Mechanism of Action of Dapsone

Introduction

Dapsone (diaminodiphenyl sulfone) is a synthetic sulfone antibiotic with antibacterial, anti-inflammatory, and immunomodulatory properties. It is most famously used in the treatment of leprosy (Hansen’s disease) and dermatitis herpetiformis, and also plays an important role in certain opportunistic infections. Dapsone is a high-yield drug in pharmacology, microbiology, dermatology, and infectious disease examinations because of its folate synthesis inhibition, similarity to sulfonamides, and characteristic adverse effects.

Mechanism of Action (Step-wise)

Dapsone inhibits bacterial folate synthesis, leading to impaired DNA synthesis and bacterial growth inhibition.

Step-wise mechanism:

1. Structural Similarity to Para-Aminobenzoic Acid (PABA)
   Dapsone is structurally similar to PABA, a substrate required for folic acid synthesis in bacteria.
2. Target Enzyme: Dihydropteroate Synthase
   Bacteria synthesize folic acid de novo using the enzyme dihydropteroate synthase.
3. Competitive Enzyme Inhibition
   Dapsone competitively inhibits dihydropteroate synthase by competing with PABA.
4. Inhibition of Dihydrofolic Acid Formation
   Blocking this enzyme prevents the formation of dihydrofolic acid.
5. Reduced Tetrahydrofolate Production
   Decreased dihydrofolate leads to reduced tetrahydrofolate availability.
6. Impaired DNA and RNA Synthesis
   Folate deficiency disrupts synthesis of purines and thymidine.
7. Bacteriostatic Effect
   Growth of susceptible organisms, especially Mycobacterium leprae, is inhibited.
8. Anti-inflammatory Action (Non-antibacterial)
   Dapsone also inhibits neutrophil myeloperoxidase activity and reduces reactive oxygen species, explaining its efficacy in inflammatory dermatoses.

Pharmacokinetics

• Absorption: Well absorbed orally
• Bioavailability: High
• Distribution: Widely distributed; concentrates in skin and peripheral nerves
• Metabolism: Hepatic acetylation and hydroxylation
• Elimination: Renal excretion (urine)
• Half-life: Long (20–30 hours; prolonged with chronic use)
• Special feature: Undergoes enterohepatic circulation

Clinical Uses

Dapsone is used in infectious and inflammatory conditions:

• Leprosy (Hansen’s disease) – part of multidrug therapy
• Dermatitis herpetiformis (drug of choice)
• Pneumocystis jirovecii pneumonia (PCP) prophylaxis (alternative)
• Toxoplasmosis prophylaxis (with pyrimethamine)
• Acne vulgaris (topical formulation)
• Immune-mediated blistering disorders

Adverse Effects

Dapsone has characteristic dose-related and idiosyncratic adverse effects:

• Hematologic:
  • Hemolytic anemia (especially in G6PD deficiency)
  • Methemoglobinemia
• Dermatologic:
  • Rash
  • Exfoliative dermatitis
• Neurologic:
  • Peripheral neuropathy (long-term use)
• Dapsone hypersensitivity syndrome:
  • Fever
  • Rash
  • Hepatitis
  • Lymphadenopathy

Regular monitoring of hemoglobin and liver function is recommended.

Comparative Analysis (must include a table + explanation)

Comparison of Folate Synthesis Inhibitors

Explanation:
Dapsone shares a sulfonamide-like mechanism but has additional anti-inflammatory effects that make it uniquely effective in leprosy and dermatitis herpetiformis. Trimethoprim acts downstream in folate synthesis, and combination therapy enhances antibacterial efficacy.

MCQs (10–15)

1. Dapsone inhibits bacterial growth by blocking synthesis of:
   a) Peptidoglycan
   b) Ergosterol
   c) Folic acid
   d) DNA gyrase

Answer: c) Folic acid

2. The enzyme inhibited by dapsone is:
   a) Dihydrofolate reductase
   b) DNA polymerase
   c) Dihydropteroate synthase
   d) Thymidylate synthase

Answer: c) Dihydropteroate synthase

3. Dapsone is structurally similar to:
   a) Folic acid
   b) Thymidine
   c) PABA
   d) Pyrimidine

Answer: c) PABA

4. Dapsone is most commonly used in:
   a) Tuberculosis
   b) Leprosy
   c) Syphilis
   d) Malaria

Answer: b) Leprosy

5. The effect of dapsone on bacteria is:
   a) Bactericidal
   b) Fungicidal
   c) Bacteriostatic
   d) Virucidal

Answer: c) Bacteriostatic

6. A major risk factor for hemolysis with dapsone is:
   a) Renal failure
   b) G6PD deficiency
   c) Iron deficiency
   d) Vitamin B12 deficiency

Answer: b) G6PD deficiency

7. Dapsone is the drug of choice for:
   a) Bullous pemphigoid
   b) Dermatitis herpetiformis
   c) Psoriasis
   d) Atopic dermatitis

Answer: b) Dermatitis herpetiformis

8. Dapsone also exerts anti-inflammatory effects by inhibiting:
   a) Mast cell degranulation
   b) Neutrophil function
   c) T-cell proliferation
   d) Complement activation

Answer: b) Neutrophil function

9. Which adverse effect is characteristic of dapsone?
   a) QT prolongation
   b) Methemoglobinemia
   c) Ototoxicity
   d) Nephrotoxicity

Answer: b) Methemoglobinemia

10. Dapsone hypersensitivity syndrome includes all EXCEPT:
    a) Fever
    b) Rash
    c) Hepatitis
    d) Nephrolithiasis

Answer: d) Nephrolithiasis

FAQs (minimum 5)

1. What is the primary mechanism of dapsone?
   Inhibition of bacterial folate synthesis by blocking dihydropteroate synthase.
2. Why is dapsone effective in leprosy?
   Mycobacterium leprae relies on folate synthesis for replication.
3. Why does dapsone cause hemolysis?
   It induces oxidative stress in red blood cells, especially in G6PD deficiency.
4. Does dapsone have anti-inflammatory effects?
   Yes, it inhibits neutrophil-mediated tissue damage.
5. Is dapsone bactericidal or bacteriostatic?
   It is bacteriostatic.
6. Why is dapsone combined with other drugs in leprosy?
   To prevent resistance and improve treatment efficacy.

References

• Goodman & Gilman’s The Pharmacological Basis of Therapeutics
  https://accessmedicine.mhmedical.com
• Katzung BG. Basic and Clinical Pharmacology
  https://accessmedicine.mhmedical.com
• Tripathi KD. Essentials of Medical Pharmacology
  https://www.jaypeebrothers.com
• Harrison’s Principles of Internal Medicine
  https://accessmedicine.mhmedical.com

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