Which drugs should be avoided in glucose-6-phosphate dehydrogenase deficiency?

Fråga: Which drugs should be avoided in glucose-6-phosphate dehydrogenase deficiency?

Sammanfattning: Drugs that should not be given in G6PD-deficient individuals are: primaquine and other antimalarials, aminophenazone, doxorubicin, glibenclamid, nalidixic acid and other quinolones, nitrofurantoin, sulfonamides (sulfapyridine and sulfamethoxazole, including co-trimoxazole), quinine, quinidine, sulfones, dapsone.

Causion is also advised with the following drugs: aspirin, cyclosporin, tacrolimus, penicillin and cefotetan, vitamin K and analogues, paracetamol and probenecid.

Svar: Similar questions have previously been dealt with in Drugline (1-6).

Glucose-6-phosphate dehydrogenase (G6PD) catalyses the first step in the pentose phosphate pathway, and thus a series of oxidation-reduction reactions: the conversion of oxidized nicotinamide adenine dinucleotide phosphate (NADP+) to its reduced form, NADPH. NADPH maintains glutathione in a reduced state. The absence of reduced glutathion due to G6PDH deficiency allows certain drugs to oxidize sulfhydryl groups on hemoglobin and the formation of disulfide bonds, leading to precipitation and hemolysis (7-9).

G6PD deficiency is the most common enzymopathy in the world affecting more than 400 million people world-wide. It occurs with a highest frequency in tropical Africa, in the Middle East, in some Mediterranean areas, in tropical and subtropical Asia and Oceania. G6PD deficiency is recessive and sex-linked to chromosome X and therfore men and homozygous women are at higher risk of suffering from side effects (1). There is a great degree of genetic heterogeniety of G6PD, with more that 400 known variants. The severity and duration of hemolytic anemia varies. However the vast majority of affected individuals are asymptomatic. There are five different types of deficiency described (14). The African (A type) and the Mediterranean (B type) variant have been studied in most detail (3).

The Mediterranean type, which is found in Greeks, Sardinians, Sephardic Jews, and Asian and northwest Indian people, is the more severe deficiency. It is affected by the widest range of drugs.

This deficiency can increase the mortality and morbidity in neonatal icterus and kernicterus (1,2).

These patients are at lower risk of infections with Malaria (Plasmodium falciparum).

Drugs that should be avoided in G6PD deficiency are listed below: Primaquine and other antimalarials (7-15); Aminophenazone (7); Glibenclamid (13); Nalidixic acid and other quinolones (7,10,15); Nitrofurantoin (7,8,10-12,14,15); Sulfapyridine, sulfamethoxazole and other sulfonamides (7,8,10,11,14,15); Quinine, quinidine (7,10); Dapsone and other sulfones (7,8,10); Acetanilide (12,13,15); Doxorubicin (12,13)

There is a certain ambiguity about which drugs should be avoided in G6PD.

Drugs that are considered safe in one reference in G6PD deficiency are: aspirin, ascorbic acid, chloramphenicol, colchicine, diphenhydramine, isoniazid, phenytoin, probenecide, pyrimethamine, trimethoprim, vitamin K (7).

Controversly others state that vitamin K analogues and chloramphenicol are, among others, known to cause hemolytic anemia (9) and aspirin is found to be a drug with possible risk of haemolysis in some G6PD-deficient patients (1,10).

Cases of drug-induced hemolytic anemia have also been described in patients treated with several different drugs such as cyclosporin, tacrolimus, penicillin, cefotetan, ciprofloxacin, as well as acetaminophen overdose (3,9,11,16). Patients with G6PD deficiency might therefore be at greater risk to develop reactions to these drugs as well.

The risk and severity of hemolysis are thought to be associated with dose, duration of therapy, and other forms of oxidative stress, such as infection, ingestion of fava beans and enviromental factors (9).

Because of these confounding factors some patients with the G6PD deficiency will experience toxicity after drug administration, and others will not (9). 1 Speight TM, Halford NHG, editors. Avery´s Drug Treatment. 4th ed. Auckland: Adis Int 1997:288, 1229-30. 2 Steensma DP, Hoyer JD, Fairbanks VF. Hereditary red blood cell disorders in Middle Eastern patients. Mayo Clin Proc 2001;76:285-93.

3 Ma MK, Woo MH, Mcleod HL. Genetic basis of drug metabolism. Am J Health-Sysr Pharm 2002;59(21):2061-9.
4 Drugline no 08354 (year 1991)
5 Drugline no 15800 (year 1999)
6 Drugline no 09536 (year 1992)
7 Drugline no 14469 (year 1997)
8 Drugline no 08153 (year 1990)
9 Drugline no 08270 (year 1990)
10 British natinal Formulary, 44 ed (Sept 2002), online ed.

11 Sklar GE. Hemolysis as a potential complication of acetaminophen overdose in a patient with glucose-6-phosphate dehydrogenase deficiency. Pharmacotherapy 2002;22(5):656-8. 12 Fauci AS, Braunwald E, Isselbacher KJ, Wilson JD, Martin JB, Kasper DL, Hauser SL, Longon DL (eds), Harrison´s, Principles of internal medicine. 14th ed. New York: McGraw-Hill Inc; 1998 p.664. 13 Davies DM, Ferner RE, de Glanville H, editors. Davie´s textbook of adverse drug reactions. 5th ed. Philadelphia: Lippincott-Raven Publishers; 1998 p.739. 14 WHO Working group. Glucose-6-phosphate dehydrogenase deficiency. Bull World Health Org 1989;67(6):601-11. 15 Lee GR, Foerster J, Lukens J, Paraskevas F, Greer JP, Rodgers GM, Wintrobe´s Clinical hematology. 10th ed. Baltimore: Williams & Wilkins; 1999 p.1182. 16 Sukumar S. Colah R, Mohanty D. G6PD gene mutation in India producing drug-induced haemoliytic anemia. Br J Haematol 2002;116:671-2.