Beta‐2 mimetics and magnesium: true or false friends¿

ARTICLE

Auteur(s) : Jean Durlach¹, Nicole Pagès², Pierre Bac³, Michel Bara⁴ Andrée Guiet-Bara⁴

¹ SDRM, Université Pierre et Marie Curie, 75252 Paris Cédex 05, France; 
² Laboratoire de Toxicologie, Faculté de Pharmacie, Strasbourg, 67400 Illkirch-Graffenstaden, France; 
³ Laboratoire de Pharmacologie, Faculté de Pharmacie, Paris XI, 92290 Chatenay-Malabry, France; 
⁴ Laboratoire de Physiologie et de Pathologie, UPMC, 75252 Paris Cedex 05, France

Introduction

– Magnesium therapies and treatment with beta-2 agonists can be used in several common indications in obstetrical and pulmonary patients particularly. Their association is possible, but may be considered as beneficial or deleterious.

– The aim of this study is to differentiate between cases where the therapeutic association of beta-2 mimetics and magnesium is welcome and cases where it is contraindicated.

We shall successively consider:

– Nature and action of beta-2 adrenergic receptors.

– The respective results of beta-2-mimetic treatment and of magnesium therapy in their common obstetrical indication.

– The respective results of beta-2-mimetic treatment and of magnesium therapy in their common pulmonary indications.

– The effects of the association of beta-2-mimetic treatment and of magnesium therapy in their common indication.

Nature and action of beta-2 adrenergic receptors

Adrenergic receptors are classified as alpha and beta on the basis of their responses to diverse adrenergic stimulations. In general the effect on alpha receptors is excitatory and that of beta receptors is inhibitory [1]. With the development of various selective agonists, several subtypes of receptors have been described: alpha-1, alpha-2, beta-1, beta-2 and beta-3.

Stimulation of diverse beta receptors brings about different effects: beta-1 receptors mainly concern the heart while beta-2 receptors are involved in smooth muscle relaxation in pulmonary, vascular and uterine apparatus particularly. Beta-3 receptors are the predominant beta adrenoreceptors in adipocytes with some distinctive links with magnesium status. Beta adrenergic receptors belong to the family of the stimulatory G[(sG)] protein dependent membraneous receptors.They interact with guanine nucleotide regulatory proteins and magnesium dependent adenylate cyclase. Their activation increases intra-cellular concentration of cyclic AMP (cAMP) which induces phosphorylation of numerous key proteins of muscle contraction through activation of a cAMP dependent-Protein Kinase A (PKA) [2-6].

For example, cAMP induces a myorelaxation by a double action on myosinekinase: it directly inhibits myosinekinase via phosphorylation by PKA and indirectly, through a decrease of cellular free Ca due to Ca uptake by sarcoplasmic reticulum.

Magnesium load may also increase cAMP level and decrease cellular free Ca, but through other mechanisms (activation of adenylate cyclase and effects of “physiological Ca antagonist”).

Inhibition of myosinekinase — the key enzyme of smooth muscle contraction — induces myorelaxation which may be obtained through both treatments: beta-2 mimetics and magnesium load [7-10].

Beta adrenergic receptors play a major role in the regulation of the magnesium status: they can modify exchanges between intra-cellular magnesium and extra-cellular magnesium. The stimulation of beta receptors may induce hypermagnesemia through an efflux of magnesium out of the cell due to an increased extrusion of cellular magnesium via a Na⁺ dependent mechanism. Activation and modulation of beta-adrenergic receptors ought to intervene among the neurohormonal factors of the physiological regulation of magnesium status [11-19; i.e. 14 (1988) p. 20, 21-23, 31, 32; updated in 19 (2000) p. 23, 26-28, 37, 44]. But this feedback mechanism of the regulation of magnesium status through beta-adrenergic receptors may become ineffective when the response is excessive. These beta-adrenergic effects similar to those observed with pharmacological use of beta-mimetics are coupled to lipolysis which reduces magnesemia mainly through the chelation of magnesium by non esterified fatty acids and through an increased magnesium uptake by adipocytes and (at least partly) by enhanced urinary excretion of magnesium [11, 12, 14, 17, 19 (i.e. in 14 (1988) p. 24, 176 and in 19 (2000) p. 27, 198), 20-22].

To sum up: the physiological beta stimulation may be involved in the regulation of magnesium status i.e. by a homeostatic increase of magnesemia during magnesium deficiency. But conversely excessive beta stimulation for example by the use of pharmacological high doses of beta mimetics may induce a deleterious decrease of magnesemia.

Nature and action of magnesium therapy

Two different types of magnesium therapy ought to be distinguished: nutritional physiological oral magnesium supplementation and pharmacological magnesium therapy. Their nature and action are basically different.

Nutritional magnesium therapy

Today the main form of magnesium therapy is oral physiological magnesium supplementation of magnesium deficiency due to an insufficient magnesium intake.

These palliative nutritional magnesium doses meant to balance magnesium deficiency are obviously devoid of any toxicity since their purpose is to restore to normal the insufficiency of the magnesium intake [12, 14, 19 (1985, 1988, 2000: Chapter V), 23].

Pharmacological magnesium therapy

In order to use the pharmacological properties of magnesium, whatever the magnesium status, it is necessary to go beyond the mechanisms of magnesium homeostasis to induce a therapeutic magnesium overload: a genuine iatrogenic hypermagnesemia. The parenteral route is suitable for acute applications and large doses of magnesium given orally are advisable for chronic indications. Both types of pharmacological magnesium treatment are capable of inducing magnesium toxicity [12, 14, 19 (1985, 1988, 2000, Chapter V), 23].

It is a real scientific fraud and an ethical misconduct to fail to differentiate between the non-existant toxic consequences of a nutritional physiological oral magnesium supplementation and the effects of high pharmacological doses which are potentially dangerous [24]. But this basic distinction between the two types of magnesium treatments is too often overlooked in papers on magnesium therapy.

Respective results of beta-2 mimetics and of magnesium treatments in their common obstetrical indications

The one common obstetrical indication for beta mimetics and magnesium is tocolysis. Preterm birth is the major cause for perinatal morbidity and morbidity in the developed world. The aim of tocolysis is to prolong pregnancy: among the agents used for myometrial relaxation beta-2 mimetics are the principal drugs [25-28]. Controversial opinions are expressed concerning magnesium: K.L. Katz et al. 1999 [29] recommend the use of intravenous high doses of MgSO₄ as first line therapy. “When comparing maternal and fetal risks, side effects and the safety profile MgSO4 is superior to beta mimetics”. But many other obstetricians consider that intravenous MgSO₄ “tocolytic” treatment has not been associated with significant prolongations in pregnancy. Moreover several randomized trials have shown that it is better than placebo at delaying preterm delivery [25, 27, 28, 30-34].

Long term tocolysis has been now given up. It has not been demonstrated that it improves perinatal or neonatal outcomes. But it increases maternal and fetal adverse effects. There is no evidence for continuing tocolytic treatment after an effective tocolysis of 48h. Short term tocolysis enables the obstetrician and neonatalogist to optimise the handling of the premature baby: through the administration of antepartum glucocorticoids to reduce hyaline membrane disease and the possibility of arranging in utero transfer to a center with neonatal intensive care facilities [25-31, 35].

Beta-2 mimetics and tocolysis

Beta-2 mimetics are the principal agents used for myometrial relaxation [25]. They are the reference tocolytic drugs in most countries [28].

Nature and mechanism of action

Beta-2 agonists are pharmacologic drugs which act via beta-2 adrenergic receptors — members of the family of sG protein dependent membraneous receptors — on the cell membrane of myometrial cells to increase cAMP levels. This mechanism is believed to involve coupling with a sG regulatory protein leading to activation of adenylcyclase. The cyclic AMP (cAMP) produced in response to beta-2 adrenergic stimulation results in inhibition of contractile activity directly acting through cAMP-dependent myosinekinase and indirectly reducing the availability of free intra-cellular myometrial Ca₂₊ [2-4, 8-10, 31].

Efficiency and side effects

There is good evidence that beta mimetics prolong pregnancy. They reduce the rate of delivery at 24h., 48h. and at 7 days. But there is no proof however for their beneficial effects on perinatal or neonatal outcomes. But there is good evidence that beta mimetics are associated with a high level of maternal and pediatric side-effects [10, 25-32, 36-44].

Tocolytic doses of beta-2 mimetics have significant maternal, fetal and neonatal side effects which may be more or less severe.

Pulmonary oedema and sudden maternal death are rare, but other side effects from beta mimetics are frequent. They concern the cardio-vascular apparatus and metabolic balances: chest pain, dyspnea, cardiac arrhythmias, palpitations, tachycardia, hypotension, headache, nasal stuffiness, nausea, vomiting, tremor, dizziness, hyperglycemia, hypokalemia and hypomagnesemia. These side effects may require the discontinuation of treatment.

Two mechanisms may be involved in these side-effects: Beta mimetic drugs used for tocolysis may have a beta-1 receptor stimulation characteristic and therefore induce noxious side-effects on the heart and lungs. Beta-2 mimetics may be used in too high doses (see for ex. lipolytic effects causing hypomagnesemia).

Several precautions ought to prevent these complications following beta mimetic mediated tocolysis: monitoring of maternal heart rate [(maximum heart rate = 120), of blood pressure, serum glucose, electrolytes (K and Mg particularly), ECG, auscultation of maternal lungs fields] and monitoring of fetal heart rate [29, 31], short term treatment (shorter than 48h.), avoidance of water and Na load (restriction of IV fluid and of simultaneous corticotherapy).

Because of the large incidence of their maternal, fetal and neonatal side effects the use of high doses of beta mimetics for suppression of premature labor have been either stopped or limited to short treatments (< 48h.) with the lowest possible doses (inducing heart rate < 120).

Magnesium therapies and tocolysis

Two types of magnesium therapy — nutritional magnesium therapy and pharmacological magnesium treatment — may be used for tocolysis.

The palliative nutritional physiological oral magnesium doses are meant to balance magnesium deficiency in the case of gestational magnesium deficiency. Conversely pharmacological magnesium treatment for suppression of premature labor may be used, whatever the magnesium status [24]. Despite the lack of clear tocolytic effects, intravenous MgSO₄ is one of the most popular tocolytics in North America [26].

Nutritional magnesium therapy for tocolysis 

Nature, mechanism of action and efficiency

Nutritional magnesium therapy for tocolysis is indicated only to restore to normal the insufficiency of maternal magnesium intake in case of gestational magnesium deficiency. This type of magnesium supplementation is physiological and obviously devoid of any toxicity [24]. Experimental and clinical data have shown that gestational magnesium deficiency may induce premature labor. Among many maternal, fetal and neonatal deleterious consequences, premature births and repeated miscarriages may be observed during experimental gestational magnesium deficiency.

Chronic primary magnesium deficiency is highly frequent: for example 23% of women in France have dietary magnesium intakes lower than the two.thirds of RDA for magnesium. Nutritional magnesium supplementation significantly reduces the incidence of premature labor and of spontaneous abortion, prolongs the period of gestation and favors the appearances that indicate a better outcome for the newborn (weight, height, head circumference). It improves the impaired development of the neonate [12 (1985, p.124), 14 (1988 p.308-110), 19 (2000 p.126), 56-78].

To identify pregnant women with gestational magnesium deficiency, the most appropriate way is to evaluate their magnesium intake. If the diet history is not easily available, the most significant clinical sign is Chvostek sign which appears to be correlated with magnesium intake, but not with serum magnesium concentration [12(1985, p.73), 14 (1988, p.65), 19 (2000, p.73), 77].

L. Spätling recommends for all pregnancies an oral atoxic magnesium supplementation with 2 or 3 single doses of 5 mMol Mg per day. A randomized placebo-controlled double blind crossover-study has indicated that this magnesium supplementation results in an efficient and well tolerated magnesium therapy [77, 79].

Side effects

The nutritional magnesium therapy which palliates gestational magnesium deficiency is atoxic since it restores a physiological magnesium balance. Positivity of the dynamic oral physiological magnesium load test constitutes the best proof of a magnesium deficiency and the first stage of its therapy [19, 80].

To sum up: the following guidelines appear logical. After a clinical diagnosis of a gestational magnesium deficiency (evaluation of the magnesium intake through a diet history, research of clinical and paraclinical signs of neural hyperexcitability due to magnesium deficit: Chvostek sign particularly), magnesium nutritional supplementation is necessary [19, 80].

Researchers skeptical about the possibility of differentiating magnesium deficient pregnant women recommend supplementation of all pregnancies with 2 or 3 doses of 5 mMol Mg per day [77, 79].

Although certain of the effects of primary gestational magnesium deficiency on pregnancy per se have been stressed, this instance of maternal malnutrition may also be involved in many other noxious consequences: sudden infant death as well as psychiatric, cardiovascular and metabolic disturbances throughout life.

To check the validity of the importance of maternal primary chronic magnesium deficiency, the protocol of a long term multicentric placebo controlled study on the effects of maternal nutritional oral magnesium supplementation on morbidity and lethality in foetus, neonates, infants, children and adults should be carried out not only during pregnancy and during the first year, but throughout life. This type of intervention trial appears as the only means to assess the importance of the consequences of maternal chronic magnesium deficiency in human beings [12, 14, 19, 76, 78].

Pharmacological magnesium therapy for tocolysis 

Nature, mechanism of action and efficiency

Regarding tocolytic pharmacological magnesium treatment, the usual route is parenteral [37-42], but large doses have been given orally, although rarely [81, 82]. Intravenous MgSO₄ is the most commonly used first line tocolytic agent among obstetricians in the United States [28, 83].

The mechanism according to pharmacological magnesium therapy used for tocolysis is the inhibition of myometrial activity. Magnesium decreases the frequency of depolarization of smooth muscle by modulating calcium uptake, binding and distribution in smooth muscle cells. The net result is inhibition of uterine contractions. But MgSO₄ lacks any specificity with regard to its relaxing action on uterine or other smooth muscle, for example intravenous MgSO₄ is able to induce not only myometrial relaxation, but also peripheral vaso-dilator effects [10, 12, 19, 23, 31, 84].

Efficacy of intravenous MgSO₄ for tocolysis has not been evaluated rigorously: the evidence that supports its use is weak. Several randomized trials did not bring evidence of tocolytic effectiveness [26, 27, 28, 84, 85]. Intravenous MgSO₄ cannot recommended as a tocolytic agent for women in preterm labour.

Although tocolytics drugs are used frequently despite limited evidence of beneficial tocolysis, their safety has not been demonstrated.

Side effects
Tocolytic doses of intravenous MgSO₄ may induce maternal, fetal and pediatric side effects.

• Maternal side effects 

– Several maternal side effects are frequent and most often of mild importance. They may be related to dosage and speed of infusion: flushing, sweating and a sensation of warmth, weakness, headache, palpitations, chest pain, shortness of breath, nausea, vomiting. Pulmonary edema is rare and furthered by concomitant corticotherapy.

– Administration to concentrations above the recommended therapeutic range can lead to depression, hypothermia, respiratory and cardiac arrest due to an excessive iatrogenic magnesium load.

• Fetal and pediatric side effects
Magnesium crosses the placental barrier and the fetal kidney does not excrete magnesium with the efficiency of mature kidney. Maternal treatment with high intravenous tocolytic MgSO₄ doses exposes the newborn to a hypermagnesemia that is correlated with the duration of the pharmacological magnesium therapy. The neonate hypermagnesemia can lead to hyporeflexia, poor sucking and, rarely, respiratory depression. This neonatal magnesium overload can affect intracardial and peripheral circulation, the APGAR score, the calcium metabolism and induce meconial discharge.

Other forms of neonatal magnesium overload with normal magnesemia may be observed. Only the myoelectric tracings reveal inhibition of neuromuscular transmissions which contraindicates any prescription that may enhance such latent curariform effects [12 (1985, p. 231-234), 14 (1988, p. 204-205), 19 (2000, p. 223-225), 84, 90-92].

Conversely several retrospective observational studies describe an association between maternal administration of tocolytic parenteral high doses of magnesium and a reduction in cerebral palsy in low birthweight infants. Predicated on this information, the hypothesis was proposed that pharmacological maternal magnesium may have a neuroprotective benefit among antenatally exposed premature infants [93-96].

In order to check whether antenatal exposure to maternal pharmacological magnesium supplementation had neuroprotective effects on premature children, several trials were conducted on this same important subject. But there was profound disappointment when a scheduled interim data safety analysis of the American trial MAGNET revealed a strong association between MgSO₄ maternal treatment and total (fetal + neonatal + post neonatal) pediatric mortalities. The reported adverse outcomes of MAGNET were subsequently criticized and defended. MAGNET was suspended after 15 months of enrolment because of excess paediatric morbidity and mortality among those exposed to MgSO₄. Contrary to the original hypotheses, the data have shown a statistically significant increase in the risk of neonatal intraventricular hemorrhage as well as total adverse paediatric outcomes among those with higher levels of ionized magnesium at delivery [97].

A retrospective case control study among 170 children with cerebral palsy and 288 control subjects has shown that maternal pharmacological magnesium exposure was not associated with a lower risk of cerebral palsy [98]. Moreover other research has shown that prenatal maternal exposure to intravenous MgSO₄ was not associated with increased neonatal morbidity or mortality [89].

Differences between the effects of antenatal pharmacological maternal therapy might be due to the dosage of MgSO₄. The median dose of tocolytic magnesium administration is higher than in other trials and there is a dose response between exposure to MgSO₄ and mortality in an animal model [99]. These different doses of the magnesium supplement could explain the beneficial or deleterious effects of magnesium maternal pharmacological antenatal administration but the possible toxicity due to the nature of the anions ought to be discussed [100].

We have been insisting for many years that MgSO₄ seemed to be the worst magnesium salt toxicologically and pharmacologically. Strangely enough in all these important clinical trials it was the one which has been routinely used although nowhere can be found any sort of justification for that choice [23, 24].

In a commentary on studies by Australian malacologists concerning the best possible condition for aquaculture of scallops, the reasons why MgCl₂ had been routinely used were stressed. MgCl₂ was more effective and less toxic than various other compounds and namely than MgSO₄. Its therapeutic ratio is therefore better than that of MgSO₄ [101].

Diverse magnesium salts may samely be used for atoxic physiological nutritional supplementation, but pharmacological doses of magnesium salt may induce toxicity which differs according to the nature of the anions. For example study of the effects of MgCl₂ and of MgSO₄ on the ionic transfer components through the isolated human amniotic membrane has shown important differences. MgCl₂ interacts with all the exchangers, while the effects of MgSO₄ are limited to paracellular components. MgCl₂ increases the ionic flux ratio of this asymetric human membrane while MgSO₄ decreases it, with all the possible deleterious fetal consequences [102]. It seems therefore necessary to determine the therapeutic ratio (LD50/ED50) of the various available salts before pharmacological use.

The best choice is the salt with the greatest margin of safety that is to say with the largest therapeutic ratio. This logical prerequisite is lacking in most protocols: MgSO₄ is used simply because it is the routine without any particular justification, and this might partly account for the lethal effects observed.

The selection of a particular magnesium salt among others should take into account reliable pharmacological and toxicological data and the comparative therapeutic ratio of the various salts, particularly: the larger its value the greater the safety margin.

The potential MgSO₄ toxicity should be discussed [97, 100, 103].

To sum up, high doses of intravenous MgSO₄ for tocolysis are less efficient and unsafe. Because of its maternal and above all pediatric side effects, this maternal pharmacological magnesium therapy should be abandoned for tocolysis. Anions other than sulfate could have a better effect on health outcomes in the neonate: it seems necessary to determine the therapeutic ratio of various magnesium salts before their clinical use.

Respective results of beta-2 mimetics and of magnesium therapies in their common pulmonary indications

The common pulmonary indications of beta-2 mimetics and of magnesium therapies are disorders with airway obstruction: mainly asthma and chronic obstructive lung (or pulmonary) disease (COLD or COPD). The specific beta-2 agonists represent the priority treatment. Combination with corticosteroids is useful and efficient. Other associated treatments have not demonstrated their efficacy as adjunctive treatments. We are going to determine the interest of magnesium treatments and of their association with beta-2 mimetics.

Beta-2 mimetics and obstructive disorders

Beta-2 agonists have been widely used in the treatment of diseases with airway obstruction: the specific beta-2 mimetics are vital drugs in asthma management.

Nature, mechanism of action and efficiency

The short acting beta-2 agonists (salbutamol, fenoterol, terbutaline, pirbuterol) are essential in emergency treatment of severe asthma and have an important prophylactic role in the prevention of exercise-induced bronchoconstriction. Routes of administration may be: inhalation, nebulisation, subcutaneous or intravenous injection. Inhaled beta-2 agonists come first. In the absence of response, the intravenous associated beta-2 agonists are useful. Other associated treatments (adrenaline, helium-oxygen mixture, intravenous MgSO₄) have not demonstrated their efficacy. The therapeutic response should be evaluated using the peak expiratory flow (PEF) determination mainly [104, 105].

Long acting beta-2 agonists (salmeterol, formeterol, bambuterol), used in inhalation or by oral routes, have provided advantages over short acting beta-2 agonists such as prolonged bronchodilation, reduced day — and night-time symptoms, improved quality of sleep and reduction of the requirement for short acting beta-2 agonists. When added to inhaled corticosteroids, they produce greater improvement in lung function than increased steroid dose alone [104-105].

The mechanism of action is pharmacodynamic.

Through stimulation of beta-2 receptor, these drugs increase the cAMP concentration which induces bronchorelaxation either directly by enzymatic stimulation or indirectly through Ca redistribution (increased Ca in sarcoplasmic reticulum and decreased intracellular cytosolic Ca) [2, 3, 104]. These mechanisms agree with the beta-adrenergic theory of atopic abnormality in bronchial asthma [106] and with the “calcium hypothesis of asthma” [107].

Beta-2 agonists represent the main treatment of airway obstructive diseases, but they are not devoid of side effects.

Side effects

Little if any benefit seems to be derived from regular use of short acting beta-2 agonists. Regular or frequent use can increase the severity of the condition.

There has been controversy about the possible relationship between use of beta-2 agonists and morbidity or mortality of asthma and COPD.

– A cohort study (12301 patients) from Saskatchevan suggested that increased asthma deaths and near-deaths could be a class effect of beta agonists rather than being due to the toxicity of one of the used short acting beta-mimetics fenoterol. The relatively non beta-2 selective agonist doubled the risk of asthma [108]. 

– Another concern has been the potential for confounding by the severity of asthma. After performing a stratified analysis utilizing markers of chronic asthma severity, the increased risk of death sometimes persisted after adjusment for confounding by the available marker of asthma severity, and sometimes disappeared. This discrepancy may have arisen from differences in the population [108-116].

– Beta-2 agonists used in the treatment of obstructive pulmonary disease can induce numerous side-effects with potential consequences on cardiac functions. There is concern about their safety because they increase heart rate, prolong the potential duration of electrical action, induce abnormal myocardial repolarisation. They may cause hyperglycemia, hypokalemia and hypomagnesaemia with low K and Mg in skeletal muscle, factors which may affect conduction pathways in the heart, induce arrhythmias and increase the risk of cardiac death [51, 115-120]. Pulmonary edema is rare and its mechanism has not been well defined [49].

Magnesium therapies for obstructive disorders

To discriminate between the two types of magnesium therapy it is necessary to remember that the only indication for nutritional magnesium therapy is the disorder related to magnesium deficiency that is to say to an insufficient magnesium intake.

Pharmacological magnesium therapy is indicated whatever the magnesium status.

Nutritional magnesium therapy for obstructive pulmonary disorders

Many disturbances of magnesium items testify to magnesium deficit in asthmatic patients. Serum (or plasma) and erythrocyte magnesium are usually normal, but both in severe asthma or acute asthma lower erythrocyte magnesium may be seen while magnesium plasma remains unchanged. Polymorphonuclear and muscle magnesium concentration decreases can be observed. Such disturbances in the distribution of magnesium agree with a magnesium depletion due to asthma or COPP per se but not with a simple magnesium deficiency [12 (1985, p. 115), 14 (1988, p. 102), 19 (2000, p. 116, 119), 122-132]. A large epidemiological study carried out in 2633 adults showed that a high dietary magnesium intake is associated with better lung function and reduced risk of airway hyperreactivity and wheezing. A low magnesium intake could be involved in the pathophysiology of asthma and COPD when nutritional magnesium supplementation brings on specific reversibility of the symptoms. Such supplementation in 20 asthmatics was associated with significant improvement of asthma symptom scores, though there was no significant improvement in forced expiratory volume in one second (FEV1), PEF variables or in decrease of use of a bronchodilator. However the duration of magnesium administration may have been too short to detect any improvement in their pulmonary functions. Another study showed a progressive decrease in airway responsiveness through nutritional magnesium supplementation during 6 weeks in 18 hyperreactive subjects [133-135].

To sum up: asthma and COPD per se may induce magnesium depletion related to a dysregulation of the control mechanisms of magnesium status which requires a correction of its causal regulation. Nutritional physiological magnesium supplementation is ineffective.

Conversely when chronic primary magnesium deficiency coexists with asthma or COPD it constitutes a decompensatory factor whose control with simple nutritional physiological oral magnesium supplementation may help for treatment of these pulmonary obstructive diseases. It occurs frequently: more than 50% of reaginic allergic asthma is accompanied by symptoms of latent tetany due to primary magnesium deficiency. On the other hand the frequency of allergic antecedents is high in cases of neural forms of primary magnesium deficit (39%). Everywhere in the world a large part of the population has a dietary intake lower than the RDAs for Mg. For example in France 23% of women and 18% of men have dietary magnesium intakes lower than the 2/3 of the RDAs for Mg [128, 133-136]. Nutritional magnesium therapy for pulmonary obstructive diseases physiologically palliates a coexistent primary magnesium deficiency. This atoxic adjuvant therapy is always beneficial without side effects.

Magnesium pharmacological therapy for obstructive pulmonary disorders

Indications for pharmacological magnesium therapy are of 3 types: purely pharmacodynamic, etiopathogenic [in 3 particular situations: emergency, necessity (when the oral form is impossible) and sometimes after failure of nutritional oral physiological therapy] and mixed when the pharmacological magnesium treatment combines its useful pharmacodynamic effects and a etiopathogenic treatment for magnesium deficiency [12 (1985, p. 269-270), 14 (1988, p. 236-237), 19 (2000, p. 257-263), 23].

Obstructive pulmonary diseases per se constitute pure pharmacodynamic indications of pharmacological magnesium therapy, irrespective of magnesium status. But their frequent association with concomitant primary magnesium deficiency [128, 133-136] constitutes a mixed indication of magnesium pharmacological treatment when the pharmacodynamic effects of the treatment add up with those of the etiopathogenic treatment for magnesium deficiency.

Nature and mechanism of action of pharmacological magnesium therapy for pulmonary obstructive diseases

Pharmacodynamic effects of pharmacological magnesium therapy in obstructive pulmonary disorders is bronchodilatation mainly, and antiinflammatory properties.

The well-known muscle relaxing effect is particularly well documented on bronchial smooth muscle. In vitro or in vivo (inhaled or intravenous), magnesium may decrease bronchoconstriction (due to pilocarpine, histamine or barium chloride), or increase FEV1 in histamine, metacholine and betanechol induced bronchoconstriction [122, 124, 137-152]. The smooth muscle relaxation induced by magnesium pharmacological doses may be linked with an increased production of cAMP through stimulation of adenylate cyclase and with the effect on Ca distribution of this natural calcium antagonist. This latter action may be one of the factors inducing the antiinflammatory effect of magnesium [106, 107, 140, 153, 154].

Efficiency and side effects of pharmacological magnesium therapy for pulmonary obstructive diseases

– Efficiency of such pharmacological magnesium therapy is dubious: the results are conflicting and sometimes negative [122, 124, 137-153]. 

– Side effects

To sum up, the efficiency of pharmacological magnesium treatment of obstructive pulmonary disease is weak with a low safety.

Effects of the combination of beta-2 mimetics and magnesium therapies

In their common indications (tocolysis and obstructive pulmonary diseases), beta-2 mimetics and magnesium therapies may be associated. But it is a scientific and ethical fraud to put on the same level nutritional magnesium supplementation devoid of any toxic effects and pharmacological magnesium treatment potentially toxic [24].

Combination of beta-2 mimetics and magnesium therapy for tocolysis

Beta-2 mimetics and nutritional magnesium therapy

Primary magnesium deficiency is one of the explanations for uterine overactivity. Nutritional magnesium therapy which reestablishes proper physiologic magnesium intake in pregnant women is evidently atoxic. It is particularly important to insure a balanced magnesium intake during pregnancy. Efficiency and tolerance of tocolysis (with beta-2 mimetics particularly) are considerably improved by nutritional magnesium both for the mother (neural, pulmonary and cardiovascular protection) and for the fetus (normal birthweight instead of underdevelopment). The dose of the beta-2 adrenergic receptor agonists used for tocolysis may perhaps be reduced by the synergic myorelaxant effects of beta-2 mimetics and of magnesium on myometrium [10, 12 (1985, p. 277) 61, 71, 77, 156, 157].

Beta-2 mimetics and intravenous pharmacological magnesium therapy

It seems essential not to add on to the cardiovascular, pulmonary, neuromuscular and metabolic side effects of tocolytic beta-2 mimetics doses, similar noxious effects caused by the release of catecholamines induced by stressful doses of tocolytic parenteral magnesium [10, 12 (1985, p. 277), 14 (1988, p. 242-243), 19 (2000, p. 269), 55, 158-164].

To sum up, the combination of nutritional magnesium therapy with tocolytic beta-2 mimetics is atoxic and beneficial. Conversely the combination of intravenous pharmacological tocolytic doses of magnesium with beta-2 mimetics is contra-indicated because of its dubious efficiency and its possible toxicity.

Combination of beta-2 mimetics and magnesium therapy for obstructive pulmonary diseases

The same conclusion can be drawn regarding the two types of magnesium therapies.

Nutritional magnesium therapy which palliates primary magnesium deficiency factor of airway obstruction is atoxic and always useful. The coexistence of other clinical manifestations of magnesium deficiency such as neuromuscular hyperexcitability ought to be investigated: CHVOSTEK sign, click, iterative EMG tracings, idiopathic mitral valve prolapse. But the dynamic oral physiological magnesium load test (5 mg/kg/day) constitutes the best evidence of magnesium deficiency [12 (1985, p. 63-64), 14 (1988, p. 55-56), 19 (2000, p. 63-64), 80, 122, 128, 133-136].

Pharmacological magnesium therapy is of dubious efficiency. But its toxicity is weaker than what is found with tocolytic high doses of magnesium. Intravenous and inhaled doses used for pulmonary indication are lower than high tocolytic doses.

Contra-indications of this latter form of pharmacological magnesium treatment combined with beta-2 mimetics for pulmonary indications are less imperative than for tocolysis [105, 165, 166].

Conclusion

In both obstetrical and pulmonary indications, combination of beta-2 mimetics and of magnesium therapies may be considered. There are two types of magnesium treatment. Nutritional magnesium therapy which palliates chronic magnesium deficiency and pharmacological magnesium therapy which induces pharmacodynamic effects irrespective of the magnesium status.

The combination of beta-2 adrenergic receptor agonist therapy with an atoxic oral physiological supplement of magnesium is always beneficial.

But the combination of beta-2 mimetic treatment with pharmacological doses of magnesium is rarely useful and may induce toxicity.

High tocolytic doses are contra-indicated and the possible role of the anion SO₄ as regards toxicity must be discussed. Contra-indications of lower intravenous and inhaled doses used for pulmonary bronchial obstruction are less imperative than for tocolysis.

The selection of a particular magnesium salt among others should take into account reliable pharmacological and toxicological data. It seems necessary to determine the therapeutic ratio (LD50/ED50) of the various available magnesium salts before pharmacological use.

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