|Histamine H2 Antagonists|
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
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 (DrŁeke 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
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.
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
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
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
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
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
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
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 (DrŁeke 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
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
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.
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
Carmel R. Current concepts in cobalamin deficiency. Ann Rev Med.
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.
DrŁeke 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.
14th ed. New York, NY: McGraw-Hill Companies Health Professional
Festen HP. Intrinsic factor secretion and cobalamin absorption. Physiology
and pathophysiology in the gastrointestinal tract. Scand J Gastroenterol.
Fisken R, Wilkinson R, Heath D. The effects of cimetidine on serum calcium
and parathyroid hormone levels in primary hyperparathyroidism. Br J Clin
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.
Hambidge M. Human zinc deficiency. J Nutr. 2000;130(5S
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. 14th
ed. New York: McGraw-Hill Companies Health Professional Division;
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.
10th 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. 14th ed. New York: McGraw-Hill
Companies Health Professional Division; 1998:2241.
Rao DS. Perspective on assessment of vitamin D nutrition. J Clin
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
Skikne BS, Lynch SR, Cook JD. Role of gastric acid in food iron absorption.
Sturniolo GC, Montino MC, Rossetto L, et al. Inhibition of gastric acid
secretion reduces zinc absorption in man. J Am Coll Nutr.
Vieth R. Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and
safety. Am J Clin Nutr.
Copyright © 2000 Integrative Medicine
CommunicationsThis publication contains
information relating to general principles
of medical care that should not in any event be construed as specific
instructions for individual patients. The publisher does not accept any
responsibility for the accuracy of the information or the consequences arising
from the application, use, or misuse of any of the information contained herein,
including any injury and/or damage to any person or property as a matter of
product liability, negligence, or otherwise. No warranty, expressed or implied,
is made in regard to the contents of this material. No claims or endorsements
are made for any drugs or compounds currently marketed or in investigative use.
The reader is advised to check product information (including package inserts)
for changes and new information regarding dosage, precautions, warnings,
interactions, and contraindications before administering any drug, herb, or
supplement discussed herein.