Subject: Magnesium - long but very informative article
From: Jeannette Leduc
 

Hi all,

It explains how magnesium is helpful with many of the health problems many have including heart problems, high blood pressure, asthma, etc.

I suggest you print it out and share it with your doctor.  IV administration of magnesium could really make a difference if you could get your doctor to try a couple of IVs to see how you do with them.

Medical Sciences Bulletin Contents

Magnesium

Reprinted from the May 1994 issue of Medical Sciences Bulletin, published by Pharmaceutical Information Associates, Ltd.
 
 

Physiology, pharmacology, therapeutics

Magnesium is a physiologic necessity. It is also a  pharmacologic  treasure. Indeed, according to cardiologists T. Millane and A. Camm, in many ways magnesium is the ideal drug: it is safe, cheap, and simple to use, with a wide therapeutic range, a short half-life, and little or no tendency towards drug interactions. As a result, this divalent cation is attracting attention for managing conditions ranging from acute myocardial infarction and cardiac arrhythmias to alcohol withdrawal and asthma. Magnesium (Mg) is the fourth most abundant cation in the body, following calcium (Ca), sodium (Na), and potassium (K), and the second most abundant intracellular cation (after K). It is involved in more than 300 different enzymatic reactions, including carbohydrate utilization, ATP metabolism, muscle contraction, transmembrane ion transport, and the synthesis of fat, protein, and nucleic acids.

In his comprehensive review of Mg that appeared in the American Journal of Medicine in January 1994, Robert McLean (Yale School of Medicine) described the metabolism and therapeutic uses of this important nutrient. One of its major functions is the regulation of Ca and K balance, said McLean. Mg influences Ca balance by interacting with para-thyroid hormone, which controls Ca metabolism. It influences Ca activity at the cellular level by interacting with Ca channels and ion transport mechanisms in the cell membrane. As a result, Mg is a Ca antagonist in vascular, cardiac, and smooth muscle cells. Mg influences K balance by acting as a cofactor for the membrane Na-K-ATPase system, thus playing a role in maintaining the transmembrane gradients of Na and K that determine the electrical potential across membranes. Mg deficiency disturbs the Na-K gradient (causing neuromuscular excitability and irritability) and impairs Na-K-chloride transport (causing K efflux through K channels). The resulting K depletion, which is refractory to K therapy, requires Mg therapy for K repletion. The Mg ion has been found to modify at least three types of K channel and two types of Ca channel.

Total body stores of Mg average about 2000 mEq, and the normal serum range is 1.4 to 2.1 mEq/L. (This parameter is difficult to use because of an apparent lack of correlation between serum and tissue Mg levels.) Extracellular Mg in serum is 33% protein bound, 12% complexed to anions, and 55% in free ionized form. Approximately 0.5% of body distribution is in erythrocytes. Mg flows between stores in bone and muscle (53% and 27% of body distribution, respectively) and the circulating extracellular compartment (soft tissue 19% and serum 0.3%). However, quantitative body stores are regulated by metabolic and hormonal effects on gastrointestinal (GI) absorption and renal excretion. Mg is absorbed along the length of the small intestines (jenunal absorption appears to require vitamin D), with the percentage absorbed varying as dietary intake varies. Free serum Mg undergoes glomerular filtration and tubular reabsorption (in the proximal tubule and loop of Henle); as serum Mg level rises and falls, tubular reabsorption decreases or increases. (Drugs that cause Mg wasting --amphotericin B, cisplatin, digoxin, pentamidine, gentamicin, cyclosporine, ethanol, and diuretics -- usually act on the renal tubule.) Overall, daily Mg losses in GI secretions and urine decline when dietary magnesium intake or serum levels decline, and increase as Mg intake or serum levels increase.

According to McLean, hypomagnesemia is common, found in 65% of an intensive care unit population and 11% of a general inpatient population. Diagnosis can be difficult, however, not only because the serum Mg level does not necessarily relate to total body stores, but also because patients may be asymptomatic even when severely deficient. Measuring urinary Mg excretion may be helpful, although it is important to collect a 24-hour sample, a secretion follows a circadian pattern (more Mg excretion occurs during the night). Collecting a 24-hour urine sample after infusion of Mg sulfate (60mEq over 12 hours) and measuring Mg retention has been used diagnostically; retention of more than 50% of the dose generally indicates Mg deficiency. Usually, Mg deficiency is diagnosed on the basis of inaccurate serum measurements and clinical manifestations (neuromuscular hyperactivity, psychiatric disturbances, Ca/K abnormalities, or cardiac effects).

 Magnesium for Acute MI

Early studies showed that patients with acute myocardial infarction (MI) are Mg deficient and this deficiency increases during the acute phase of infarction. Later studies showed that Mg infusion in patients with suspected acute MI can prolong survival, and a meta-analysis of several of these studies suggested that the reduction in mortality is 25% to 50%. The Mg ion has multiple effects on the myocardium, among them antiplatelet, antiarrhythmic, and coronary vasodilator effects. However, its efficacy for prolonging post-MI survival is probably due to its ability to preserve left ventricular function by reducing Ca-mediated ischemic damage.

During ischemia, hypoxia and acidosis limit the production of ATP from ADP, a step that normally requires Mg. As Mg utilization drops, intracellular free Mg concentrations rise rapidly. Then during reperfusion, Mg is reincorporated into ATP and Mg levels fall, leaving a reciprocal Ca overload. This Ca overload is thought to be responsible for myocardial is stunning, ä a mechanical impairment of the heart that develops within thefirst minute of reperfusion and is associated with an uncontrolled rise in intracellular Ca, depletion of high-energy phosphates, and contractile dysfunction. During reperfusion, normal or high concentrations of Mg restore high-energy phosphates and Na-K balance, and may also block the release of catecholamines from the adrenal gland (catecholamines cause vasoconstriction, tachycardia, thrombosis, and oxygen-wasting). Increasing the extracellular Mg concentration by therapeutic Mg infusion thus speeds recovery from stunning, provided that the Mg is given before reperfusion (whether reperfusion is spontaneous or induced by thrombolytic agents). (Millane TA, Camm AJ. Br Med J. 1992; 68: 441-442. Yusuf S et al. Circulation. 1993; 87: 2043-2046. Woods K, Fletcher S. Lancet. 1994; 343:816- 819.)

The LIMIT-2 and ISIS-4 studies

Two landmark trials completed in recent years have studied the effects of Mg sulfate administered IV to patients with suspected acute MI. In the second Leicester Intravenous Magnesium Intervention Trial (LIMIT-2), Mg sulfate was administered within 3 hours of onset of chest discomfort in2316 patients with suspected MI. The trial was randomized, placebo controlled, and double blind. In the treatment group, Mg 16 mEq (8 mmol) was infused over a period of 5 minutes, followed by a maintenance dose of130 mEq administered over 24 hours. When thrombolytics were used (in 35% of patients), they were given after Mg infusion. The primary endpoint was28-day outcome. In treated patients, IV Mg reduced the incidence of left ventricular failure during ICU stay by 25%, with a corresponding reduction of 24% in mortality rate. (Woods +KL, Fletcher S. Lancet. 1992; 339:1553-1558.)

The Fourth International Study of Infarct Survival (ISIS-4) did not find the same benefits with Mg infusion. It studied 55,000 patients receiving Mg(16 mEq over 15 minutes followed by 144 mEq over 24 hours) with or without thrombolytic therapy, captopril 6.25 mg orally, and mononitrates. There are probably several reasons for the different findings in LIMIT-2 and ISIS-4,including demographic differences, geographic differences (e.g., Mg concentration in the water supply), differences in Mg status (uneven randomization), concurrent drug therapies, and use of thrombolytics (moreISIS-4 patients received thrombolytics). According to LIMIT-2 investigators K. Woods and S. Fletcher, a more important difference may be the timing of Mg administration.

Patients in LIMIT-2 were given Mg a median 3 hours after the onset of chest discomfort and before reperfusion (spontaneous or thrombolytic). By contrast, ISIS-4 patients were not even randomized until 8 hours after the onset of symptoms, and thrombolytic therapy was given and lysis completed before treatment with Mg. Since reperfusion injury is immediate, the administration of Mg after completion of lysis was too late to protect against myocardial stunning. Timing is critical, said Woods and Fletcher.  The loading dose of Mg should be given before thrombolysis, and patients who are not given a thrombolytic agent should have Mg infused during the period when spontaneous reperfusion is likely to occur. (Spontaneous reperfusion usually occurs later than thrombolytic reperfusion, because thrombolytic therapy provides a measure of control not available with spontaneous reperfusion.) (Woods KL, Fletcher S. Lancet. 1994; 343:816-819.)

In his editorial comment on the LIMIT-2 and ISIS-4 studies, W. Casscells noted that study results so far indicate that early Mg treatment is beneficial for certain patients, such as those with hypertension, diabetes, or congestive heart failure, those taking diuretics and digoxin, and those with poor diet. So what do we do while awaiting the results of further trials? According to Casscells, ã A reasonable course would be to give 8-10mmol of magnesium as an intravenous bolus to all patients seen in the first6 hours of acute myocardial infarction except those with hypotension, bradycardia, or atrioventricular block, or those who might be expected to have a high magnesium concentration (due to magnesium supplementation, including antacids, or chronic renal failure). Aspirin should be given first (one tablet crushed and swallowed with a drink of warm water), followed immediately by magnesium, then heparin. This regimen will help prevent the procoagulation side-effects of tPA or streptokinase, which should be given next (intransmural infarction), followed by a 6.5-mg tablet of captopril.ä Nitrates and morphine can be used for chest pain, beta-blockers can be used toãbluntä residual tachycardia and hypertension (except in patients with asthma or heart block), and lidocaine can be used for selected patients with certain ventricular arrhythmias. Calcium antagonists, however, have little use, says Casscells. Angioplasty may be indicated, if an experience dinterventional cardiologist is immediately available. (Casscells W. Lancet.1994; 343: 807-809.)

Magnesium and Acute MI, 3 Years later

What is the effect of Mg therapy on long-term survival? Left ventricular failure after MI is the strongest predictor of subsequent mortality. Since Mg-treated patients enrolled in LIMIT-2 showed a 25% reduction in early left ventricular failure (relative to patients receiving placebo), their long-term survival should be correspondingly increased. LIMIT-2 patients have now been monitored for up to 5.5 years (mean 2.7 years), and the initial increase in survival seen in the Mg-treated group has indeed been maintained long term. Reductions in mortality rates of 21% (from ischemic heart disease) and 16% (from all causes) were observed in Mg- treated patients compared with untreated patients.

The treatment regimen described here is safe, cheap, and simple to administer, said the investigators, and the early benefits are reflected in improved long-term survival. The most common side effect (cutaneous flushing) is infrequent if the loading dose is given over 15 minutes. The maintenance dose may need to be reduced in patients with moderate to severer enal impairment, since Mg is excreted via the kidneys. To achieve these improvements in long-term survival, one must remember that myocardial stunning develops within minutes of reperfusion, so Mg administration must be prompt. (Woods KL, Fletcher S. Lancet. 1994; 343: 816- 819.)

Magnesium for Angina, Arrhythmias

Evidence suggests that IV Mg therapy may be beneficial in a cardiac conditions other than MI, such as variant angina, exercise- induced angina, ischemic heart disease without vasospasm, and cardiac arrhythmias. Patients with these conditions are often Mg-deficient relative to healthy controls, and epidemiologic studies have demonstrated a higher cardiac mortality rate in regions with ãsoftä (i.e., low- Mg) water. In postmortems of patients with ischemic heart disease (particularly sudden death), myocardial Mg was reduced by as much 20%, while Ca was up to 6 times as high as innonischemic controls.

Mg is well established as therapy for certain cardiac arrhythmias. Mg infusion prolongs the PR interval, prolongs sinoatrial conduction time, increases the atrioventricular nodal refractory period, and raises the fibrillation threshold. In a dose of 5 to 10 mmol over 5 to 10 minutes, Mg sulfate will abolish torsade de pointes, reduce digoxin-associated arrhythmias, and terminate many episodes of sustained ventricular tachycardia. Prophylactic administration after cardiac surgery may reduce the frequency of postoperative arrhythmias. In many cases Mg has been effective for restoring sinus rhythm when used as a last resort after administration of several other agents.  Cardiac arrhythmias are often associated with hypomagnesemia, although hypokalemia is also present. However, Mg modifies ventricular tachycardia and other arrhythmias regardless of serum Mg concentrations in many patients who are not Mg deficient (or who are at low risk for Mg deficiency). Adenosine, verapamil, and digitalis are effective for most supraventricular tachyarrhythmias, but Mg should also be considered as part of the therapeutic arsenal for supraventricular and ventricular arrhythmias.

The Mg ion also has antiischemic and antiplatelet effects, which may prove useful in patients with angina. When given orally, Mg may reduce blood pressure. Patients with hypertension and those receiving loop and thiazide diuretics would probably benefit from long-term oral Mg therapy, but there are no strict guidelines for oral therapy, regarding dosage or type of formulation. (Millane TA, Camm AJ. Br Med J. 1992; 68: 441-442. McLean RM.Am J Med. 1994; 96: 63-76.)

Magnesium for Asthma, Alcohol Withdrawal, Pre-eclampsia

Mg has been used for conditions ranging from asthma and alcohol withdrawal to pre-eclampsia. In asthmatics, Mg may act as a bronchial smooth muscle relaxant. Although not effective in nebulized form, Mg given IV improves1-second forced expiratory volume in asthmatics at all stages of  bronchoconstriction, from no constriction (patients not having an asthma attack), to mild constriction (patients having a mild attack), to severe constriction (emergency- room patients having a severe refractory attack, or hospitalized patients receiving IV steroids, aminophylline, and beta-2 agonists).

Mg has also been used for alcohol withdrawal. Alcoholics often have Mg deficiency because of poor dietary intake and excess renal excretion.  Indeed, some of the metabolic disturbances in alcoholics may result from hypomagnesemia. Mg is a cofactor, with thiamine, for liver transketolase; thiamine replacement is standard treatment for alcoholic patients, yet even when thiamine is replaced the enzyme shows markedly reduced activity in the presence of Mg depletion. Mg also suppresses epileptic foci, although its role in alcohol withdrawal seizures is unknown. Some alcoholics with hypomagnesemia have reportedly been given Mg repletion as sole treatment, with resolution of symptoms.

While the use of Mg for asthma and alcoholism is still investigational and anecdotal, its use for pre-eclampsia of pregnancy is well established. Mg reduces systemic and cerebral vasospasm, possibly via Ca antagonism within the cell or at membrane Ca channels, or possibly by altering the prostaglandin system (Mg promotes the release of the vasodilator prostacyclin). (McLean RM. Am J Med. 1994; 96: 63-76.)

Magnesium Safety Profile

There are very few complications associated with Mg administration. The most common side effect is transient facial flushing with rapid IV infusion. Hypermagnesemia, which occurs primarily in patients with impaired renal function, may be associated with nausea, vomiting, and cutaneous flushing. Only at markedly elevated serum levels are toxic effects seen in cardiovascular (hypotension, cardiac arrest) and neuromuscular (weakness, reduction of deep tendon reflexes, respiratory arrest). Serious toxicity has been reported in patients who have consumed massive oral doses of Mg-containing cathartics or antacids. On the other hand, large parenteral doses have been administered to women with pre-eclampsia (up to 49 mEq infused over 30 minutes, followed by 16-25 mEq per hour for 4-8 hours) with no clinical toxicity. According to McLean, there is "low likelihood of elevating the serum magnesium level into toxic ranges when giving the routine therapeutic doses of 16-32 mEq of magnesium to patients with normal renal function." Given its low cost, low toxicity, and broad spectrum, Mg use should increase as more studies demonstrate its clinical efficacy. (McLean RM. Am J Med. 1994;96: 63-76.)