• Cimetidine
  
• Famotidine
  
• Nizatidine
  
• Ranitidine Bismuth Citrate
  
• Ranitidine Hydrochloride
  

In several trials, cimetidine reduced calcium absorption which was thought to be secondary to the effects of the drug on vitamin D metabolism rather than inhibition of gastric acid secretion (Bo-Linn et al. 1984; Caron et al. 1987; Ghishan et al. 1981). However, in a double-blind, placebo-controlled crossover study with 8 primary hyperparathyroid patients treated with cimetidine or placebo for 2 months, serum calcium levels declined significantly in only one patient and parathyroid hormone was affected in only one patient (Fisken et al. 1982). Periodic assessment of calcium levels and/or bone density may be appropriate in patients on chronic cimetidine therapy, particularly postmenopausal women.

Osteoporosis is the primary disease associated with chronic calcium deficiency; it can result in pathologic fractures associated with bone pain, spinal deformity, and premature morbidity and mortality (Cashman and Flynn 1999; Covington 1999). Other signs and symptoms of depleted serum calcium levels include arrhythmias, neuromuscular irritability, and mental status changes such as depression and psychosis (Potts 1998).

Calcium supplementation in the form of citrate, malate, gluconate, or carbonate salts may range from 1000 mg to 1500 mg or more daily (Adler and Rosen 1999; Covington 1999). Doses as high as 3000 mg/day with 10 to 50 mcg/day of 25-OH-D3 may be appropriate if plasma calcium and phosphate levels are stable and within normal range (Drüeke 1999). In cases where calcium deficits are associated with vitamin D deficiency, up to 6000 mg/day of calcium (acetate or carbonate) may be warranted. These values should be adjusted on an individual basis depending upon the patient's age, gender, clinical presentation, serum calcium levels, dietary habits, and medication regimen. Calcium replacement should be part of a comprehensive approach to the evaluation and treatment of osteoporosis.

High doses of H2 receptor antagonists may significantly reduce non-heme iron absorption by reducing gastric acid secretion (Aymard et al. 1988; Skikne et al. 1981).

Iron deficiency may be associated with oxidative DNA damage (Ames 2000). In children, iron deficiency leads to cognitive dysfunction. Other pathologies associated with depleted levels of iron include anemia and compromised immune function. Symptoms include dizziness, fatigue, shortness of breath, pallor, and tachycardia (Covington 1999).

Therapeutic doses for replacement therapy for adults range from 100 to 200 mg/day (2 to 3 mg/kg/day) of elemental iron, usually in 3 divided doses (Covington 1999). Iron levels should be monitored carefully; excess levels could also be associated with oxidative DNA damage as well as increased risk of cancer and heart disease (Ames 2000). The oral lethal dose of elemental iron is estimated to be 200 to 250 mg/kg with symptoms presenting after ingestion of 30 to 60 mg/kg (Covington 1999). Iron supplements can cause GI irritation; administering the supplement with food will prevent GI upset and bleeding (Hines Burnham et al. 2000).

Chronic use of H2 receptor antagonists may cause folic acid deficiency, particularly if the diet is already low in folate; the optimum pH for folic acid absorption is 5.5 to 6.0 (Russell et al. 1988). Cimetidine reduces folate absorption by decreasing gastric acid secretion and increasing the pH of the proximal small intestine. However, folate absorption was not significantly affected by ranitidine, even though this drug also increased the pH of the proximal small intestine. Folic acid depletion has not been reported with famotidine or nizatidine, but may occur with nizatidine because it also increases gastric pH.

Low levels of folate have been linked to colon cancer, heart disease, cognitive deficits, and birth defects, specifically neural tube defects (Ames 2000; Covington 1999). Deficiency increases chromosome breakage and elevates serum homocysteine. Vitamin B9 deficiency may also lead to megaloblastic anemia.

The recommended dietary allowance (RDA) for adults is 300 to 600 mcg/day (Covington 1999). However, recommendations of doses of folic acid as high as 2000 mcg/day have been reported in the literature (Mayer et al. 1996). For replacement therapy, doses should be based upon the patient's individual needs, considering the clinical presentation, age, gender, dietary habits, and medication regimen.

H2 receptor antagonists can cause vitamin B12 deficiency by reducing gastric acid secretion (Force and Nahata 1992). Gastric acid helps cleave vitamin B12 from food and is necessary for B12 absorption (Festen 1991; Force and Nahata 1992).

Low vitamin B12 levels could increase the risk of colon cancer, heart disease, brain dysfunction, birth defects, and irreversible neuropathy (Ames 2000; Covington 1999). Irritability, weakness, numbness, fatigue, glossitis, anorexia, headache, palpitations, and altered mental status, including personality and behavioral changes, are some of the signs and symptoms of vitamin B12 depletion (Covington 1999). Prolonged deficiency leads to pernicious or megaloblastic anemia that may be associated with leukopenia and thrombocytopenia.

Doses of 25 to 250 mcg/day of vitamin B12 have been used to correct nutritional deficiency (Covington 1999). Oral doses between 500 to 1000 mcg/day have been recommended for the treatment of pernicious anemia (Carmel 2000). Replacement therapy should be based on the patient's individual needs, considering the clinical presentation, serum B12 levels, age, gender, dietary habits, and medication regimen.

Short-term treatment with cimetidine may inhibit vitamin D-hydroxylase activity and alter vitamin D metabolism (Bengoa et al. 1984; Odes et al. 1990). This has not been reported with famotidine, nizatidine, or ranitidine. Whether chronic cimetidine therapy can contribute to a calcium or vitamin D deficiency is unknown.

Because vitamin D is fat-soluble, prolonged periods of deficiency are required to produce symptoms (National Research Council 1989). While the long evolution is often asymptomatic (Rao 1999), depleted levels are characterized by inadequate mineralization of the bone, which could lead to rickets (in children) and osteomalacia (in adults) (Covington 1999; National Research Council 1989; Rao 1999). Other signs and symptoms of low levels of vitamin D include increased risk of fractures, osteoporosis, phosphaturia, hyperparathyroidism, chronic muscle weakness, hypovitaminosis D, bone pain, pseudofractures, waddling gait, or severe, chronic hypocalcemia (Holick et al. 1998; National Research Council 1989; Rao 1999; Vieth 1999). Subclinical vitamin D deficiency has been reported in postmenopausal women with osteoporosis (Rao 1999). The prevalence of vitamin D deficiency is more common in women, certain ethnic populations, and increases with age.

Doses of vitamin D3 ranging from 1000 to 2000 IU/day or 25-OH-D3 ranging from 10 to 25 mcg/day have been used to treat vitamin D deficiency, which is characterized by low plasma levels of 25-OH-D3 (Drüeke 1999). Other recommendations involve doses between 200 to 800 IU/day for adults (Rao 1999) and 50,000 IU/month for elderly patients with osteomalacia (Holick et al. 1998).

Optimal pH for zinc absorption is 3 or less (Henderson et al. 1995). Famotidine reduces zinc absorption by increasing gastric pH above five. Likewise, ranitidine reduces zinc absorption by inhibiting gastric acid secretion and increasing gastric pH (Sturniolo et al. 1991). Cimetidine and nizatidine may also reduce zinc absorption by decreasing gastric acid secretion; research indicates that zinc levels in the prostate gland are depleted by cimetidine (Pinelli et al. 1987).

Clinically, signs and symptoms of zinc deficiency include alopecia, dermatitis, diarrhea, growth retardation, increased susceptibility to infection, and loss of appetite or sense of taste (Ames 2000; Falchuk 1998). Severe zinc deficiency further impacts dermatologic, gastrointestinal, immune, nervous, reproductive, respiratory, and skeletal systems (Ames 2000; Hambidge 2000).

Doses of zinc up to 50 mg/day may be recommended (Hambidge 2000). This upper limit includes an adult's total daily intake, which may be higher than anticipated because of the increasing trend to fortify foods with zinc. It is important to be mindful of this limit, even if decisions are deliberately made to temporarily exceed this level for anticipated pharmacological benefits.

This information is intended to serve as a concise reference for healthcare professionals to identify substances that may be depleted by many commonly prescribed medications. Depletion of these substances depends upon a number of factors including medical history, lifestyle, dietary habits, and duration of treatment with a particular medication. The signs and symptoms associated with deficiency may be nonspecific and could be indicative of clinical conditions other than deficiency. The material presented in these monographs should not in any event be construed as specific instructions for individual patients.

Adler RA, Rosen CJ. Glucocorticoids and osteoporosis. Endocrinol Metab Clin North Am. 1999;23:641-654.

Ames BN. Micronutrient deficiencies: A major cause of DNA damage. Ann NY Acad Sci. 2000;889:87-106.

Aymard JP, Aymard B, Netter P, et al. Haematological adverse effects of histamine H2-receptor antagonists. Med Toxicol Adverse Drug Exp. 1988;3(6):430-448.

Bengoa JM, Bolt MJ, Rosenberg IH. Hepatic vitamin D 25-hydroxylase inhibition by cimetidine and isoniazid. J Lab Clin Med. 1984;104(4):546-552.

Bo-Linn GW, Davis GR, Buddrus DJ, et al. An evaluation of the importance of gastric acid secretion in the absorption of dietary calcium. J Clin Invest. 1984;73(3):640-647.

Carmel R. Current concepts in cobalamin deficiency. Ann Rev Med. 2000;51:357-375.

Caron P, Gaillard J, Barousse C, et al. [Cimetidine treatment of primary hyperparathyroidism]. Biomed Pharmacother. 1987;41(3):143-146.

Cashman K, Flynn A. Optimal nutrition: calcium, magnesium and phosphorus. Proc Nutr Soc. 1999;58:477-487.

Covington T, ed. Nonprescription Drug Therapy Guiding Patient Self-Care. St Louis, MO: Facts and Comparisons; 1999:467-545.

Drüeke T. Medical management of secondary hyperparathyroidism in uremia. Am J Med Sci. 1999;317(6):383-389.

Falchuk KH. Disturbances in Trace Elements. In: Fauci A, Braunwald E, Isselbacher KJ, et al, eds. Harrison's Principles of Internal Medicine. 14^th ed. New York, NY: McGraw-Hill Companies Health Professional Division; 1998:490-491.

Festen HP. Intrinsic factor secretion and cobalamin absorption. Physiology and pathophysiology in the gastrointestinal tract. Scand J Gastroenterol. 1991;188:1-7.

Fisken R, Wilkinson R, Heath D. The effects of cimetidine on serum calcium and parathyroid hormone levels in primary hyperparathyroidism. Br J Clin Pharm. 1982;14:701-705.

Force RW, Nahata MC. Effect of histamine H2-receptor antagonists on vitamin B12 absorption. Ann Pharmacother. 1992;26(10):1283-1286.

Ghishan FK, Walker F, Meneely R, Patwardhan R, Speeg KV Jr. Intestinal calcium transport: effect of cimetidine. J Nutr. 1981;111(12):2157-2161.

Hambidge M. Human zinc deficiency. J Nutr. 2000;130(5S Suppl):1344S-1349S.

Henderson LM, et al. Effect of intragastric pH on the absorption of oral zinc acetate and zinc oxide in young healthy volunteers. JPEN J Parenter Enteral Nutr. 1995 Sep-Oct;19(5):393-397.

Hines Burnham T, et al, eds. Drug Facts and Comparisons. St. Louis, MO: Facts and Comparisons; 2000:31.

Holick MF, Krane SM, Potts JT. Calcium, phosphorus, and bone metabolism: calcium-regulating hormones. In: Fauci AS, Braunwald E, Isselbacher KJ, et al, eds. Harrison's Principles of Internal Medicine. 14^th ed. New York: McGraw-Hill Companies Health Professional Division; 1998:2221-2222.

Mayer EL, Jacobsen DW, Robinson K. Homocysteine and coronary atherosclerosis. J Am Coll Cardiol. 1996;27(3):517-527.

National Research Council, Recommended Dietary Allowances. 10^th ed. Washington, DC: National Academy Press; 1989.

Odes HS, Fraser GM, Krugliak P, et al. Effect of cimetidine on hepatic vitamin D metabolism in humans. Digestion. 1990;46(2):61-64.

Pinelli P, Trivulzio S, Colombo R, et al. Antiprostatic effect of cimetidine in rats. Agents Actions. 1987:22(3-4):197-201.

Potts JT. Diseases of the parathyroid gland and other hyper- and hypocalcemic disorders. In: Fauci AS, Braunwald E, Isselbacher KJ, et al, eds. Harrison's Principles of Internal Medicine. 14^th ed. New York: McGraw-Hill Companies Health Professional Division; 1998:2241.

Rao DS. Perspective on assessment of vitamin D nutrition. J Clin Densitom. 1999:2(4):457-464.

Russell RM, Golner BB, Kransinski SD, et al. Effect of antacid and H2 receptor antagonists on the intestinal absorption of folic acid. J Lab Clin Med. 1988;112)4):458-463.

Skikne BS, Lynch SR, Cook JD. Role of gastric acid in food iron absorption. Gastroenterol. 1981;81(6):1068-1071.

Sturniolo GC, Montino MC, Rossetto L, et al. Inhibition of gastric acid secretion reduces zinc absorption in man. J Am Coll Nutr. 1991;10(4):372-375.

Vieth R. Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. Am J Clin Nutr. 1999;69:842-56.