Understanding G6PD Deficiency and Drug-Induced Haemolysis

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked inherited enzyme defect that impairs the red blood cell's ability to generate NADPH via the hexose monophosphate shunt. NADPH is essential for maintaining reduced glutathione, which protects haemoglobin and the red cell membrane from oxidative damage. When G6PD-deficient red cells are exposed to oxidant drugs, this defence fails, leading to haemoglobin denaturation (Heinz body formation), membrane damage, and acute intravascular/extravascular haemolysis.

Why All Four Drugs Carry a Definite Haemolytic Risk

Standard pharmacology and haematology references (including WHO guidance and Goodman & Gilman) classify a specific list of drugs as having a definite (well-documented) risk of causing clinical haemolysis in G6PD-deficient individuals. All four drugs listed in the question belong to this "definite risk" category:

• 1. Primaquine: An 8-aminoquinoline antimalarial and one of the classic, most potent oxidant drugs; it is the prototype agent used to screen for G6PD deficiency because of its strong, dose-dependent haemolytic potential.
• 2. Dapsone: A sulfone used in leprosy, dermatitis herpetiformis, and PCP prophylaxis; its hydroxylamine metabolites are strong oxidants and it is well established as causing definite haemolysis in G6PD-deficient patients.
• 3. Cotrimoxazole (Sulfamethoxazole-Trimethoprim): The sulfonamide component is a recognised oxidant drug and is listed among agents with a definite risk of clinically significant haemolysis in G6PD deficiency, not merely a "possible" one.
• 4. Nitrofurantoin: A urinary antiseptic that is a classic and long-recognised trigger of acute haemolytic anaemia in G6PD-deficient individuals; it is consistently placed in the "definite risk" list in standard pharmacology texts.

Why the Correct Answer is All Four (1, 2, 3 and 4)

Since Primaquine, Dapsone, Cotrimoxazole, and Nitrofurantoin are all established, textbook examples of drugs with a definite risk of precipitating clinical haemolysis in G6PD deficiency, the correct code is 1, 2, 3 and 4.

Why the Other Options Are Incorrect

• 1, 3 and 4: Incorrectly excludes Dapsone, which is equally well documented as a definite haemolytic risk drug.
• 2, 3 and 4 only: Incorrectly excludes Primaquine, despite it being the prototype and most classic oxidant drug causing haemolysis in G6PD deficiency.
• 1 and 2 only: Incorrectly excludes Cotrimoxazole and Nitrofurantoin, both of which are standard, well-recognised members of the "definite risk" drug list, not merely drugs with uncertain or minimal risk.

Therefore, the scientifically accurate and correct answer is 1, 2, 3 and 4, since all four drugs are established to carry a definite risk of clinical haemolysis in persons with G6PD deficiency.