Calcium carbonate, chemically CaCO3, is a resonance-stabilized inorganic salt therapeutically used as a food additive, a dietary supplement, an antacid, and phosphate binder. Calcium carbonate is among the most abundant compounds found in the earth's crust and commonly found in organic substances, such as egg and oyster shells, crustaceans exoskeletons, and dark leafy greens, such as broccoli and kale.[1] Calcium carbonate uses extend beyond medicine. Calcium carbonate has industrial uses as filler in paint, paper, fire extinguishers, and adhesives, a component of agricultural and mining dust, an ingredient in household cleaners, as a food coloring compound, and as an ingredient in cosmetics.[1] In pharmaceuticals, calcium carbonate is a food additive used for nutritional benefits, is a calcium supplement used to treat low serum calcium conditions, is an antacid for gastrointestinal ailments, is a phosphate binder for chronic kidney disease, and is a tableting excipient used in the making of other pharmaceutical agents and foodstuffs.[1][2]

Calcium carbonate is indicated for low serum calcium conditions, such as osteoporosis, osteomalacia, hypothyroidism, hypoparathyroidism, pseudohypoparathyroidism, DiGeorge syndrome, kidney dysfunction, pancreatitis, rheumatoid arthritis, Fanconi syndrome, pregnancy, nursing mothers, post-menopausal women, and while using certain medications.[2][3][4][5][6][7][8] The medications that require concurrent calcium supplement use include:[9][10][11]

• Rifampin (antibiotic)
• Loop-diuretics
• Anti-seizure medications (phenytoin and phenobarbital) 
• Bisphosphonates (alendronate, ibandronate, zoledronic acid, and risedronate)
• Calcitonin
• Chloroquine
• Corticosteroids
• Plicamycin
• Citrate use during apheresis (anticoagulant)

As an antacid, calcium carbonate is indicated for use in heartburn caused by gastroesophageal reflux disease (GERD), NSAID upper gastrointestinal mucosal damage, duodenal and gastric ulcers, biliary reflux, stress gastritis exocrine pancreatic insufficiency, bile acid-mediated diarrhea, Non-ulcer dyspepsia, and urinary alkalization.[1][2][12][13][14] Like aluminum and magnesium salts, calcium carbonate increases gut motility and also has indications for use in constipation treatment.[12][15]

Calcium carbonate is also indicated for use in the treatment of hyperphosphatemia seen in chronic kidney disease, as a phosphate binder, as a way of treating overdose by causing urinary alkalization, and as a prophylactic treatment in pregnant patients before birth to prevent aspiration pneumonitis.[12][14][16][17]

New research suggests that the indications for calcium carbonate may also include cancer treatment by using calcium supplements to treat colorectal adenomas and using rare-earth-doped calcium carbonate with cerium to kill tumor cells via X-ray induced photodynamic therapy.[18][19]

Calcium is naturally present in the body. Most of the body's stored calcium is within the bones and teeth, as hydroxyapatite. The rest of the body's calcium is in blood, extracellular fluid, muscle, and other body tissues.[20] In the blood, 40% of calcium is bound to albumin, 13% binds to an anion, like phosphate and lactate, and the majority, 47% is free, unbound, ionized calcium (Ca2+).[1][20] The amount of ionized calcium found in the blood is important and tightly regulated by homeostatic controls because it is physiologically active and plays a vital role in the cellular processes of excitable tissues, such as blood vessels, muscles, glands, and nerves.[1][10][20]

Calcium absorption occurs in the small intestine by active transport dependent on Vitamin D and diffusion.[1] The fractional calcium absorption, the amount of calcium absorbed over the amount ingested, changes throughout life, being highest in infancy, early puberty, and last two trimesters of pregnancy for women and steadily declining as an individual progresses into old age with a marked decrease starting after menopause for women and late '50s for men.[20]

Calcium carbonate has three separate mechanisms of action that have pharmacologic effects. Calcium affects the stomach, small intestine, and blood.[21]

As an antacid, calcium carbonate neutralizes gastric acid by acting as a buffer in the stomach's acidic environment. When CaCO3 enters the stomach, it dissociates into ionized calcium (Ca2+) and a carbonate anion (CO32-). The carbonate anion will then bind to the free protons (H+) found in the stomach to increase the pH, by decreasing the concentration of hydrogen ions in the stomach. By increasing the pH in the stomach, pepsin, bile acids, and the toxins of Helicobacter pylori become inhibited.[22]

The inhibition of pepsin, an enzyme that can degrade tissue protein, and inhibition of bile acid helps reduce damage to and promote the healing of ulcers in the mucosal lining of the stomach and duodenum and injury to the esophagus caused by GERD.[22] There is still some criticism regarding the ulcer-healing effects of calcium carbonate being solely due to its acid-neutralizing mechanism because calcium carbonate can cause acid rebound by increasing plasma gastrin levels and has been shown to increase prostaglandins PGE2 and PGF2 after long term use that may explain an alternative mechanism to ulcer healing.[14][23][24][25]

As an antacid, calcium carbonate also increases gastrointestinal motility and initiates peristalsis.[15][26] When the calcium carbonate is chewed and partially digested, the free calcium stimulates peristalsis in the esophagus to move the acid into the stomach and decrease heartburn symptoms.[26]   

As a phosphate binder and drug chelator, calcium carbonate works in the small intestines. In individuals with hyperphosphatemia or overdose, calcium will bind to form an insoluble compound blocking dietary phosphate or excess drug absorption and excreting it in feces.[1] Additionally, calcium carbonate used as a calcium supplement also acts in the small intestine by chelating with oxalate to prevent absorption and renal calculi formation.[1]

Lastly, calcium carbonate also works in the blood to treat or prevent negative calcium balance seen in low serum calcium conditions.[1] After being absorbed in the small intestines actively with the help of vitamin D and passively via diffusion, ionized calcium circulates in the blood. 

Manufacturing, Bioavailability, and Absorption

Calcium carbonate comes in tablet, chewable, oral suspension, or powder form. Tablets should be swallowed while drinking a full glass of water. The oral suspension should be well shaken before measuring the dose, to ensure the ingestion of the proper amount. The bioavailability of calcium from calcium carbonate is higher as a powder.[27] Although calcium citrate has higher bioavailability of calcium than calcium carbonate, in foods fortified with calcium, calcium carbonate allows for better absorption than other calcium fortification compounds.[1][27][28]

Dosing depends on the indicated condition and patient age. For adult use for heartburn, dosing exceeds 1 gram (1000 mg), but should not exceed 7 grams in a day. For adult use for calcium supplementation, 1 to 1.2 grams may be taken orally per day, divided, and taken at meals. For adults with hyperphosphatemia, 1.5 to 3 grams per day effectively achieves optimal phosphate control in 65% of patients.[29] If the patient misses a regular dose, they should take it when they remember it, unless it is close to the next dose. At the time of the next dose, they should take the regular dose, and not double the dose.

Beyond age and form of calcium carbonate, absorption of calcium can be affected by the dose given, pH of the stomach, size of the patient, estrogen status, vitamin D level, and genetic polymorphisms.[1][12] The fractional absorption is highest at 500 mg when taken with food, and the stomach is acidic.[1][4][30] Fractional absorption also increases when the person has sufficient vitamin D, does not have an absorption disorder, is young, has more estrogen, and has a larger body size.[1][4][30] Absorption of calcium carbonate decreases if an individual has a mucosal lining disorder or achlorhydria.[31]

Distribution, Metabolism, and Elimination

As previously mentioned, calcium storage in the body is primarily in bones and teeth. However, in the blood, most of the calcium is found as the ionized, physiologically active form. Calcium carbonate is not metabolized in the traditional pharmacokinetic sense. Calcium carbonate is excreted in the feces as unabsorbed calcium carbonate, in the urine depending on glomerular filtration and renal tubule reabsorption controlled by parathyroid hormone (PTH) and Vitamin D, and as carbon dioxide from the lungs.[1]

Pregnancy and Breast Feeding

Calcium can travel through the placenta and into breast milk during nursing. Calcium carbonate is safe to use for pregnant patients who have GERD, for aspiration prophylaxis before labor, and for nursing.[2][13]   

Storage and Drug Interactions

Calcium carbonate should be stored at room temperature and not frozen or exposed to heat.[13] Calcium carbonate should not be administered with other drugs known to decrease its absorption, such as histamine-2 receptor antagonists, glucocorticoids, and thiazide diuretics, but rather rescheduled to be taken at separate times.[1][32] Conversely, vitamin D will increase the absorption of calcium carbonate if coadministered, and patients are encouraged to take them together.[1][4]

Additionally, calcium carbonate will limit many drugs' effectiveness if taken together by increasing stomach pH and decreasing their absorption.[12] These drugs include bisphosphonates, fluoroquinolones, tetracyclines, thyroid hormones, proton-pump-inhibitors, such as omeprazole, iron, and anti-arrhythmic drugs like verapamil.[1][12][33] Calcium carbonate can also interact with the excretion of many drugs as it causes urine alkalization and will quicken the excretion of drugs that exist as weak acids and lengthen the excretion of drugs that exist as weak bases in the blood.[12]

Due to the short term, periodic nature of calcium carbonate/antacid use, and the small dose of calcium carbonate used for supplementation, most adverse effects are minor. However, if large doses are taken for an extended time or abused, overdose can occur. The moderate to severe side effects of overdose include:[34][35][36][37][38][39]

• Coma
• Confusion
• Irregular heart rhythms
• Muscle twitching
• Bone pain
• Abdominal pain
• Pancreatitis
• Acute renal failure
• Kidney stones
• Headache
• Milk-alkali syndrome
• Gall stones 

Milk-alkali syndrome was historically a much more common severe side effect.[34] Milk-alkali syndrome results from hypercalciuria, and alkaluria predisposing renal calculi and causing sequelae such as pancreatitis and acute renal failure.[34] 

Common Side Effects:[2]

• High calcium levels
• Low phosphate levels
• Vomiting
• Nausea
• Constipation
• Gas
• Loss of appetite/anorexia
• Irritability
• Xerostomia
• Acid rebound

Additional side-effects occur in individuals taking calcium carbonate as a phosphate binder for the treatment of hyperphosphatemia, including calcification of vascular tissues and death.[29]

Calcium carbonate use is contraindicated in cases of hypersensitivity, renal calculus, high urine calcium levels, elevated serum calcium, low serum phosphate, achlorhydria, or suspected digoxin toxicity.

Care is necessary for patients with a history of kidney disease, heart failure, edema, or endocrine disorders, such as hypoparathyroidism.[40][41] Additionally, calcium carbonate users should never be prescribed ceftriaxone as an antibiotic because of the increased risk of end-organ failure and death.[42]