Rx Side Effects

Group lectures and one on one consult available on this topic (contact)

The side effects of NSAIDs (nonsteroidal antiinflammatory drug) are not appreciated by the average consumer. A recent review by Wolfe et. al.1 helps put the problem in perspective for one of the problems, i.e. gastrointestinal toxicity. On the basis of conservative figures "...the annual number of hospitalizations in the United States for serious gastrointestinal complications is estimated to be at least 103,000. At an estimated cost of $15,000 to $20,000 per hospitalization, the annual direct costs of such complications exceed $2 billion." The emphasis of cost fails to recognize the more important mortality rate for patients hospitalized for NSAID-induced upper gastrointestinal bleeding which is reported by Wolfe et. al.1 as about 5 to 10 percent. They further report, "It has been estimated conservatively that 16,500 NSAID-related deaths occur among patients with rheumatoid arthritis or osteoarthritis every year in the United States. This figure is similar to the number of deaths from the acquired immunodeficiency syndrome [AIDS] and considerable greater than the number of deaths from multiple myeloma, asthma, cervical cancer, or Hodgkin's disease."

NSAIDs cause problems in the entire gastrointestinal tract,2 ranging from peptic ulcers3,4,5 to small intestine6 and colon problems. In a study to determine the safety of low-dose daily aspirin therapy in the gastrointestinal tract, it was concluded that the safety of even 10 mg of daily aspirin is questionable,7 which is way below the typical baby aspirin dosage of 80 mg. The problems do not stop in the gut; the breakdown of the gut mucous membranes leads to leaky gut syndrome with all of its ramifications, including liver toxicity.

One of the most common reasons for taking NSAIDs is to relieve joint pain. Unfortunately the very thing that is expected to gain relief often makes the condition worse by blocking glycosaminoglycans (GAGS) production necessary for repair,8,9,10 in one in vitro study by as much as 60-70%.11 Therapeutic levels of aspirin in vitro have effects of suppressing proteoglycan biosynthesis in normal and degenerating articular cartilage similar to several other NSAIDs12 and permeate osteoarthritic cartilage 35% more than in normal cartilage.13,14 Glucosamine is in the popular press as an aid to improve the symptoms of osteoarthritis or joint pain. It is one of the glycosamionglycans.and the more NSAIDs are taken to control joint pain the more the very thing that repairs the joints is destroyed. It is a vicious circle.

1. Wolfe, Michael M., et al, "Gastrointestinal Toxicity of Nonsteroidal Antiinfammatory Drugs" New Eng Jn of Med Vol 340, No 24 (Jun 17, 1999)

2. Roth, S.H., “Nonsteroidal anti-inflammatory drugs: Gastropathy, deaths, and medical practice,” Ann Intern Med, Vol 109, No 5 (Sep 1, 1988).

3.Gabriel, S.E., L. Jaakkimainen, & C. Bombardier, “Risk for serious gastrointestinal complications related to use of nonsteroidal anti-inflammatory drugs. A meta-analysis,” Ann Intern Med, Vol 115, No 10 (Nov 15, 1991).

4.Griffin, M.R. et al., “Nonsteroidal anti-inflammatory drug use and increased risk for peptic ulcer disease in elderly persons,” Ann Intern Med, Vol 114, No 4 (Feb 15, 1991).

5.Langman, M.J. et al., “Risks of bleeding peptic ulcer associated with individual non-steroidal anti-inflammatory drugs,” Lancet, Vol 343 (Apr 30, 1994).

6.Melo Gomes, J.A. et al., “Double-blind comparison of efficacy and gastroduodenal safety of diclofenac/misoprostol, piroxicam, and naproxen in the treatment of osteoarthritis,” Ann Rheum Dis, Vol 52, No 12 (Dec 1993).

7.Cryer, B., & M. Feldman, “Effects of very low dose daily, long-term aspirin therapy on gastric, duodenal, and rectal prostaglandin levels and on mucosal injury,” Gastroenterology, Vol 117, No 1 (Jul 1999).

8. Dekel, S., J. Falconer, & M.J. Francis, “The effect of anti-inflammatory drugs on glycosaminoglycan sulphation in pig cartilage,” Prostaglandins Med, Vol 4, No 3 (Mar 1980).

9. de Vries, B.J., W.B. van den Berg, & L.B. van de Putte, “Salicylate-induced depletion of endogenous inorganic sulfate. Potential role in the suppression of sulfated glycosaminoglycan synthesis in murine articular cartilage,” Arthritis Rheum, Vol 28, No 8 (Aug 1985).

10. Hugenberg, S.T., K.D. Brandt, & C.A. Cole, “Effect of sodium salicylate, aspirin, and ibuprofen on enzymes required by the chondrocyte for synthesis of chondroitin sulfate,” J Rheumatol, Vol 20, No 12 (Dec 1993).

11. Yoo, J.U., R.S. Papay, & C.J. Malemud, “Suppression of proteoglycan synthesis in chondrocyte cultures derived from canine intervertebral disc,” Spine, Vol 17, No 2 (Feb 1992).

12. Brandt, K.D., & M.J. Palmoski, “Effects of salicylates and other nonsteroidal anti-inflammatory drugs on articular cartilage,” Am J Med, Vol 77, No 1A (Jul 13, 1984).

13. Brandt, K.D., “Effects of nonsteroidal antiinflammatory drugs on chondrocyte metabolism in vitro and in vivo,” Am J Med, Vol 83, No 5A (Nov 20, 1987).

14. Palmoski, M.J., R.A. Colyer, & K.D. Brandt, “Marked suppression by salicylate of the augmented proteoglycan synthesis in osteoarthritis cartilage,” Arthritis Rheum, Vol 23, No 1 (Jan 1980).

Pharaceuticals Side effects and Depletions

1. Anti-inflammatory Medications

2. Antibiotic Medications

3. Anticonvulsant Medications

4. Antidepressant Medications

5. Antidiabetic Medications

6. Antihypertensive Medications

7. Cardiovascular Medications

8. Cholesterol-Lowering Medications

9. Corticosteroids Diuretics

10, Gastrointestinal Medications

11. Oral Contraceptives

12. Osteoporosis Medications

13. Psychotherapeutic Medications

1. Anti-inflammatory Medications Nonsteroidal Anti-inflammatory Drugs (NSAIDs)

Diclofenac (Cataflam® Oral; Solaraze™ Topical; Voltaren® Ophthalmic; Voltaren® Oral; Voltaren®-XR Oral)

Diflunisal (Dolobid®)

Etodolac (Lodine®; Lodine® XL)

Fenoprofen (Nalfon®)

Ibuprofen (Advil® Migraine Liqui-Gels [OTC]; Advil®[OTC]; Children's Advil® Oral Suspension [OTC]; Children's Motrin® Oral Suspension [OTC]; Genpril®[OTC]; Haltran®[OTC]; Junior Strength Motrin®[OTC]; Menadol®[OTC]; Midol® IB [OTC]; Motrin®; Motrin® IB [OTC]; Motrin® Migraine Pain [OTC]; Nuprin®[OTC])

Indomethacin (Indocin®)

Ketoprofen (Actron®[OTC]; Orudis®; Orudis® KT [OTC]; Oruvail®)

Ketorolac Tromethamine (no brand names listed)

Meclofenamate (no brand names listed)

Nabumetone (Relafen®)

Naproxen (Aleve®[OTC]; Anaprox®; EC-Naprosyn®; Naprelan®; Naprosyn®)

Oxaprozin (Daypro™)

Piroxicam (Feldene®)

Sulindac (Clinoril®)

Tolmetin (Tolectin®; Tolectin® DS)

Depletions

Iron

Mechanism

NSAIDs can damage the stomach as well as the small and large intestines, causing ulceration, chronic bleeding, and eventually iron deficiency (Bertschinger et al. 1996; Bjarnason and Macpherson 1994; Davies 1995).

Significance of Depletion

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).

Replacement Therapy

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).

Melatonin

Mechanism

Plasma levels of melatonin were significantly reduced after administration of both ibuprofen (400 mg) and indomethacin (75 mg) compared to controls, perhaps through interference with prostaglandin synthesis (Surrall et al. 1987).

Significance of Depletion

Alterations in melatonin levels have been associated with disturbances in the sleep-wake cycle and jet lag (Avery et al. 1998).

Replacement Therapy

Optimal doses for melatonin therapy have not been established (Avery et al. 1998). Commonly available doses range from 0.3 to 5 mg. Physiological blood levels are achieved with doses of 0.3 mg; higher doses (1 mg) result in supraphysiological levels of melatonin in the blood. The efficacy of melatonin supplementation is dependent upon the time of administration, as effects are related to circadian rhythms.

Vitamin B9 (Folic Acid)

Mechanism

Non-steroidal antiinflammatory drugs (NSAIDs), such as ibuprofen, have antifolate activity (Baggott et al. 1992). It is not known if chronic ibuprofen treatment will cause a folate deficiency.

Significance of Depletion

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.

Replacement Therapy

Zinc

Mechanism

Administration of naproxen (250 mg tid) in ten healthy volunteers for either 7 or 14 days resulted in a 35% increase in urinary zinc excretion but serum zinc levels remained unchanged (Elling et al. 1980). However, another report indicates that serum zinc levels were altered by NSAID therapy and decreased to 10.47 mmol/L in patients treated with NSAIDs (Balogh et al. 1980).

Significance of Depletion

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).

Replacement Therapy

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.

References

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

Avery D, Lenz M, Landis C. Guidelines for prescribing melatonin. Ann Med. 1998;30:122-130.

Baggott JE, Morgan SL, Ha T, et al. Inhibition of folate-dependent enzymes by non-steroidal anti-inflammatory drugs. Biochem J. 1992;282(Pt 1):197-202.

Balogh Z, El-Ghobarey AF, Fell GS, et al. Plasma zinc and its relationship to clinical symptoms and drug treatment in rheumatoid arthritis. Ann Rheum Dis. 1980;39:329-332.

Bertschinger P, Zala GF, Fried M. [Effect of non-steroidal antirheumatic agents on the gastrointestinal tract: clinical aspects and pathophysiology]. Schweiz Med Wochenschr. 1996;126(37):1566-1568.

Bjarnason I, Macpherson AJ. Intestinal toxicity of non-steroidal anti-inflammatory drugs. Pharmacol Ther. 1994;62(1-2):145-157.

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

Davies NM. Toxicity of nonsteroidal anti-inflammatory drugs in the large intestine. Dis Colon Rectum. 1995;38(12):1311-1321.

Elling H, Kiilerich S, Sabro J, Elling P. Influence of a non-steroid anti-rheumatic drug on serum and urinary zinc in healthy volunteers. Scand J Rheumatol. 1980;9:161-163.

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 Division; 1998:490-491.

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

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

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

Surrall K, Smith JA, Bird H, Okala B, Othman H, Padwick DJ. Effect of ibuprofen and indomethacin on human plasma melatonin. J Pharm Pharmacol. 1987;39(10):840-843.

2. Antibiotic Medications

Antibiotic Combination: Sulfa Drugs

Antibiotic Combination: Sulfa Drugs Co-Trimoxazole Trimethoprim-Sulfamethoxazole Cephalosporin Antibiotics Cefprozil Cefuroxime Loracarbef Macrolide Antibiotics Azithromycin Clarithromycin Erythromycin, Systemic Penicillin Derivatives Amoxicillin Amoxicillin and Clavulanate Potassium Penicillin V Potassium Quinolone Antibiotics Cinoxacin Ciprofloxacin Enoxacin Gatifloxacin Levofloxacin Lomefloxacin Moxifloxacin Nalidixic Acid Norfloxacin Ofloxacin Sparfloxacin Trovafloxacin Tetracycline Derivatives Doxycycline Minocycline Tetracycline

Co-Trimoxazole (Bactrim™; Bactrim™ DS; Septra®; Septra® DS; Sulfatrim®; Sulfatrim® DS)

Trimethoprim-Sulfamethoxazole (no brand names listed)

Depletions

Probiotics; Bifidobacteria bifidum; Lactobacillus Acidophilus; Saccaromyces boulardii

Mechanism

Alteration of intestinal microflora is a common side effect of antibiotic treatment (Nord 1993; Beaugerie 1996). These changes can affect the availability of vitamins B and K.

Significance of Depletion

Altering the balance of probiotic organisms in the gastrointestinal tract may reduce resistance to infection and disease. Symptoms of deficiency include gas, abdominal distress, diarrhea, and yeast infections (Galland 1997).

Replacement Therapy

Prophylactic administration of a combination of L. acidophilus and L. bulgaricus prevents ampicillin-induced diarrhea (Gotz et al. 1979). Other bacterial strains that may prevent or treat antibiotic-induced diarrhea include L. casei GG, Saccaromyces boulardii, and Bifidobacterium longum (either alone or combined with L. acidophilus) (Elmer et al. 1996). Administration of preparations containing 1 to 2 billion organisms are typically required (Murray and Pizzorno 1998). Positive results have been observed with S. boulardii at doses of 250 mg bid (Surawicz et al. 1989) or 1 g/day containing 3 x 1010 colony-forming units (the equivalent of 2 x 250 mg capsules bid) (McFarland et al. 1995).

Vitamin B2 (Riboflavin); Vitamin B12 (Cobalamin); Vitamin H (Biotin)

Mechanism

Intestinal bacteria synthesize vitamin K and B vitamins such as biotin, B2, B12, and folic acid; they are a potentially rich source of these nutrients (Albert et al. 1980; Hill 1997). Although it is unusual to see measurable deficiencies, chronic antibiotic therapy could deplete these vitamins by altering and destroying the normal intestinal bacteria that synthesize them (Hill 1997).

Significance of Depletion

Vitamin B2: Riboflavin deficiency usually occurs as a result of deficiencies in dietary protein and is associated with other B vitamin deficiencies (Covington 1999). Depleted levels of riboflavin affect carbohydrate and amino acid metabolism by interfering with enzyme systems involved in the production of ATP. Lack of an adequate supply of riboflavin disturbs several physiological and biochemical processes and results in retarded growth in infants and children (Covington 1999; Powers 1999). Symptoms include corneal vascularization, glossitis, cheilosis, seborrheic dermatitis, and impaired wound healing (Covington 1999).

Vitamin B12: Symptomatic vitamin B12 deficiency is rare because complications may appear only after the deficiency has existed for 10 to 15 years (Berger 1985; Carpentier et al. 1976). 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.

Vitamin H: Although biotin deficiency is uncommon, nonspecific symptoms such as changes in skin color as well as the development of non-pruritic dermatitis, alopecia, and muscle pain may be indicative of depleted biotin levels (Covington 1999). Additionally, low levels of this nutrient may be associated with hypercholesterolemia, anemia, anorexia, depression, and insomnia

Replacement Therapy

Note: B vitamins are best if given as B-complex.

Vitamin B2: Doses of 5 to 25 mg/day are recommended for the treatment of riboflavin deficiency (Covington 1999). For replacement therapy, doses should be based upon the patient's individual needs, considering the clinical presentation, serum riboflavin levels, age, gender, dietary habits, and medication regimen.

Vitamin B12: 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.

Vitamin H: Biotin deficiency is treated with doses between 1 mg and 10 mg to resolve symptoms and prevent recurrence (Mock et al. 1996). Replacement therapy should be based upon the patient's clinical presentation, serum biotin levels, age, gender, dietary habits, and medication regimen.

Vitamin B9 (Folic Acid)

Mechanism

Trimethoprim acts as a folate antagonist by inhibiting dihydrofolate reductase; high-dose trimethoprim therapy decreases serum folate concentrations (Lambie and Johnson 1985; Naderer et al. 1997). Co-Trimoxazole does not appear to depress serum folate levels to the same extent as trimethoprim monotherapy (Bateson et al. 1976). However, there have been reports of co-trimoxazole affecting folate metabolism, usually following long-term or high-dose therapy (Taraszewski et al. 1989). Patients with compromised folate status prior to co-trimoxazole therapy may be at greater risk for developing a folate deficiency.

Significance of Depletion

Replacement Therapy

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, serum folate levels, age, gender, dietary habits, and medication regimen. Folate therapy has had a negative outcome on AIDS patients diagnosed with pneumocystis carinii pneumonia (Bygbjerg et al. 1988; Safrin et al. 1994). Therefore, folic acid supplementation may not be warranted in this population of patients.

Note: Folate may be administered concomitantly without interfering with the antibacterial action of trimethoprim (Hines Burnham et al. 2000).

Vitamin K

Mechanism

Broad spectrum antibiotics reduce hepatic vitamin K2 (menaquinone) stores as well as gut microflora, which can deplete vitamin K by diminishing bacterial synthesis of this nutrient (Conly and Stein 1994; Stieger et al. 1992).

Significance of Depletion

Interference with intestinal synthesis of vitamin K is usually not sufficient to cause a deficiency (Covington 1999). However, a reduction in prothrombin and other vitamin K-dependent factors may indicate a deficiency (Olson 1999). Severe deficiency may be associated with detectable plasma levels of descarboxyprothrombin (Vermeer and Schurgers 2000). Signs and symptoms of deficiency include coagulation disorders manifested by hypoprothrombinemia with internal and external hemorrhage (Covington 1999).

Replacement Therapy

Generally, 45 to 80 mcg/day are recommended for daily intake to maintain overall health (Covington 1999). Individual requirements should be tailored to the patient's clinical presentation, serum levels, age, gender, dietary habits, and medication regimen.

References

Albert MJ, Mathan VI, Baker SJ. Vitamin B12 synthesis by human small intestinal bacteria. Nature. 1980;283(5749):781-782.

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

Bateson MC, Hayes JP, Pendharker P. Cotrimoxazole and folate metabolism. Lancet. 1976;2(7981):339-340.

Beaugerie L. [Diarrhea caused by antibiotic therapy]. Rev Prat. 1996;46(2):171-176.

Berger W. Incidence of severe side effects during therapy with sulfonylureas and biguanides. Horm Metab Res Suppl. 1985;15:111-115.

Bygbjerg IC, Lund JT, Hording M. Effect of folic and folinic acid on cytopenia occurring during co-trimoxazole treatment of Pneumocystis carinii pneumonia. Scand J Infect Dis. 1988;20(6):685-686.

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

Carpentier JL, Bury J, Luyckx A, Lefebvre P. Vitamin B12 and folic acid serum levels in diabetics under various therapeutic regimens. Diabetes Metab. 1976;2(4):187-190.

Conly J, Stein K. Reduction of vitamin K2 concentrations in human liver associated with the use of broad spectrum antimicrobials. Clin Invest Med. 1994;17(6):531-539.

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

Elmer GW, Surawicz CM, McFarland LV. Biotherapeutic agents. A neglected modality for the treatment and prevention of selected intestinal and vaginal infections. JAMA. 1996;275(11):870-876.

Galland L. The Four Pillars of Healing. New York, NY: Random House; 1997:186-199.

Gotz, V, Romankiewicz JA, Moss J, et al. Prophylaxis against ampicillin-associated diarrhea with a lactobacillus preparation. Am J Hosp Pharm. 1979;36(6):754-757.

Hill MJ. Intestinal flora and endogenous vitamin synthesis. Eur J Cancer Prev. 1997;6(Suppl 1):S43-45.

Hines Burnham, et al, eds. Drug Facts and Comparisons. St. Louis, MO:Facts and Comparisons; 2000:1346.

Lambie DG, Johnson RH. Drugs and folate metabolism. Drugs. 1985;30(2):145-155.

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

McFarland LV, Surawicz CM, Greenberg RN, et al. Prevention of Beta-lactam-associated diarrhea by Saccharomyces boulardi compared with placebo. Am J Gastroenterol. 1995;90(3):439-448.

Mock DM. Biotin. In: Ziegler EE, Filer LJ, eds. Present Knowledge in Nutrition. 7th ed. Washington, DC: ILSI Press; 1996:231.

Murray, M, Pizzorno, J. Encyclopedia of Natural Medicine 2nd ed. Rocklin: Prima Publishing; 1998:435.

Naderer O, Nafziger AN, Bertino JS Jr. Effects of moderate-dose versus high-dose trimethorprim on serum creatinine and creatinine clearance and adverse reactions. Antimicrob Agents Chemother. 1997;41(11):2466-2470.

Nord CE. The effect of antimicrobial agents on the ecology of the human intestinal microflora. Vet Microbiol. 1993;35(3-4):193-197.

Olson RE. Vitamin K. In: Shils, ME, Olson JA, Shike, M, eds. Modern Nutrition in health and disease. 9th ed. Media, PA: Williams & Wilkins; 1999:363-380.

Powers HJ. Current knowledge concerning optimum nutritional status of riboflavin, niacin and pyridoxine. Proc Nutr Soc. 1999;58(2):435-440.

Safrin S, Lee BL, Sande MA. Adjunctive folinic acid with trimethoprim-sulfamethoxazole for Pneumocystis carinii pneumonia in AIDS patients is associated with an increased risk of therapeutic failure and death. J Infect Dis. 1994;170(4):912-917.

Stieger R, Baumgartner K, Neff U. [Dangerous hypothrombinemic hemorrhage in antibiotic therapy]. Helv Chir Acta. 1992;58(6):775-778.

Surawicz CM, Elmer GW, Speelman P, et al. Prevention of antibiotic-associated diarrhea by Saccharomyces boulardii: A prospecive study. Gastroenterol. 1989;96(4):981-988.

Taraszewski R, Harvey R, Rosman P. Death from drug-induced hemolytic anemia. Postgrad med. 1989;85(7):79-80, 84.

Vermeer C, Schurgers LJ. A comprehensive review of vitamin K and vitamin K antagonists. Hematol Oncol Clin North Am. 2000;14(2):339-353.

4. Antidepressant Medications

Selective Serotonin Reuptake Inhibitors (SSRIs)

Fluoxetine (Prozac®; Prozac® Weekly™; Sarafem™)

Depletions

Melatonin

Mechanism

In a controlled clinical study, melatonin levels were reduced significantly in study participants treated with fluoxetine (20 mg/day) for six weeks (Childs et al. 1995). The decrease in melatonin levels associated with this drug may be explained by down-regulation of b-adrenoreceptors, reduction in cAMP accumulation, or interference with suprachiasmatic nucleus output.

Significance of Depletion

Alterations in melatonin levels have been associated with disturbances in the sleep-wake cycle and jet lag (Avery et al. 1998).

Replacement Therapy

Protein & Amino Acids

Mechanism

Fluoxetine reduces leucine absorption by 37% in vitro and 30% in vivo; it may affect the nutritional status of patients by reducing absorption of neutral amino acids (Urdaneta et al. 1998). More research is needed to confirm these effects.

Significance of Depletion

Deficiencies of protein are characterized by compromised immune status, generalized decreases in function and strength, apathy, weight loss, increased susceptibility to infection, impaired wound healing, and growth retardation in children (Covington 1999). Severe depletion may be characterized by muscle wasting, deterioration in skin and hair, decreased heart rate, blood pressure, and body temperature.

Replacement Therapy

Nutritional repletion through dietary means is the preferred treatment approach in cases of protein depletion or deficiency (Covington 1999). Adopting a balanced diet consisting of high levels of calories, protein, vitamins, and minerals is one option available for the treatment of patients with depleted levels of protein. Oral or parenteral supplementation offers another therapeutic approach to restore nutritional status, maintain caloric intake, and achieve recommended dietary allowances for protein (generally 600 to 800 mg/kg protein) (Reeds and Beckett 1996).

References

Avery D, Lenz M, Landis C. Guidelines for prescribing melatonin. Ann Med. 1998;30:122-130.

Childs PA, Rodin I, Martin NJ, et al. Effect of fluoxetine on melatonin in patients with seasonal affective disorder and matched controls. Br J Psychiatry. 1995;166:196-198.

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

Reeds P, Beckett P. Protein and amino acids. In: Ziegler E, Filer LJ, eds. Present Knowledge in Nutrition. 7th ed. Washington, DC: International Life Sciences Institute; 1996:67-86.

Urdaneta E, Idonte I, Larraldo J. Drug-nutrient interactions: inhibition of amino acid intestinal absorption by fluoxetine. Br J Nutr. 1998;79(5):439-446.

4 Antidepressant Medications PLUS

Tricyclic Antidepressants

Amitriptyline (Elavil®; Vanatrip®)

Amoxapine (Asendin)

Clomipramine (Anafranil®)

Desipramine (Norpramin®)

Doxepin (Sinequan® Oral; Zonalon® Topical Cream)

Imipramine (Tofranil-PM®; Tofranil®)

Nortriptyline (Aventyl®; Pamelor®)

Protriptyline (Vivactil®)

Trimipramine (Surmontil®)

Depletions

Coenzyme Q10

Mechanism

In vitro, tricyclic antidepressants (TCAs) inhibited CoQ10-NADH-oxidase and CoQ10-succinate dehydrogenase, two enzymes that are important for cardiac function because they donate electrons to CoQ10 in the mitochondria (Kishi et al. 1980). Inhibiting these enzymes disrupts mitochondrial function and may play a role in the development of cardiotoxic side effects associated with psychotropic drugs.

Significance of Depletion

Although CoQ10 is manufactured by the body, deficiencies occur in some physiological and pathological conditions (Artuch et al. 1999). CoQ10 deficiency may be related to certain conditions such as gingivitis (Nakamura et al. 1974); breast cancer (Jolliet et al. 1998); congestive heart failure (Munkholm et al. 1999); angina pectoris (Kamikawa et al. 1985); acute myocardial infarction (Singh et al. 1998); mitochondrial encephalomyopathies (Chan et al. 1998); hypertension, and cardiac function (Singh et al. 1999). In addition, CoQ10 depletion may contribute to aging and photoaging (Hoppe et al. 1999). Low levels of CoQ10 may also compromise immune function (Folkers et al. 1993) and play a role in male infertility (Overvad et al. 1999).

Replacement Therapy

Daily doses as high as 200 mg for periods of 6 to 12 months or 100 mg for up to 6 years have not been associated with reports of serious adverse effects in clinical studies (Overvad et al. 1999). The addition of low concentrations of CoQ10 reverses TCA-induced inhibition of CoQ10-NADH-oxidase and CoQ10-succinate dehydrogenase (Kishi et al. 1980). CoQ10 treatment may prevent some of the cardiac side effects associated with tricyclic antidepressant treatment. More research is needed to confirm these effects.

Vitamin B2 (Riboflavin)

Mechanism

Amitriptyline may enhance vitamin B2 excretion (Tinguely et al. 1985) and inhibit its metabolism to flavin-adenine dinucleotide (FAD) in tissues (Pinto et al. 1981; Pinto et al. 1982).

Significance of Depletion

Riboflavin deficiency usually occurs as a result of deficiencies in dietary protein and is associated with other B vitamin deficiencies (Covington 1999). Depleted levels of riboflavin affect carbohydrate and amino acid metabolism by interfering with enzyme systems involved in the production of ATP. Lack of an adequate supply of riboflavin disturbs several physiological and biochemical processes and results in retarded growth in infants and children (Covington 1999; Powers 1999). Signs and symptoms include corneal vascularization, glossitis, cheilosis, seborrheic dermatitis, and impaired wound healing (Covington 1999).

Replacement Therapy

Doses of 5 to 25 mg/day are recommended for the treatment of riboflavin deficiency (Covington 1999). For replacement therapy, doses should be based upon the patient's individual needs, considering the clinical presentation, serum riboflavin levels, age, gender, dietary habits, and medication regimen.

References

Artuch R, Colome C, Vilaseca MA, et al. Ubiquinone: metabolism and functions. Ubiquinone deficiency and its implications in mitochondrial encephalopathies. Treatment with ubiquinone. Rev Neurol. 1999;29(1):59-63.

Chan A, Reichmann H, Kogel A, et al. Metabolic changes in patients with mitochondrial myopathies and effects of coenzyme Q10 therapy. J Neurol. 1998;245(10):681-685.

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

Folkers K, Morita M, McRee J Jr. The activities of coenzyme Q10 and vitamin B6 for immune responses. Biochem Biophys Res Commun. 1993;19391):88-92.

Hoppe U, Bergemann J, Diembeck W, et al. Coenzyme Q10, a cutaneous antioxidant and energizer. Biofactors. 1999;9(2-4):371-378.

Jolliet P, Simon N, Barre J, et al. Plasma coenzyme Q10 concentrations in breast cancer: prognosis and therapeutic consequences. Int J Clin Pharmacol Ther. 1998;36(9):506-509.

Kamikawa T, Kobayashi A, Yamashita T, et al. Effects of coenzyme Q10 on exercise tolerance in chronic stable angina pectoris. Am J Cardiol. 1985;56(4):247-251.

Kishi T, Makino K, Okamoto T, et al. Inhibition of myocardial respiration by psychotherapeutic drugs and prevention by coenzyme Q. Biomedical and Clinical Aspects of Coenzyme Q. Vol 2. Yamamura Y, et al, eds. Elsevier/North-Holland Biomedical Press: Amsterdam; 1980.

Munkholm H, Hansen HH, Rasmussen K. Coenzyme Q10 treatment in serious heart failure. Biofactors. 1999;9(2-4):285-289.

Nakamura R, Littarru GP, Folkers R, et al. Study of CoQ10-enzymes in gingiva from patients with periodontal disease and evidence for a deficiency of coenzyme Q10. Proc Natl Acad Sci USA. 1974;71(4):1456-1460.

Overvad K, Diamant B, Holm L, Holmer G, Mortensen SA, Stender S. Coenzyme Q10 in health and disease. Eur J Clin Nutr. 1999;53:764-770.

Pinto J, et al. Inhibition of riboflavin metabolism in rat tissues by chlorpromazine, imipramine, and amitriptyline. J Clin Invest. 1981;67(5):1500-1506.

Pinto J, Huang YP, Pelliccione N, et al. Cardiac sensitivity to the inhibitory effects of chlorpromazine, imipramine and amitriptyline upon formation of flavins. Biochem Pharmacol. 1982;31(21):3495-3499.

Powers HJ. Current knowledge concerning optimum nutritional status of riboflavin, niacin and pyridoxine. Proc Nutr Soc. 1999;58(2):435-440.

Singh RB, Niaz MA, Rastogi SS, et al. Effect of hydrosoluble coenzyme Q10 on blood pressure and insulin resistance in hypertensive patients with coronary heart disease. J Hum Hypertens. 1999;13(3):203-208.

Singh RB, Wander GS, Rastogi A, et al. Randomized, double-blind placebo-controlled trial of coenzyme Q10 in patients with acute myocardial infarction. Cardiovasc Drugs Ther. 1998;12(4):347-353.

Tinguely D, Jonzier M, Schopf J, et al. Determination of compliance with riboflavin in an antidepressive therapy. Arzneimittelforschung. 1985;35(2):536-538.

9 Corticosteroids

Inhalant, Systemic, and Topical Preparations

Beclomethasone (Beclovent®; Beconase®; Beconase® AQ; QVAR™; Vancenase®; Vancenase® AQ; Vanceril®)

Budesonide (Pulmicort Respules™; Pulmicort® Turbuhaler®; Rhinocort®; Rhinocort® Aqua™)

Dexamethasone (AK-Dex® Ophthalmic; Baldex®; Dalalone D.P.®; Dalalone L.A.®; Dalalone®; Decadron®; Decadron® Phosphate; Decadron®-LA; Decaject-LA®; Decaject®; Decaspray®; Dexacort® Phosphate Turbinaire®; Dexasone®; Dexasone® L.A.; Dexone®; Dexone® LA; Hexadrol®; Hexadrol® Phosphate; Maxidex®; Solurex L.A.®; Solurex®)

Fluticasone (Cutivate™; Flonase®; Flovent®; Flovent® Diskus®; Flovent® Rotadisk®)

Hydrocortisone (A-hydroCort®; Ala-Cort®; Ala-Scalp®; Anucort-HC® Suppository; Anusol-HC® Suppository; Anusol® HC 1 [OTC]; Anusol® HC 2.5% [OTC]; Cetacort®; Clocort® Maximum Strength; Cort-Dome®; Cortaid® Maximum Strength [OTC]; Cortaid® With Aloe [OTC]; Cortef®; Cortef® Feminine Itch; Cortenema®; Corticaine®; Cortifoam®; Cortizone®-10 [OTC]; Cortizone®-5 [OTC]; Delcort®; Dermacort®; DermiCort®; Dermolate®[OTC]; Dermtex® HC With Aloe; Eldecort®; Gynecort®[OTC]; Hemril-HC® Uniserts®; Hi-Cor® 1.0; Hi-Cor® 2.5; Hycort®; Hydrocort®; Hydrocortone® Acetate; Hydrocortone® Phosphate; HydroTex®[OTC]; Hytone®; LactiCare-HC®; Lanacort®[OTC]; Locoid®; Nutracort®; Orabase® HCA; Pandel®; Penecort®; Procort®[OTC]; Proctocort™; S-T Cort®; Scalpicin®; Solu-Cortef®; Synacort®; Tegrin®-HC [OTC]; Texacort®; Westcort®)

Methylprednisolone (A-methaPred® Injection; depMedalone® Injection; Depo-Medrol® Injection; Depoject® Injection; Depopred® Injection; Duralone® Injection; M-Prednisol® Injection; Medralone® Injection; Medrol® Oral; Solu-Medrol® Injection)

Mometasone Furoate (Elocon®; Nasonex®)

Prednisone (Deltasone®; Liquid Pred®; Meticorten®; Orasone®; Prednicen-M®)

Triamcinolone (Amcort®; Aristocort®; Aristocort® A; Aristocort® Forte; Aristocort® Intralesional; Aristospan® Intra-Articular; Aristospan® Intralesional; Atolone®; Azmacort™; Delta-Tritex®; Flutex®; Kenacort®; Kenaject-40®; Kenalog-10®; Kenalog-40®; Kenalog®; Kenalog® H; Kenalog® in Orabase®; Kenonel®; Nasacort®; Nasacort® AQ; Tac™-3; Tac™-40; Tri-Kort®; Tri-Nasal®; Triacet™; Triam Forte®; Triam-A®; Triderm®; Trilog®; Trilone®; Tristoject®)

Depletions

Calcium

Mechanism

Corticosteroids increase renal calcium excretion and decrease intestinal calcium absorption (Gennari 1993; Lems et al. 1998). By altering normal calcium metabolism and reducing osteoblast activity, corticosteroids increase not only bone loss, but the risk for developing osteoporosis as well (Nielson et al. 1988; Reid and Ibbertson 1986).

Significance of Depletion

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).

Replacement Therapy

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.

Dehydroepiandrosterone (DHEA)

Mechanism

Long-term treatment with corticosteroids suppresses DHEA production in post-menopausal women (Smith et al. 1994).

Significance of Depletion

Decreased plasma levels of DHEA have been linked to various pathologies such as certain cancers, cardiovascular disorders, inflammatory diseases, and type II diabetes mellitus (Hinson and Raven 1999).

Replacement Therapy

Daily doses of 50 mg in patients aged 40 to 70 years produced DHEA levels equivalent to those found in young adults within 2 weeks of initiation of replacement therapy (Morales et al. 1994). These levels were maintained for 3 months of the study and patients reported improvements in their general sense of physical and psychological well-being; no side effects were associated with DHEA therapy at this dose. It has been suggested that doses should not exceed 25 mg/day for women or 50 mg/day for men (Huppert et al. 2000). Long-term safety and efficacy of DHEA supplementation has not been established (Murray and Pizzorno 1998).

Magnesium

Mechanism

Corticosteroids reduce magnesium levels in serum and bone (Atkinson et al. 1998; Rolla et al. 1990; Simeckova et al. 1985).

Significance of Depletion

Magnesium deficiency affects calcium and vitamin D metabolism and is primarily associated with hypocalcemia (Cashman and Flynn 1999). Clinically, neuromuscular hyperexcitability may be the first symptom manifested in patients with hypomagnesemia (reflected in a serum concentration of 17 mg/L or less). Recent evidence supports a possible connection between chronically low magnesium levels and various illnesses such as cardiovascular disease, hypertension, diabetes, and osteoporosis.

Replacement Therapy

The current recommended dietary allowance (RDA) for magnesium ranges from 30 to 420 mg/day, depending upon age and gender (Cashman and Flynn 1999). For replacement therapy, doses should be tailored to the patient's clinical condition, taking into account serum magnesium levels, dietary habits, and medication regimen.

Melatonin

Mechanism

Corticosteroids may reduce nocturnal melatonin levels (Demisch et al. 1988).

Significance of Depletion

Alterations in melatonin levels have been associated with disturbances in the sleep-wake cycle and jet lag (Avery et al. 1998).

Replacement Therapy

Note: Corticosteroid effects on the immune system may be modulated by melatonin (Rogers et al. 1997). In vitro, the combination of melatonin and corticosteroids produced significantly greater suppression of lymphocyte proliferation than corticosteroids alone.

Potassium

Mechanism

Corticosteroids enhance potassium excretion (Adam et al. 1984; Stanton et al. 1985).

Significance of Depletion

Potassium depletion as a consequence of prolonged drug therapy is usually associated with chloride deficiency and manifests as hypokalemic, hypochloremic metabolic acidosis (Covington 1999). Signs and symptoms of deficiency include anorexia, apprehension, drowsiness, listlessness, fatigue, nausea, muscle cramps and weakness, tetany, excessive thirst, altered mental status, and irrational behavior. Severe hypokalemia could also result in clinical manifestations of cardiac arrythmia, including primarily palpitations, cardiac arrest, and death. A loss from total body stores of approximately 100 to 200 mEq of potassium is usually required to cause a decrease in serum potassium levels of 1 mEq/L.

Replacement Therapy

The usual range of treatment is 20 to 100 mEq/day of potassium (PDR 2000). The appropriate doses for replacement therapy should be determined on an individual basis, considering the patient's age, gender, clinical presentation, serum potassium levels, dietary habits, and medication regimen. The chloride salt is appropriate treatment for cases of alkalosis (Covington 1999). In cases of acidosis, other potassium salts such as bicarbonate, citrate, acetate, or gluconate are preferred.

Protein & Amino Acids

Mechanism

Corticosteroids may cause protein wasting (Garrel et al. 1988).

Significance of Depletion

5.Antidiabetic Medications

Biguanide Agent

Metformin (Glucophage®; Glucophage® XR)

Depletions

Vitamin B9 (Folic Acid); Vitamin B12 (Cobalamin)

Mechanism

Several studies have shown reduced absorption of vitamin B12 in approximately 1/3 of patients treated with biguanides or other medications that are part of this class of compounds (Adams et al. 1983; Berger 1985; Rieder et al. 1980). In another trial, metformin treatment significantly decreased levels of vitamin B12 and folate and increased homocysteine levels as well (Carlsen et al. 1997).

Significance of Depletion

Vitamin B9: 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.

Vitamin B12: Symptomatic vitamin B12 deficiency is rare because complications of vitamin B12 deficiency may appear only after the deficiency has existed for 10 to 15 years (Berger 1985; Carpentier et al. 1976). 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. Only five cases of megaloblastic anemia associated with metformin therapy have been reported; no increased incidence of neuropathy has been observed (Hines Burnham et al. 2000).

Replacement Therapy

Vitamin B9: 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.

References

Adams JF, Clark JS, Ireland JT, et al. Malabsorption of vitamin B12 and intrinsic factor secretion during biguanide therapy. Diabetologia. 1983;24(1):16-18.

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

Berger W. Incidence of severe side effects during therapy with sulfonylureas and biguanides. Horm Metab Res Suppl. 1985;15:111-115.

Carlsen SM, Folling I, Grill V, et al. Metformin increases total and serum homocysteine levels in non-diabetic male patients with coronary heart disease. Scand J Clin Lab Invest. 1997;57(6):521-527.

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

Carpentier JL, Bury J, Luyckx A, Lefebvre P. Vitamin B12 and folic acid serum levels in diabetics under various therapeutic regimens. Diabetes Metab. 1976;2(4):187-190.

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

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

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

Rieder HP, Berger W, Fridrich R. [Vitamin status in diabetic neuropathy]. Z Ernahrungswiss. 1980;19(1):1-13.

Antidiabetic Medications

Sulfonylureas

Glimepiride (Amaryl®)

Glyburide (Diabeta®; Glynase™ PresTab™; Micronase®)

Depletions

Coenzyme Q10

Mechanism

Patients with non-insulin-dependent diabetes mellitus (NIDDM) have significantly lower serum coenzyme Q10 levels compared to healthy controls (Miyake et al. 1999). Because glyburide inhibits NADH-oxidase, an enzyme that donates electrons to CoQ10, it could lead to a deficiency in diabetic patients with already low CoQ10 levels (Kishi et al. 1976).

Significance of Depletion

Although CoQ10 is manufactured by the body, deficiencies occur in some physiological and pathological conditions (Artuch et al. 1999). CoQ10 deficiency may be related to certain conditions such as gingivitis (Nakamura et al. 1974); breast cancer (Jolliet et al. 1998); congestive heart failure (Munkholm et al. 1999); angina pectoris (Munkholm et al. 1999); acute myocardial infarction (Singh et al. 1998); mitochondrial encephalomyopathies (Chan et al. 1998); hypertension, and cardiac function (Singh et al. 1999). In addition, CoQ10 depletion may contribute to aging and photoaging (Hoppe et al. 1999). Low levels of CoQ10 may also compromise immune function (Folkers et al. 1993) and play a role in male infertility (Overvad et al. 1999).

Replacement Therapy

Daily doses of coenzyme Q10 as high as 200 mg for periods of 6 to 12 months or 100 mg for up to 6 years have not been associated with reports of serious adverse effects in clinical studies (Overvad et al. 1999). CoQ10 supplementation (100 mg bid) was well tolerated and did not interfere with glycemic control in one study with NIDDM patients (Eriksson et al. 1999).

References

Artuch R, Colome C, Vilaseca MA, et al. [Ubiquinone: metabolism and functions. Ubiquinone deficiency and its implications in mitochondrial encephalopathies. Treatment with ubiquinone]. Rev Neurol. 1999;29(1):59-63.

Chan A, Reichmann H, Kogel A, et al. Metabolic changes in patients with mitochondrial myopathies and effects of coenzyme Q10 therapy. J Neurol. 1998;245(10):681-685.

Eriksson JG, Forsen TJ, Mortensen SA, Rohde M. The effect of coenzyme Q10 administration on metabolic control in patients with type 2 diabetes mellitus. Biofactors. 1999;9(2-4):315-318.

Folkers K, Morita M, McRee J Jr. The activities of coenzyme Q10 and vitamin B6 for immune responses. Biochem Biophys Res Commun. 1993; 28(19391):88-92.

Hoppe U, Bergemann J, Diembeck W, et al. Coenzyme Q10, a cutaneous antioxidant and energizer. Biofactors. 1999;9(2-4):371-378.

Jolliet P, Simon N, Barre J, et al. Plasma coenzyme Q10 concentrations in breast cancer: prognosis and therapeutic consequences. Int J Clin Pharmacol Ther. 1998;36(9):506-509.

Munkholm H, Hansen HH, Rasmussen K. Coenzyme Q10 treatment in serious heart failure. Biofactors. 1999;9(2-4):285-289.

Kishi T, Kishi H, Watanabe T, Folkers K. Bioenergetics in clinical medicine. XI. Studies on coenzyme Q and diabetes mellitus. J Med. 1976;7(3-4):307-321.

Miyake Y, Shouzu A, Nishikawa M, et al. Effect of treatment with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on serum coenzyme Q10 in diabetic patients. Arzneimittelforschung. 1999;49(4):324-329.

Munkholm H, Hansen HH, Rasmussen K. Coenzyme Q10 treatment in serious heart failure. Biofactors. 1999;9(2-4):285-289.

Overvad K, Diamant B, Holm L, Holmer G, Mortensen SA, Stender S. Coenzyme Q10 in health and disease. Eur J Clin Nutr. 1999;53:764-770.

Singh RB, Wander GS, Rastogi A, et al. Randomized, double-blind placebo-controlled trial of coenzyme Q10 in patients with acute myocardial infarction. Cardiovasc Drugs Ther. 1998;12(4):347-353.

9 Cortocosteriods

Replacement Therapy

Selenium

Mechanism

Corticosteroids may deplete selenium levels (Peretz et al. 1987).

Significance of Depletion

Selenium deficiency may lead to oxidative DNA damage (Ames 2000). Chronically low levels of this trace element are associated with pathologies such as cardiovascular disease, rheumatic disorders, muscle, and digestive problems (Navarro-Alarcon and Lopez-Martinez 2000). In addition, there may be a connection between depleted selenium levels and cancer, cirrhosis, and diabetes.

Replacement Therapy

The recommended dietary allowance (RDA) for selenium ranges from 0.70 to 3.50 mg/day (Ames 2000). Doses of 0.02 to 0.05 mg/day have been suggested to prevent selenium deficiency and its associated disorders (Navarro-Alarcon and Lopez-Martinez 2000). Optimal and toxic levels of this nutrient have not been established (Ames 2000). Selenium supplementation may play a role in cancer prevention, including prostate, breast, colon, and cervical carcinoma.

Vitamin B6 (Pyridoxine)

Mechanism

Corticosteroids may deplete vitamin B6 levels (Sur et al. 1993).

Significance of Depletion

Usually, vitamin B6 deficiency is accompanied by depletions of other B vitamins (National Research Council 1989). Signs and symptoms of low levels of this vitamin include epileptiform convulsions with abnormal EEG findings, dermatitis, anemia, weakness, mental confusion, irritability, nervousness, insomnia, and abnormal tryptophan metabolism (Covington 1999; National Research Council 1989; Wilson 1998). Depleted levels may increase the risk of colon and prostate cancers, heart disease, brain dysfunction, and birth defects (Ames 2000).

Replacement Therapy

Neuropathology resulting from vitamin B6 deficiency should be treated with doses of 50 to 200 mg/day (Covington 1999). Dietary deficiency usually responds to doses of 10 to 20 mg/day. Doses should be tailored to account for the patient's age, gender, clinical presentation, serum vitamin B6 levels, dietary habits, and medication regimen.

Vitamin B9 (Folic Acid)

Mechanism

Corticosteroids may deplete folic acid levels (Frequin et al. 1993).

Significance of Depletion

Replacement Therapy

Vitamin B12 (Cobalamin)

Mechanism

Corticosteroids may deplete vitamin B12 levels (Frequin et al. 1993).

Significance of Depletion

Symptomatic vitamin B12 deficiency is rare because complications may appear only after the deficiency has existed for 10 to 15 years (Berger 1985; Carpentier et al. 1976). 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.

Replacement Therapy

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.

Vitamin C (Ascorbic Acid)

Mechanism

Corticosteroids may inhibit cellular uptake of ascorbic acid and reduce concentrations in the aqueous humor and testicular tissues (Chowdhury and Kapil 1984; Levine and Pollard 1983; Mehra et al. 1982).

Significance of Depletion

Patients with depleted levels of vitamin C may present with anemia, icterus, edema, lethargy, fatigue, fever, ecchymoses, hypotension, convulsions, gum disorders, tooth loss, emotional changes, and perifollicular hyperkeratotic papules (Carr and Frei 1999; Covington 1999; National Research Council 1989; Wilson 1998). In addition, they may exhibit signs of poor wound healing, increased susceptibility to infection, and markedly defective collagen synthesis. Severe deficiency results in scurvy, which is potentially fatal (Carr and Frei 1999; National Research Council 1989; Wilson 1998). Scurvy involves degenerative changes in capillaries, bone, and connective tissue, resulting in clinical symptoms that include weakness, joint tenderness and swelling, and spontaneous hemorrhages (Carr and Frei 1999; Covington 1999; National Research Council 1989; Wilson 1998). Patients with vitamin C deficiency may also be at increased risk of developing cataracts and heart disease (Ames 2000).

Replacement Therapy

Treatment of scurvy requires doses between 300 and 1000 mg/day for adults (Covington 1999). Other recommendations range from the recommended dietary allowance (RDA) of 60 mg to 2000 mg/day for adults (Carr and Frei 1999; Wilson 1998). One study proposes that no adult receive more than 1000 mg/day because higher doses could cause nausea and diarrhea (Ausman 1999). To minimize the possibility of gastric upset, buffered and sustained-release vitamin C preparations are recommended. Specific doses account for the patient's age, gender, overall health status, dietary habits, and medication regimen. Smokers must consume 2 to 3 times more vitamin C than non-smokers (Ames 2000).

Vitamin D

Mechanism

Corticosteroid therapy reduces serum 1,25-dihydroxyvitamin-D3 in children (Chesney et al. 1978).

Significance of Depletion

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.

Replacement Therapy

Coadministration of vitamin D with calcium offsets the bone loss induced by chronic corticosteroid therapy (Frauman 1996; Hachulla and Cortet 1998; Weryha et al. 1998). 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).

Zinc

Mechanism

Corticosteroids alter zinc metabolism and can cause depletion (Flynn et al. 1971; Fodor et al. 1975; Fontaine et al. 1991; Yunice, et al. 1981).

Significance of Depletion

Replacement Therapy

References

Adam WR, Goland GJ, Wellard RM. Renal potassium adaptation in the rat: role of glucocorticoids and aldosterone. Am J Physiol. 1984;246(3 Pt 2):F300-F308.

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.

Atkinson SA, Halton JM, Bradley C, Wu B, Barr RD. Bone and mineral abnormalities in childhood acute lymphoblastic leukemia: influence of disease, drugs and nutrition. Int J Cancer Suppl. 1998;11:35-39.

Ausman LM. Criteria and recommendations for vitamin C intake. Nutr Review. 1999;57(7):222-229.

Avery D, Lenz M, Landis C. Guidelines for prescribing melatonin. Ann Med. 1998;30:122-130.

Berger W. Incidence of severe side effects during therapy with sulfonylureas and biguanides. Horm Metab Res Suppl. 1985;15:111-115.

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

Carpentier JL, Bury J, Luyckx A, Lefebvre P. Vitamin B12 and folic acid serum levels in diabetics under various therapeutic regimens. Diabetes Metab. 1976;2(4):187-190.

Carr AC, Frei B. Toward a new recommended dietary allowance for vitamin C based on antioxidant and health effects in humans. Am J Clin Nutr 1999;69:1086-1087.

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

Chesney RW, Maxess RB, Harnstra AJ, et al. Reduction of serum-1,12-dihydroxyitamin- D3 in children receiving glucocorticoids. Lancet. 1978;2(8100):1123-1125.

Chowdhury AR, Kapil N. Interaction of dexamethasone and dehydroepiandrosterone on testicular ascorbic acid and cholesterol in prepubertal rat. Arch Androl. 1984;12(1):65-67.

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

Demisch L, et al. Influence of dexamethasone on nocturnal melatonin production in healthy adult subjects. J Pineal Res. 1988;5(3):317-322.

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

Flynn A, Pories WJ, Strain WH, et al. Rapid serum-zinc depletion associated with corticosteroid therapy. Lancet. 1971;2(7735):1169-1172.

Fodor L, Ahnefeld FW, Fazekas AT. [Studies on the glucocorticoid control of zinc metabolism]. Infusionsther Klin Ernahr. 1975;2(3):210-213.

Fontaine J, Neve J, Peretz A, et al. Effects of acute and chronic prednisolone treatment on serum zinc levels in rats with adjuvant arthritis. Agents Actions. 1991;33(3-4):247-253.

Frauman AG. An overview of the adverse reactions to adrenal corticosteroids. Adverse Drug React Toxicol Rev. 1996;15(4):203-206.

Frequin ST, et al. Decreased vitamin B12 and folate levels in cerebrospinal fluid and serum of multiple sclerosis patients after high-dose intravenous methylprednisolone. J Neurol. 1993;240(5):305-308.

Garrel DR, Delmas PD, Welsh C, et al. Effects of moderate physical training on prednisone-induced protein wasting: a study of whole-body and bone protein metabolism. Metab. 1988;37(3):257-262.

Gennari C. Differential effect of glucocorticoids on calcium absorption and bone mass. Br J Rheumatol. 1993;32(Suppl 2):11-14.

Hachulla E, Cortet B. [Prevention of glucocorticoid induced osteoporosis]. Rev Med Interne. 1998;19(7):492-500.

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

Hinson JP, Raven PW. DHEA deficiency syndrome: a new term for old age? J Endocrinol. 1999;163:1-5.

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; 1998:2221-2222.

Huppert FA, Van Niekerk JK, Herbert J. Dehydroepiandrosterone (DHEA) supplementation for cognition and well-being. Cochrane Database Syst Rev 2000;(2):CD000304.

Lems WF, Jacobs JW, Netelenbos JC, et al. [Pharmacological prevention of osteoporosis in patients on corticosteroid medication]. Ned Tijdschr Geneeskd. 1998;142(34):10904-10908.

Levine MA & Pollard HB. Hydrocortisone inhibition of ascorbic acid transport by chromaffin cells. FEBS Lett. 1983;158(1)L134-L138.

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

Mehra KS, Kumar A, Dubey SS, Palodhi GR. The effect of vitamin A and cortisone on ascorbic acid content in the aqueous humor. Ann Ophthalmol. 1982;14(11):1013-1015.

Morales AJ, Nolan JJ, Nelson JC, Yen SS. Effects of replacement dose of dehydroepiandrosterone in men and women of advancing age. Endocrinol Metab. 1994;78(6):1360-1367.

Murray M, Pizzorno J. Encyclopedia of Natural Medicine. 2nd ed. Rocklin, CA: Prima Publishing; 1998.

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

Navarro-Alarcon M, Lopez-Martinez MC. Essentiality of selenium in the human body: relationship with different diseases. Sci Total Environ. 2000;249:347-371.

Nielson HK, Charles P, Mosekilde L. The effect of single oral doses of prednisone on the circadian rhythm of serum osteocalcin in normal subjects. J Clin Endocrinol Metab. 1988;67(5):1025-1030.

Peretz A, Neve J, Vertongen F, et al. Selenium status in relation to clinical variables and corticosteroid treatment in rheumatoid arthritis. J Rheumatol. 1987;14(6):1104-1107.

Physicians' Desk Reference, 54th ed. Montvale, NJ: Medical Economics Company; 2000:459.

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 Densitom. 1999:2(4):457-464.

Reeds P, Beckett P. Protein and amino acids. In: Ziegler E, Filer LJ, eds. Present Knowledge in Nutrition. 7th ed. Washington, DC: International Life Sciences Institute; 1996:67-86.

Reid IR, Ibbertson HK. Calcium supplements in the prevention of steroid-induced osteoporosis. Am J Clin Nutr. 1986;44(2):287-290.

Rogers N, van den Heuvel C, Dawson D. Effect of melatonin and corticosteroid on in vitro cellular immune function in humans. J Pineal Res. 1997;22(2):75-80.

Rolla G, Bucca C, Bugiani M. Hypomagnesemia in chronic obstructive lung disease: effect of therapy. Magnes Trace Elem. 1990;9(3):132-136.

Simeckova A, Neradilova M, Reisenauer R. Effect of prednisolone on the rat bone calcium, phosphorus and magnesium concentration. Physiol Bohemoslov. 1985;34(2):155-160.

Smith BJ, et al. Does beclomethasone dipropionate suppress dehydroepiandrosterone sulfate in postmenopausal women? Aust N Z J Med. 1994;24(4):396-401.

Stanton B, Giebisch G, Klein-Robbenhaar G, et al. Effects of adrenalectomy and chronic adrenal corticosteroid replacement on potassium transport in rat kidney. J Clin Invest. 1985;75(4):1317-1326.

Sur S, Camara M, Buchmeier A, Morgan S, Nelson HS. Double-blind trial of pyridoxine (vitamin B6) in the treatment of steroid-dependant asthma. Ann Allergy. 1993;70(2):147-152.

Vieth R. Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. Am J Clin Nutr. 1999;69:842-856.

Weryha G, Klein M, Guillemin F, Leclere J. [Corticosteroid osteoporosis in the adult]. Presse Med. 1998;27(32):1641-1646.

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Yunice, AA, Czerwinski AW, Lindeman RD. Influence of synthetic corticosteroids on plasma zinc and copper levels in humans. Am J Med Sci. 1981;282(2):68-74.

6. Antihypertensive Medications

Alpha2-Adrenergic Agonist

Clonidine (Catapres-TTS® Transdermal; Catapres® Oral; Duraclon®)

Depletions

Coenzyme Q10

Mechanism

Clonidine inhibits myocardial CoQ10-NADH-oxidase, an enzyme important for cardiac function (Kishi et al. 1975). Some of the adverse myocardial reactions that occur during clonidine treatment may be related to depletion of this enzyme.

Significance of Depletion

Replacement Therapy

Daily doses of coenzyme Q10 as high as 200 mg for periods of 6 to 12 months or 100 mg for up to 6 years have not been associated with reports of serious adverse effects in clinical studies (Overvad et al. 1999). There are no known studies showing clinical benefits of CoQ10 replacement in the presence of clonidine specifically.

References

Chan A, Reichmann H, Kogel A, et al. Metabolic changes in patients with mitochondrial myopathies and effects of coenzyme Q10 therapy. J Neurol. 1998;245(10):681-685.

Folkers K, Morita M, McRee J Jr. The activities of coenzyme Q10 and vitamin B6 for immune responses. Biochem Biophys Res Commun. 1993; 28(19391):88-92.

Hoppe U, Bergemann J, Diembeck W, et al. Coenzyme Q10, a cutaneous antioxidant and energizer. Biofactors. 1999;9(2-4):371-378.

Jolliet P, Simon N, Barre J, et al. Plasma coenzyme Q10 concentrations in breast cancer: prognosis and therapeutic consequences. Int J Clin Pharmacol Ther. 1998;36(9):506-509.

Kamikawa T, Kobayashi A, Yamashita T, et al. Effects of coenzyme Q10 on exercise tolerance in chronic stable angina pectoris. Am J Cardiol. 1985;56(4):247-251.

Kishi H, Kishi T, Folkers K. Bioenergetics in clinical medicine. III. Inhibition of coenzyme Q10-enzymes by clinically used anti-hypertensive drugs. Res Commun Chem Pathol Pharmacol. 1975;12(3):533-540.

Munkholm H, Hansen HH, Rasmussen K. Coenzyme Q10 treatment in serious heart failure. Biofactors. 1999;9(2-4):285-289.

Overvad K, Diamant B, Holm L, Holmer G, Mortensen SA, Stender S. Coenzyme Q10 in health and disease. Eur J Clin Nutr. 1999;53:764-770.

Singh RB, Wander GS, Rastogi A, et al. Randomized, double-blind placebo-controlled trial of coenzyme Q10 in patients with acute myocardial infarction. Cardiovasc Drugs Ther. 1998;12(4):347-353.

7. Cardiovascular Medications

Angiotensin-Converting Enzyme (ACE) Inhibitors

Benazepril (Lotensin®)

Captopril (Capoten®)

Enalapril (Vasotec®; Vasotec® I.V.)

Fosinopril (Monopril®)

Lisinopril (Prinivil®; Zestril®)

Moexipril (Univasc®)

Perindopril Erbumine (Aceon®)

Quinapril (Accupril®)

Ramipril (Altace™)

Spirapril (no brand names listed)

Trandolapril (Mavik®)

Depletions

Zinc

Mechanism

The ACE inhibitors benazepril, captopril, and enalapril significantly reduce serum zinc levels and increase urinary zinc excretion (Golik et al. 1998; Peczkowska. 1996). The effect is more pronounced with captopril; depletion of zinc from red blood cells occurs after three months of use (Golik et al. 1990). Hypertensive patients treated with captopril or enalapril may be at risk for zinc deficiency (Golik et al. 1998). Although it has not yet been reported, zinc loss could theoretically occur with fosinopril, lisinopril, quinapril, and ramipril.

Significance of Depletion

Replacement Therapy

References

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

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

Golik A, Modai D, Averbukh Z, et al. Zinc metabolism in patients treated with captopril versus enalapril. Metab. 1990;39(7):665-667.

Golik A, Zaidenstein R, Dishi V, et al. Effects of captopril and enalapril on zinc metabolism in hypertensive patients. J Am Coll Nutr. 1998;17(1):75-78.

Peczkowska M. [Influence of angiotensin I converting enzyme inhibitors on selected parameters of zinc metabolism]. Pol Arch Med Wewn. 1996;96(1):32-38.

7. Cardiovascular Medications PLUS

Beta-Adrenergic Blockers

Acebutolol (Sectral®)

Atenolol (Tenormin®)

Betaxolol (Betoptic®; Betoptic® S; Kerlone®)

Bisoprolol (Zebeta®)

Carteolol (Cartrol® Oral; Ocupress® Ophthalmic)

Celiprolol (no brand names listed)

Esmolol (Brevibloc® Injection)

Labetalol (no brand names listed)

Levobetaxolol (Betaxon®)

Levobunolol (AKBeta®; Betagan® Liquifilm®)

Metipranolol (OptiPranolol® Ophthalmic)

Metoprolol (Lopressor®; Toprol XL®)

Nadolol (Corgard®)

Penbutolol (Levatol®)

Pindolol (Visken®)

Propranolol (Inderal®; Inderal® LA)

Sotalol (Betapace AF™; Betapace®)

Timolol (Betimol®; Blocadren®; Timoptic-XE®; Timoptic®; Timoptic® OcuDo