Calcium is the most abundant cation and the fifth most common inorganic element in the human body. Calcium is essential for the maintenance of the nervous, muscular, and skeletal systems, and for cell membrane and capillary permeability. Its role in bone structure and muscle contraction is well known, but calcium is also important for blood coagulation, nerve conduction, and electrical conduction in the myocardium. In general, calcium salts are used to treat or prevent calcium depletion. Calcium gluconate is also designated an orphan drug for use as a wash for hydrofluoric acid spills on human skin. Calcium and magnesium are, in some ways, physiological opposites, and calcium can be used for the temporary control of cardiac arrhythmias associated with hypokalemia. However, the use of parenteral calcium during cardiac arrest has become more restricted, and is recommended for the treatment of cardiac arrest or life-threatening cardiac arrhythmias, only when associated with hypocalcemia, hyperkalemia or hypermagnesemia.1 Calcium is now recognized as an important agent in preventing osteoporosis, especially in postmenopausal women.2 It has been suggested that refined calcium or calcium chelates be used in place of calcium derived from bonemeal or oyster shells, which can contain potentially toxic amounts of lead. Growing evidence suggests that calcium accumulates readily in atherosclerotic plaques, although this does not appear to be related to exogenous calcium administration. Calcium stimulates gastrin secretion, which offsets the utility of oral calcium carbonate as a treatment of peptic ulcer disease.
Mechanism of Action: Calcium is the primary component of skeletal tissue, providing structural integrity and support for individual growth. Bone undergoes constant remodeling and turnover. Mineral release during the process of bone resorption buffers hydrogen ions. Whereas, the formation of bone generates hydrogen ions. Thus, bone serves as a calcium depot and as a reservoir for electrolytes and buffers. Inhibition of bone resorption is primarily the function of the hormone, calcitonin. The control of plasma calcium concentration is primarily maintained by parathyroid hormone, thyroxine, and 1,25 dihydroxycholecalciferol. Ionized calcium is the physiologically active form. Basic metabolic functions involve the cardiac, neuromuscular, structural, and blood coagulation systems.345
Calcium acetate works as a phosphate binder. When taken with meals, it combines with dietary phosphate, forming an insoluble calcium-phosphate complex, which is then eliminated in the feces. This in turn lowers serum phosphorus concentrations.6
Pharmacokinetics: Calcium is required by all body tissues. Approximately 98% of the body's calcium is stored in the bone, primarily as the hydroxyapatite. Constant bone remodeling and turnover of the skeleton release calcium into the systemic circulation which is then re-accumulated by the bone on a daily basis. Calcium is 40% bound to plasma proteins, primarily albumin, and 10% is in a chelated form. Approximately 50% of serum calcium is ionized, which is considered the physiologically active form. The ultrafiltratable calcium (nonprotein-bound) is distributed to the protein-poor regions of the body, such as the cerebrospinal and extracellular fluids. Calcium is primarily excreted in the feces and bile (80%). Urinary excretion accounts for the remainder (20%). However, approximately 99% of filtered calcium is reabsorbed by the kidney with less than 1% excreted.7 Parathyroid hormone, calcitonin, and 1,25 dihydroxycholecalciferol are primarily responsible for controlling calcium equilibrium. Insulin, thyroxine, growth hormone, androgens, estrogens, adrenal corticosteroids, and inorganic phosphate also contribute.489
Affected cytochrome P450 isoenzymes: none
Calcium chloride is more bioavailable than calcium gluconate and results in greater increases in serum ionized calcium concentrations than does calcium gluconate.10
Elemental Calcium Content
NOTE: Different calcium formulations are not directly exchangeable on a mg per mg basis; the different salts contain roughly the following amounts of elemental calcium (1 mEq elemental calcium is equivalent to about 20 mg elemental calcium):
Calcium Formulation: (Elemental Calcium content per g)
- Calcium Acetate: 250 mg (12.5 mEq) per g
- Calcium Carbonate: 400 mg (20 mEq) per g
- Calcium Chloride: 270 mg (13.5 mEq) per g
- Calcium Citrate: 210 mg (10.5 mEq) per g
- Calcium Glubionate: 64 mg (3.2 mEq) per g
- Calcium Gluconate: 93 mg (4.65 mEq) per g
- Calcium Lactate: 130 mg (6.5 mEq) per g
For the treatment of acute hypocalcemia:
NOTE: IV dosages should be used in patients with tetany.
NOTE: Monitor ionized serum calcium concentrations to individualize dosage.
NOTE: For the treatment of ionized hypocalcemia during CPR, see dosing for CPR.
Intravenous dosage (calcium gluconate):
Adults: 2—3 g IV slowly at a rate not exceeding 5 ml/min (47.5 mg/min of calcium ion). For tetany, give over 5—10 minutes. Repeat every 6 hours, as needed, as determined by serum calcium concentrations and patient response. Maximum dosage is 15 g/day. Alternatively, an intravenous infusion of 15 mg/kg of elemental calcium (167 mg/kg calcium gluconate) over 4—6 hours may be administered if symptoms recur after initial IV calcium replacement.
Children and Infants: 200—500 mg/kg/day IV as a continuous infusion or given in 4 divided doses, at a rate not exceeding 5 ml/min (47.5 mg/min of calcium ion). For tetany, an initial dose of 100—200 mg/kg IV given over 5—10 minutes is recommended. This dose may be repeated after 6 hours or followed by 500 mg/kg/day IV as a continuous infusion or given in 3—4 divided doses.
Neonates: 200—800 mg/kg/day IV as a continuous infusion or administered in 3—4 divided doses. For tetany, initial doses of 100—200 mg/kg IV are recommended, followed by 500 mg/kg/day IV as a continuous infusion or given in 3—4 divided doses.
For hypocalcemia secondary to citrated blood infusion:
Adults, Children, and Neonates: 0.45 mEq elemental calcium for each 100 ml of citrated blood infused.
For nutritional supplementation to prevent hypocalcemia in patients receiving total parenteral nutrition (TPN):
Adults: 10—15 mEq IV per day admixed with TPN. The choice of parenteral product and dosage depends upon the clinical condition of the patient (i.e. electrolyte balance, acid-base status) and compatibility with chosen parenteral fluids and additives. Several factors influence the amount of calcium that can be safely added to parenteral nutrition solutions.
Children and Infants, including premature Neonates: The choice of parenteral product and dosage depends upon the age and clinical condition of the patient (i.e. electrolyte balance, acid-base status) and compatibility with chosen parenteral fluids and additives. Several factors influence the amount of calcium that can be safely added to parenteral nutrition solutions.
For the treatment of verapamil toxicity or calcium antagonist toxicity (e.g., myocardial depression, hypotension, cardiac conduction defects or cardiac arrhythmias):
Intravenous dosage (calcium gluconate):
Adults: 500—800 mg IV. Maximum dose is 3 g IV. NOTE: Calcium chloride is the preferred agent.
Infants and Children: 100 mg/kg IV. Maximum dose is 3 g IV. NOTE: Calcium chloride is the preferred agent.
Therapeutic Drug Monitoring: Ionized calcium concentrations are the preferred measure to determine true hypocalcemia. If total serum calcium concentrations are obtained, calcium concentrations should be adjusted if hypoalbuminemia or hyperalbuminemia is present. The corrected calcium concentration may be estimated from the following formula:47
- Corrected calcium (mg/dl) = serum calcium (mg/dl) + 0.8 [4- serum albumin (g/dl)]
- Administered intravenously as the gluconate or chloride salts. Do NOT administer intramuscularly or subcutaneously.811
- Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
- Calcium chloride and calcium gluconate 10% (100 mg/mL) contain 27.2 mg/mL and 9 mg/mL of elemental calcium, respectively.811
Intermittent IV Infusion
- May dilute in compatible IV solution (i.e., 0.9% Sodium Chloride injection, 5% Dextrose injection, 10% Dextrose injection) to a usual concentration of 10 to 40 mg/mL.
For calcium chloride, administration into a large vein or a central line is preferred; avoid extravasation.81213 In a safety analysis of peripheral intravenous administration of calcium chloride solutions to adult patients, concentrations of approximately 3 mg/mL resulted in a low incidence of infusion site reactions.14 Concentrations of 1 mg/mL or less have been recommended for peripheral lines for neonates.15
For calcium gluconate, a recommended concentration for peripheral lines is 3 mg/mL for neonates; however, concentrations as high as 100 mg/mL have been used for bolus doses. Observe the infusion line closely. Higher concentrations have been given via central lines.15
- Do not administer via scalp vein catheter.
- Generally, infuse a bolus dose over 30 to 60 minutes.12 Calcium gluconate may be administered at a rate not exceeding 200 mg/minute.11 Calcium chloride may be administered at a rate not exceeding 100 mg/minute.8
- In general, inject IV 10% calcium gluconate products slowly, at a rate of 1.5 mL/minute (150 mg/minute) or less to avoid adverse reactions. The absolute maximum rate of 2 mL/minute (200 mg/minute) should not be exceeded. Administer through a small needle into a large vein.11
- Inject IV 10% calcium chloride by slow IV injection. Do not to exceed 1 mL/minute (100 mg/minute), preferably in a deep or central vein. Following injection, the patient should remain recumbent for a short time.8
Contraindications: Calcium salts are contraindicated in patients with preexisting hypercalcemia.
Calcium salts should not be used in patients with preexisting hypercalciuria, especially if renal calculi are present.
Calcium salts should not be used in patients with sarcoidosis because hypercalcemia can occur.
Calcium chloride and calcium gluconate injections should not be given by intramuscular administration or subcutaneous administration. Severe necrosis and sloughing may occur. Caution should be undertaken to avoid extravasation or accidental injection into perivascular tissues.
Parenteral calcium salts are contraindicated in patients with ventricular fibrillation and should be used cautiously in patients with preexisting cardiac arrhythmias. Calcium salts are no longer recommended for ACLS algorithms for pulseless electrical activity or asystole during cardiopulmonary resuscitation, except when indications exist to counterbalance electrolyte disturbances.1 Parenteral calcium salts should not be used in patients with digitalis toxicity because of an increased risk of developing arrhythmias. Cardiac glycosides and calcium salts both increase intracellular calcium, so calcium salts can worsen digitalis toxicity. Cardiac glycoside therapy, however, does not preclude the use of calcium salts.
Calcium supplements should be used with caution in patients with dehydration.
Calcium supplements should be used with caution in patients with diarrhea or malabsorption because fecal excretion can be increased.
Calcium supplements should be used with caution in patients with chronic renal failure due to the increased risk of developing hypercalcemia. Oral calcium salts, however, are often used to treat hyperphosphatemia in these patients; when administered with meals, the calcium binds with phosphate within the intestine and is excreted. To avoid transiently increasing the calcium-phosphate product, many clinicians first attempt to lower the serum phosphate with aluminum-based phosphate 'binders' and then substitute them with calcium-based phosphate binders. Calcium phosphate should not be used in patients with hypoparathyroidism or renal disease because there is an increased risk of developing hyperphosphatemia.
Calcium salts should be used cautiously, if at all, in patients with vitamin D toxicity or hyperparathyroidism. Hypercalcemia is likely to occur in either of these conditions.
Adverse effects have not been reported with the normal daily intake of calcium salts within the recommended dietary daily intakes for a pregnant female.16 The use of calcium salts in excess of the recommended dietary allowance during normal pregnancy should be avoided unless, in the judgment of the physician, potential benefits in a specific, unique case outweigh the significant hazards involved.16
Calcium salts appear to be safe and effective to use during breast-feeding to help meet maternal nutritional requirements. Human breast milk naturally contains calcium and other minerals; maternal calcium intake appears to have no significant effect on the amount of calcium normally found in human milk.1617 Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.
Pregnancy: Adverse effects have not been reported with the normal daily intake of calcium salts within the recommended dietary daily intakes for a pregnant female.16 The use of calcium salts in excess of the recommended dietary allowance during normal pregnancy should be avoided unless, in the judgment of the physician, potential benefits in a specific, unique case outweigh the significant hazards involved.16
Breast-feeding: Calcium salts appear to be safe and effective to use during breast-feeding to help meet maternal nutritional requirements. Human breast milk naturally contains calcium and other minerals; maternal calcium intake appears to have no significant effect on the amount of calcium normally found in human milk.1617 Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.
Adverse Reactions: Calcium salts irritate tissue when given by IV or SC injection. Mild to severe local irritation can occur. Calcium chloride and calcium gluconate should not be administered subcutaneously, intramuscularly or into perivascular tissue (extravasated) because severe tissue necrosis and sloughing can occur. Intravenous injections should be given through a small needle into a large vein to avoid a rapid increase in local concentrations and necrosis. Calcium chloride is more irritating to the veins compared with calcium gluconate, and therefore, is not the preferred salt form in children, particularly neonates.9 Patients receiving IV calcium salts should be monitored for an injection site reaction.1118
Calcium salts should be used with caution in patients with electrolyte imbalance. Hypercalcemia (may manifest as anorexia, confusion, constipation, drowsiness, hypertension, nausea/vomiting, premature ventricular contractions (PVCs), and polyuria) rarely occurs if appropriate doses of calcium are administered to otherwise healthy patients; however, patients with renal failure or patients receiving vitamin D can develop hypercalcemia readily. Severe hypercalcemia (Ca > 12 mg/dl) may result in delirium, stupor, and coma. Levels > 15 mg/dl may be life-threatening. Parenteral solutions of calcium salts can cause hypotension (dizziness and syncope), flushing, nausea/vomiting, tingling sensation (i.e., paresthesias), and a calcium or chalky taste (i.e., dysgeusia). Rapid IV injection can cause sinus bradycardia or AV block, cardiac arrhythmias (including ventricular fibrillation), and/or cardiac arrest, especially in the digitalized patient.
A rare, but serious, side effect of calcium salts is calcific nephrolithiasis.5
Milk-alkali syndrome, characterized by hypercalcemia and metabolic alkalosis and, if left untreated, renal failure can occur during prolonged therapy with oral calcium salts that are alkaline, such as calcium citrate, calcium acetate, or calcium lactate.19
Isolated cases of pruritus have been reported with calcium acetate oral formulations (PhosLo) and may represent allergic reactions.20
Hypophosphatemia, though rare, can potentially occur in patients during chronic calcium acetate therapy if dietary phosphate levels are low due to the malabsorption of phosphate from the diet as oral calcium acetate binds with phosphate in the gut.21
Muscle cramps have been reported in patients receiving chronic calcium acetate therapy, and might be possible with administration of other calcium salts.21
Diarrhea was commonly reported (13.2%) with calcium acetate oral solution in adult patients in a clinical study and was more common than the incidence observed with the solid formulation.6 Other calcium oral solutions, such as calcium glubionate, are hyperosmotic and may also cause gastric irritation and diarrhea.22
- 1. a. b. Guidelines 2000 for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Part 6: advanced cardiovascular life support. Circulation 2000;102(8 Suppl):112-165.
- 2. Reid IR, Ames RW, Evans MC, et al. Effect of calcium supplementation on bone loss in postmenopausal women. N Engl J Med 1993;328:460-4.
- 3. Roberts KE. Pediatric fluid and electrolyte balance: Critical care case studies. Crit Care Nurs Clin N Am 2005;17:361-373.
- 4. a. b. c. Umpaichitra V, Bastian W, Castells S. Hypocalcemia in children: Pathogenesis and management. Clin Pediatr (Phila) 2001;40(6):305-312.
- 5. a. b. Emkey RD, Emkey GR. Calcium metabolism and correcting calcium deficiencies. Endocrinol Metab Clin North Am 2012;41(3):527-556.
- 6. a. b. Calcium acetate oral solution (Phoslyra) package insert. Waltham, MA: Fresenius Medical Care North America; 2011 Apr.
- 7. a. b. Reber PM, Heath H, III. Hypocalcemic emergencies. Med Clin North Am 1995;79:93-106.
- 8. a. b. c. d. e. f. Calcium chloride 10% injection syringe package insert. Lake Forest, IL: Hospira, Inc.; 2009 Nov.
- 9. a. b. Hsu SC, Levine MA. Perinatal calcium metabolism: physiology and pathophysiology. Semin Neonatol 2004;9(1):23-36.
- 10. Broner CW, Stidham GL, Westenkirchner DF, et al. A prospective, randomized, double-blind comparison of calcium chloride and calcium gluconate therapies for hypocalcemia in critically ill children. J Pediatr 1990;117:986-989.
- 11. a. b. c. d. e. Calcium gluconate 10% injection package insert. Shirley, NY: American Regent, Inc.; 2011 July.
- 12. a. b. Hegenbarth MA. Preparing for pediatric emergencies: drugs to consider. Pediatrics 2008;121:433-43.
- 13. Lin CY, Hsieh KC, Yeh MC, et al. Skin necrosis after intravenous calcium chloride administration as a complication of parathyroidectomy for secondary hyperparathyroidism: report of four cases. Surg Today 2007;37:778-781.
- 14. Anger KE, Belisle C, Colwell MB, et al. Safety of compounded calcium chloride admixtures for peripheral intravenous administration in the setting of a calcium gluconate shortage. J Pharm Pract 2014;27:474-477.
- 15. a. b. Zenk KE, Sills JH, Koeppel RM. Neonatal medications and nutrition. A comprehensive guide. 3rd ed. Santa Rosa: NICU Ink Book Publishers; 2003.
- 16. a. b. c. d. e. f. Standing Committee on the Scientific Evaluation of Dietary Reference Intakes - Panel on Dietary Reference Intakes, Food and Nutrition Board, Institute of Medicine (IOM). Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D, and
- 17. a. b. Lawrence RA. Chapter 9: Diet and dietary supplements for the mother and infant. In: Breastfeeding- A Guide for the Medical Profession. 5th ed. St. Louis MO: Mosby, Inc.; 1999.
- 18. Calcium chloride 10% injection package insert. Shirley, NY: American Regent, Inc.; 2011 July
- 19. Whiting SJ, Wood R, Kim K. Calcium supplementation. J Am Acad Nurse Pract 1997;9(4):187-192.
- 20. Calcium acetate (PhosLo) gelcaps package insert. Waltham, MA: Fresenius Medical Care; 2006 Oct.
- 21. a. b. Saif I, Halim A, Altaf A, et al. Comparison of calcium acetate with calcium carbonate as phosphate binder in patients on maintenance haemodialysis. J Ayub Med Coll Abbottabad 2007;19:26-28.
- 22. Calcionate (calcium glubionate) syrup package insert. Duluth, GA: Rugby; 2008 Sept.