1. Sara E Parli, PharmD Assistant Professor (Adjunct) Critical Care Pharmacist Trauma/Acute Care Surgery Disorders of Electrolyte Homeostasis – Calcium and Phosphorus

2. Calcium Physiology Mostly found in bone (99%) – Osteoclasts – Osteoblasts Moderately bound to plasma proteins (46%) – Primarily albumin Normal serum Ca = 8.5-10.5 mg/dL – Corrected serum Ca = measured serum Ca + [0.8 x (4 – measured albumin)] Check an ionized serum calcium, normal = 4.4 – 5.4 mg/dL, in acid-base disorders – Affects protein binding

3. Homeostatic Mechanisms Parathyroid hormone (PTH) – Stimulates Ca release from bone (resorption) – Reduces Ca excretion – Increases activation of vitamin D (to 1,25-dihyroxyvitamin D3) Vitamin D – Promote Ca absorption from GI tract Calcitonin – Inhibits osteoclastic bone resorption (released when serum calcium concentrations increase) Normal functions – Muscle cell contraction, electrophysiologic slow-channel response in cardiac smooth muscle, bone metabolism

5. Hypercalcemia (>10.2 mg/dL) Pathophysiology—increased absorption, decreased elimination, or increased bone resorption Neoplasms—most common cause, especially carcinomas of lung, breast, multiple myeloma (up to 40%) – PTH-related protein released Medications – Increased renal reabsorption—thiazides, lithium Endocrine diseases Immobilization, Paget’s disease, rhabdomyolysis

6. Hypercalcemia: Signs and Symptoms Renal – Nephrolithiasis – Renal tubular dysfunction – Polyuria, polydipsia GI – Anorexia – Constipation – N/V Cardiovascular – QT interval shortening – Ventricular arrhythmias Musculoskeletal Lancet 1998;352:305-11.

7. Hypercalcemia: Treatment Expand intravascular volume – Hydration first! Then promote calcium excretion – Loop diuretics block Ca reabsorption in the loop of Henle Avoid in fluid restricted patients  may need dialysis – Calcitonin (Miacalcin)—fast onset (1-2 hours), derived from salmon SC or IM, IV can cause flushing, N/V Intranasal is less potent, shorter duration Tachyphylaxis with chronic therapy

8. Hypercalcemia: Treatment Avoid IV phosphate Bisphosphonates – Oral route not recommended for initial use – First line for cancer associated hypercalcemia – Concentrations decline in 2 days, nadir in 7 days – Caution in renal insufficiency, controversial in renal osteodystrophy secondary to chronic kidney disease Bisphosphonates Etidronate Pamidronate (Aredia) Zoledronate (Zometa) Ibandronate (Bonvia)

9. Hypercalcemia: Treatment Corticosteroids may be used in hypercalcemia caused by multiple myeloma and other malignancies – Reduce serum calcium in 3-5 days – Renal excretion in 7-10 days

10. Hypocalcemia (<6.5 mg/dL) Pathophysiology – inadequate intake, excessive losses Hypoparathyroidism (after surgery) Vitamin D deficiency – induced metabolism, decreased release, decreased intake can cause osteomalacia, Rickets, CKD Hypomagnesemia impairs PTH secretion Oral phosphorous therapy, sodium phosphate bowel preparations

11. Drug-Induced Hypocalcemia Loop diuretics Phenytoin Calcitonin Barbiturates Oral phosphorus preparations Medications causing hypomagnesemia Loop diuretics Furosemide (Lasix) Bumetandie (Bumex) Torsemide (Demadex) Ethacrynic acid

12. Hypocalcemia: Clinical presentation Tetany is hallmark – Facial, extremity muscle spasms, cramps Neuro – Weakness, fatigue, seizures, confusion – Depression, memory loss (chronic) Cardiovascular – Hypotension, bradycardia, QT prolongation, unresponsiveness to vasopressors

13. Hypocalcemia: Treatment Correct underlying cause Check albumin Chronic – Check vitamin D, PTH – PO calcium supplements, vitamin D if needed Acute symptomatic – 100-300mg elemental IV calcium – Calcium gluconate 2-3 grams (9% elemental) OR – Calcium chloride 1 gram (27% elemental) – Then 0.5-2mg/kg/hr, reduce dose later

14. Calcium Supplements

15. Disorders of Calcium Homeostasis Predominantly exists in bone, highly bound to albumin, normal serum calcium = 8.5-10.5mg/dl Regulated by PTH, calcitonin, vitamin D Neoplasm is a common cause of hypercalcemia – Hydration, calciuresis, calcitonin, bisphosphonates Hypocalcemia can be caused by hypomagnesemia, hypoparathyroidism – IV and PO calcium supplementation

16. Phosphorus Homeostasis Mostly found in skeleton (~ 85%) and ICF, about 1% found in ECF Major intracellular anion – Exists as ATP, 2,3- diphosphoglycerate (DGP), fructose 1,6 diphosphate – Inorganic phosphate (PO 4 ) mostly found in ECF and small amount in ICF Normal serum phosphate (inorganic) 2.5 to 4.5 mg/dL Primarily renal elimination by filtration (~ 80 to 90% reabsorbed in proximal tubule)

17. Phosphorus Homeostasis Am J Med 2005;118:1094-1101.

18. Hyperphosphatemia (>4.5 mg/dL) Etiology – Impaired phosphorus excretion Renal failure – Redistribution of phosphorus to the ECF Rhabdomyolysis – Increased phosphorus intake Medications

19. Hyperphosphatemia: Clinical Presentation Paresthesias ECG changes – QT prolongation – Prolonged ST segment Metastatic calcifications – Calcium phosphate precipitation can cause obstructive nephropathy Likely when calcium x phosphate = 50-60 Goal < 55 in CKD

20. Hyperphosphatemia: Treatment ↓ GI phosphate absorption w/binders – Calcium preferred Am J Health-System Pharm 2005;62:2355-61.

21. Hypophosphatemia (<2.5 mg/dL): Extracellular to intracellular redistribution – Rapid refeeding Decreased absorption Enhanced excretion Acute volume expansion Hypophosphatemia Mild to moderate1 to 2.4 mg/dL Severe<1 mg/dL

22. Hypophosphatemia: Clinical Presentation Depletion of intracellular ATP – Impaired respiratory function, myalgias, muscle weakness, bone pain, impaired cardiac muscle function Decreased 2,3-DPG concentrations in RBCs – Decreased oxygen delivery – Rigid RBCs become trapped in spleen – Impaired WBC functions

23. Hypophosphatemia: Treatment Severe – IV, sodium or potassium phosphate, 15 mmol will correct by 0.5 to 0.8 mg/dl – Suggested maximum infusion rate = 9 mmol phosphate/hr Risk of symptomatic hypocalcemia, soft tissue calcification, rapid K + infusion (> 10 mEq/hr) adverse effects Mild-moderate – PO, 30-60 mmol/day in divided doses – Dose-limiting adverse event = osmotic diarrhea – Caution in kidney disease

24. Disorders of Phosphorous Homeostasis Normal serum phosphorous = 2.5-4.5 mg/dL Major intracellular anion  ATP Hyperphosphatemia with cell lysis, decreased elimination – Phosphate binders Hypophosphatemia is common in critical illness – PO, IV replacement