How is magnesium toxicity treated

Pharmacology and Clinic for the Administration of Potassium and Magnesium

Arrhythmia

by Rudy Susilo, Alsdorf, and Ernst Mutschler, Frankfurt am Main, Wolfgang Vierling, Munich

Potassium and magnesium are minerals in the body that perform important physiological functions. They play a crucial role in maintaining the electrical stability of excitable cells. Both ions are therefore important in order to prevent cardiac arrhythmias or to break through existing arrhythmias.

Four important minerals are present in the body as cations: sodium, calcium, potassium and magnesium. Sodium is of great importance for the water and osmoregulation of the body and cells, but is also significantly involved in the development of electrical excitation of cells. Calcium, an important component of the bone, plays an essential role as an intracellular signaling substance, for example for triggering the contraction of skeletal muscles, smooth muscles and heart muscles, as well as for triggering the secretion of glands. Calcium is also important for tissue excitability. A decrease in the extracellular concentration can lead to neuromuscular overexcitability and thus to tetany.

In addition to calcium, potassium and magnesium are particularly important for the electrical stability of the cell. The resting potential of the cell membrane is based on a potassium balance, that is, it is determined by the concentration gradient of potassium between the intra- and extracellular space. Both a decrease and an excessively high increase in potassium ions can lead to electrical instability. Magnesium improves the electrical stability by reducing the excitability of the cells, preventing calcium overloading of the cells and reducing the release of excitation-promoting transmitter substances.

Potassium and magnesium should be supplied to the body in sufficient quantities to maintain physiological extra- and intracellular concentrations. A potassium deficiency is often combined with a magnesium deficiency. This is often the result of long-term administration of diuretics.

Cardiac arrhythmias should be treated very cautiously with antiarrhythmic drugs because of the high risk of proarrhythmic and other undesirable effects. The CAST study (Cardiac Arrhythmia Suppression Trial; 6) in particular contributed to this finding, in which it was shown that the survival rate can be worsened by antiarrhythmic drugs. With all arrhythmias it is important to ensure that the minerals and especially potassium and magnesium are present in sufficient serum concentrations.

In the case of non-life-threatening arrhythmias, one should always try to suppress or alleviate them by administering potassium and magnesium. Potassium and magnesium can have a supportive effect in the case of dangerous disorders that are treated with antiarrhythmics. There are also indications that the additional administration of the two cations can weaken the adverse effects of the antiarrhythmics and thereby improve their tolerability.

Potassium on its way into the cell

About 100 mmol of potassium are ingested daily with food. The mineral is almost completely absorbed, mainly in the jejunum. After diffusion through the intestinal wall, a relatively large proportion is secreted back into the gastrointestinal tract. In the course of the further gastrointestinal passage, most of the potassium is reabsorbed.

When the concentration of potassium ions in the plasma increases, they are introduced into the cell via hormonal regulations or excreted via the kidneys. This avoids hyperkalemia. Insulin and catecholamines promote the uptake of potassium into the cell, aldosterone increases renal excretion. About 90 mmol of potassium are excreted through the kidneys every day.

The normal plasma levels are between 3.5 and 5.0 mmol / l. If the potassium concentration in the plasma increases (above 6.5 mmol / l), side effects such as cardiac arrhythmias can occur. If potassium is taken with food or in therapeutic doses, a plasma concentration exceeding the upper limit of the normal range is not to be expected with normal kidney function.

Sufficient magnesium intake is important

The organism needs about 12 mmol of magnesium daily. A third of this is absorbed, two thirds are excreted in the stool. Magnesium is also mainly absorbed in the jejunum, whereby the higher the intake, the relative decrease.

When taking in small amounts, the saturable portion plays a dominant role in the absorption processes. In the other case, the unsaturable diffusion through the intestinal wall predominates. For example, when 5 mmol of magnesium is taken in, 65 percent is absorbed, whereas only 11 percent is absorbed when 40 mmol is taken (15). The absolutely absorbed portion nevertheless increases with increasing intake. The absorbed amount of magnesium (about 4 mmol / day) is almost completely excreted through the kidneys. The regulatory mechanisms that move the absorbed magnesium into the intracellular space and the deep compartments (storage) are still largely unknown.

The normal magnesium plasma levels are between 0.7 and 1.0 mmol / l; this upper limit is not exceeded if the kidney function is intact. In special cases, parenteral administration can increase the serum level to significantly higher values ​​(up to 1.5 mmol / l) without toxic effects being expected.

With regard to the bioavailability of different magnesium salts, studies have shown that magnesium oxide is relatively poorly bioavailable. Magnesium chloride, lactate and aspartate, on the other hand, are readily bioavailable (15 a). The ratios for potassium salts are likely to be similar. Ultimately, the respective formulation decides in a comparison of two organic or inorganic salts which one has a better bioavailability.

Distributed intra- and extracellularly

Potassium and magnesium are mainly present intracellularly. The extracellular proportion is low at 1.2 percent of the total amount in the body for potassium and 0.7 percent for magnesium in the interstitium and 0.4 and 0.3 percent in plasma. The majority of potassium (60 percent) is found in the muscles, that of magnesium (50 percent) in the bones. The bone also serves as a magnesium store.

The Mg2 + -dependent Na + / K + pump integrated into the cell membrane generates a concentration gradient for sodium from the outside to the inside and for potassium from the inside to the outside. This gradient enables the diffusion of potassium from the intracellular into the extracellular space. Since the cell membrane of the myocardial muscle cell is almost exclusively permeable to potassium at rest, a diffusion potential develops which, at normal extra- and intracellular potassium concentrations, roughly corresponds to the resting membrane potential.

Intracellular magnesium is mainly found in bound form. Of the approximately 10 mmol / l magnesium in the heart muscle cell, only around 0.6 mmol / l exist as free ions. The concentration of free magnesium ions is roughly the same intra- and extracellularly. Due to the negative membrane potential on the inside, magnesium, in contrast to potassium, tends to flow into the cells from the outside. If the equilibrium distribution is determined using the Nernst equation, the free magnesium ion concentration in the cytosol is far below the equilibrium distribution (13). The cell can only maintain this state with the use of energy, because intracellular magnesium ions have to be transported out of the cell. The underlying mechanisms have not yet been sufficiently clarified.

Causes of a Deficiency

The causes that lead to a reduced mineral intake, an increased requirement or an increased excretion are similar for potassium and magnesium. Therefore, potassium and magnesium deficiencies often occur together (32). A reduced intake can be due to a poor diet, for example alcoholism. This favors the cardiac arrhythmias observed with alcohol abuse.

There is an increased need during pregnancy. Increased excretion is observed particularly in therapy with diuretics and digitalis glycosides as well as numerous pharmaceuticals (overview in 1, 30, 31).

Even with normal extracellular concentrations of potassium and magnesium, there may be an intracellular deficit. In the case of potassium, this can be related to pH-dependent shifts between the intra- and extracellular space. In addition, a chronic magnesium deficit can reduce the intracellular potassium concentration. This is attributed to the fact that magnesium is necessary for the transport of potassium into the cell. If there is a lack of both ions, a potassium deficiency can in part only be corrected by administering both cations together (33).

The panel of experts "The National Council on Potassium in Clinical Practice" developed practical guidelines for the therapeutic use of potassium in the USA, which correspond to the current state of clinical knowledge (9). Accordingly, the Society for Magnesium Research in Germany has drawn up guidelines for the diagnosis and treatment of magnesium deficiency (8, 26).

How potassium works in the heart

The risk of cardiac arrhythmias increases when the difference between the resting and threshold potential decreases. A decrease in the intracellular potassium concentration and an increase in the extracellular potassium concentration beyond the normal range reduce the membrane potential, which makes it easier for the cell to spontaneously excite.

However, a decrease in the extracellular potassium concentration also destabilizes the electrical properties of the heart muscle cells. In this way, certain cells (working myocardium) can be hyperpolarized, while others that belong to the excitation control system (Purkinje cells) can be depolarized. This is based on the fact that the conductivity of the potassium channels decreases when the extracellular potassium concentration is reduced; As a result, the resting membrane permeability for sodium ions, which is present at the same time, predominates, and the membrane potential decreases. In addition, the Na + / K + pump is less stimulated and more sodium accumulates in the heart muscle cells. Secondly, the cell is loaded with more calcium, which in turn promotes arrhythmias.

For the extracellular potassium there is therefore an optimal range in which

  • the membrane potential in all cells is relatively high and stable,
  • calcium loading is avoided and
  • the risk of arrhythmias is low.

Highly normal potassium concentrations in the plasma (4.0 to 5.0 mmol / l) are in this optimal range.

Magnesium increases arousal threshold

Magnesium reduces the influx of calcium ions into the heart muscle cells in vitro (10). An extracellular magnesium concentration increased by 1.2 mmol / l reduces the calcium flow by about 20 percent. Magnesium also shifts the current-voltage curve to more positive potentials. The cell has to be depolarized to a greater extent so that the calcium channels can be opened.

If the magnesium concentration is increased from 1 mmol / l to 10 mmol / l, the threshold potential for triggering excitation falls from -62 to -54 mV (18). In order to trigger an excitation now, the depolarization must be 8 mV stronger. In contrast to class I antiarrhythmics, magnesium increases the excitation threshold without reducing the speed of depolarization of the action potential in the atrium and ventricle and thus also the speed of excitation transmission. The increase in the excitation threshold and the shift in the current-voltage relationship for the calcium current result from a reduction in the membrane surface potential of the cell (30). Magnesium also inhibits the release of excitatory transmitters such as noradrenaline and adrenaline, which can significantly contribute to the development of arrhythmias.

Highly normal concentrations (0.8 to 1.0 mmol / l) are therefore important to

  • to avoid calcium overload of the cell,
  • to keep the threshold for triggering extra excitement high,
  • to reduce the release of excitatory transmitters and
  • reduce the risk of cardiac arrhythmias.

By increasing the serum concentration above the normal range, the beneficial effects of magnesium can be enhanced.

Potassium and magnesium complement each other

In addition to the effects described (increasing the threshold of excitability, calcium antagonism and inhibiting the release of transmitters), magnesium can also prolong the repolarization in the heart again if it has been accelerated by a reduced potassium concentration (28). Similar effects were observed under hypoxic conditions (5). Both minerals were able to suppress hypoxia-induced arrhythmias. The effect was additive: by increasing potassium and magnesium, the highest antiarrhythmic effect was achieved.

Depolarization due to increased extracellular potassium concentration can be compensated for by increasing the extracellular magnesium concentration. The voltage sensors of the ion channels activated by depolarization are brought back to their original position by reducing the surface potential of the cell. This antagonistic effect between magnesium and potassium may explain why unfavorable effects of an increase in potassium can be compensated for by magnesium (30).

The interaction between potassium and magnesium and the effect of antiarrhythmic drugs was investigated in an experimental study on rat myocytes (4). It was possible to induce both early (EAD) and late (LAD) post-depolarizations, which are likely to cause cardiac arrhythmias.

Both d-sotalol and quinidine shift the threshold potential in a negative direction, i.e. EAD could be triggered even with moderate membrane depolarization. The proarrhythmic effect of 3 mmol / l quinidine was more pronounced than that of 100 mmol / l sotalol. An increase in both potassium and magnesium concentrations suppressed the early depolarizations induced by sotalol or quinidine. The potassium effect was apparently based on an acceleration of the repolarization, while magnesium acts through other mechanisms. A combined use of both minerals therefore makes sense.

 

Combination of potassium and magnesium Due to the physiological effects and clinical findings, there are several indications for the combined use of potassium and magnesium:

  • Extrasystole with and without proven potassium or magnesium deficiency;
  • Therapy and prophylaxis of cardiac arrhythmias in patients prone to hypokalaemia and hypomagnesaemia; especially in patients being treated with diuretics, for example people with heart failure or hypertension;
  • Support of therapy and improvement of tolerability when using classic antiarrhythmics from Class I and III, for example sotalol;
  • Support in therapy with digitalis glycosides.

 

An investigation of the triggerability and properties of late post-depolarizations (LAD) also showed proarrhythmic effects of antiarrhythmic drugs and antiarrhythmic effects of potassium and magnesium. An increase in potassium and magnesium concentrations reduced the amplitude and frequency of the LAD. The time until the first occurrence of the first post-oscillation was significantly delayed. The effects of the two cations were also observed in the presence of d-sotalol (4).

In tests on isolated human heart muscle preparations it was shown that increased potassium and magnesium concentrations improve the tolerance of cardiac digitalis glycosides. An increase in the Mg2 + concentration to 2 mmol / l significantly extended the time until digitalis-induced toxic effects occurred (p <0.05). Increasing potassium concentrations reduced toxicity, while lower concentrations increased toxicity (24).

Deficiency promotes arrhythmias

Highly normal extracellular potassium and magnesium serum concentrations reduce the risk of cardiac arrhythmias, while low concentrations promote arrhythmias (29). Life-threatening arrhythmias, for example of the Torsade des Pointes type, when antiarrhythmic drugs are administered, especially class III (amiodarone, sotalol), are favored by hypokalaemia and hypomagnesaemia (21, 25). In patients who received quinidine, the prolonged QT time was shortened again by infusion of potassium (7). Patients with heart failure also showed a prolongation of the QT time - phenomena that could be suppressed by administration of potassium.

In heart failure, hypokalaemia and hypomagnesaemia are relatively common, which predisposes to cardiac arrhythmias (17, 23). Likewise, after a heart attack, patients tend to have reduced serum concentrations of potassium and magnesium (11, 20), so that substitution may be necessary to avoid arrhythmias.

Intravenously

In patients receiving diuretics who developed ventricular extrasystoles (PVCs), intravenous administration of potassium alone improved the arrhythmia only slightly (12). In contrast, the use of potassium plus magnesium reduced the extrasystoles by 70 percent. In another study, the parenteral administration of both ions also greatly reduced the frequency of PVCs (22). Both inorganic (e.g. chloride) and organic salts such as aspartate are used.

A special form of supraventricular tachycardia, multifocal atrial tachycardia, which often occurs in patients with chronic asthma, has also been successfully treated with potassium plus magnesium (19).

The intravenous administration of potassium with reaching supranormal serum concentrations belongs to the classic therapy of cardiotoxic symptoms (arrhythmias) that occur when taking cardiac digitalis glycosides. Potassium displaces the digitalis glycoside from its binding site on the sodium-potassium pump and thus weakens its effect. A combination with magnesium makes sense.

Intravenous administration is also recommended in the case of severe hypokalaemia and hypomagnesaemia, especially if the cause is resorption disorders.

Given perorally

Various studies show an antiarrhythmic effect of combined oral use of potassium and magnesium. Arrhythmias decreased in 78 percent of patients with ventricular extrasystoles, the majority of whom suffered from coronary artery disease and many had had a heart attack (2). This was confirmed in another study (3). The tolerance of cardiac glycosides was significantly improved by oral administration of potassium and magnesium. A large study found that the combined application reduced the number of ventricular extrasystoles and decreased membership in the high Lown classes, which can be viewed as a reduction in the risk of arrhythmias (36).

In a small double-blind study, the antiarrhythmic effect of potassium and magnesium in patients with coronary artery disease was comparable to that of the antiarrhythmic prajmalin; however, only side effects occurred with prajmaline (16). However, the conclusiveness of this study is limited as it no longer meets the modern requirements for study design.

This does not apply to the placebo-controlled, double-blind randomized MAGICA study (34). 232 patients with normal serum concentrations of potassium and magnesium were enrolled if they had more than 720 ventricular extrasystoles (PVCs) within 24 hours. After a one-week placebo lead-up phase, 120 patients still showed more than 720 PVCs / 24h. They then took potassium and magnesium aspartate or placebo orally for three weeks. During verum therapy, the PVCs decreased significantly (by 17.4 percent). In a retrospective subgroup analysis, it became clear that potassium and magnesium therapy is particularly beneficial for patients over fifty years of age, with coronary heart disease or other pre-existing myocardial diseases (35).

A small, single-center, double-blind, randomized placebo-controlled study showed that the administration of potassium and magnesium aspartate can reduce the QT prolongation induced by antiarrhythmic drugs (14). 66 patients (mean age: 65.4 years) with persistent atrial fibrillation were treated according to an individual dosage regimen with sotalol, as a representative of a QT-prolonging antiarrhythmic, in order to maintain the sinus rhythm after electrocardioversion. In addition, they received either potassium and magnesium (24 mmol potassium and 12 mmol magnesium hydrogen aspartate) or placebo daily for five days. Patients with overt hypokalaemia (below 3.8 mmol / l) or a corrected QT interval greater than 430 ms were excluded. The additional administration of potassium and magnesium significantly reduced the QT prolongation (14). From this finding, the authors deduce that potassium and magnesium improve the tolerance of the antiarrhythmic. However, further studies are necessary to clarify to what extent the relationship between effect and side effect is changed.

Other potassium and magnesium salts have also been tested in clinical studies with positive results in various forms of cardiac arrhythmia. Significant improvements were found in patients with chronic atrial fibrillation after infusion of magnesium sulfate and potassium chloride (18 a), in Wolff-Parkinson-White syndrome with the same electrolytes (24 a), and in ventricular extrasystoles with magnesium hydroxide and potassium hydrochloride (21 a).

Studies to date show that the effectiveness of potassium and magnesium in ventricular extrasystoles has been best documented. According to a survey of 826 resident doctors, extrasystole was the most frequently mentioned diagnosis among the cardiac arrhythmias occurring in practice. This disorder has often been treated with a combination of potassium and magnesium (27).

 

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the authors

Rudy Susilo studied pharmacy and biochemistry at the Free University of Berlin and received his doctorate at the Berlin Institute for Pharmacognosy and Phytochemistry in 1987 with a thesis on natural product research sponsored by the Ernst Reuter Society. After working as a scientist at the Institute for Neuropsychopharmacology at the Free University of Berlin, he switched to the pharmaceutical industry in 1987 in the field of clinical research, product management and medical-scientific information. Since 1999, Dr. Susilo heads the research and development department at Trommsdorff GmbH & Co. KG, Alsdorf near Aachen.

Ernst Mutschler, doctor and pharmacist, is known to all colleagues as the longstanding director of the Institute for Pharmacology for Natural Scientists at the Goethe University in Frankfurt, as a researcher, speaker, moderator and above all as the author of the textbook "Drug Effects". Professor Mutschler has received many awards for his scientific achievements. An outstanding achievement in science policy was the merger of the two pharmaceutical companies in East and West during his tenure as President of the DPhG. Mutschler is an honorary member of the DPhG.

Wolfgang Vierling studied medicine at the Universities of Erlangen and Munich and received his doctorate in 1968. Since 1970 he has worked at the Institute for Pharmacology and Toxicology at the Technical University of Munich; he is a specialist in pharmacology and toxicology. After completing his habilitation in the field of pharmacology and toxicology at the Technical University of Munich, he was appointed professor in 1988. Scientifically, Vierling deals, among other things, with the influence of cations, especially calcium and magnesium, on the heart function and the molecular interactions of plant constituents and the calcium channel.

 

For the writers
Professor Dr. Wolfgang Vierling
Institute for Pharmacology and Toxicology at the Technical University of Munich
Biedersteiner Strasse 29
80802 Munich
[email protected]

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