Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency and Oxidative Drugs

Name: Audria Graciela Student ID: 030.08.047

FACULTY OF MEDICINE TRISAKTY UNIVERSITY JAKARTA, 2011

Preface

First of all, I would like to thank God for His blessing all through my works so I could finish this paper in time. I would like to thank Prof. dr. Muzief Munir, Sp.A (K) for his guidance and help on this paper. I arranged this paper titled Glucose-6Phosphate Dehydrogenase (G6PD) Deficiency and Oxidative Drugs in order to complete my English assignment for Medical English 3rd subject in Faculty of Medicine, Trisakti University. I apologize for all mistakes that I made in this paper and I hope this paper could be useful for its reader.

Jakarta, June 2011

Audria Graciela 030.08.047

Content
Preface 2 Content 3 Abstract 4 Chapter I : Introduction 5 Chapter II : Discussion 6 Chapter III : Conclusion 11 Reference 12

Abstract

Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency is the lack of glucose-6 phosphate dehydrogenase, an enzyme present in red blood cells (RBC), which can cause a type of anemia known as hemolytic anemia. Red blood cells carry oxygen in the body and G6PD protects these cells from natural oxygen chemicals (oxidative substances) that may build up. If there are too many of these chemicals, they can destroy the red blood cells prematurely. Once the trigger is removed or resolved, the symptoms of G6PD deficiency usually disappear fairly quickly, typically within a few weeks. Newborns may develop persistent and more serious jaundice as a result of G6PD deficiency. 1

Keyword : G6PD

Chapter I Introduction

G6PD deficiency is the most important disease of the hexose monophosphate pathway and is responsible for two clinical syndromes, and episodic hemolityc anemia induced by infection, certain drugs, or, rarely fava beans and a spontaneous chronic nonspherocytic hemolytic anemia. This X-linked enzyme deficiency affects more than 200 million people worldwide, and it represents an example of balanced polymorphism in which there is an evolutionary advantage of resistance to falciparum malaria in heterozygous females that outweighs the small negative effect of affected hemizygous males. 2 The deficiency is caused by inheritance of any of a large number of abnormal alleles of the gene responsible for the synthesis of the G6PD molecule. The result of the G6PD cloned are sequenced showed at least 90 mutations, and some of these mutation cause episodic versus chronic hemolysis. Milder disease is associated with mutations near the amino terminus of the G6PD molecule, and chronic nonspherocytic hemolytic anemia with mutation clustered near the carboxyl terminus. The normal enzyme found in most population is designated G6PD B +. a normal variant designated G6PD A+ is common in the African-American population. More than 100 distinct enzyme variants of G6PD are associated with a wide spectrum of hemolytic disease. 2

Chapter II Discussion

I. Epidemiology Glucose 6 phosphate dehydrogenase (G6PD) deficiency is the most common enzymopathy in man. It is estimated to affect over 400 million people worldwide. It was discovered by Alving and coworkers, while investigating unusual hemolytic reaction that occurred in ethnic black individuals following the administration of primaquin, an 8-aminoquinoline, for the treatment of malaria. Its incidence and clinical presentation vary considerably among different ethnic groups. 3 Populations with common G6PD deficiency are distributed in the Mediterranean region, across the Middle East, India, Indochina, and South China as well as middle frica. Its incidence in the Arab world ranges from 8% to 50%. About 13% of male African-Americans have a mutant enzyme that results in a deficiency of red blood cell (RBC) G6PD activity to 5-15% or less of normal. Italians, Greeks and other Mediterranean, Middle Eastern, African, and Asian ethnic groups also have a high incidence, raging from 5-40%, of a variant designated G6PD Mediterranean. 3

II. Etiology Synthesis of RBC in G6PD is determined by a gene on the X chromosome. Disease involving this enzyme deficiency therefore occur more frequently in males than in females. In these variants, the G6PD activity of homozygous females or homozygous

males is less than 5% of normal. Heterozygous females have an intermediate enzymatic activity and, as an example of X chromosome inactivation (Lyon hypothesis), have two population of RBCs : one is normal, and the other is is deficient in G6PD activity. Most heterozygous females do not have clinical hemolysis after exposure to oxidant drugs. Rarely, the majority of the RBCs are G6PD deficient in heterozygous females because of random inactivation of the normal X chromosome. A large number of other rare enzyme variants have been associated with drug-induced hemolysis. 2 III. Pathophysiology G6PD is a central enzyme in the hexose monophosphate shunt of glucose metabolism and catalyzes the conversion of glucose-6-phosphate (G6P) to 6-phosphogluconic acid (6PG). NADPH is produced in this process and is necessary to maintain glutathione in the reduced state, that is GSSG GSH. Glutathione is present in the red cell in millimolar amounts and acts to neutralize agents that potentially oxidize either hemoglobin or components of the red cells membrane. If reduced glutathione cannot be sustained to remove oxygen radicals generated by oxidant drugs, the hemoglobin precipitates forming Heinz bodies, and the red cell membrane is critically damaged. The precipitation of hemoglobin and damage to membrane result in premature red cell destruction or hemolysis. 2

IV.

Oxidative Drugs

Oxidative drugs that can induced hemolytic anemia in G6PD deficiency are: Definite Risk of Hemolysis Antihelmintics -Naphthol Niridazole Stibophen Possible Risk of Hemolysis Analgesics Acetylsalicylic acid (Aspirin) Acetanilide Paracetamol (Acetaminophen) Aminophenazone (Aminopyrine) Dipyrone (Metamizole) Phenacetin Phenazone

Antibiotics

Antimalarials

Antimethemoglobinaemic Agents Antimycobacterials

Nitrofurans - Nitrofurantoin - Nitrofurazone Quinolones - Ciprofloxacin - Moxifloxacin - Nalidixic acid - Norfloxacin - Ofloxacin Chloramphenicol Sulfonamides - Co-trimoxazole (Sulfamethoxazole + Trimethoprim) - Sulfacetamide - Sulfadiazine - Sulfadimidine - Sulfamethoxazole - Sulfanilamide - Sulfapyridine - Sulfasalazine (Salazosulfapyridine) - Sulfisoxazole (Sulfafurazole) Mepacrine Pamaquine Pentaquine Primaquine Methylene blue Dapsone Para-aminosalicylic acid Sulfones - Aldesulfone sodium (Sulfoxone) - Glucosulfone - Thiazosulfone Doxorubicin Rasburicase Phenazopyridine (Pyridium) Acetylphenylhydrazine Phenylhydrazine

Antibiotics

(Antipyrine) Phenylbutazone Tiaprofenic acid Furazolidone Streptomycin Sulfonamides - Sulfacytine - Sulfaguanidine - Sulfamerazine - Sulfamethoxypyridazole

Anticonvulsants Antidiabetics Antidotes

Phenytoin

Glibenclamide Dimercaprol (BAL)

Antineoplastic Adjuncts Genitourinary Analgetics Others

Antihistamines Antihypertensi ves Antimalarials

Antazoline (Antistine) Diphenhydramine Tripelennamine Hydralazine Methyldopa Chloroquine & derivatives Proguanil 8

 Pyrimethamine Quinidine Quinine Antimycobacte Isoniazid rials Antiparkinsoni Trihexyphenidyl sm Agents (Benzhexol) Cardiovascular Dopamine (L-dopa) Drugs Procainamide Quinidine Diagnostic Toluidine blue Agent for Cancer Detection Gout Colchicine Preparations Probenecid Hormonal Mestranol Contraceptives Nitrates Isobutyl nitrite Vitamin K Menadiol Na sulfate Substance Menadione Menadione Na bisulfite Phytomenadione Vitamins Ascorbic acid (Vit C) (rare) Others Arsine Berberine (in Coptis chinensis) Fava beans Naphthalene (in mothballs) Para-aminobenzoic acid
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V.

Clinical Manifestation

In the usual pattern of G6PD deficiency, symptoms develop 24-48 hours after a patient has ingested a substance that has oxidant properties. Drugs that have these properties include aspirin, sulfonamides, and antimalarials such as primaquine. The degree of hemolysis varies with the inciting agent, the amount ingested, and the severity of the enzyme deficiency in the patient. In the severe cases, hemoglobinuria and jaundice result, and the hemoglobin concentration may fall precipitously and be life threatening. Some spontaneous recovery of the hemolysis may be observed. The associated reticulocytosis produces a compensated hemolytic process. 2

VI.

Laboratory Finding

The onset of acute hemolysis results in a precipitous fall in hemoglobin and hematocrit. If the episode is severe, the hemoglobin-binding proteins such as haptoglobin are saturated, and free hemoglobin may appear in the plasma and subsequently in the urine. Unstained or supravital preparations of RBCs reveal Heinz Bodies ( precipitated hemoglobin ). The blood films reveals reticulocytosis. 2 VII. Prevention and Treatment

Prevention of the hemolysis constitutes the most important therapeutic measure. When possible, males belonging to ethnic groups with a significant incidence of G6PD deficiency should be tested for the defect before known oxidant drugs are given. When hemolysis has occurred, supportive therapy may require blood transfusions, although recovery is the rule when the oxidant agent is removed. 5

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Chapter III Conclusion

Glucose-Phosphate 6 Dehydrogenase (G6PD) Deficiency is the most common enzymatic cause of hemolytic anemia. G6PD is needed in the hexose monophosphate pathway to produce NADPH, an anti-oxidant that protects the red blood cells from the oxidative substance, such as : oxidative drugs. Synthesis of RBC G6PD is determined by a gene on the X chromosome and mostly occur in males than in females. 6 There are certain drugs to avoid in G6PD Deficiency patients, such as : some of antimalarials, antibiotics, analgesics, vitamins. In the usual pattern of G6PD deficiency, symptoms develop 24-48 hours after a patient has ingested a substance that has oxidant properties. When hemolysis has occurred, supportive therapy may require blood transfusions, although recovery is the rule when the oxidant agent is removed.

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References

1. Greenberg S. G6PD Deficiency. 2009. Available at: http://www.utoronto.ca/kids/G6PD.htm.

2. Segel GB. Enzymatic Defects. In: Behrman, Kliegman, Jenson, editors. Nelson Textbook of Pediatrics 17th ed. Philadelphia: Saunders press; 2006.p.1636-1638.

3.

Arrayed SSA. Frequency of Deficiency among Bahraini students: A Ten Years Study. Bahrain Med Bull. 2010;32:1-7.

4. MIMS. 103rd ed. Drugs to avoid in G6PD Deficiency. 2006. Available at: http://web02.cych.org.tw/pharm/MIMS%20Summary%20TableG6PD.pdf.

5. Rinaldi I, Sudoyo AW. Anemia Hemolitik Non Imun. In: Sudoyo AW et al, editors. Buku Ajar Ilmu Penyakit Dalam. Jakarta: InternaPublishing; 2009.p.1157-1164.

6. Bakta IM. Hematologi Klinik Ringkas. 1st ed. Jakarta: Penerbit Buku Kedokteran EGC; 2007.

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