French edition (Le magnesium en pratique cliniques. Published
in 1985 by J. B. Baillière, Editions Médicales
Internationales, 62 rue des Mathurins, 75008 Paris, France
First English language edition published in 1988 by
John Libbey & Company Ltd, 80/84 Bondway, London SW8 1SF, England (01) 582 5266
John Libbey Eurotest Ltd, 6 rue Blanche, 92120 Montrouge, France (1) 47 35 85 52
Excerpt. Pages 103-106.
Magnesium has for a long time had only a modest place in therapeutics, being used only for its cathartic or neutralizing properties in oral preparations or for its sedative or antispasmodic properties parenterally.
Today continually increasing knowledge of magnesium deficit is allowing us to determine in what circumstances and in what manner we can remedy it using physiologic doses of magnesium. Correct use of magnesium therapy must prevent magnesium overload accidents for which we must also still know the treatment. In a few specific cases, parenteral and local magnesium therapy and, even still more rarely, the induction of magnesium deficit show why they should he used.
We will consider the following in order:
• The dietetic and medicinal elements of magnesium therapy.
•The indications for and techniques of oral magnesium therapy, less in strong cathartic doses than in palliative physiologic doses for magnesium deficit.
• The indications for and techniques of parenteral and local magnesium therapy.
• The treatment of magnesium overload.
• The exceptional case of induction of a therapeutic magnesium deficit.
• Finally, the absolute and relative contraindications for magnesium therapy.
1. The dietetic and medicinal elements of magnesium therapy
In developed countries magnesium intake in the diet is inadequate.
We will consider successively,
• the causes of this relative deficiency,
• research on correcting it by changes in diet.
• the particular value of amounts in drinking water.
1.1 Dietetic magnesium
1.11 The "marginal magnesium intake" in developed countries
1.111 The nature and mechanism of marginal dietary deficiency
The average magnesium requirement for the adult has an advisable lower limit of about 6mg/kg/day (36, 332, 380, 391, 831, 834, 836, 837, 1161, 1163, 1165, 1167) and the recommended dietary allowance of the U.S. National Academy of Sciences has been set at the slightly lower level of 5 mg/kg/day. Yet the normal magnesium intake in developed countries remains, in the majority of cases, inadequate. This is even more true when magnesium requirements are at their highest and especially during anabolic periods like exercise, growth, pregnancy and lactation when requirements may he doubled (36, 332, 380, 391, 831, 834, 836, 1161, 1163, 1165, 1167). Agricultural and food preparation techniques lead to a decrease in the levels of magnesium in the produce and meats that we consume. The bolting of flour, polishing of rice and refining of sugar reduce the levels of magnesium in these foods. White salt has a magnesium level four to five times less than that of grey salt. Cooking of foods makes them lose 30 to 75 percent of their magnesium in the cooking water which is normally thrown out. In order to correct this inadequate magnesium intake, it would he ideal to act "upstream" from the consumer. We must improve our agricultural practices and select the species that are the most able to take up magnesium from the soil (334, 391).
1.112 The difficulties involved in correcting dietary deficiencies
While waiting for the success of the efforts of agronomists, the physician must try to correct marginal magnesium deficiency by increasing the level of magnesium in the diet. But foods that are rich in magnesium are few in number, dissimilar and absorbed in varying degrees (334, 391) (Table 17).
Table 17 - Magnesium levels in selected foods (mg/100g).
In J. Durlach, V. Rayssiguier, A. Laguitton, Le besoin en magnésium et son apport dans la ration. Medecine et nutrition, 16, 1, 15-21, 1980.
The classification of foods according to their level of magnesium shows that foods rich in this ion are not significant elements of the diet.
Moreover, the most easily used items are also high in calories and increasing them is not generally compatible with a balanced energy intake.
We must emphasize the quantitative and qualitative importance of magnesium in drinking water.
It is easy to replace large crystal, white cooking salt with "grey" salt, but its consistency makes it unusable as table salt (334). Certain synthetic forms of salt rich in potassium and magnesium escape this criterion however (1007).
It is possible to advise increasing the amount of certain foods in the diet, for example. chocolate, nuts, dried fruits, bananas, seafood or snails, but the first of these foods increase the already normally excessive calorie intake from our diets while the last two are only rarely eaten (296,334,391). The absorbability of magnesium in bran and therefore in whole cereals is still debated. It is improved however if the chelating capacity of bran has been saturated by simultaneous intake of calcium (addition of CaCO3 during bread making, use of bran mixed with yogurt or of whole cereals with low fat milk or biscuits with bran and calcium caseinate) (71, 349, 391, 397).
In practice the only simple dietetic means of increasing magnesium intake consists of using only water with a sufficient level of magnesium as drinking or cooking water.
1.12 The importance of magnesium in water
1.121 The quantitative importance of magnesium in water
Quantitatively, intake of magnesium from water is significant, whether by direct consumption (drinking water, soups, tea, coffee or infusions) or indirectly by effects on the level of magnesium in foods cooked in water. There is in fact an inverse relationship between the level of magnesium lost from a food and the level of magnesium in the water in which it is cooked (269, 272, 391, 402, 560, 848). It is especially important that artificially softened hot water for domestic use not be used for cooking. It causes in fact a maximum decrease in the magnesium level of the food thus cooked. It is preferable to use normally mineralized tap water that has not been softened. It is moreover of interest to note that the precipitation of salts which softens water when it is heated occurs preferentially at the expense of calcium and thus preserves most of the magnesium (402).
Thus the amounts of magnesium in water, directly when it is consumed and indirectly by reducing the loss of magnesium in foods cooked in water to a minimum, can quantitatively reach the "critical" levels of intake that make a marginal diet go from deficiency to an adequate status.
One would hope that water treatment plants could provide water in which the magnesium level was monitored, trying to reach the desirable level of 30 mg per liter. Treatment of corrosive soft water by alkaline earth filtration should be concerned about the level of magnesium in the water obtained (402).
1.122 The qualitative importance of magnesium in water
The value of magnesium in water cannot however he reduced to this quantitative aspect. It seems that in experimental animals (1311) as well as in humans (187, 402, 752, 778, 954), magnesium in water is the magnesium that is most rapidly absorbed and used.
This particular availability would account for the value of intake of magnesium in water which becomes immediately usable at breakfast during the transition from nocturnal rest to daily activity (778). It would also allow us to understand the importance of not overworking the neuro-endocrine systems for magnesium homeostasis by consuming a minimum level of magnesium in water (402). In fact, in both rats and humans, the absence of an adequate amount of magnesium from water in one’s magnesium intake, even when the diet is not deficient in magnesium, can lead to hypertension associated with related disorders, either neuro-endocrine or ionic (sodium-potassium or phosphorus-calcium) (954).
Thus it is important never to reduce magnesium intake from tap water intended for cooking or drinking by using a softener and, if there is no water with adequate magnesium levels, to use bottled water that has at least 30 mg of Mg per liter (402, 537, 552).
1.2 Magnesium salts
We will first describe the nature of the magnesium salts that are available for use in therapy and then show how difficult it is to compare them in their oral prescriptions for remedying magnesium deficit. We will then review briefly the pharmacodynamic properties of parenteral or local magnesium.
1.21 The characteristics of magnesium salts
In addition to simple magnesium oxide, a large number of magnesium salts have been used therapeutically, either mineral (chloride, sulfate, nitrate, carbonate) or organic (acetate, bicitrate, methionate, levulinate, ascorbate, glycero-phosphate, gluconate, aspartate, propionate, lactate, fumarate, glutamate, pyrrolidone-carboxylate).
Orally, soluble salts are thought to he better tolerated and absorbed than insoluble salts (521, 522, 748, 1267) and organic salts more active than mineral salts (691).
The use of dolomite as a source of natural magnesium should be prohibited since this mineral can be a source of toxic metals (Pub, Hg, Cd ...) (1086).
In reality, comparing aspects of the oral intake of physiologic doses of different magnesium salts depends on the conditions of the magnesium deficit for which they are being compared. We can disregard the specific properties of their anions since only the amount of cation that is absorbed is significant. If it is a question of correcting a deficiency, of which the most typical form is intake deficiency, all magnesium salts have a comparable bioavailability with only slight differences (255, 1043, 1044, 1373). In human therapy, there is no great problem in reducing such a deficiency since it is sufficient to increase intake of the deficient cation. But the difficult problem in magnesium therapy consists in correcting deficits where there is, at least partially, a depletion. One must then try to rank magnesium salts, determining those that are the best absorbed and penetrate the deficient tissues the best since these are the most active and are retained the best.
1.22 Bioavailability and therapeutic effectiveness of physiologic doses of oral magnesium
Since magnesium salts are poorly absorbed, it would be valuable to have magnesium salts of high bioavailability.
The classic measure of the bioavailability of a drug depends on the variations of its level in plasma after oral and intravenous administration. This is not possible for a physiologic parameter like plasma magnesium that is subject to strict homeostatic control.
The use of isotopes does not resolve this problem either. 28Mg has too short a half life and the stable isotope 26Mg exists at a high endogenous level which makes its use as a marker difficult (1155, 1156, 1157, 1158).
One can however with a subject who is in neutral magnesium balance and is on a diet with controlled ionic intake consider an increase in urinary magnesium as a positive indication of absorption, especially if it is verified by initial hourly sampling which leaves little time for a hypothetical tissue accumulation (534, 713, 778, 945).
In the absence of animal models of magnesium depletion that are close to the cases found in humans, one can try to compare the rate and amount of absorption and the penetration and activity of different magnesium salts in various tissues of animals made deficient in magnesium. The quickest and most adequate correction of the parameters of deficiency in animals — biologic (Mg in plasma. erythrocyte. urine and the femur, Mg/Ca and cAMP/cGMP ratios...), neurophysiologic (e.g., the study of spontaneous motility) and cardiovascular... — should allow us to rank different treatments even though still inadequate, for magnesium depletion. Using a method of this type to compare three magnesium salts for their effects on initial and then cumulative urine levels of magnesium during the first two days in the deficient rat, it has been possible to show, as has been done in humans, better absorption for MgCl2 than for MgSO4 or magnesium oxide and better retention for MgCl2, in relation to the same absorbed amounts of the other two salts (938).
But this original experimental approach in animals regarding the "therapeutic effectiveness" of a physiologic dose of oral magnesium for magnesium depletion can only be confirmed by the success of a loading test. Intake of an oral physiologic dose (5 mg/kg/day) of a magnesium salt that leads to control of subjective and objective parameters, tracings and dosages for magnesium depletion constitutes the only proof of the therapeutic effectiveness of a magnesium salt for magnesium depletion. One can compare, to some extent at least, a study of this type with one that shows the superiority of pyrrolidone-carboxylate over sulfate in volunteers that were theoretically healthy but had low erythrocyte magnesium levels (894). However, given the current state of our knowledge, no magnesium salt has clearly shown its superiority in overt cases of magnesium depletion.
1.23 The pharmacodynamics of larges doses of magnesium given orally or by parenteral or topical routes
While physiologic doses of magnesium do not have any pharmacodynamic properties, magnesium in high oral doses or given parenterally or topically does have pharmacodynamic activity. The effects are particularly well defined in iatrogenic magnesium overload during massive parenteral magnesium therapy with its ability to cause bradycardia and hypotension, its curariform and ganglioplegic effects and its anticoagulant, cytoprotective and calcium antagonist activity (204, 384, 756, 916, 933, 943). The comparative analysis of the virtues of the different salts of magnesium in such models is equally valuable for the corresponding indications by these same routes and in these same doses (83, 131, 204, 227, 541, 884). In contrast they do not permit any extrapolation to the comparative virtues of these same magnesium salts as therapeutic for magnesium deficit in oral physiologic doses.
1.3 Magnesium-sparing drugs
There are two types, those that cause low urinary magnesium, thus reducing magnesium loss, and magnesium-fixing agents of which the main activity is to enhance magnesium penetration into the cell and its maintenance there.
1.31 Drugs that reduce urinary magnesium
Two types of diuretics are capable of reducing urinary magnesium, inhibitors of carbonic anhydrase and distal or so called "potassium-sparing" diuretics.
1.311 Carbonic anhydrase inhibitors
Acetazolamide (332, 1281) and metazolamide (154, 332) combine reduction of urinary magnesium levels with induction of metabolic acidosis (due to loss of bicarbonate and retention of H+). It may help in reducing neuromuscular hyper-excitability. These carbonic anhydrase inhibitors often cause low potassium levels. Administration of potassium salts may reduce this.
1.312 "Potassium-sparing" distal tubule diuretics
These can he divided into aldosterone antagonists (spironolactone and canrenone) and distal diuretics with direct renal action (triamterene and amiloride) (363).
Among the aldosterone antagonists, spironolactone is the most active in regard to magnesuria. Moreover it exerts interesting general effects on ionic transfers (883). But it also has many side effects.
Among the direct distal diuretics, we prefer amiloride, since triamterene creates the risk of precipitation (779) and does not seem to maintain its effects over the long term (1332).
1.313 Anti-stress drugs
In addition to drugs classified as specific renal agents that lower urinary magnesium, we must consider treatments for stress as true agents that lower urinary magnesium indirectly. Stress is in fact one of the major causes of renal loss of magnesium. The frequency of its association with any type of magnesium deficit demands that anti-stress treatments which are logically used with therapy for the forms of magnesium deficit that are secondary to this dysfunction be mentioned among the customary agents for lowering urinary magnesium.
Beyond their important specific effects that are unrelated to magnesium, i.e., on neuromuscular hyperexcitability, the usefulness of hygienic prescriptions, psychotherapy, relaxation drugs, muscle relaxants, anti-lipolytic agents and sedative or autonomic nervous system treatments must be judged by their effects in reducing urinary magnesium levels.
1.32 Magnesium-fixing compounds
Among magnesium-fixing compounds the most often used are vitamin B6 and vitamin D.
The intake of sulfur amino acids (cystine, methionine), of glutathione and the vitamins needed in their metabolism (B6, C) which tends to increase available taurine is of only theoretical interest.
The use of insulin and progesterone is limited by their specific properties.
1.321 Vitamin B6
There are close links between B6 and Mg. The formation of complexes between Mg, B6 and amino acids permits active transport of these three compounds and places the vitamin at the head of the list of magnesium-fixing agents. Moreover magnesium is necessary for the activating phosphorylation of vitamin B6. B6 and Mg are both necessary for protein synthesis, especially for enzymes and are involved in numerous physiologic functions at more or less closely connected steps which allows their association to have frequent simple or reinforcing synergic effects: psycho-neurosedative, muscle relaxing, cardiovascular and liver protective, antihypoxic or antilithiasis, etc. (6, 97, 213, 333, 358, 363, 364, 499,726, 733, 746, 747, 844, 845, 967, 1374, 1375).
To obtain the best magnesium-fixing effects the best ratio of vitamin B6 to physiologic doses of Mg2+ is 2.5 parts pyridoxine hydrochloride to one part magnesium ion. One has to use pharmacologic doses, and not physiologic doses (743), of vitamin B6 while remaining well below those that have caused problems of excess, i.e., more than two grams a day such as in B6 megavitamin therapy (1141). This method of magnesium therapy with its precise pharmacodynamic doses of vitamin B6 has never caused such problems in spite of its widespread use (101,155, 213, 332, 333, 345, 346, 358, 363, 364, 371, 380, 401a, 484, 726).
1.322 The D vitamins
The physiologic forms of vitamin D (D3 or cholecalciferol) or the synthetic forms D2 (or ergocalciferol) as well as their hydroxylated derivatives whether physiologic 25-(OH)D3. (or calcidiol) and 1,25-(OH)2D3, the hormone-like vitamin (or calcitriol) or synthetic, 1-(OH)D3 (or Unalpha®) promote the passage of extracellular Mg into the tissues. As such the D vitamins can be classified as magnesium fixing agents. Moreover they increase the absorption of magnesium (318, 332, 345, 358, 363, 364, 371, 380, 713, 1211). Unfortunately the D vitamins have as their main effect increasing the absorption and accumulation of calcium. Beyond the risks of these properties that promote calcinosis, they increase urinary magnesium either by raising blood calcium levels or by a specific renal effect. Depending on the degree of this urinary magnesium loss in relation to their other effects on magnesium retention, the D vitamins may or may not be used as magnesium-fixing agents (318, 322, 332, 345, 358, 363, 364, 371, 380).
1.323 Sulfur compounds
Since taurine has magnesium-sparing properties (361, 398, 401), it is tempting to try to increase available levels of it. Because this sulfonic amino acid is poorly absorbed, it is logical to increase its precursors and to try to reduce their utilization for synthesis of glutathione. Intake of methionine, cystine and glutathione is therefore theoretically desirable (397). Vitamins B6 and C (in addition to their own therapeutic value) should favor these metabolic goals (358, 397, 997).
Insulin unquestionably facilitates entry into the cell of the two principal intracellular cations, Mg and K (1356) as well as that of the two major alkaline earth elements, Mg and Ca (396). Since there is much more free K+ (87%) than free Mg in the cell (30%), insulin acts more on potassium metabolism than on magnesium metabolism (336, 1356). By adding a calcium ionophore effect to its magnesium ionophore capacity, insulin combines with the desired magnesium effect an action that is harmful in relation to cellular calcium overloading during magnesium deficit. Moreover it may cause tetany through its own action on membranes even without hypoglycemia (332). It is therefore a less than perfect magnesium-fixing agent and its use is necessarily limited to the parenteral1 (332, 336).
Experimentally progesterone causes magnesium retention in the rat (519). If this fact is confirmed in women in the particular cases where this hormone is useful, such as, for example, premenstrual syndrome and certain pregnancies that are at risk, progesterone can be used as a magnesium-fixing agent.
Its positive effect on magnesium balance does not occur with progestagens like norethisterone (519).
1.4 Partial magnesium "analogues"
Perfect magnesium "analogues" should be able to relieve all the effects of magnesium deficit without magnesium.
If no substance can today meet such a definition, partial magnesium "analogues" are capable of replacing magnesium to some extent in counteracting the effects of magnesium deficiency.
Vitamin B6 would only deserve such a classification if one thought pyridoxine could be equated with vitamin G (333) since the latter may control tetany due to magnesium deficit in the rat (526).
1 .41 Propranolol
Propranolol, by non-specific effects on membrane stability (363, 394) and perhaps also by specific effects that re-establish the activity of beta-adrenergic dependent magnesium channels (204, 457) may occasionally meet such a definition. This possibility corresponds to a minority of the cases of latent tetany due to magnesium deficit which propranolol controls (309).
1.42 Calcium antagonists
Verapamil and nifepidine both partially control various effects of experimental magnesium deficiency (28, 32, 208, 228, 457, 961). In symmetry with the idea that attributes many of the effects of magnesium to its physiologic action as a calcium antagonist (204, 756, 943), intake of calcium antagonists has been used to try to counteract magnesium deficit as a factor in tissue calcium overload. If there is currently no one that relieves all the consequences of magnesium deficit, the cardiac effects of the deficit seem to be the most sensitive to this therapeutic remedy. Verapamil seems to be the most active of calcium antagonists as a partial magnesium "analogue" in spite of its different sites of action (1006).
1 .43 Anticonvulsants
Various anticonvulsants of different chemical families and different mechanisms of action (phenytoin, valproic acid, baclofen, phenobarbital, clonazepam, carbamazepine) are capable of controlling the major manifestations of neuromuscular hyperexcitability due to magnesium deficit (67, 363, 394). They can thus he classified as partial magnesium "analogues" and magnesium deficiency can he classified among the models for studying anticonvulsants (18, 67, 175, 749, 1012). But they have no effect on the other manifestations nor on the final prognostication of the deficiency. We must however reserve a special place for phenytoin due to its concomitant antitetanic and anti-arrhythmic properties (363, 370, 394, 399, 723) and for baclofen because of its muscle relaxing ability (158, 363, 1021, 1132).
The utilization of these partial magnesium "analogues" that are particularly effective for certain aspects of magnesium deficit has a role of choice among the adjuvant treatments of the corresponding clinical forms that are resistant to magnesium therapy.
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