Magnesium metabolism-1.pptx nephrologist perspective

ajaakcknc kasnjnf aknmafmar marmfaknf awkfnkerjeqr klnenrk nfn asnf ktj4otskfkfslfs dadn akfn k

1. Disorders of Magnesium balance and physiological changes in pregnancy - Dr.Ambar Khalwadekar Senior Resident, Nephrology

2. Magnesium is the second most abundant intracellular divalent cation . Magnesium serves several important functions in the human body, including intracellular signaling, serving as a cofactor for protein and DNA synthesis, oxidative phosphorylation, cardiovascular tone, neuromuscular excitability, and bone formation.

3. The total body magnesium content in adults is approximately 24 g . 99% - intracellular , stored predominantly in bone, muscle, and soft tissue and 1% - present in the extracellular space . Normal total serum magnesium concentration is in the range of 1.4–2.2 mEq /l, or 1.7–2.6 mg/dl. 60 % of serum magnesium exists in the ionized, free , physiologically active form, which is important for its physiologic functions . 10 % of serum magnesium exists complexed to serum anions . 30 % of serum magnesium is albumin-bound.

4. Serum magnesium concentration is regulated by the dynamic balance and interplay between intestinal and renal transport and bone exchange.

5. REGULATION OF MAGNESIUM HOMEOSTASIS A normal diet adequate in magnesium normally contains 200 to 300 mg of magnesium. Of ingested dietary magnesium, 75 to 150 mg is absorbed in the jejunum and ileum, primarily by paracellular passive processes. The Trpm6 protein is localized to the apical membrane of intestinal epithelial cells and mediates transcellular magnesium absorption .

6. About 30 mg of magnesium is secreted into the intestine via pancreatic and intestinal secretions, giving a net magnesium absorption of approximately 130 mg/24 hr. Magnesium that is not absorbed in the intestine and is secreted into the intestinal lumen eventually appears in the feces (125 to 150 mg). Absorbed magnesium enters the extracellular fluid pool and moves in and out of bone and soft tissues. Approximately 130 mg of magnesium (equivalent to the net amount absorbed in the intestine) is excreted in the urine.

7. Feeding a diet low in magnesium results in a rapid decrease in urinary and fecal magnesium and the development of a negative magnesium balance. Conversely, the administration of magnesium is associated with an increase in the renal excretion of magnesium. Unlike calcium and phosphorus, however, no hormones or molecules have been identified that alter magnesium transport in the intestine or alter the renal excretion of magnesium in response to changes in magnesium balance.

8. Intestinal Magnesium Absorption Typical magnesium ingestion is approximately 300 mg/d. Intestinal absorption can range from 25% when eating magnesium-rich diets to 75% when eating magnesium depleted diets. Intestinal magnesium absorption occurs via a saturable transcellular pathway and a nonsaturable paracellular passive pathway.

9. The majority of magnesium is absorbed by the small intestine and, to a lesser extent, by the colon. Transcellular magnesium absorption is permitted by the transient receptor potential melastatin (TRPM) cationic channels TRPM6 and TRPM7. Mutations in TRMP6 result in hypomagnesemia with secondary hypocalcemia . TRMP7 also plays an important role in intestinal magnesium absorption. It has been noticed that heterozygote TRMP7-deficient mice develop hypomagnesemia due to decreased intestinal magnesium absorption, whereas renal magnesium excretion is low to compensate for the decreased intestinal magnesium absorption

10. When dietary magnesium intake is normal, transcellular transport mediates 30% of intestinal magnesium absorption. This fraction increases when dietary magnesium intake is lower. When dietary magnesium is higher, then the majority of intestinal magnesium absorption occurs via the paracellular pathway, which is regulated by proteins comprising the tight junction, including claudins , occludin , and zona-occludens-1.

11. Tight junction assembly and function can be modulated by a number of signaling molecules that alter the phosphorylation state of the tight junctional proteins and the ionic permeability of the paracellular pathway. Paracellular transport depends on the transepithelial electrical voltage, which is approximately 5 mV lumen-positive with respect to blood. In addition, luminal magnesium concentrationsrange between 1.0 and 5.0 mmol /l compared with serum magnesium concentrations of between 0.70 and 1.10 mmol /l, which also provides a transepithelial chemical concentration gradient favoring absorption.

12. Renal Regulation of Magnesium Assuming a normal GFR, the kidney filters approximately 2000–2400 mg of magnesium per day. This takes into account the fact that only 70% of total serum magnesium (30% is protein-bound) is available for glomerular filtration. Under normal conditions, 96% of filtered magnesium is reabsorbed in the renal tubules by several coordinated transport processes and magnesium transporters.

13. Proximal Tubule 10%–30% of the filtered magnesium is absorbed in the proximal tubule. Although the exact mechanisms are not known, magnesium is believed to be absorbed via a paracellular pathway aided by a chemical gradient generated by Na gradient–driven water transport that increases intraluminal magnesium as well as lumen-positive potential.

14. Thick Ascending Limb A paracellular pathway in the thick ascending limb absorbs 40%–70% of filtered magnesium, mostly enhanced by lumen-positive transepithelial voltage, in which claudin-16 and claudin-19 play an important role. The NKCC2 cotransporter mediates apical absorption of Na, K, and Cl. The apical ROMK mediates apical recycling of K back to the tubular lumen and generation of lumen-positive voltage. The Cl channel ClC -Kb mediates Cl exit through the basolateral membrane. Na,K,-ATPase also mediates Na exit through the basolateral membrane and generates the Na gradient for Na absorption.

15. The tight junction proteins claudin-16 and claudin-19 play a prominent role in magnesium absorption. The CaSR has also been determined to regulate magnesium transport in this segment: upon stimulation, magnesium transport is decreased. Basolateral receptor activation inhibits apical K channels and possibly Na-2C1-K cotransport in the rat thick ascending limb. This inhibition would be expected to diminish transepithelial voltage and, in turn, passive transport of magnesium within the cortical thick ascending limb.

16. Bartter’s syndrome is caused by mutations in NKCC2,or ROMK, or ClC -Kb, or Barttin (an essential b-subunit forClC -Ka and ClC -Kb chloride channels), and/or CaSR . Mutations in CLDN16 or CLDN19 encoding the tightjunction proteins claudin-16 and claudin-19 result in increasedurinary magnesium excretion, hypomagnesemia,increased urinary calcium excretion, and nephrocalcinosis .

17. Loop diuretics inhibit chloride (Cl2) absorption by NKCC2 and also decrease basolateral Cl2 efflux. This results in loss of lumen-positive potential, thereby decreasing the driving force for paracellular magnesium reabsorption via claudin-16 and claudin-19.

18. Distal Convoluted Tubule The remaining 5%–10% of magnesium is reabsorbed in the distal convoluted tubule mainly by active transcellular transport mediated by TRPM6. The apical K channel Kv1.1 potentiates TRPM6- mediated magnesium absorption by establishing favorable luminal potential. Basolateral K channel Kir4.1 and the g-subunit of Na, K- ATPase also increase magnesium reabsorption by generating a sodium gradient. This also makes it possible for the thiazide sensitive NCC to facilitate sodium transport from the apical lumen to the cytosol .

19. The absorbed magnesium is then extruded via a recently identified magnesium/sodium exchanger SLC41A1 family across the basolateral membrane. Interestingly, mutations in SLC41A1 result in a nephronophthisis -like phenotype.

20. Disorders of Magnesium homeostasis

21. HYPOMAGNESEMIA The plasma magnesium concentration is not usually measured as part of routine blood tests. Thus, the identification of patients with hypomagnesemia often requires clinical suspicion in patients with risk factors for hypomagnesemia ( eg , chronic diarrhea, proton pump inhibitor therapy, alcoholism, diuretic use ) or Those with clinical manifestations of hypomagnesemia ( eg , unexplained hypocalcemia , refractory hypokalemia , neuromuscular disturbances, ventricular arrhythmias) 

22. The terms hypomagnesemia and magnesium deficiency tend to be used interchangeably . However, ECF magnesium accounts for only 1% of total body magnesium, so serum Magnesium concentrations have been found to correlate poorly with overall magnesium status. In patients with magnesium deficiency, serum magnesium concentrations may be normal or may seriously underestimate the severity of the magnesium deficit. Approximately 50% to 60% of magnesium is in the skeleton and most of the remaining 40% to 50% is intracellular. No satisfactory clinical test to assay body magnesium stores is available

23. The magnesium tolerance test has been proposed to be the best test of overall magnesium status. It is based on the observation that magnesium-deficient patients tend to retain a greater proportion of a parenterally administered magnesium load and excrete less in the urine than normal individuals.

24. The results of a magnesium tolerance test correlate well with magnesium status , as assessed by skeletal muscle magnesium content and exchangeable magnesium pools. However, the test is invalid in patients who have impaired renal function or a renal magnesium-wasting syndrome or in patients taking diuretics or other medications that induce renal magnesium wasting. Thus, and also because of the time and effort required to perform the magnesium tolerance test, it is used primarily as a research tool.

25. The serum magnesium concentration, although an insensitive measure of magnesium deficit, remains the only practical test of magnesium status in widespread use. The functionally important value is believed to be the ionized Mg2+ concentration , which is less than total serum magnesium due to protein binding. Measurements with ion selective electrodes have found ionized Mg2+ concentrations that are approximately 70% of the total serum magnesium, a proportion that is fairly constant among the general population . However, in critically ill patients, there is a poor correlation between total and ionized serum magnesium levels.

26. Absorption related Nutritional : Unusual because almost all foods contain significant amounts of magnesium, and renal adaptation to conserve magnesium is very efficient. Thus, magnesium deficiency of nutritional origin is observed primarily in two clinical settings—alcoholism and parenteral feeding. Alcoholics decreased nutritional intake and impaired mg renal reabsorption contributes Refeeding - overzealous parenteral feeding of severely malnourishedpatients causes hyperinsulinemia , as well as rapid cellular uptake of glucose and water, together with phosphorus, potassium, and magnesium.

27. In fat malabsorption with concomitant steatorrhea , free fatty acids in the intestinal lumen may combine with magnesium to form nonabsorbable soaps, a process termed saponification . In bariatric surgery by jejunoileal bypas .. but fortunately does not occur with the modern technique of gastric bypass.

28. Proton pump inhibitors (PPIs) have been reported to cause hypomagnesemia . Impaired intestinal magnesium absorption, rather than renal absorption is implicated. Potential mediators include Increased intestinal magnesium secretion, Decreased active transcellular magnesium absorption due to decreased TRPM6 activity Secondary to decreased intestinal acidity, or Decreased paracellular magnesium absorption

29. Diarrhea and Gastrointestinal Fistula- Magnesium losses from both the upper and lower gastrointestinal tract can induce hypomagnesemia . In general, magnesium depletion is more commonly due to diarrhea than to vomiting . This is because the magnesium content of lower tract secretions is significantly higher (up to 15 mEq /L versus approximately 1 mEq /L for upper tract).  Cutaneous Loss Serum magnesium concentrations fall 20% on average after a marathon run. Hypomagnesemia occurs in 40% of patients with severe burn injuries during the early period of recovery. The major cause is loss of magnesium in the cutaneous exudate , which can exceed 1 g/day.

30. Redistribution to Bone Compartment Hypomagnesemia accompany the profound hypocalcemia of hungry bone syndrome observed in some patients with HPT and severe bone disease immediately after parathyroidectomy . sudden removal of excess PTH is believed to result in virtual cessation of bone resorption , with a continued high rate of bone formation and consequent sequestration of calcium and magnesium into bone mineral.

31. Diabetes Mellitus Multifactorial causes ; contributing factors include decreased oral intake of magnesium rich foods, poor intestinal absorption due to diabetic autonomic neuropathy, Increased renal excretion . Renal excretion ↑ - caused by glomerular hyperfiltration , osmotic diuresis , or decreased thick ascending limb and distal tubule magnesium reabsorption caused by functional insulin deficiency. Some studies have suggested that magnesium deficiency might itself impair glucose tolerance , thus partly explaining the association. Conversely, genetic variants in the magnesium transport channels, TRPM6 and TRPM7 , may increase the risk of type 2 diabetes mellitus in women on a diet with less than 250 mg/day of magnesium.

32. Renal Magnesium Wasting- Polyuria Increased urine output from any cause is often accompanied by increased renal losses of magnesium accompanied by increased renal losses of magnesium. Renal magnesium wasting occurs with osmotic diuresis , also occurs during the polyuric phase of recovery from acute renal failure in a native kidney, during recovery from ischemic injury in a transplanted kidney , and in postobstructive diuresis . In such cases, it is likely that residual tubule reabsorptive defects persisting from the primary renal injury play as important a role as polyuria itself in inducing renal magnesium wasting.

33. ECF Volume Expansion In the proximal tubule, magnesium reabsorption is passive and driven by the reabsorption of sodium and water in this segment. Extracellular volume expansion, which decreases proximal sodium and water reabsorption , also increases urinary magnesium excretion. Thus, chronic therapy with magnesium-free parenteral fluids , crystalloid or hyperalimentation , can cause renal magnesium wasting, as can hyperaldosteronism .

34. Inhibitors of EGF receptors Cetuximab or panitumumab , utilized for treatment of EGF responsive cancers , are able to induce hypomagnesemia by interfering with magnesium transport in the kidney. Autocrine or paracrine activation of the receptor stimulates redistribution of TRPM6 to the apical membrane via a Rac1-dependent signaling pathway and presumably increases transepithelial magnesium reabsorption . Thus, EGF receptor blockade likely causes renal magnesium wasting by antagonizing this pathway. Increases with increasing duration of therapy, reaching almost 50% in patients treated for longer than 6 months. The median time to onset of hypomagnesemia after beginning treatment is 99 days , and it generally reverses 1 to 3 months after discontinuing therapy EGF increases magnesium transport through TRPM6.

35. Hypercalcemia  Calcium and magnesium functionally compete for transport in the thick ascending limb of the loop of Henle .  Calcium binds to the basolateral CaSR . This leads to generation of prostaglandins and cytochrome P450 metabolites in the cell, which inhibit the apical potassium channel (ROMK ) Inhibition of ROMK inhibits sodium chloride reabsorption in the thick ascending limb and reduces paracellular magnesium and calcium reabsorption . Inhibition of ROMK in this nephron segment resulting from stimulation of the CaSR is the mechanism underlying type V Bartter syndrome. Thus, hypercalcemia can produce a Bartter-like phenotype. In addition, stimulation of the CaSR decreases paracellular permeability of the thick ascending limb to both magnesium and calcium, likely due to increased expression of claudin-14, which negatively regulates claudin-16 and claudin-19. 

36. Tubule Nephrotoxins Cisplatin - Hypomagnesemia is almost universal at a monthly dose of 50 mg/m2 The occurrence of Mg wasting does not appear to correlate with the incidence of cisplatin induced acute renal failure . Renal magnesuria continues after cessation of the drug for a mean of 4 to 5 months, but can persist for years. Although the nephrotoxic effects of cisplatin are manifested histologically as acute tubular necrosis confined to the S3 segment of the proximal tubule, the magnesuria does not correlate temporally with the clinical development of acute renal failure secondary to acute tubular necrosis. Furthermore, patients who become hypomagnesemic are also subject to the development of hypocalciuria ,thus suggesting that the reabsorption defect may actually be in the DCT.

37. Cisplatin may also impair intestinal magnesium absorption. Carboplatin , an analogue of cisplatin , is considerably less nephrotoxic and only rarely causes acute renal failure or hypomagnesemia .

38. Amphotericin B is a well-recognized tubule nephrotoxin that can cause renal potassium wasting, distal renal tubular acidosis, and acute renal failure, Tubule necrosis and calcium deposition noted in the DCT and TAL on renal biopsy. Amphotericin B causes renal magnesium wasting and hypomagnesemia related to the cumulative dose administered , but these effects may be observed after as little as a 200-mg total dose. Interestingly, the amphotericin induced magnesuria is accompanied by the reciprocal development of hypocalciuria so, as with cisplatin , the serum calcium concentration is usually preserved, suggesting that the functional tubule defect resides in the DCT .

39. Aminoglycosides cause a syndrome of renal magnesium and potassium wasting with hypomagnesemia , hypokalemia , hypocalcemia , and tetany . Hypomagnesemia may occur despite levels in the appropriate therapeutic range. Most patients reported that they had delayed onset of hypomagnesemia occurring after at least 2 weeks of therapy, and received total doses in excess of 8 g , thus suggesting that it is the cumulative dose of aminoglycoside that is the key predictor of toxicity. In addition, no correlation was found between the occurrence of aminoglycoside -induced acute tubular necrosis and hypomagnesemia . Magnesium wasting persists after cessation of the aminoglycoside , often for several months.

40. All aminoglycosides in clinical use have been implicated, including gentamicin , tobramycin , and amikacin , as well as neomycin when administered topically for extensive burn injuries. This form of symptomatic aminoglycoside -induced renal magnesium wasting is now relatively uncommon because of heightened general awareness of its toxicity. However, asymptomatic hypomagnesemia can be observed in one third of those treated with a single course of an aminoglycoside at standard doses (3 to 5 mg/kg/day, for a mean of 10 days).

41. Cyclosporine and Tacrolimus Cause renal magnesium wasting and hypomagnesemia in patients after organ transplantation. The mechanism is thought to be downregulation of the distal tubule magnesium channel, TRPM6.

42. Inherited Renal Magnesium-Wasting Disorders Primary Magnesium-Wasting Disorders . Bartter syndrome , particularly the late-onset cases due to mutations in  CLCNKB  (Bartter syndrome type 3) that resemble Gitelman syndrome, may also present with hypomagnesemia due to defective reabsorption in the thick ascending limb

43. Calcium Sensing Disorders In FHH , the hypercalcemia is due to inactivating mutations in CaSR . As a consequence of the inactivated CaSR , the normal magnesuric response to hypercalcemia is impaired, patients are paradoxically mildly hypermagnesemic . Activating mutations in CaSR cause the opposite syndrome, autosomal dominant hypoparathyroidism . Most such patients are mildly hypomagnesemic , presumably because of TAL magnesium wasting.

44. EAST ( SeSAME ) syndrome  — EAST syndrome (also known as SeSAME syndrome) Autosomal recessive disorder Presents in infancy with epilepsy, ataxia, sensorineural deafness, mental retardation, and a renal salt-losing tubulopathy that resembles Gitelman syndrome and manifests as hypokalemic metabolic alkalosis with hypomagnesemia . This syndrome is caused by loss-of-function mutations in the gene encoding the potassium channel, KCNJ10 (Kir4.1 ), which is expressed on the basolateral membrane of the distal convoluted tubule and regulates expression of the thiazide -sensitive sodium chloride cotransporter .

45. Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) Autosomal Recessive and associated with  hypercalciuria ; Affected patients usually present in childhood or adolescence with symptomatic hypocalcemia Recurrent nephrolithiasis and nephrocalcinosis are also seen, and progression to renal insufficiency and an acidification defect are common. Affected patients may also have polyuria and polydipsia due to nephrogenic diabetes insipidus . Mutations in the claudin-16 gene (also known as paracellin-1 ) are the major cause of FHHNC. FHHNC may occasionally be due to mutations in claudin-19.

46. CNNM2 ( cyclin M2) has also been identified as a gene involved in renal Mg handling in patients of two unrelated families with unexplained dominant hypomagnesemia . In the kidney, CNNM2 was predominantly found along the basolateral membrane of distal tubular segments involved in Mg2+ reabsorption

47. Mutations in PCBD1 (pterin-4a-carbinolamine dehydratase / dimerization cofactor of hepatocyte NF 1 homeobox A) were recently shown to cause hypomagnesemia secondary to renal magnesium wasting. PCBD1 is a dimerization cofactor for the transcription factor HNF1B . PCDB1 binds HNF1B to costimulate the FXYD2 (sodium/potassium transporting ATPase gamma chain [a protein that in humans is encoded by the FXYD2 gene]) promoter, which increases renal tubular magnesium reabsorption in the distal convoluted tubule.

48. EVALUATION In patients diagnosed with hypomagnesemia , the cause can usually be obtained from the history. If no etiology is apparent, the distinction between gastrointestinal and renal losses can be made by measuring the 24-hour urinary magnesium excretion or the fractional excretion of magnesium ( FEMg ) on a random urine specimen.         

49.                   UMg  x   PCr   FEMg  =  —————————————  x  100 percent                       (0.7  x   PMg )  x   UCr The plasma magnesium concentration is multiplied by 0.7 since only approximately 70 percent of the circulating magnesium is free (not bound to albumin) and therefore able to be filtered across the glomerulus .

50. A daily excretion of more than 10 to 30 mg (in a 24-hour urine specimen) or a fractional excretion of magnesium above 3 to 4 percent in a person with hypomagnesemia and normal kidney function indicates renal magnesium wasting. By contrast, a 24-hour urinary magnesium excretion less than 10 mg or a fractional excretion of magnesium less than 2 percent usually indicates an extrarenal source of magnesium losses (typically gastrointestinal).

51. Symptoms Neuromuscular manifestations Neuromuscular hyperexcitability ( eg , tremor, tetany, convulsions), weakness, apathy, delirium, and coma. The effects of magnesium deficiency on brain neuronal excitability may be mediated by increased glutamate-activated depolarization in the brain  Cardiovascular manifestations (Changes reflect abnormal cardiac repolarization) widening of the QRS and peaking of T waves with moderate magnesium depletion, and widening of the PR interval, diminution of T waves, and atrial and ventricular arrhythmias Effects on myocardial ion fluxes esp (Na-K-ATPase). Mg is an obligate cofactor in all reactions that require adenosine triphosphate (ATP) Hypocalcemia is a classical sign of hypomagnesemia. In hypomagnesemic patients, symptomatic hypocalcemia is almost always associated with plasma magnesium levels below 1 mEq /L The major factors resulting in hypocalcemia in hypomagnesemic patients are hypoparathyroidism, parathyroid hormone (PTH) resistance, and vitamin D deficiency.

52. Normomagnesemic magnesium depletion   A small number of patients have been reported with hypocalcemia responsive to magnesium administration in the  absence  of detectable hypomagnesemia Usually seen in patients such as alcoholism or diarrhea Hypokalemia ( occur in 40 to 60 percent ) 1. Partly due to underlying disorders that cause both magnesium and potassium loss, such as diarrhea and diuretic therapy . 2. Increased potassium secretion in the connecting tubule and the cortical collecting tubule mediated by luminal potassium (ROMK) channels, a process that is inhibited by intracellular magnesium. Hypokalemia in this setting is relatively  refractory   to potassium supplementation and requires correction of the magnesium deficit 

53. Treatment Severe symptoms — Symptomatic patients, such as those with tetany , arrhythmias, or seizures Remarks Hemodyanamically unstable ( eg . torsades de pointes) 1 to 2 grams of  magnesium sulphate  (8 to 16 mEq can be given initially over 2 to 15 minutes. Hemodynamically stable patients     same as above f/b infusion 4 to 8 grams of  Mg sulphate  (32 to 64 mEq ) given slowly over 12 to 24 hours Symptomatic with creatinine clearance less than 30 mL /min/1.73 m 2 reduce the IV magnesium dose in such patients by 50 percent or more and closely monitoring magnesium concentrations. Risk of hypermagnesemia No or minimal symptoms Oral replacement - A typical daily dose in a patient with normal kidney function is 240 to 1000 mg (20 to 80 mEq of elemental magnesium in divided doses. Diarrhea is dose limiting

54. IV REPLETION IN STABLE PATIENTS SERUM MAGNESIUM LEVEL DOSE MILD less than 1 mg/ dL give 4 to 8 grams (32 to 64 mEq )  over 12 to 24 hours MOD 1 to 1.5 mg/ dL give 2 to 4 grams (16 to 32 mEq ) over 4 to 12 hours. SEVERE 1.6 to 1.9 mg/ dL give 1 to 2 grams (8 to 16 mEq )  over one to two hours In stable hospitalized patients receiving magnesium therapy, the plasma magnesium concentration should be measured daily or more frequently if indicated. Repeat doses are given based upon the follow-up measurement.

55. Inefficiency of intravenous magnesium supplementation  —  Plasma magnesium concentration inhibits magnesium reabsorption in the loop of Henle , the major site of active magnesium transport Thus, when an IV magnesium infusion is given, an abrupt but temporary elevation in the plasma magnesium concentration will partially inhibit the stimulus to magnesium reabsorption in the loop of Henle . Thus, up to 50 percent of the infused magnesium will be excreted in the urine. In addition, magnesium uptake by the cells is slow, and therefore adequate repletion requires sustained correction of the hypomagnesemia . Because of the inefficiencies of IV magnesium just described, oral replacement therapy should be given to asymptomatic patients whenever the oral route of administration is available and oral magnesium supplements can be tolerated.

56. Oral Mg treatment Tablets Mild hypomagnesemia Two to four tablets (10 to 28 mEq ) severe magnesium depletion Six to eight tablets (30 to 56 mEq ) Sustained-release preparations have the advantage that they are slowly absorbed and thereby minimize renal excretion of the administered magnesium. Duration of therapy  — Serum magnesium levels usually rise quickly with therapy, but intracellular stores take longer to replete. It is therefore advisable in patients with normal kidney function to continue magnesium repletion for at least one to two days after the serum magnesium concentration normalizes.

57. HYPERMAGNESEMIA In states of body magnesium excess, the kidney has a very large capacity for magnesium excretion. Once the apparent renal threshold is exceeded, most of the excess filtered magnesium is excreted unchanged into the final urine; the serum magnesium concentration is then determined by the GFR. Thus, hypermagnesemia generally occurs only in two clinical settings, compromised renal function and excessive magnesium intake.

58. In CKD patients , the r emaining nephrons adapt to the decreased filtered load of magnesium by markedly increasing their fractional excretion of magnesium. As a consequence , serum magnesium levels are usually well maintained until the creatinine clearance falls below about 20 mL /min. Even in advanced renal insufficiency, significant hypermagnesemia is rare unless the patient has received exogenous magnesium in the form of antacids, cathartics,or enemas. Increasing age is an important risk factor for hypermagnesemia in individuals with apparently normal renal function; it presumably reflects the decline in GFR that normally accompanies old age.

59. Symptoms of increased magnesium Plasma magnesium levels symptoms 4 to 6 mEq /L (4.8 to 7.2 mg/ dL Nausea, flushing, headache, lethargy, drowsiness, and diminished deep tendon reflexes. 6 to 10 mEq /L (7.2 to 12 mg/d Somnolence, hypocalcemia , absent deep tendon reflexes, hypotension, bradycardia , and electrocardiogram (ECG) changes. above 10 mEq /L (12 mg/ dL   Muscle paralysis leading to flaccid quadriplegia, apnea and respiratory failure, complete heart block, and cardiac arrest

60. TREATMENT Cessation of magnesium therapy IV calcium as a magnesium antagonist to reverse the neuromuscular and cardiac effects of hypermagnesemia . The usual dose is 100 to 200 mg of elemental calcium over 5 to 10 minutes. Loop (or even thiazide ) diuretics can be used to increase renal excretion Dialysis may be required, especially if there are severe neurologic manifestations ( eg , paralysis, somnolence, coma) or cardiovascular manifestations ( eg , bradycardia , electrocardiographic abnormalities, hypotension)