Magnesium physiology

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effect of epidural opioids. It manifests as a decrease in respiration rate and an increase in arterial carbon dioxide tension in dogs receiving morphine (Troncy et al., 2002). Usually the respiratory depression is related to a wide rostral spread and is delayed in relation to the time of administration. Additionally, urinary retention is described as an adverse effect, which occurs more commonly in humans (Valverde, 2008). Other adverse effects reported in humans are nausea and vomiting due to action on the medullary chemoreceptor trigger zone in the brain (Inturrisi, 2002).

Adverse effects due to epidural injections are rare and epidural techniques are relatively safe. In humans, post-dural puncture headaches are reported as well as neurological symptoms (Kokki, 2012). Mechanical injury, abscesses and spinal cord infection have been described (Remedios et al., 1996; Swalander et al., 2000). Accidental intravascular injection can lead to systemic toxicity (Mulroy et al., 1997). However, the side effects are reduced and the analgesic effect is improved with epidural administration compared with systemic drug administration (Valverde, 2008).

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(bound to phosphates and citrate, 15–25%). It is suspected that there is a shift between the free ionized form and the complex form (DiBartola, 2006).

The maintenance of an adequate magnesium balance is complex and mainly controlled by intestinal absorption and renal excretion. It is closely linked to other electrolytes like sodium, potassium and calcium (Reinhart, 1990).

The absorption of magnesiumtakes place between the ileum and the colon. Two pathways for intestinal magnesium absorption are well known. One pathway is the passive paracellular route, through the tight junctions between epithelial cells. The forces for this movement are the transepithelial magnesium concentration gradient, the transepithelial voltage gradient formed by water and salt absorption and the permeability of the tight junction to magnesium. The transepithelial magnesiumgradient is influenced by the gut intraluminal Mg²⁺ concentration and the total dietary intake of magnesiumas well as the amount of magnesiumthat is chelated. A small positive intraluminal voltage created by net movement of salt and water results in transepithelial cation movement.

Additionally, cation movement results in solvent drag created by sodium and water absorbtion. The permeability of the tight junction is created by numerous ion channels. A specific magnesiumion channel has not been conclusively identified (DiBartola, 2006).

The second existing pathway in the gut is the active transcellular route. At the moment there are a lot of investigations in this field of study, which focus on the hypothesis that several magnesiumtransport proteins exist (Quamme and Rouffignac, 2000). Parathyroid hormone (PTH) has been identified to have a positive influence on the magnesium absorption in the gut (Hardwick et al., 1991). The primary factor of the percentage of magnesium absorbed by transcellular and paracellular mechanisms is the dietary concentration of magnesium. A high magnesium intake creates a large concentration gradient and most absorption occurs through the paracellular route. Conversely, a poor magnesium intake results in a less efficient paracellular absorption and active transcellular magnesium transport becomes more important for adequate magnesium balance (DiBartola, 2006).

Magnesium transport in the kidney is influenced by calcium and several hormones. It is likely that similar control mechanisms influence magnesiumabsorption in the gut. The kidney provides the most sensitive control for magnesium balance (Quamme

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and Rouffignac, 2000). In the glomerulus, 80% of total serum magnesium is filtered.

Approximately only a small fraction of 15% is reabsorbed within the proximal tubuli. The reabsorbtion is mainly via passive and unsaturable mechanisms through paracellular transport. A large amount of magnesium (60%) is reabsorbed in the cortical thick ascending loop of Henle. Paracellular pathways through tight junctions seem to be the most important mechanism. The principal force allowing magnesiumtransport is the electropositive luminal environment created by the movement of sodium and chloride from the lumen to the interstitial space. In addition, magnesium movement in the interstitial space occurs as a result of solvent drag through the tight junctions. This mechanism implies that a change in transepithelial voltage influence the permeability for magnesiumand additionally increase the absorption of magnesium. An increase in salt movement from the lumen will elevate the transepithelial electrical potential and facilitate magnesiumabsorption. Calcitonin, PTH, glucagon, antidiuretic hormone, aldosterone and insulin are known to increase magnesium absorption. On the other hand, prostaglandins, hypocalcaemia, hyphosphataemia and acidosis can decrease magnesium absorption. The distal convoluted tubuli do not act as mass transporter of magnesiumbut constitute the site that determine the final amount of magnesiumexcretion. Reabsorbtion of magnesium in this area appears to be mainly through active transcellular routes (Quamme and Rouffignac, 2000).

Magnesiumhas a fundamental role in many cellular functions. It is involved as a co-factor in more than 300 enzymatic reactions related to energy metabolism and nucleic acid synthesis (Fawcett et al., 1999). Magnesiumhas modulatory effects on sodium and potassium currents by regulating the Na²⁺-K⁺-ATPase, thus mediating a membrane stabilising effect (Herroeder et al., 2011). Magnesiumacts by regulating and controlling different ion channels and its calcium antagonistic effects are well studied. Magnesium regulates calcium channels in cell membranes and sarcoplasmic reticulum. These results in a direct competitive antagonistic action directed against calcium influx into cells and outflow of calcium from the sarcoplasmic reticulum (Dubé and Granary, 2003).

In muscles, magnesium and calcium and have opposite effects.

Hypomagnesaemia results in contraction and hypocalcaemia induces relaxation. The mechanism behind this effect is that hypomagnesaemia causes a rapid passive release of calcium by the sarcoplasmic reticulum, which leads to contraction. Magnesium influences

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the neuromuscular transmission by blocking the entry of calcium into presynaptic endings which leads to a decrease in acetylcholine release. The decrease in acetylcholine has been shown to increase the threshold for axonal excitation. In conclusion, hypermagnesaemia causes neuromuscular weakness while hypomagnesaemia induces neuromuscular hyperexcitability (Dubé and Granary, 2003).

Magnesiumis known to inhibit catecholamine release by blocking calcium channels thus preventing calcium influx into symphathetic nerve endings. This results in modulation of the sympathetic reaction to nociceptive stimuli and stress response (Shimosawa, 2004).

In the spinal cord, Mg²⁺ is a natural non-competitive NMDA-receptor antagonist and leads to an increased activation threshold (Mayer et al., 1984). It has been shown to induce analgesia (Mayer et al., 1984; Woolf, 2000; McCartney et al., 2004; Soave et al., 2009) and has neuroprotective effects (Simpson et al., 1994).

The measurement of magnesium to diagnose magnesiumdeficits is difficult and controversial. At present there is no simple, rapid and accurate laboratory test available to assess the amount of total body magnesium(Swaminathan, 2003). The fact that only 1%

of the body magnesiumis extracellular and only 55% of this is in the ionized form presents a diagnostic challenge to detect deficits. There are two different methods to assess magnesium clinically: either Mg²⁺ or the total magnesium in various tissues, most commonly blood.

Total serum magnesium is the most commonly used method of assessing magnesiumas it is easy to obtain serum samples from patients and the assay is easy to perform and widely available (DiBartola, 2003). Other tissues (red blood cells, white blood cells, muscle tissue) have been used to measure magnesium concentration.

However, because of the complexity of the assays, these methods are not routinely used in clinical practice.

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Another method to assess magnesiumdeficit is to assess the renal magnesium handling by testing the renal retention of magnesium. This assay is based on the idea that renal retention of magnesiumoccurs during magnesium deficit. Consequently, this assay can not be used in patients with inadequate renal function. However, these assays are not widely used in veterinary practice (DiBartola, 2003).

Normal total serum magnesiumconcentration for humans ranges between 0.75–

0.95 mmol/l (Musso, 2009), 0.76–0.96 mmol/l (Fawcett et al., 1999), 0.7–1 mmol/l (Herroeder et al., 2011), and 0.7–1.1 mmol/l (Swaminathan, 2003). In dogs, the normal range is 0.6–1.2 mmol/l (Clinical Pathology Laboratory reference range, Department of Companion Animal Clinical Studies, University of Pretoria).

Magnesiumdisorders such as hypomagnesaemia can be found in hospitalised patients and it is common in critically ill patients. Hypomagnesaemia is often associated with other metabolic disorders, as for example, hypokalaemia and hypophosphatemia.

There are several causes of hypomagnesaemia. Common causes include disorders of the two regulating organs: kidney and gut. This results in a lack of input, less absorption or excessive elimination. Some of these conditions are for example: malnutrition, malabsorption, inflammatory bowel disease, diarrhoea, pancreatitis, hypercalcaemia, hyperaldosteronism, diabetes mellitus and hypoparathyroidism (Dubé and Granary, 2003). Hypomagnesaemia manifests typically as cardiac and/or neuromuscular disorders.

Clinical symptoms of hypomagnesaemia include anorexia, nausea, vomiting, generalized weakness, convulsion, tetani and changes in the electrocardiogram (Dubé and Granary, 2003; Herroeder et al., 2011).

Hypermagnesaemia is less frequent and occurs in patients with chronic renal failure and due to rhabdomyolysis, or iatrogenically after excessive use of antacids or laxatives containing magnesium-salts or treatments for hypomagnesaemia. Clinical symptoms can range from nausea, vomiting and somnolence to deep coma (Dubé and Granary, 2003).

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