During a routine Physical Health Assessment (PHA), a 22 y/o active duty, African American male's test for G6PD deficiency came back as high/critical.  The nurse assigned to that panel asked the pharmacy which drugs she and the patient's PCM (primary care manager) should avoid in this patient?

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a hereditary condition. This condition is a disorder of the hexose monophosphate shunt, responsible for the production of NADPH in erythrocytes (RBCs), which keeps glutathione in a reduced state. Reduced glutathione is a substrate for glutathione peroxidase, which removes peroxide from RBCs and protects them from oxidative stress. Without this protection, oxidative drugs may oxidize the sulfhydryl groups of hemoglobin, causing hemolysis.

G6PD deficiency is an X-linked (sex linked) genetic disorder. It affects millions of people. The most common types occur in American and African blacks (approximately 10-11%). Other ethnic groups commonly affected are those of Mediterranean descent (esp Greeks, Sardinians, Khurdic and Sephartic Jews), and Asians. The more severe form appears to be the Mediterranean variety, which may be triggered via oxidative drugs as well as ingestion of fava beans.

The degree of enzyme deficiency and amount of oxidative stress determines the degree of hemolysis. The dose that precipitates hemolysis is often below the prescribed therapeutic dose. Severe hemolysis is rare. A list of oxidative drugs is included later in this Pearl as well as some clinical case report details of anemia secondary to G6PD deficiency.

The G6PD deficiency disorder is sex-linked with transmission from mother to son.  It is estimated that over 100 million people carry the trait for hereditary G6PD deficiency.  The trait is fully expressed in males but female heterozygotes have a mix of normal and deficient red blood cells and as such, will demonstrate less severe manifestations of the disease.

Over 150 variants of the enzyme have been identified with the most common being A- (African) and the Mediterranean types.

The most common populations affected are native Africans and southern Europeans to include Sardinian Italians, Greeks, and Kurdish Jews.  Approximately 10 percent of African-Americans carry a less severe form of the A- variant.  In this case, individuals are asymptomatic unless an episode is precipitated by oxidant stress.  The stress can be caused by medications.  The most common, but not the only drugs, are hydroxychloroquine, dapsone, sulfa derivatives, phenazopyridine, or primaquine.  Non-medication precipitants include infection, diabetic ketoacidosis, unknown factors during neonatal development, and ingestion of fava beans or broad beans.

Other populations affected by G6PD variants are Sephardic Jews, Asians, and American Indians with rare cases reported in western Europeans and Scandinavians.

A classification system is used in G6PD deficiency.  Class I is the most severe form and is manifested by an ongoing hemolytic process even in the absence of oxidant stress.  Class II is marked by G6PD activity of less than 10 percent of normal but with severe hemolytic episodes instead of chronic hemolysis.  Class III is defined as having occasional hemolytic episodes with identifiable precipitating factors.  Class IV has normal G6PD activity.  Class V actually has increased G6PD enzyme activity.

The degree of hemolysis in all cases is proportional to the amount of enzyme deficiency and strength of the oxidant stimulus.  With medications, the oxidant potential and dose are related to the severity of the response.

DRUG-INDUCED HEMOLYTIC ANEMIA IN G-6-PD DEFICIENCY

The following drugs have been associated with hemolytic anemia in patients with varying degrees of G6PD:

Acetanilid (3)
Aminopyrine (1) not in blacks
Ascorbic Acid (1) large doses
Aspirin (1,2) in conjunction with fever or other ppt factors
Chloramphenicol (1)
Chloroquine (1,2) suspected G6PD association
Dapsone (1,2) doses above 200 to 300 mg/d
Dimercaprol (1)
Hydroxychloroquine (2)
Methylene Blue (1,2)
Nalidixic Acid (1,2)
Naphthalene (2)
Niridazole (3)
Nitrofurantoin (1,2)
Para-aminosalicylic acid (2)
Penicillamine (1)
Pentaquine (3)
Phenacetin (2)
Phenylhydrazine (3)
Primaquine (1,2)
Probenecid (2)
Quinacrine (1,2) usually with recurrent infection or other ppt factors
Quinidine (1) not in blacks
Quinine (1,2) not in blacks
Sulfasalazine (1)
Sulfonamides (1,2)
Thiazolesulfone (3)
Toluidine Blue (3)
Trinitrotoluene (3)
Vitamin K (1,2) usually with concurrent infection or other ppt factors
Key: (1)= Troutman, 1994.
        (2)= Stumpf & Townsend, 1992.
        (3)= Wintrobe et al, 1981.

CONCLUSION:

Drugs with oxidizing properties may cause hemolysis in G6PD deficient patients with the severity of the disease dependent on the type of G6PD deficiency and on the sex of the patient. The degree of hemolysis induced by a drug may be accentuated by the presence of additional factors (ie, infection or disease state). In conclusion, G6PD deficiency is not an absolute contraindication to the use of sulfonylureas, but these agents should be instituted with caution and patients with G6PD deficiency should be monitored closely for adverse effects.

REFERENCES:

1. Babior RM & Stossel TP: Hematology: A Pathophysiological Approach. New York, NY: Churchill Livingstone Inc, 1984; 121-126.

2. Beutler E: Glucose 6-phosphate dehydrogenase deficiency, In: Williams WJ et al (Ed): Hematology, 2nd ed. McGraw Pub, San Francisco, 1977; pp 471-472.

3. Davies DM: Pathogenesis of Adverse Drug Reactions. Textbook of Adverse Drug Properties. Oxford England: Oxford University Press, 1981; 25-26.

4. Stumpf JL & Townsend KA: Other Anemias. In: Herfindal ET et al (eds): Clinical Pharmacy and Therapeutics, 5th ed. Williams & Wilkins, Baltimore, 1992.

5. Swanson M: Drugs and chemical induced hemolysis. Drug Intell Clin Pharm 1973; 7:6-24.

6. Troutman WG: Drug-induced Diseases, In: Knoben JE & Anderson PO (eds): Handbook of Clinical Drug Data, 7th ed. Drug Intelligence Publications, Hamilton, IL, 1994

7. Wintrobe MM, Lee GR, Boggs DR et al (eds): Clinical Hematology, 8th ed. Lea & Febiger, Philadelphia, 1981.

List of contributors:
W Lee,  Philip D. Hall, R.Ph. PharmD Candidate, John D. Ostrosky, PharmD

ASCORBIC ACID - ADVERSE EFFECTS FOLLOWING MEGADOSE THERAPY

Megavitamin therapy has been advocated in the treatment of various conditions including schizophrenia, cancer, and the common cold. A mega dose is generally considered to be ten or more times the recommended daily allowance (RDA). It has been alleged that mega doses of vitamins are relatively harmless; however, toxicity has been seen with these doses. Among the most common water soluble vitamins to cause toxicity are niacin, pyridoxine, folic acid and ASCORBIC ACID (AA) (Dipalma, 1978).

In recommended daily amounts, AA functions to hold tissues together and prevent scurvy and its associated symptoms. In quantities exceeding enzyme saturation, the vitamin acts as a chemical and is free to enter into non-enzymatic reactions (Herbert, 1979). Because it is a strong reducing agent, AA can not only interact with other dietary components, but also can change the disposition of other drugs or alter the results of laboratory tests (Herbert, 1979).

The most common side effect of AA ingestion is DIARRHEA. However, other major toxicities have been reported. The main deficiency state associated with AA is scurvy. Although this condition caused by inadequate dietary intake is rare today, scurvy can develop in infants born to mothers taking large doses of AA (Herbert, 1979; Gossel & Wuest, 1982). It appears that both the mother and fetus increase their metabolic destruction of AA after administration of large doses. Once the fetus is born, the AA obtained in the normal diet is degraded rapidly, thus leading to a deficiency state. This can also occur in adults who become dependent on large doses of AA (Herbert, 1979; Gossel & Wuest, 1982). It is therefore recommended that mega doses be tapered by 10-20% daily until discontinued or the patient is maintained on lower doses.

Herbert & Jacob (1974) have reported that AA in doses as low as 250 mg may destroy up to 81% of the vitamin B12 in a moderate vitamin B12-containing meal, and up to 25% in a high vitamin B12-containing meal. The degree of destruction appears to be dependent on the various other ingredients in the meal, such as iron in moderate amounts and nitrates, which may counteract AA's effect on vitamin B12. To diminish the possibility and magnitude of such destruction, it is suggested that AA be taken 2 or more hours after meals. While AA may still destroy a substantial amount of the normally excreted vitamin B12 and possibly lower vitamin B12 in serum and body stores, frank megaloblastic anemia would require mega doses of AA ingested over several years.

A number of investigators have reported the possibility of 1 g doses of AA precipitating renal cysteine or OXALATE STONES in susceptible individuals (Lamden & Chrystowski, 1954; Roth et al, 1976). Lambden & Chrystowski (1954) studied 11 healthy adult males given 0.25 to 9 g of extra-dietary AA per day. Statistically significant increases in urinary oxalate excretion were found with doses of 8 and 9 g per day (p less than 0.01). Less than 4 g per day showed a negligible increase in urinary oxalate excretion.

After 8 days of ingesting 8 grams of AA per day (in 4 equal doses, at meals and at bedtime), a 25-year-old man developed hematuria. His urine on that day contained numerous single calcium oxalate dihydrate crystals and large, jagged calcium oxalate dihydrate crystal aggregates. AA supplementation was terminated. Five days later, there were no crystals or blood evident in the urine (Auer et al, 1998).

Lawton et al (1985) reported acute RENAL FAILURE secondary to tubular obstruction with calcium oxalate crystals with a single 45 g IV dose of ascorbic acid in a 58 year old female with amyloidosis and nephrotic syndrome.

Ascorbic acid-induced uricosuria has also been reported (Mitch et al, 1981; Berger et al, 1977; Stein et al, 1976). Stein et al (1976) studied 14 patients - 6 normals, 5 with gout and 3 with asymptomatic increased urinary urate. Single AA doses of 0.5, 2 and 4 g were given with a 48 hour washout period between each trial. Significant increases of urate excretion were seen with 4 g doses (p less than 0.01) while serum urate remained constant. With chronic administration of 8 g of AA to 3 patients, a significant increase in urate excretion occurred (p less than 0.01) and serum urate levels declined by 1.5, 3.1, and 1.2 mg/dl within of 7 days. This raises the possibility of precipitating urate stones or an acute attack of gout in predisposed patients. Mitch et al (1981) found that urinary urate excretion assessed by an analytic method was not increased in normal subjects given AA 4 g or 12 g/d. Basal AA excretion did increase seven- to twelve-fold with 4 g per day and it is suggested that non-specific assays such as the phosphotungstate reduction method may not distinguish this from urinary urate, thus showing a falsely elevated urate excretion value.

A more serious and possibly lethal effect of large doses of AA occurs in certain ethnic groups such as American blacks, Sephardic Jews and Orientals who may have a congenital glucose-6-phosphate-dehydrogenase (G6PD) deficiency (Herbert, 1979). In these persons hemolytic anemia may be activated by the reducing action of megadoses of AA. Such was the case with a 60-year-old black man being treated for acute renal failure and given 80 g of AA intravenously each day for 2 consecutive days. Hemolytic anemia and disseminated intravascular coagulation developed, and the patient died on the twenty-second hospital day (Anon, 1976; Campbell et al, 1975).

Lab test interferences by AA may also have serious consequences in certain patients. Diabetic patients may obtain inaccurate results in testing urine glucose for the adjustment of insulin dose (Herbert, 1979). Ascorbic acid may also interfere with occult blood test results in the diagnosis of intestinal disorders including carcinoma of the colon. Although some conditions may be clinically apparent, they may not be confirmed by laboratory testing (Herbert, 1979).

Because of AA's potential for altering urinary pH, the possibility exists for the activity of some concurrently administered drugs to be altered as a result of effects on drug ionization and urinary excretion.

REFERENCES:

1. Anon: Nutr Rev 1976; 34:236-237.

2. Auer BL, Auer D & Rodgers AL: Relative hyperoxaluria, crystalluria and haematuria after megadose ingestion of vitamin C. Eur J Clin Invest 1998; 28(9):695-700.

3. Berger L et al: Am J Med 1977; 62:71-76.

4. Campbell GD et al: Ann Intern Med 1975; 82:810.

5. Dipalma JR: Am Fam Physician 1978; 16:106-109.

6. Gossel TA & Wuest JR: US Pharmacist 1982; July:48-54.

7. Herbert V & Jacob E: JAMA 1974; 230:241.

8. Herbert VD: NY State J Med 1979; 79:278-279.

9. Lamden MP & Chrystowski GA: Proc Soc Exp Biol Med 1954; 85:190-192.

10. Lawton JM, Conway LT, Crosson JT et al: Acute oxalate nephropathy after massive ascorbic acid administration. Arch Intern Med 1985; 145:950-951.

11. Mitch WE et al: Clin Pharmacol Ther 1981; 29:318-321.

12. Roth DA & Breitenfield RV: JAMA 1977; 237:768.

13. Stein HB et al: Ann Intern Med 1976; 84:385.

List of contributors: Leroy C Knodel, PharmD, Claudia Kamper, PharmD

The author, from the California Department of Health Services, reports on possible adverse reactions to some commonly used herbal preparations.......... Goldenseal may antagonize heparin and produce hemolysis in infants with G6PD deficiency, and is contraindicated in pregnancy or neonatal jaundice.

ANEMIA - G6PD DEFICIENCY (Acetaminophen)

HEMOLYSIS occurred in a 39-year-old Greek male with G6PD deficiency. The patient developed the hemolytic episode about 1 hour after taking a 500 mg dose and had not had any apparent exposure to other agents that can induce hemolysis in a patient with G6PD deficiency (Bartsocas et al, 1982).

The effect of 1000 mg of acetaminophen 3 times a day for 2 weeks administered to a G6PD deficient (Mahidol variant) patient using radiolabelled erythrocytes (Pootrakul & Panich, 1983). A decrease in erythrocyte half-life was found that was not clinically significant in this patient. Acetaminophen should be used prudently in known G6PD individuals.

ANEMIA - G6PD DEFICIENCY (ISDN)

Two cases of G6PD anemia (Mediterranean type) induced by isosorbide dinitrate have been reported, with one case confirmed by rechallenge (Aderka et al, 1983). One case was confirmed by rechallenge and both cases were of the Mediterranean type.

ANEMIA - G6PD DEFICIENCY (primaquine)

Primaquine is an oxidizing agent and can cause HEMOLYTIC ANEMIA in patients with a glucose-6-phosphate dehydrogenase (G6PD) deficiency. The hemolysis generally appears 2 to 3 days after primaquine administration and continues for 5 to 7 days. The severity of red blood cell hemolysis is dependent on the dose of the drug, the degree of enzyme deficiency, and other factors that can increase hemolysis (other drugs, liver disease, infection) (Clyde, 1981; Reynolds, 1990).

Cases of acute intravascular hemolysis in G-6PD-deficient persons following standard malaria treatment with PRIMAQUINE, including a single 45 milligrams dose, has been reported (Reeve et al, 1992).

ANEMIA - G6PD DEFICIENCY (Topical Silver Sulfadiazine Cream)

Hemolytic anemia induced by SILVER SULFADIAZINE was reported in a 20-year-old male with G6PD (glucose-6-phosphate dehydrogenase) deficiency. The patient received BID applications of SILVER SULFADIAZINE 1% cream on burns covering 35% of his body. After 4 days of therapy, the patient developed acute hemolytic anemia, which fully resolved upon discontinuation of SILVER SULFADIAZINE (Eldad et al, 1991).

Since G6PD deficiency is considered a disease state and not a medication allergy, CHCS does not have the capability to use the allergy field to screen for these patients.  There are some alternatives.  One is to use "Other" as an allergy and list G6PD deficiency in that field.  The second option is to enter each of the most commonly suspected medications such as hydroxychloroquine and enter "G6PD deficiency" in the comment field for the medication.

References:

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- Brumfitt W, Hamilton-Miller JMT & Kosmidis J: Trimethoprim-sulfamethoxazole: present position. J Infect Dis 1973; 128(Suppl):S778-791.

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- Hardman JG, Gilman AG & Limbird LE (Eds): Goodman and Gilman's The Pharmacological Basis of Therapeutics, 9th ed. McGraw-Hill, New York, NY, 1996.

- Koch-Weser J et al: Adverse reactions to sulfisoxazole, sulfamethoxazole and nitrofurantoin. Arch Intern Med 1971; 128:399.

- Kucers A & Bennett N M: The Use of Antibiotics, 4th ed. Lippincott, Philadelphia, PA, 1987.

- Marabani M, Madhok R & Capell HA: Leucopenia during sulphasalazine treatment for rheumatoid arthritis. Ann Rheum Dis 1989; 48:505-507.

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- Tapp H & Savarirayan R: Megaloblastic anaemia and pancytopenia secondary to prophylactic cotrimoxazole therapy. J Paediatr Child Health 1997; 33:166-167.

- Van de Pette JEW, Cunnah DTE & Shallcross TM: Bone marrow necrosis after treatment with sulphasalazine. Br Med J 1984; 289:798.

- Wand EK et al: Pulmonary infiltrates and eosinophilia associated with sulfasalazine. Mayo Clin Proc 1984; 59:343-346.

- Westerholm B: Adverse reactions from chemotherapeutic agents as seen in National Monitoring Center. Int J Clin Pharmacol Res 1974; 9:26.

- Ko, R., West J Med 171:181, September 1999. ADVERSE REACTIONS TO WATCH FOR IN PATIENTS USING HERBAL REMEDIES (107 references)