Why does a patient with glucose‑6‑phosphate dehydrogenase (G6PD) deficiency develop hemolysis when exposed to oxidant drugs such as dapsone and sulfonamides?

Mechanism of Drug-Induced Hemolysis in G6PD Deficiency

Patients with G6PD deficiency develop hemolysis when exposed to oxidant drugs like dapsone and sulfonamides because these medications generate oxidative metabolites that overwhelm the red blood cell's already-compromised antioxidant defense system, leading to membrane damage, protein aggregation, and premature red cell destruction. 1, 2

The Fundamental Biochemical Defect

• G6PD catalyzes the first and rate-limiting step of the pentose phosphate pathway, which is the sole source of NADPH in red blood cells. 3, 4
• NADPH is essential for regenerating reduced glutathione (GSH), the primary antioxidant that protects red blood cells from oxidative damage. 4
• G6PD-deficient red blood cells cannot produce sufficient NADPH, leaving them unable to regenerate GSH and defenseless against oxidative stress. 4
• This vulnerability is particularly severe in red blood cells because, unlike other cells, mature erythrocytes cannot synthesize new G6PD enzyme to compensate for the deficiency. 5

How Oxidant Drugs Trigger Hemolysis

Dapsone-Specific Mechanism

• Dapsone itself is not directly hemolytic—it must be metabolized to dapsone hydroxylamine (DDS-NOH), which is the major hemolytic metabolite. 5, 6
• DDS-NOH generates oxidative stress that G6PD-deficient red blood cells cannot neutralize, resulting in a blockage of terminal glycolysis with cellular accumulation of pyruvate. 5
• The FDA drug label explicitly warns that hemolysis and Heinz body formation may be exaggerated in individuals with G6PD deficiency because dapsone acts as an oxidant that depletes the already-limited antioxidant capacity. 2

Sulfonamides and Other Oxidant Drugs

• Sulfonamides (sulfanilamide and related compounds) are listed among drugs that produce significant hemolysis in G6PD-deficient patients by similar oxidative mechanisms. 2
• These oxidant drugs generate reactive oxygen species and drug metabolites that damage red blood cell membranes through mechanisms distinct from traditional immune-mediated pathways. 6

The Cascade of Red Blood Cell Damage

Oxidative Protein Damage

• Oxidative stress causes hemoglobin to denature into hemichromes, which deposit on the inner red blood cell membrane. 4
• The band 3 protein—a critical component of the red blood cell cytoskeleton—undergoes tyrosine phosphorylation and aggregation when exposed to oxidative stress. 6, 4
• Extensive clustering of band 3 protein and formation of band 3-complement complexes mark the cells for removal by the immune system. 4

Membrane Remodeling and Vesiculation

• Oxidative damage leads to membrane cross-bonding, vesiculation, and loss of membrane integrity. 4
• IgG antibodies bind to aggregated band 3-complement complexes, creating immune recognition signals that target damaged cells for phagocytosis. 4

Cellular Fate

• Damaged G6PD-deficient red blood cells undergo either temporary sequestration (with potential return to circulation) or permanent removal by phagocytosis, depending on the severity of oxidative damage. 5
• G6PD-deficient red blood cells are predominantly permanently removed, while G6PD-sufficient cells are mostly sequestered and can return to circulation. 5
• The term "hemolytic anemia" is misleading—red blood cells do not actually lyse intravascularly but are removed by phagocytosis in the spleen and liver. 4

Variant-Specific Severity

• The Mediterranean G6PD variant (Gdmed) typically causes more severe, life-threatening hemolysis requiring strict avoidance of all oxidant drugs. 1, 7
• The African variant (GdA-) produces milder, self-limited hemolysis that may not require absolute contraindication of all oxidants. 1, 7
• Patients with enzyme activity <30% of normal have severe deficiency and face the highest risk of life-threatening hemolysis with oxidant drug exposure. 3

Clinical Recognition

• Early signs of hemolysis that patients should recognize include dark urine, sudden fatigue or pallor, jaundice, and abdominal or back pain. 1
• Laboratory findings include anemia, elevated indirect bilirubin, hemoglobinuria, and the presence of Heinz bodies on blood smear. 2, 8

Critical Pitfall to Avoid

• Never assume topical formulations are safe—even topical dapsone gel 5% has caused changes suggestive of mild hemolysis in some G6PD-deficient patients. 9, 1