostasis disorders because of the possible increased risk of neurotoxicity.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Magnesium coadministration prevents magnesium deficiency and subsequent neurotoxicity resulting from CsA; it may also reduce the severity of nephrotoxicity. In the event of cyclosporine-induced depletion, the prescribing physician should be consulted before any form of magnesium administration is initiated. Renal function testing is advised at baseline and at 6-month intervals, through creatinine clearance and albumin excretion, along with assessment of markers NAG and ALP ( D-glucosaminidase and alkaline phosphatase, respectively) for tubular toxicity. Furthermore, initial evaluation and regular monitoring of magnesium levels are necessary in individuals undergoing cyclosporine therapy. Nutritionally oriented physicians generally find that monitoring RBC magnesium levels, rather than serum magnesium, is a more accurate method for diagnosing a deficiency.

	Drug-Induced Nutrient Depletion, Supplementation Therapeutic, Not Requiring Professional Management
	Prevention or Reduction of Drug Adverse Effect
	Adverse Drug Effect on Nutritional Therapeutics, Strategic Concern
	Adverse Drug Effect on Nutritional Therapeutics, Strategic Concern

Mixed

Effect and Mechanism of Action

Digoxin decreases intracellular magnesium and causes increased urinary magnesium loss. Hypomagnesemia may predispose to digitalis toxicity.

Oral magnesium compounds may interfere with digoxin absorption and bioavailability. Conversely, the occurrence of insoluble chelates will also reduce the bioavailability for the magnesium and interfere with its therapeutic efficacy.

Research

Digoxin decreases intracellular magnesium and reabsorption of magnesium from the kidneys, causing increased urinary magnesium loss, and digitalis (and diuretics) can intensify an underlying magnesium deficiency. ^5,100-103 Magnesium deficiencies induced by concomitant diuretic use are especially common in individuals prescribed digoxin. ^104,105 Adequate magnesium concentration enhances digoxin's antiarrhythmic activity, particularly by diminishing ventricular response during atrial fibrillation. However, hypomagnesemia inhibits the therapeutic efficacy of digoxin in controlling atrial fibrillation and can increase the risk of cardiac glycoside toxicity, particularly refractory arrhythmias. ^73,106-108 Magnesium is also necessary to intracellular potassium repletion in diuretic-treated hypertensive patients.

Magnesium intake, particularly in the form of antacids such as magnesium trisilicate, may result in adsorption of digoxin, reduced absorption in the GI tract, and decreased bioavailibility, ¹⁰⁹ although most likely only to a negligible degree. ^110-112 In single-dose studies with 10 healthy volunteers, Brown and Juhl ¹⁰⁹ found that antacids containing magnesium hydroxide, and particularly magnesium trisilicate, substantially reduced digoxin absorption, apparently through physical adsorption of digoxin by the antacids in the GI tract. However, subsequent research by D’Arcy and McElnay ¹¹² determined that magnesium trisilicate did not significantly interfere with digoxin absorption. Using an in vitro model, previously proven to correlate well with absorption across a physiological membrane in vivo, ¹¹⁰ research by McElnay et al. ¹¹¹ suggests that magnesium carbonate only weakly impairs digoxin absorption. Overall, research findings are inconclusive.

Reports

Kinlay and Buckley ¹¹³ described a patient with digoxin toxicity, associated with ventricular tachycardia, who achieved a more stable junctional rhythm after IV magnesium sulfate (two doses of 10 mmol).

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Digoxin and magnesium both play important therapeutic roles in the treatment of heart failure and related conditions. Normal magnesium levels need to be maintained during digoxin treatment. Given that individuals taking digoxin are especially likely to demonstrate hypomagnesia, supervised nutrient support can be even more important. Hypomagnesemia is known to produce a wide variety of clinical presentations, including neuromuscular irritability, cardiac arrhythmias, and increased sensitivity to digoxin.

Many physicians are aware of the need to monitor and prescribe for potassium depletion but do not consider the issue of magnesium deficiency unless serum levels fall below acceptable levels. Furthermore, many physicians experienced in nutritional assessment consider serum magnesium to be a very poor indicator of how much magnesium is actually in the intracellular compartment. Serum magnesium concentration is maintained within a narrow range by the kidney and small intestine; under conditions of magnesium deprivation, both organs increase their fractional absorption of magnesium. If magnesium depletion continues, the bone store contributes by exchanging part of its content with extracellular fluid. The serum [Mg ⁺⁺ ] can be normal in the presence of intracellular Mg ⁺⁺ depletion, and the occurrence of a low level usually indicates significant magnesium deficiency. Hypomagnesemia is frequently encountered in hospitalized patients and most often in those admitted to intensive care units. The detection of magnesium deficiency can be increased by monitoring RBC magnesium levels, measuring [Mg ⁺⁺ ] in the urine, or using the parenteral magnesium load test. Assessment of magnesium status may be appropriate but is often not essential since deficiency status is not required for patients to benefit from magnesium administration. However, renal function testing is advisable before initiating such treatment because increased magnesium intake can carry significant risks in patients with renal insufficiency and is usually contraindicated in such cases.

Physicians prescribing digoxin should discuss with their patient the potential benefit of concomitant magnesium as part of a program of integrative care and to counter the depleting effects of the medication. A typical dose in such situations would be 300 to 500 mg of magnesium daily, depending on the individual's diet, age, genetic predisposition, medications, and other factors. Refractory hypokalemia and hypocalcemia can be caused by concomitant hypomagnesemia and can potentially be corrected with magnesium therapy. ^80,104 A multimineral formulation would add support against parallel depletions of other vulnerable minerals. To avoid potential interference with digoxin absorption, mineral preparations should be taken at least 2 hours before or after digoxin. Clinical care within an integrative setting might also emphasize a diet rich in minerals, vitamins, and antioxidants and incorporate fish oil, hawthorn (Crataegus oxyacantha), L-carnitine, coenzyme Q10, and other nutrients as part of an evolving and individualized approach to cardiovascular therapeutics.

	Drug-Induced Nutrient Depletion, Supplementation Therapeutic, Not Requiring Professional Management
	Prevention or Reduction of Drug Adverse Effect
	Adverse Drug Effect on Nutritional Therapeutics, Strategic Concern

Consensus

Effect and Mechanism of Action

Loop and thiazide diuretics, to varying degrees, inhibit passive magnesium absorption and increase urinary excretion of magnesium, as well as sodium and potassium, and usually deplete blood levels of magnesium. ^5,114-121 In turn, the drug-induced magnesium deficiency can contribute to further potassium depletion. Furthermore, hypokalemia reduces magnesium transport in the distal tubule, increasing urinary magnesium excretion. ¹²² Ultimately, the relationship between these two patterns of depletion can be difficult to determine, and practically, they need to be treated together in most patients. ^{73,101,104,105} Although loop and thiazide diuretics inhibit Mg ⁺⁺ reabsorption, the tendency to hypomagnesemia may be moderated because of increased proximal tubular reabsorption of Mg ⁺⁺ induced by the volume depletion. ⁶

Research

Diuretics are generally prescribed to individuals with congestive heart failure (CHF) and other conditions typically associated with hypomagnesemia and other electrolyte imbalances that may increase myocardial electrical instability, as well as risk of malignant arrhythmias and sudden death. ^123-126 In particular, hypomagnesemia and hypokalemia occur in a high percentage of patients receiving thiazide monotherapy. ¹²⁷ Generally, potassium depletion in diuretic-treated hypertensive patients has been linked to an increased incidence of ventricular ectopy and sudden death. In such cases, potassium alone is generally inadequate, and concomitant magnesium administration is required to reestablish intracellular potassium repletion. ^73,105 The associated tendency of patients receiving diuretic therapy, especially those with CHF, to chloride loss and subsequent metabolic alkalosis also interferes with potassium repletion. Consequently, the combination of magnesium and potassium (and possibly chloride) is often appropriate. ¹²⁸

The extent of magnesium depletion inherently depends on the interaction between the patient's individual physiology and the pharmacological characteristics of the particular diuretic, its drug class, dosage, duration of therapy, and other factors. ¹²⁹ Furthermore, the time frame of symptom manifestation can vary significantly since extended drug-induced depletion may cause magnesium recruitment from bones to sustain blood levels; tissue levels may be profoundly depleted, even though serum levels are still normal such that low serum levels usually suggest a significant or severe deficiency status. ^5,130 Magnesium depletion and hypomagnesemia are common among furosemide-treated patients with chronic CHF. Cohen et al. ¹³¹ analyzed clinical, biochemical, and ECG variables relating to serum magnesium aberrations and outcomes in 404 consecutive patients diagnosed with CHF and previously treated with furosemide for at least 3 months. Hypomagnesemia was found in 50 patients (12.3%) and ultimately, after adjustment for renal failure, old age, and severity of CHF, emerged as being significantly associated with shorter survival.

Individuals with Gitelman's syndrome, associated with hypocalciuria and a defect in the gene encoding for the thiazide-sensitive Na ⁺ /Cl ⁻ cotransporter, are particularly at risk for hypomagnesemia and hypokalemia caused by primary renal tubular Mg ⁺⁺ wasting. ^6-8

Dorup et al. ¹³² examined 76 consecutive patients receiving diuretic therapy for 1 to 17 years for arterial hypertension or CHF and found that muscle concentrations of magnesium, potassium, and sodium-potassium pumps were significantly reduced compared with matched controls. When 36 patients with depleted muscle magnesium and/or potassium levels were subsequently given oral magnesium hydroxide for 2 to 12 weeks or 26 weeks, magnesium muscle parameters initially increased, but muscle concentrations of magnesium, potassium, and sodium-potassium pumps did not normalize, in most cases, until after 26 weeks of magnesium administration. Thus, the authors concluded that at least 6 months of oral magnesium therapy appeared to be necessary to restore diuretic-induced disturbances in the concentrations of magnesium, potassium, and sodium-potassium pumps in skeletal muscle. ¹³²

Ruml and Pak ¹²⁸ investigated the effect of potassium magnesium citrate, magnesium citrate, and potassium citrate on thiazide-induced hypokalemia and magnesium loss in 62 healthy subjects. They found that all three mineral compounds increased serum potassium concentration compared with that resulting from thiazide alone, and that potassium magnesium citrate and potassium citrate, but not magnesium citrate, significantly increased urinary pH and citrate values. They concluded that potassium magnesium citrate not only corrects thiazide-induced hypokalemia, but also may avert magnesium loss while providing an alkali load. In a related trial, Ruml et al. ¹³³ tested the efficacy of three different dosages of a potassium and magnesium combination, including up to 800 mg/day of magnesium, and found that four tablets daily (24 mEq potassium, 12 mEq magnesium, 36 mEq citrate) was adequate to overcome hypokalemia and magnesium loss induced by thiazide (50 mg/day) and increased urinary pH and citrate. Likewise, after administering oral magnesium citrate (300 mg daily for 30 days) to 10 patients with severe CHF maintained on high-dose furosemide, Cohen et al. ¹³⁴ observed a significant increase in peripheral blood mononuclear cell magnesium content and serum potassium levels, whereas the other related parameters remained unchanged.

Parallel attempts at addressing the depleting effects of diuretics have not been as straightforward or as effective as mineral supplementation. Triamterene, a potassium-sparing diuretic, has sometimes been combined with hydrochlorothiazide as a means of mitigating potassium and hydrogen loss. Although often effective at partly compensating for the kaliuretic effect of hydrochlorothiazide, many diabetic patients thus treated either remained or became hypokalemic. ¹³⁵ However, sometimes the combination of hydrochlorothiazide and lisinopril, an angiotensin-converting enzyme (ACE) inhibitor, has been found to be effective in attenuating thiazide-induced potassium loss, thereby reducing magnesium wasting, because of lisinopril's ability to reduce production of aldosterone. Likewise, in some cases a magnesium-potassium-sparing diuretic such as amiloride (e.g., 5-10 mg) may negate the potassium-wasting effect of 40 mg furosemide. ⁵ However, Dorup ¹²⁹ reported that such a furosemide-amiloride combination still produced hypomagnesemia in 12% of those thus treated. Importantly, the combined use of magnesium supplementation and potassium-sparing diuretic(s) could theoretically introduce a risk of hypermagnesemia, although the likelihood of this seems unlikely with normal renal function and oral supplementation.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

In practice, it is generally advisable to coadminister both potassium and magnesium when prescribing any potassium-depleting diuretic, except in those with renal insufficiency. Severe magnesium deficiency may require IM or IV magnesium sulfate or chloride to achieve rapid correction. For long-term care, administration of magnesium at 300 to 600 mg daily is usually appropriate, depending on the individual's diet, age, genetic predisposition, and medications and other factors. Magnesium deficiency status can be evaluated by monitoring RBC magnesium levels, measuring [Mg ⁺⁺ ] in the urine, using x-ray spectroscopy of sublingual cell scrapings, or using the parenteral magnesium load test. Assessment of magnesium status may be appropriate but is often not essential because deficiency status is not required for patients to benefit from magnesium administration. However, since magnesium augmentation can be risky, and is usually contraindicated, in patients with renal insufficiency, kidney function tests are critical before initiating, and periodically during, concomitant repletion therapy.

As indicated by research findings, concomitant magnesium needs to be maintained for 6 months to compensate for any drug-induced tissue depletion pattern and during and possibly after relevant diuretic therapy. A typical dose for most individuals would be 300 to 500 mg of magnesium daily. A multimineral formulation would add support against parallel depletions of other vulnerable minerals. In the event that diarrhea appears during magnesium administration, switching to magnesium gluconate or glycinate may alleviate this adverse effect. Beyond magnesium and potassium, clinical care within an integrative setting might also emphasize a diet rich in minerals, vitamins, and antioxidants and incorporate dandelion (Taraxacum officinale, as a mineral-rich nutritive diuretic), essential fatty acids, coenzyme Q10, calcium, and other elements as part of an evolving and individualized approach to cardiovascular therapeutics involving health care professionals trained and experienced in multiple therapeutic disciplines.

	Drug-Induced Nutrient Depletion, Supplementation Therapeutic, Not Requiring Professional Management
	Adverse Drug Effect on Nutritional Therapeutics, Strategic Concern

Effect and Mechanism of Action

Exogenous estrogen, as oral contraceptive (OC) or estrogen replacement therapy (ERT), enhances magnesium uptake and utilization by soft tissues and bone, thereby moving magnesium from the blood, lowering serum levels, and depleting body stores of magnesium. ^136-138

Research

Decreased levels of serum magnesium have been associated with OCs, in pregnancy, and during ERT in postmenopausal women. ^139,140 Seelig ¹³⁸ has suggested that one mechanism by which estrogen provides cardiovascular support is through its effects on magnesium, particularly the resistance of young women to heart disease and osteoporosis. She also notes that “estrogen-induced shifts of Mg can be deleterious when estrogen levels are high and Mg intake is suboptimal. The resultant lowering of blood Mg can increase the Ca/Mg ratio, thus favoring coagulation. With Ca supplementation in the face of commonly low Mg intake, risk of thrombosis increases.” In a controlled clinical study involving 25 healthy women at varying age and duration of menopause and 15 healthy, cycling women of childbearing age, Muneyyirci-Delale et al. ¹⁴¹ found that serum levels of magnesium were inversely related to the serum level of estrogen in both groups.

The use of OCs is associated with unfavorable alterations in magnesium status. In a controlled study, Olatunbosun et al. ¹⁴² found that women being administered exogenous estrogen in OC form had significantly lower serum magnesium levels as circulating magnesium shifted from serum to tissues. In a later clinical study of 32 women, mean age 24.2 years, administered an OC containing ethinyl estradiol (0.03 mg) and levonorgestrel (0.15 mg), Blum et al. ¹³⁷ reported a 26% decrease in serum magnesium after 6 months compared to baseline levels; no clinical signs of magnesium deficiency were observed among these women. Subsequently, Hameed et al. ¹⁴³ studied serum mineral levels in 50 women taking OCs (Lofeminal) and 50 taking injectable contraceptive (depot medroxyprogesterone acetate and Norigest) and found that there was significant decrease in serum levels of calcium, magnesium, and phosphorus in women taking OCs but significant increase in these minerals in women taking injectable contraceptives.

In a preliminary trial, Herzberg et al. ¹⁴⁴ found that osteoporotic postmenopausal women demonstrated reduced urinary excretion of zinc, magnesium, and hydroxyproline after HRT (conjugated estrogens and medroxyprogesterone) for 1 year. Combined use of estrogen and calcium increases the need for magnesium, particularly in the treatment of osteoporosis. ¹³⁶

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Although the clinical research thus far has not focused specifically on the clinical implications of the interaction between estrogen and magnesium, the basic trend suggested by relevant findings points in a clear and relatively consistent direction. Premenstrual syndrome (PMS) and other gynecological conditions are associated with, or more likely to result in, aggravated symptoms or adverse outcomes in the presence of compromised magnesium status, particularly when estrogen dominance or exogenous estrogens are present. The signs of symptomatic hypomagnesemia and those of PMS and related conditions share many features, including appetite loss, nausea and vomiting, sleepiness, weakness, muscle spasms, tremors, and personality changes. Thus, magnesium deficiency is associated with increased risk of PMS, ^145,146 and magnesium supplementation can play an important role in preventing and treating PMS, ^147,148 particularly in those with hypomagnesemia. Likewise, magnesium and estrogen (at least endogenous estrogen) both have important roles to play toward the therapeutic goals of preventing osteoporosis and supporting cardiovascular health.

The coadministration of magnesium and exogenous estrogen requires an individualized, flexible, and evolving approach to integrative care and clinical management to achieve the desired clinical outcomes effectively. Further research into the characteristic, mechanism, and clinical implications of the interaction between magnesium and estrogen is clearly warranted by its potential importance with both preventive and therapeutic agendas. Pending the outcome of such focused study, supplementation with magnesium, 250 to 350 mg per day, can provide a safe support against estrogen-induced stress on magnesium function and potential drug-induced depletion. Likewise, the coadministration of the two agents might prove advantageous, especially in reducing the risk of adverse effects of exogenous estrogen. Within the practice of integrative medicine, other approaches to supporting hormonal balance and liver conjugation of estrogen are often considered as appropriate to the characteristics and needs of the particular patient, such as exercise, vitamin B ⁶ , natural progesterone, chaste tree (Vitex agnus-castus), and Chinese herbal formulae such as Xiao Chai Hu Tang or Xiao Yao San.

	Beneficial or Supportive Interaction, with Professional Management
	Prevention or Reduction of Drug Adverse Effect

Effect and Mechanism of Action

Not specified; speculatively, magnesium may reset nerve activation thresholds, thus lessening the level of anesthesia necessary to prevent pain.

Research

In a randomized double-blind study involving 46 patients, split into two groups, undergoing arthroscopic knee surgery under total IV anesthesia, Konig et al. ¹⁴⁹ found that in a clinical setting with almost identical levels of surgical stimulation, IV magnesium sulfate administration significantly reduced intraoperative and postoperative analgesic requirements using fentanyl for induction and postoperative analgesia, compared with isotonic sodium chloride solution administration.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Fentanyl is an opioid analgesic administered intravenously or through a patch. Further research is warranted to explore the positive findings in this preliminary clinical trial of the synergistic interaction between fentanyl and magnesium sulfate during surgery. Related research into whether oral magnesium administration might interact similarly in patients using fentanyl patches remains to be done. Since all opioids significantly slow intestinal peristalsis, which frequently results in constipation when used for more than a few days, the laxative effects of oral magnesium can also be used as part of a program to normalize bowel function during opioid analgesic therapy.

	Impaired Drug Absorption and Bioavailability, Precautions Appropriate
	Adverse Drug Effect on Nutritional Therapeutics, Strategic Concern

Effect and Mechanism of Action

Magnesium salts may decrease the absorption of fluorinated quinolone antibiotics. Numerous studies have demonstrated that antacids containing magnesium, and by extension other magnesium compounds, readily chelate with and reduce absorption of fluoroquinolone antibiotics when administered concurrently. ^150-155 Specifically, the antimicrobials appear to be rendered inactive when the 3-carbonyl and 4-oxo functional groups characteristic of medications in this class form chelates with multivalent metal cations, particularly aluminum, magnesium, calcium, iron, and zinc, but also copper, manganese, and possibly sodium. ^153,155-166 For example, the absorption of ciprofloxacin is reduced by 50% to 90% in the presence of antacids containing magnesium and aluminum.

Research

Although there is general agreement as to the pattern of interaction between fluoroquinolones and multivalent cations, no published research has specifically involved magnesium supplements. Numerous minerals are known to form chelated complexes with fluoroquinolone antibiotics, or otherwise significantly reduce their absorption and bioavailability (AUC). Research involving magnesium has largely focused on antacids containing magnesium (or conclusions have been extrapolated from research involving aluminum-based antacids). ^{152,156,157,164,167-174} Given the nature of the apparent mechanism of action and the consensus on the pharmacological principles involved, the probability of similar interactions occurring with magnesium supplements can be reasonably extrapolated from the observed phenomena. Nevertheless, despite similarities, the evidence available on the degree of reduction in fluoroquinolone C ^max and AUC attributable to aluminum-based antacids cannot reasonably be extrapolated to magnesium supplements.

Clinical Implications and Adaptations

Physicians prescribing fluoroquinolone antibiotics should instruct patients to take magnesium and other mineral supplements (as well as related antacids) as far apart as possible from the medications (at least 6 hours before or 2 hours after antibiotics is usually adequate) to avoid the potential interaction. It is important to note that this interaction concern is only relevant to oral administration of both agents.

Drug-Induced Nutrient Depletion, Supplementation Therapeutic, with Professional Management

Effect and Mechanism of Action

Magnesium depletion, acute ionized hypocalcemia and hypomagnesemia, hypokalemia, and hypo/hyperphosphatemia are common and often severe adverse effects associated with IV foscarnet. The mechanisms by which foscarnet induces these changes, especially in ionized cations, are not completely understood, although renal impairment is the major toxicity of Foscavir. Foscarnet causes increased elimination of magnesium and other electrolytes in the urine and induces changes in plasma concentrations of total and ionized calcium and magnesium. Foscarnet binds preferentially to the magnesium ion. ¹⁷⁵ Foscarnet-induced ionized hypomagnesemia might contribute to ionized hypocalcemia by impairing excretion of preformed PTH or by producing target organ resistance. ¹⁷⁶

Research

In a clinical trial involving 13 male HIV-positive patients who had no active cytomegalovirus (CMV)–associated disease, Noormohamed et al. ¹⁷⁵ observed significant foscarnet-induced changes in plasma concentrations of total and ionized calcium and magnesium. The maximal decreases in ionized calcium and magnesium were much more rapid and larger than changes in the plasma concentrations of total calcium and magnesium, and the relative changes in the plasma concentration of ionized magnesium were greater than those of ionized calcium.

In a small study of solid-organ transplant recipients with ganciclovir-resistant CMV infection, Mylonakis et al. ¹⁷⁷ reported that magnesium depletion occurred in all six patients within 72 to 96 hours after initiating treatment with a combination of ganciclovir and daily IV foscarnet.

Huycke et al. ¹⁷⁶ conducted a randomized, double-blind, placebo-controlled crossover trial involving 12 patients with AIDS and CMV disease to investigate the effect of IV magnesium sulfate on foscarnet-induced ionized hypocalcemia and hypomagnesemia. Parenteral MgSO ⁴ , administered in increasing doses, reduced or eliminated foscarnet-induced, acute ionized hypomagnesemia. However, it had no discernible effect on foscarnet-induced, ionized hypocalcemia or associated symptoms, despite significant increases in serum PTH levels.

Reports

In 1993, Gearhart and Sorg ¹⁷⁸ reported the first known case of severe hypomagnesemia and other electrolyte disorders (hypocalcemia, hypokalemia, hypophosphatemia) in a patient with AIDS being treated for an exacerbation of CMV retinitis with foscarnet. The symptoms of muscle twitches, tremulousness, and anxiety resolved, and laboratory indices returned to normal after administration of magnesium and other electrolytes and discontinuation of foscarnet.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Although the general consensus is that foscarnet causes magnesium depletion, the issue of an effective therapeutic response to foscarnet-induced hypomagnesemia and hypocalcemia remains unresolved. Physicians prescribing and administering foscarnet are advised to monitor magnesium and other electrolytes frequently during foscarnet therapy. Huycke et al. ¹⁷⁶ concluded that routine IV administration for patients with normal serum magnesium levels is not recommended during treatment with foscarnet. However, divergent opinions remain as to the accuracy of various methods of assessing magnesium. The duration of treatment with foscarnet will generally affect both the clinical implications of the magnesium depletion pattern and the appropriate diagnostic approach. Furthermore, Gearhart and Sorg ¹⁷⁸ noted that concomitant therapy with antianxiety medications may mask the symptoms of electrolyte disorders and should be undertaken with caution. Further research into the clinical significance of these issues and integrative therapeutic options is clearly warranted.

Beneficial or Supportive Interaction, with Professional Management

Effect and Mechanism of Action

Glucosuria-related hypomagnesuria, nutritional factors and hyperinsulinemia-related hypermagnesuria all contribute to the well-established tendency for magnesium deficiency in patients with diabetes mellitus. Magnesium improves insulin sensitivity as well as insulin secretion in patients with type 2 diabetes. ¹⁷⁹

Research

Diabetes is associated with low magnesium status, ¹⁸⁰ and general consensus has existed since the early 1990s on the recognition of “strong associations … between magnesium deficiency and insulin resistance.” ¹⁸¹

Most researchers have found that magnesium improves insulin sensitivity as well as insulin secretion in patients with type 2 diabetes. ¹⁸² In a small clinical trial involving eight older, non–insulin-dependent diabetes mellitus (NIDDM) subjects, Paolisso et al. ¹⁸³ demonstrated that long-term magnesium administration (2 g/day) can elevate plasma magnesium levels and improve insulin response and action. In a subsequent double-blind trial, dosage appeared crucial, with 1000 mg/day magnesium producing a favorable effect that was not obtained with half that dosage. ¹⁸⁴ Eibl et al. ¹⁸⁵ showed that a 3-month course of replacement therapy with oral magnesium corrected hypomagnesemia in patients with type 2 diabetes. Johnsen et al. ¹⁸⁶ similarly reported that well-regulated NIDDM patients with marked magnesium deficiency responded favorably to oral magnesium. Two studies of the effect of magnesium administration on glucose tolerance in nondiabetic elderly subjects produced mixed results. ^187,188

Nadler et al. ¹¹ found that healthy subjects receiving a low-magnesium diet, adequate to demonstrate reductions in both serum magnesium and intracellular free magnesium in RBCs, produced a significant decrease in insulin sensitivity as well as increased thromboxane synthesis. In a clinical trial involving 16 subjects with insulin-dependent type 1 diabetes mellitus and 30 healthy controls, Sjogren et al. ¹⁸⁹ found that oral administration of magnesium hydroxide (500 mg/day) reduced insulin requirements, without changing levels of glycosylated hemoglobin (HbA ^1c ) and glucose, and corrected muscular magnesium and potassium deficiency in the diabetic patients. However, a decade later, in a clinical trial with 50 moderately controlled, insulin-requiring type 2 diabetic patients, randomized to 15 mmol oral magnesium or placebo daily for 3 months, De Valk et al. ¹⁹⁰ reported that plasma [Mg ⁺⁺ ] was higher after magnesium than after placebo, but that significant differences were lacking with regard to erythrocyte [Mg ⁺⁺ ], glycemic control, lipids, or blood pressure.

Diabetic patients with severe retinopathy have a lower plasma magnesium level than those without retinopathy, ¹⁹¹ and a prospective study demonstrated that plasma magnesium concentration are inversely related to occurrence or progression of retinopathy. ¹⁹²

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Insulin and magnesium represent important elements of a comprehensive repertoire of therapeutic options appropriate for consideration within a personalized and evolving program of care for individuals with diabetes and cardiovascular sequelae, along with dietary changes, exercise, alpha-lipoic acid, chromium, and omega-3 fatty acids such as fish oil. Initial assessment of renal function and magnesium status as well as regular monitoring and adjustment of insulin levels are important before beginning administration of oral magnesium, which is typically prescribed in the range of 200 to 600 mg of elemental magnesium per day.

Drug-Induced Effect on Nutrient Function, Supplementation Contraindicated, Professional Management Appropriate

Effect and Mechanism of Action

Magnesium and lithium are chemically related and appear to interact and sometimes compete within various physiological functions. ^193-195 The consumption of lithium carbonate may cause high blood levels of magnesium. ^196-198 >

Research

Ramasamy and de Freitas ¹⁹⁴ have observed competition between Li ⁺ and Mg ⁺⁺ for ATP in human erythrocytes in vitro using a 31P NMR and optical spectroscopy study. Herzberg and Herzeberg ¹⁹⁸ reported a significant gender difference in mean plasma magnesium levels in 44 depressed patients. The authors concluded that such findings suggested an unknown interaction between lithium and magnesium and that magnesium metabolism could play an important role in bipolar disorder and the mode of action of lithium. In a small clinical trial, researchers found that antacids containing magnesium hydroxide did not significantly alter bioavailability of lithium carbonate in six healthy subjects. ¹⁹⁹

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Although based on reasonable pharmacological principles and representing a plausible likelihood of occurrence, the clinical significance of the proposed interaction between lithium and magnesium remains largely unstudied. Nevertheless, physicians prescribing lithium carbonate are advised to ask such patients if they are taking magnesium. Initial assessment of magnesium status (and renal function) and regular monitoring of both lithium levels and magnesium levels are important to avoid excessive magnesium levels, if it is determined that both agents are therapeutically appropriate and strategically necessary.

	Drug-Induced Nutrient Depletion, Supplementation Therapeutic, Not Requiring Professional Management
	Prevention or Reduction of Drug Adverse Effect

Effect and Mechanism of Action

Some macrolide antibiotics, including erythromycin, may interfere with the absorption and activity of magnesium and other nutrients, particularly with extended treatment.

Research

The evidence pertaining to the effects of most macrolide antibiotics on magnesium is strongly suggestive but remains preliminary or inconclusive. ²⁰⁰

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians prescribing extended courses of erythromycin or other macrolide antibiotics may find it prudent to recommend magnesium supplementation (e.g., 300 mg/day orally) given the potential for interference with magnesium absorption and functions. Monitoring of magnesium levels and compensatory supplementation may be especially appropriate for patients with cardiovascular conditions or pathophysiological dysfunction in whom magnesium depletion might be clinically significant.

	Minimal to Mild Adverse Interaction—Vigilance Necessary
	Drug-Induced Effect on Nutrient Function, Supplementation Contraindicated, Professional Management Appropriate

Effect and Mechanism of Action

The most common adverse effect associated with misoprostol, a prostaglandin E ¹ analog, is mild, transient diarrhea, often accompanied by abdominal cramps. Excessive magnesium intake can also cause diarrhea. Concomitant use of the two agents might result in an additive effect and subsequent occurrence or aggravation of diarrhea or other adverse effects. ²⁰¹

Research

No specific evidence; possibility of occurrence is considered pharmacologically self-evident.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians prescribing misoprostol are advised to inform patients of the risk of diarrhea associated with the medication and the potential aggravation of adverse effects by concomitant magnesium intake. Drug-induced diarrhea can usually be minimized by administration of misoprostol after meals and at bedtime. Magnesium administration might be temporarily held in abeyance in some cases where the nutrient is considered strategically important but secondary in importance to the misoprostol in terms of tactical therapeutics.

	Minimal to Mild Adverse Interaction—Vigilance Necessary
	Bimodal or Variable Interaction, with Professional Management
	Beneficial or Supportive Interaction, with Professional Management

Effect and Mechanism of Action

Magnesium salts, particularly magnesium sulfate given parenterally, can increase and prolong (up to eightfold) the effects of neuromuscular blocking agents. ^202-207 Many substances alter the pharmacokinetics of neuromuscular blockers, especially those that depend on renal excretion, such as magnesium. Furthermore, some degree of additive effect is also operative because magnesium itself exerts significant neuromuscular blocking activity. These effects are at least partly caused by magnesium's marked inhibitory effect on acetylcholine release. ²⁰⁸

Research

In a study involving women with toxemia of pregnancy undergoing cesarean birth, Morris and Giesecke ²⁰² reported that patients receiving IV magnesium required approximately 65% of the dosage of succinylcholine (compared with those not receiving magnesium) to achieve adequate neuromuscular blocking activity.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Concomitant use of IV magnesium may enable neuromuscular blocking activity to be achieved with lower doses of neuromuscular blockers. Beyond such intentional coadministration, this interaction pattern is primarily of clinical significance in patients with increased serum magnesium concentrations; in such patients, unintentional additive effects could be of major severity. Physicians administering neuromuscular blocking agents are advised to assess initial magnesium status and closely monitor parameters of both substances if present together.

Effect and Mechanism of Action

Penicillamine and magnesium salts tend to form complexes, resulting in reduced magnesium absorption and inhibited activity of both substances. However, magnesium administration may reduce adverse effects of penicillamine in individuals who are magnesium deficient or who have become magnesium depleted due to action of the drug.

Research

The primary action of penicillamine is chelation of minerals and inhibition of their absorption and bioavailability. Formation of such complexes with magnesium inherently reduces availability of penicillamine for its intended therapeutic action. In a randomized crossover trial involving six healthy men given a single 500-mg oral dose of penicillamine, Osman et al. ²⁰⁹ observed that coadministration of a magnesium-containing antacid reduced the peak plasma level of penicillamine to 66% of those with the fasting dose. However, the antacid used contained both magnesium hydroxide and aluminum hydroxide, and the researchers did not attempt to distinguish the respective effects of the two components.

Use of high doses of penicillamine over an extended time can result in significant inactivation of magnesium and subsequent depletion. Seelig ²¹⁰ hypothesized that autoimmune complications of D-penicillamine could result from magnesium and zinc depletion and pyridoxine inactivation. In a clinical trial involving more than 50 patients on long-term high-dose penicillamine therapy for advanced stages of autoimmune diseases, she found that coadministration of magnesium, along with zinc, pyridoxine, and vitamins B ¹ , B ¹² , and E, resulted in fewer adverse reactions than usual for patients treated with penicillamine alone.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians prescribing penicillamine are advised to assess magnesium (and zinc) status at the initiation of treatment, especially when anticipating long-term high-dose penicillamine therapy. When magnesium has been determined to represent an essential element of the therapeutic strategy for the given patient, penicillamine should be administered at least 2 hours away from magnesium preparations (or magnesium-containing antacids).

	Drug-Induced Nutrient Depletion, Supplementation Therapeutic, with Professional Management
	Prevention or Reduction of Drug Adverse Effect

Effect and Mechanism of Action

Pentamidine, an antiprotozoal medication, is known to decrease magnesium levels. ⁵

Research

In vitro research suggests that pentamidine binds to a magnesium-binding site of the ribozyme in the target microbe. Zhang et al. ²¹¹ demonstrated that pentamidine inhibits catalytic activity of group I intron Ca.LSU from the transcripts of the 26S rRNA gene of Candida albicansby altering RNA folding.

Reports

Cortes et al. ²¹² reported two cases of hypocalcemia and hypomagnesemia associated with pentamidine therapy in patients with human immunodeficiency virus (HIV) infection. Otsuka et al. ²¹³ reported a case in which torsades de pointes developed subsequent to pentamidine therapy for Pneumocystis cariniipneumonia in a patient with acute myelogenous leukemia. Torsades de pointes resolved with administration of magnesium sulfate and discontinuation of the IV pentamidine; however, sinus bradycardia and prolonged QT interval persisted. The authors recommended “careful monitoring of the electrocardiogram” during IV pentamidine therapy.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians prescribing pentamidine are advised initially to assess and then regularly monitor magnesium (and potassium) status and administer compensatory nutrients as appropriate. Complementary therapies to support healthy cardiovascular and immune systems are usually appropriate in an integrative approach to treatment of immunocompromised individuals.

	Beneficial or Supportive Interaction, with Professional Management
	Prevention or Reduction of Drug Adverse Effect
	Drug-Induced Nutrient Depletion, Supplementation Therapeutic, with Professional Management

Effect and Mechanism of Action

Quinidine, and other antiarrhythmic drugs, may worsen cardiac rhythm disorders and increase the risk of death, especially in individuals with a history of a heart attack. In particular, quinidine causes torsades de pointes under certain conditions, particularly hypokalemia, hypomagnesemia, and other electrolyte abnormalities. Potent suppression of a potassium channel subunit current by quinidine is a likely contributor to torsades de pointes arrhythmias. ²¹⁴ Magnesium may prevent or reverse such quinidine-induced aggravation of cardiac arrhythmias. However, research into antacid-drug interactions shows that intragastric release of free aluminum and magnesium ions can induce potent effects on drug pharmacokinetics and GI function, particularly with drug-induced changes in GI motility or alterations in gastric and urinary pH. Direct adsorption by magnesium, or other mineral salts, may also result in decreased drug bioavailability, although not necessarily to a clinically significant degree. ²¹⁵

Research

Hypomagnesemia, especially in the presence of hypokalemia or other electrolyte abnormalities, is associated a range of adverse effects, including quinidine-related torsades de pointes, and interference with the antiarrhythmic activity of quinidine. Mutations in a gene encoding a potassium channel subunit (HERG) can be related to the long-QT (LQT) syndrome characteristic of torsades de pointes, a polymorphic ventricular arrhythmia. Pharmacological suppression of repolarizing potassium currents is also a mechanism causing the acquired LQT syndrome. Intravenous magnesium sulfate is often effective in reversing torsades de pointes induced by quinidine or other drugs, but the molecular basis of the mechanism involved in this action is not fully understood. In an in vitro study, Po et al. ²¹⁴ found that increasing extracellular Mg ⁺⁺ did not relieve the inhibition of HERG currents by quinidine, but did cause additional suppression. These authors concluded that modulation of this important K ⁺ current is not the mechanism by which IV magnesium terminates drug-induced LQT and torsades de pointes. Further research into electrolyte function in cardiac tissue, related drug interactions and depletion, and individual genomic and pharmacogenomic variability is warranted and can benefit from an integrative approach to multidisciplinary therapeutic interventions.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Within a comprehensive therapeutic repertoire, quinidine and magnesium represent important options appropriate for consideration in crafting a program of care for individuals with arrhythmias and other cardiovascular conditions. Treatment of arrhythmias, hypertension, or other cardiovascular conditions using medications that do not deplete vital nutrients or otherwise introduce electrolyte abnormalities is preferable, especially patients at risk of arrhythmias or receiving drugs such as quinidine. Regular monitoring and appropriate nutrient administration are important therapeutic tools when recourse to more deleterious agents is deemed necessary. Low potassium and magnesium concentrations not only contribute to or cause cardiac arrhythmias, but also interfere with the efficacy or enhance the toxicity of many drugs typically used to treat patients with heart disease. Physicians prescribing quinidine, especially in conjunction with potassium-depleting diuretics, are advised initially to assess and then periodically monitor potassium and magnesium status and consider recommending coadministration of both minerals. Clinical care within an integrative setting might also emphasize a diet rich in vitamins, minerals, and antioxidants and incorporate hawthorn (Crataegus oxyacantha),L-carnitine, coenzyme Q10, and other nutrients as part of an individualized and evolving approach to cardiovascular therapeutics.

	Drug-Induced Nutrient Depletion, Supplementation Therapeutic, with Professional Management
	Adverse Drug Effect on Nutritional Therapeutics, Strategic Concern

Effect and Mechanism of Action

Sodium polystyrene sulfonate (SPSS), often administered for the acute and chronic treatment of hyperkalemia, may alter magnesium levels and interfere with the therapeutic effects of magnesium. SPSS appears to increase sodium levels because of exchange for calcium and magnesium, thereby increasing susceptibility to magnesium depletion. ²¹⁶

Research

In vitro research investigating methods for reducing potassium intake indicates that, when used in hyperkalemia as a pretreatment for making a low-potassium formula, SPSS appears to lower calcium and magnesium levels while elevating sodium levels. ²¹⁶

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Concomitant administration of SPSS may reduce the efficacy of therapeutic or supplemental magnesium intake and could potentially induce a nutrient depletion pattern impacting magnesium. Such repercussions may simply need to be taken into account when adopting SPSS as an appropriate therapeutic tactical element and introduce no significant clinical complications. However, compensatory magnesium intake may be necessary if magnesium constitutes an essential component of the therapeutic strategy and long-term SPSS is contemplated.

Effect and Mechanism of Action

Magnesium compounds may reduce absorption and bioavailability of some beta blockers. Unintentional coadministration of some beta blockers, such as sotalol, and a magnesium-containing antacid appear to reduce serum levels of the drug. ²¹⁷ However, beta blockers can induce numerous metabolic disturbances, including dose-related decreases in plasma potassium, phosphate, and corticosteroids and significant hypocalcemia and hypomagnesemia, that may result in excessive cardiac depressant effects, such as bradycardia, asystole, and sinus arrest. In particular, sotalol can produce an arrhythmia known as torsades de pointes. Intravenous magnesium sulfate can be effective in reversing torsades de pointes and has been observed to abolish inadequate kinetics of frequency adaptation of the Q-aT interval, ²¹⁸ but the molecular basis of this effect is not understood. ²¹⁴ Further, magnesium can theoretically exert many effects similar to those of a calcium channel blocker, so standard cautions regarding the potential for an additive interaction with beta blockers may be relevant to magnesium administration.

Research

Magnesium appears to be an effective adjuvant to beta-blocker therapy, especially in cases involving arrhythmia or atrial fibrillation. As with other antiarrhythmic drugs, beta blockers can also induce ventricular arrhythmias. Stark et al. ²¹⁸ investigated the effects of sotalol alone and in combination with MgSO ⁴ and the Q-aT interval during abrupt changes in heart rate. In an animal experiment, they found that sotalol led to inadequate kinetics of rate adaptation of the Q-aT interval (indicated by high amplitude of Q-aT interval change, especially within first beat after abrupt change in pacing rate) and that magnesium sulfate abolished this adverse effect. Frick et al. ²¹⁹ investigated the effect of administering sotalol and magnesium on the incidence of atrial fibrillation after elective direct-current cardioversion of persistent atrial fibrillation. They found that occurrence of atrial fibrillation was significantly reduced by the administration of sotalol or magnesium individually, but that combination therapy was even more effective. Subsequently, in a randomized clinical trial with 207 consecutive coronary artery bypass patients, Forlani et al. ²²⁰ determined that the concomitant administration of sotalol and magnesium can prevent atrial fibrillation, a common complication after coronary artery bypass grafting.

Reports

In at least two published reports, IV magnesium effectively treated torsades de pointes in individuals taking sotalol. ^221,222

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Research on coadministration of magnesium with sotalol appears promising, but available evidence is inadequate to warrant a general recommendation that individuals prescribed sotalol also take an oral magnesium supplement to prevent known adverse effects. When the patient's history and cardiac risk factors indicate that magnesium coadministration might be clinically appropriate, initial and regular monitoring of magnesium (and potassium) levels is necessary. Nevertheless, prudence suggests that any magnesium preparation should be taken at least 2 hours away from sotalol or related medications, even though the cautionary research is based on magnesium-containing antacids. Such metabolic monitoring is inherently part of critical care situations where IV magnesium (sulfate) may be indicated.

	Minimal to Mild Adverse Interaction—Vigilance Necessary
	Potentially Harmful or Serious Adverse Interaction—Avoid
	Bimodal or Variable Interaction, with Professional Management
	Potential or Theoretical Beneficial or Supportive Interaction, with Professional Management
	Beneficial or Supportive Interaction, with Professional Management

Effect and Mechanism of Action

Magnesium intake may improve insulin sensitivity and secretion. ¹⁷⁹ Concomitant ingestion of magnesium hydroxide, observed primarily in the form of antacids, with glipizide and glyburide can significantly enhance the rate and extent of absorption and efficacy of both medications and thereby facilitate early insulin and glucose responses. ^223-226 These pharmacokinetic and pharmacodynamic interactions, as well as the cumulative effect of two therapies that can effectively alter blood glucose response, result in a potentially significant combination that might excessively lower blood glucose levels or enable more effective therapy or modification of dosage regimen.

Research

Diabetes is associated with low magnesium status, ¹⁸⁰ and general consensus has existed since the early 1990s on the recognition of “strong associations … between magnesium deficiency and insulin resistance.” ¹⁸¹

Most researchers have found that oral magnesium improves insulin sensitivity as well as insulin secretion in patients with type 2 diabetes. ¹⁸² In a small clinical trial involving eight older, non-insulin-dependent diabetes mellitus (NIDDM) subjects, Paolisso et al. ¹⁸³ demonstrated that long-term magnesium administration (2 g/day) can elevate plasma magnesium levels and improve insulin response and action. In a subsequent double-blind trial, dosage appeared crucial, with 1000 mg/day of magnesium producing a favorable effect that was not obtained with half that dosage. ¹⁸⁴ Eibl et al. ¹⁸⁵ showed that a 3-month course of replacement therapy with magnesium corrected hypomagnesemia in patients with type 2 diabetes. Johnsen et al. ¹⁸⁶ similarly reported that well-regulated NIDDM patients with marked magnesium deficiency responded favorably to oral magnesium. Two studies of the effect of magnesium supplementation on glucose tolerance in nondiabetic elderly subjects produced mixed results. ^187,188

Looking at a group of poorly controlled type 2 diabetic patients with hypomagnesemia, hypermagnesuria, and hypercalciuria, McBain et al. ²²⁷ observed that treatment with glipizide was associated with a significant rise in serum magnesium levels. Numerous pharmacological studies have demonstrated that the rate and extent of absorption of glipizide and glyburide, as well as their efficacy, are significantly enhanced by the concomitant administration of magnesium hydroxide. ^223-226 For example, in a randomized trial with eight healthy people, Kivisto and Neuvonen ²²⁴ found that 850 mg magnesium hydroxide accelerated absorption of glipizide and increased early insulin and glucose responses.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

The clinical implications of potential interaction(s) between magnesium and sulfonylurea drugs, particularly glipizide, glimepiride, and glyburide, largely depend on physician-patient communication and clinical management based on a coherent strategy. Magnesium can play an important role within a comprehensive, individualized, and evolving approach to clinical management of insulin resistance, dysglycemia, diabetes, and cardiovascular sequelae in conjunction with very-low-fat (and/or high-protein) diet, aerobic exercise, and appropriate weight reduction, as well as a coordinated nutraceutical program including chromium, multiple networked antioxidants (including mixed tocopherols and alpha-lipoic acid), soluble fiber, and possibly taurine. ²²⁸ Within a clinical context of collaboration by health care professionals trained and experienced in both conventional pharmacology and nutritional therapeutics, using magnesium in conjunction with sulfonylurea drugs at least can address the probability of magnesium deficiency in the susceptible individuals and may enhance the blood glucose–lowering effects of the medication. However, such concomitant use outside of integrative therapeutics and regular monitoring may increase the risk of hypoglycemia from an excessive additive interaction.

	Impaired Drug Absorption and Bioavailability, Precautions Appropriate
	Adverse Drug Effect on Nutritional Therapeutics, Strategic Concern
	Bimodal or Variable Interaction, with Professional Management

Effect and Mechanism of Action

Magnesium salts can chelate with tetracycline medications and thereby interfere with their absorption and possibly reduce their bioavailability and effectiveness; although one study suggests that the complexed tetracycline may be more bioavailable. ^229-236 This interaction occurs not only with supplemental magnesium but also with many antacids (e.g., Pepto-Bismol) that contain aluminum-magnesium hydroxide. Conversely, the formation of such complexes inherently reduces magnesium absorption and bioavailability and could contribute to magnesium depletion over an extended period. Furthermore, in vitro studies indicate that chelates of magnesium and tetracycline may play a role in the toxicity of tetracycline.

Research

The findings of Neuvonen ²²⁹ (1976) are typical of most subsequent research in concluding that tetracyclines form chelates with divalent and trivalent cations, including iron, aluminum, magnesium, and calcium. The team of Lambs, Brion, and Berthon has written extensively in the area of metal ion–tetracycline interactions. One paper states that simultaneous ingestion of minocycline and magnesium (as well as calcium, iron, or zinc) can decrease the absorption of both the medication and the mineral. ²³² In another paper, however, they reported that although magnesium-tetracycline complexes are likely to form, the resulting complex may actually be more bioavailable than uncomplexed tetracycline because of a higher degree of membrane diffusion. ²³¹

Nutritional Therapeutics, Clinical Concerns, and Adaptations

In general, physicians prescribing tetracycline-class antibiotics should advise their patients to avoid using magnesium-based antacids and supplemental magnesium unless a patient's clinical care demands otherwise. Neuvonen ²²⁹ noted that the “pharmacokinetic interactions in absorption of tetracyclines [are] likely to be clinically significant in cases where the infecting pathogens are moderately resistant to tetracyclines and relatively high serum concentrations are needed for proper bacteriostasis.” Nevertheless, tetracycline and antacids are often used together in combination therapies for Helicobacter pyloriinfection.

It is generally recommended that tetracycline be taken on an empty stomach, with a full glass of water, 1 hour before or 2 hours after ingestion of any supplements, food, or other drugs. However, an interval of 3 hours between the ingestion of tetracyclines and minerals such as magnesium is usually more effective in preventing this potential interaction.

Effect and Mechanism of Action

Theophylline therapy is associated with magnesium depletion in the chronic asthmatic patient population characterized by magnesium deficiency. Magnesium can be an effective bronchodilator and, in various forms, is used in the treatment of chronic and acute asthma.

Research

Preliminary evidence indicating that theophylline can promote hypomagnesemia and hypokalemia concurs with clinical observations of a tendency for individuals taking this medication to develop potassium and magnesium deficiency. ^237,238 In a study involving 869 patients treated with theophylline, Flack et al. ²³⁹ found that patients with measurable theophylline (concentrations >5.5 μmol/L) had a higher risk of hypokalemia, hyponatremia, hyperglycemia, hypophosphatemia, and hypomagnesemia than individuals in a control group of 350 inpatient and outpatient adults and children with no history of reactive airways disease or theophylline exposure. ²³⁹ Likewise, in a study of 93 chronic stable asthmatic patients on regular follow-up in an asthma clinic, Alamoudi ¹⁷ found that magnesium deficiency is associated with the occurrence and severity of asthma, particularly airway hyperreactivity, wheeze, and impairment of lung function. This paper concluded that hypomagnesemia is common in chronic asthmatic patients, and those with low serum magnesium tend to be hospitalized more than those with normal magnesium. Hypomagnesemia is also associated with more severe asthma.

Reports

Numerous case reports have documented hypomagnesemia and its respiratory, neurological, and cardiac sequelae subsequent to chronic theophylline therapy or theophylline overdose. ^240-243 Chevalier et al. ²⁴⁴ reported the case of a patient with ischemic heart disease complicated by left ventricular failure and chronic asthma who had ventricular tachycardia induced by theophylline overdose and responded to IV magnesium chloride.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Magnesium as a nutritional therapy in chronic care and as an infusion in emergency care can play an important role in an integrative approach to the prevention and treatment of asthma, particularly to prevent or reverse hypomagnesemia resulting from, and or act therapeutically in concert with, theophylline therapy. Administration of oral magnesium (300-600 mg/day) is often appropriate for individuals with asthma (or other magnesium-responsive conditions), in whom theophylline use over an extended period might induce magnesium depletion and interfere with magnesium's therapeutic or preventive action. Physicians prescribing theophylline are advised initially to assess and then regularly monitor magnesium status and correspondingly test renal function in individuals at risk for compromised ability to tolerate sustained magnesium administration, if determined to be appropriate. Magnesium sulfate infusions may be efficacious in the emergency care of individuals with acute asthma exacerbations, either in conjunction with beta-2 agonists via nebulizer, IV aminophylline, corticosteroids, or other first-line conventional therapies or in nonresponders. ²⁴⁵

	Impaired Drug Absorption and Bioavailability, Precautions Appropriate
	Minimal to Mild Adverse Interaction—Vigilance Necessary
	Adverse Drug Effect on Nutritional Therapeutics, Strategic Concern

Effect and Mechanism of Action

Magnesium, as well as other minerals such as iron and zinc, may bind with warfarin or dicumarol. ²⁴⁶ However, the evidence is mixed as to whether such chelation reduces or enhances absorption and activity of dicumarol anticoagulants. ^226,247 Formation of such complexes might also reduce magnesium absorption and bioavailability and could interfere with the effectiveness of oral magnesium as a preventive or therapeutic agent. Magnesium also exerts some degree of effect on the warfarin-albumin interaction.

Research

Testing four antacid preparations using an in vitro experimental model, McElnay et al. ²⁴⁸ found that magnesium trisilicate, a poorly absorbable form of magnesium never used as a nutrient source, although sometimes used in laxative preparations, decreased intestinal absorption of warfarin sodium by 19%. However, Neuvonen and Kivisto ²²⁶ reviewed the relevant literature and noted that magnesium hydroxide, as an antacid, increased absorption of dicumarol most likely because of chelate formation. In contrast, antacids containing both aluminium hydroxide and magnesium hydroxide appeared to produce no net change in the absorption of dicumarol, with aluminium hydroxide counterbalancing the enhancing effect of magnesium hydroxide. ²⁴⁹ Following the work of van der Giesen and Wilting ²⁵⁰ on the magnesium effect on the warfarin-albumin interaction, Perez Gallardo ²⁵¹ conducted an in vitro experiment investigating the binding of warfarin to human serum albumin in the presence of several concentrations of calcium and magnesium, as chloride compounds. He found that the free fraction of warfarin remained constant until calcium or magnesium reached concentrations of 50 mmol/L, at which point the binding fell to 92%. He concluded that displacement of bound warfarin can be expected only if the plasma concentrations of calcium or magnesium and chloride are significantly elevated.

Clinical Implications and Adaptations

Although the chemistry of common mineral nutrients binding warfarin is well founded, the frequency of occurrence is uncertain, its nature remains unclear and effects potentially variable, and conclusive evidence of the clinical significance of this interaction is lacking. Nevertheless, physicians prescribing warfarin are advised to recommend to patients that they separate warfarin administration from intake of magnesium (or iron or zinc) supplements (or magnesium-containing antacids) by at least 2 hours. Physician-patient communication is especially important in the event that individuals undergoing anticoagulant therapy are taking magnesium or any other mineral supplements. Regular monitoring of international normalized ratio (INR) is critical so that warfarin levels can be adjusted accordingly.

Captopril (Capoten); combination drug: captopril and hydrochlorothiazide (Acezide, Capto-Co, Captozide, Co-Zidocapt).

Both captopril (an ACE inhibitor) and magnesium can be used in the treatment of hypertension. Captopril increases lymphocyte magnesium levels, although possibly only in patients with preexisting low levels. ^252,253 This report of an observed interaction may be considered as preliminary or clinically insignificant. However, the therapeutic role of magnesium can be especially important in the population who would most likely be prescribed captopril. In particular, individuals with CHF, such as those noted in the research, tend both to be deficient in magnesium and to benefit therapeutically from magnesium. Thus, the issue of initial and regular monitoring of magnesium levels, along with cardiac function and other prognostic parameters, is essential to effective management of integrative therapeutics.

Cholestyramine (Locholest, Prevalite, Questran).

In animal research, cholestyramine produced an increased urinary excretion of magnesium, as well as other metabolic alterations. ²⁵⁴ A pattern of magnesium depletion resulting from this potential interaction could be counterproductive to the overall therapeutic strategy and detrimental to achieving the desired clinical outcomes (i.e., reducing mortality from cardiovascular disease). Supplementation with oral magnesium, typically 300 to 400 mg per day, preferably as part of a balanced multimineral formulation, could prevent nutrient depletion and deficiency. Evaluation of initial magnesium status and regular monitoring may be appropriate in some patients, especially anyone at risk of compromised renal function. Supplementation with fat-soluble vitamins is generally also indicated in patients taking cholestyramine.

Cycloserine (Seromycin).

Cycloserine may interfere with absorption of magnesium (and calcium). ²⁵⁵ On the other hand, pharmacokinetics of cycloserine are minimally affected by magnesium-containing antacids ²⁵⁶ and thus at least as unlikely to be affected by supplemental magnesium. The probability of occurrence and clinical significance of these potential interactions remain uncertain pending substantive evidence from controlled clinical trials. Concomitant magnesium may be appropriate to address the potential for magnesium depletion with cycloserine use over an extended period and might be particularly relevant in patients with cardiovascular disease, asthma, or other conditions that tend to be magnesium-sensitive.

Docusate (Colace, Surfak).

A single case report suggests that chronic use of docusate as a stool softener during and after pregnancy resulted in hypomagnesemia in a woman and her newborn infant. ²⁵⁷ The clinical significance and probability of occurrence of this potential interaction remains uncertain pending substantive evidence from controlled clinical trials. Supplemental magnesium may be appropriate to address the potential for magnesium depletion with docusate use over an extended period, particularly in patient populations at increased risk of magnesium deficiency.

Epinephrine (Adrenaline, epi; Adrenalin, Ana-Gard, AsthmaHaler, AsthmaNefrin, Bronchaid, Bronkaid Mist, Brontin Mist, Epifin, Epinal, EpiPen, Epitrate, Eppy/N, Medihaler-Epi, Primatene Mist, S-2, Sus-Phrine; epinephrine, injectable: Adrenalin Chloride Solution, EpiPen Auto-Injector).

Hormones associated with stress response, including epinephrine, are known to reduce intracellular concentrations of potassium and magnesium. ²⁵⁸ Thus, endogenous catecholamine release during stress or acute illness can contribute to the hypomagnesemia, such as that seen in acutely ill patients. ²⁵⁹ In particular, catecholamines can intensify cellular magnesium depletion. The detrimental and mutually enhancing effects of catecholamine excess and magnesium deficiency can be particularly deleterious to the myocardium. Animal research has shown that magnesium supplementation can reduce the ultrastructural features of myocardial damage induced by epinephrine without an effect on changes in intracellular distribution of calcium induced by epinephrine. ²⁶⁰ Also, magnesium is indicated for surgery of pheochromocytoma based on its calcium channel–blocking properties and its activity of lowering the release of epinephrine. ²⁶¹ Even though controlled human trials investigating the effects of epinephrine administration on magnesium status are lacking, physicians prescribing epinephrine for extended periods can consider whether supplementing magnesium is appropriate, especially in individuals susceptible to magnesium depletion and its potential sequelae.

Cimetidine (Tagamet; Tagamet HB), famotidine (Pepcid RPD, Pepcid, Pepcid AC), nizatidine (Axid, Axid AR), ranitidine (Zantac); ranitidine, bismuth, and citrate (Tritec).

Concerns regarding potential interaction between H ² blockers, particularly ranitidine, and magnesium does not primarily originate with a drug-nutrient interaction per se. Instead, research on the interaction between magnesium hydroxide and ranitidine has found that some antacids reduce the bioavailability of the H ² receptor antagonists. This is particularly true when ranitidine is used at the same time as high doses of the relevant antacids. Bachmann et al. ²⁶² found that among healthy subjects (i.e., who would not normally use the drug) a magnesium-aluminum hydroxide antacid decreased ranitidine absorption by 20% to 25% when the two substances were taken at the same time.

In relation to antacid use, the potential for interaction can be reduced by taking the H ² blocker at least 2 hours before or after any antacid containing aluminum or magnesium. There is concern that a multivitamin/mineral supplement containing magnesium could have the same effect, especially if the magnesium is in the form of magnesium hydroxide. In such cases, caution would advise taking the H ² blocker at least 2 hours before or after the magnesium-containing supplement.

Hydroxychloroquine (Plaquenil), chloroquine (Aralen, Aralen HCl).

Research involving chloroquine ²⁶³ suggests that oral magnesium intake may reduce blood levels of hydroxychloroquine and thereby decrease its effectiveness. Pending clinical trials providing more conclusive evidence and clarification, physicians prescribing hydroxychloroquine for conditions such as arthritis are advised to instruct patients to take magnesium preparations separate from these medications.

Isoniazid (isonicotinic acid hydrazide, INH; Laniazid, Nydrazid); combination drugs: isoniazid and rifampicin (Rifamate, Rimactane); isoniazid, pyrazinamide, and rifampicin (Rifater).

Isoniazid appears to interfere with the activity of many nutrients, including magnesium. Human trials indicate that coadministration of magnesium-based antacids does not significantly alter isoniazid parameters. ²⁶⁴ Supplementation with a multivitamin/mineral formulation is advised for individuals undergoing long-term isoniazid therapy.

Magnesium carbonate combination drug: magnesium carbonate, aluminum hydroxide, alginic acid, and sodium bicarbonate (Gaviscon Extra Strength Tablets, Gaviscon Regular Strength Liquid, Gaviscon Extra Strength Liquid); magnesium hydroxide (Phillips’ Milk of Magnesia MOM); combination drugs: magnesium hydroxide and aluminum hydroxide (Advanced Formula Di-Gel Tablets, Co-Magaldrox, Di-Gel, Gelusil, Maalox, Maalox Plus, Mylanta, Wingel); magnesium hydroxide and calcium carbonate (Calcium Rich Rolaids); magnesium hydroxide, aluminum hydroxide, calcium carbonate, and simethicone (Tempo Tablets); magnesium trisilicate and aluminum hydroxide (Adcomag trisil, Foamicon); magnesium trisilicate, alginic acid, and sodium bicarbonate (Alenic Alka, Gaviscon Regular Strength Tablets).

Concomitant use of supplemental magnesium and these antacids for an extended period might theoretically induce a magnesium excess. However, apart from individuals with compromised renal function, this is doubtful in light of general knowledge of magnesium, its minimal toxicity, and the difficulty in accumulating excessive magnesium levels in tissue.

The potential for interactions involving antacids depends on the chemistry and physical properties of the antacid preparation. The intragastric release of free aluminum and magnesium ions has potent effects on GI function and on drug pharmacokinetics. Antacid-drug interactions may occur secondary to changes in GI motility or alterations in gastric and urinary pH. Direct adsorption also results in decreased drug bioavailability. ²¹⁵

Mycophenolate (CellCept).

Oral magnesium salts, particularly within antacids, can inhibit absorption of mycophenolate, an immunosuppressive agent. However, even though a magnesium-containing antacid can reduce absorption and lower AUC of mycophenolic acid 15% and C ^max by 37% (compared with fasting), and plasma mycophenolic acid parameters similarly, such “changes are small in comparison with the interpatient variability and are not likely to have clinically major effects.” ²⁶⁵

Evidence: Metformin (Dianben, Glucophage, Glucophage XR).

Extrapolated, based on similar properties: Buformin (Andromaco Gliporal, Buformina); metformin combination drugs: glipizide and metformin (Metaglip); glyburide and metformin (Glucovance); phenformin (Debeone, Fenformin).

Looking at a group of poorly controlled type 2 diabetic patients with hypomagnesemia, hypermagnesuria, and hypercalciuria, McBain et al. ²²⁷ observed that patients treated with metformin therapy demonstrated reduced urinary magnesium excretion but remained hypomagnesemic and hypercalciuric. Given the known associations between magnesium levels and insulin sensitivity, controlled clinical research is warranted. Pending such trials, the clinical significance of this potential interaction remains unclear.

Nitrofurantoin (Furadantin, Macrobid, Macrodantin).

Mannisto ²⁶⁶ reported that coadministration of nitrofurantoin (100 mg) and a magnesium-aluminum antacid reduced the bioavailability of the nitrofurantoin by approximately 25%. In a study with six healthy male subjects, Naggar and Khalil ²⁶⁷ observed that magnesium trisilicate, a poorly absorbable form of magnesium never used as a nutrient, but sometimes used in combination with other mineral salts as a laxative, reduced the rate and extent of intestinal absorption and thus the bioavailability of nitrofurantoin. An in vitro experiment showed that magnesium oxide, a form of magnesium often used in supplements, exhibited intermediate adsorptive powers. After administering oral nitrofurantoin (200 mg) to 11 subjects in five different suspension materials, Soci and Parrott ²⁶⁸ found that the viscosity effect of colloidal magnesium aluminum silicate slowed absorption and urinary excretion of the medication, thus delaying the time of the maximum excretion rate without a decrease in bioavailability. The clinical significance of these findings remains unclear, particularly their relationship, if any, to magnesium supplements. Nevertheless, physicians prescribing nitrofurantoin may find it prudent to recommend to patients that magnesium in any form be taken at least 2 hours away from the medication.

Amiloride (Midamor), spironolactone (Aldactone), triamterene (Dyrenium).

Combination drugs: amiloride and hydrochlorothiazide (Moduretic); spironolactone and hydrochlorothiazide (Aldactazide); triamterene and hydrochlorothiazide (Dyazide, Maxzide).

See Diuretics: Loop Diuretics and Thiazide Diuretics.

Magnesium deficiency tends to be common among individuals undergoing diuretic therapy, and magnesium supplementation often plays an important role in prevention and treatment of cardiovascular conditions for such patients. According to preliminary studies involving rats, amiloride has a magnesium-sparing effect in addition to its potassium-sparing effect. ²⁶⁹ Consequently, individuals who take a magnesium supplement while also taking amiloride possibly could theoretically build up excessively high levels of magnesium. Thus the concurrent use of hydrochlorothiazide and amiloride would make this accumulation unlikely given the magnesium-depleting action of hydrochlorothiazide; for example, 5 to 10 mg of amiloride may negate the potassium-wasting effect of 40 mg of furosemide. ⁵ Nevertheless, Dorup et al. ¹³² reported that a furosemide-amiloride combination still produced hypomagnesemia in 12% of those treated with such a regimen. Similarly, triamterene may inhibit the urinary excretion of magnesium, according to preliminary research in animals. Initial assessment and regular monitoring of renal function and magnesium status are important to appropriate clinical management of individuals being administered both a potassium-sparing diuretic and a magnesium supplement.

Sulfamethoxazole (Gantanol).

Related: Sodium sulfacetamide (AK-Sulf, Bleph-10, Sodium Sulamyd), sulfanilamide (AVC), sulfasalazine (Salazosulfapyridine, salicylazosulfapyridine, suphasalazine; Apo-Sulfasalazine, Azulfidine, Azulfidine EN-Tabs, PMS-Sulfasalazine, Salazopyrin, Salazopyrin EN-Tabs, SAS), sulfisoxazole (Gantrisin); combination drug: sulfamethoxazole and trimethoprim (cotrimoxazole, co-trimoxazole, SXT, TMP-SMX, TMP-sulfa; Bactrim, Bactrim DS, Cotrim, Septra, Septra DS, Sulfatrim, Uroplus); triple sulfa (Sultrin Triple Sulfa).

Sulfonamides, including sulfamethoxazole, can decrease absorption of magnesium, as well as of calcium and vitamin B ¹² . Although this potential depletion patterns may not be clinically significant when prescribing sulfamethoxazole for less than 2 weeks, physicians prescribing the medication for longer than 2 weeks are advised to monitor magnesium status and supplement when indicated.

High alcohol intake increases renal excretion of magnesium, and hypomagnesemia is very common in alcoholics (e.g., 30% of alcoholic patients admitted to hospital care).

Magnesium intake from food and supplements is associated with bone mineral density. ²⁷⁰ However, high calcium intake may inhibit magnesium absorption. Such competition does not appear to exert a significant effect on overall magnesium status. ^271-273 Calcium supplementation, as well as cessation of magnesium administration, is typically used in treating hypermagnesemia.

Numerous in vitro, animal, and human studies have raised the issue of interactions between magnesium and iron. ^159,274 In a clinical trial involving 111 healthy women ages 18 to 40 years, of whom 45 were either iron deficient or iron deplete, Newhouse et al. ²⁷⁵ observed that although therapeutic iron dose (320 mg elemental iron daily as Slow-Fe tablets) for 12 weeks was successful in raising mean serum ferritin values and did not significantly effect serum zinc and magnesium levels during the supplementation period, there was a downward trend through the discontinuation phase; at 18 and 24 weeks, serum zinc and magnesium levels were significantly lower than baseline. These researchers also noted that oral contraceptive use was associated with elevated serum copper and ferritin values and lowered serum magnesium levels.

Rodent studies, single-dose experiments using healthy subjects, and a clinical trial involving two groups of pregnant women with moderately reduced hemoglobin levels showed that concomitant iron gluconate and magnesium- L-aspartate hydrochloride were well tolerated, stabilized hemoglobin levels, and moderated progesterone-induced constipation (during pregnancy), without interfering with iron absorption. ²⁷⁶

Individuals supplementing with manganese may need concomitant supplemental magnesium.

Individuals with high phosphorus intake may experience decreased magnesium absorption. After oral administration, magnesium and other divalent cations can bind to oral phosphate in the GI tract, reducing bioavailability and therapeutic effect of both substances. ^6,277 This interaction can usually be avoided by separating oral intake of the two substances by 2 hours. Increased dosage of magnesium may also be medically appropriate for preventive or therapeutic purposes in some individuals.

Potassium and magnesium deficiency often occur together and need to be treated concomitantly. ^{3,101,104,127,129} For example, magnesium (and sometimes sodium) supplementation often needs to accompany potassium supplementation to correct intracellular potassium depletion in hypertensive patients who develop ventricular ectopy and other potassium deficiency effects subsequent to diuretic therapy. ¹⁰⁵ However, some research shows that such coadministration may not provide efficacy beyond that of potassium alone in the treatment of some conditions, such as ventricular extrasystoles. ²⁷⁸ Most individuals who benefit from magnesium supplementation also often benefit from potassium supplementation or increased dietary potassium intake. Initial assessment and regular monitoring of renal function and potassium status are important to safe and effective administration of both minerals. Clinically effective levels of potassium require a physician's prescription. A diet rich in fruits, vegetables, and whole grains provides several grams of potassium daily.

One case report described a patient in whom cardiac beriberi with polyneuritis developed after protracted use of large amounts of magnesium trisilicate, ²⁷⁹ a poorly absorbable form of magnesium never used as a nutrient, but sometimes used in combination with other mineral salts as a laxative, and widely used as a flowing agent in the tableting and food industries.

Pyridoxine is necessary for cellular accumulation of magnesium (and zinc), and its presence increases the amount of magnesium that can enter cells. Concurrent administration of both nutrients may enhance therapeutic efficacy.

Magnesium bioavailability appears to be enhanced by vitamin D.

Supplementation with zinc may increase magnesium intake needs, possibly through an inhibitory effect on magnesium absorption and adverse effect on magnesium metabolic balance. ²⁷⁷