Dapsone

Diamino-diphenylsulfone (DDS) = Dapsone

  • Sulfone drug
  • Good bioavailability + liposolubility: contribute to increased effectiveness of dapsone
  • ½ life ~36 hours + with enterohepatic recirculation: ½ life prolonged ~30 days after a single dose (seldom benefit with divided doses)
  • Pregnancy category C
  • Secreted in breast milk & can induce hemolysis in infant (however can be used in lactating mothers for the treatment of leprosy)

Oral

  • 50-200 mg
  • daily (Response within 48-72 hours)

Topical

  • 5% & 7.5%
  • (No labs/ monitoring required, safe to use in Glucose-6-phosphate dehydrogenase (G6PD) deficiency)

Metabolism

  • In liver by two methods: N-acetylation & N-hydroxylation
  • N-hydroxylation via cytochrome-P450 (CYP3A4, CYP2C9, CYP2E1) produces N-hydroxy-dapsone (dapsone hydroxylamine), metabolite which is responsible for majority of hematologic side effects (Strong oxidant on red blood cells membrane)
  • Glucose-6-phosphate dehydrogenase (G6PD): antioxidant enzyme 
  • N-hydroxylation can be inhibited by Cimetidine via CYP2C9 & CYP3A4 inhibition

Excretion

  • Hepatic & renal

  1. Decreased neutrophil chemotaxis (inhibit 5 lipogenase & inhibit Leukotriene B4 binding)
  2. Inhibition of myeloperoxidase (respiratory burst) in neutrophils, eosinophils & monocytes
  3. Inhibition of 5-lipooxygenase, decreasing inflammatory damage to tissue
  4. Inhibits IgA adherence
  5. Dapsone major metabolites (monoacetyl diaminodiphenylsulfone (MADDS) & dapsone nitrosamine have intrinsic anti-inflammatory properties & are toxic) 
  6. Mechanism of action in leprosy via inhibition of dihydropteroate synthetase (folic acid pathway)

Food & drug administration (FDA)

  • Dermatitis herpetiformis 
  • Leprosy
  • Topical: acne

Consistent efficacy

  • linear IgA bullous dermatosis (LABD), bullous Lupus, erythema elevatum diutinum

Variable

  • Autoimmune bullous (Bullous pemphigoid, mucous membrane pemphigus, epidermolysis bullosa acquisita, pemphigus vulgaris, pemphigus foliaceous, immunoglobulin A (IgA) pemphigus)
  • Vasculitis (leukocytoclastic vasculitis, urticarial vasculitis)     
  • Neutrophilic dermatoses (pyoderma gangrenosum, Sweet, Behçet, aphthous stomatitis)
  • Others (subacute cutaneous lupus, relapsing polychondritis, pustular psoriasis, granulomatous, eosinophilic, brown recluse)

Absolute

  • Agranulocytosis
  • Drug induced hypersensitivity syndrome

Relative

  • Hematologic (including Glucose-6-phosphate dehydrogenase (G6PD) deficiency)
  • Allergy to sulfonamide antibiotics
  • Cardiopulmonary disease
  • Liver disease
  • Renal insufficiency 
  • Pre-existing peripheral motor neuropathy

Pharmacologic (Dapsone active metabolite: hydroxylamine):

  1. Hemolytic anemia & falsely low hemoglobin A1c (HbA1C) due to influx of new red blood cells as old have lysed
  2. Methemoglobenemia (MgHb)

Symptoms of anemia- headache, lethargy, cardiopulmonary symptoms, worse with low baseline red blood cells

Idiosyncratic

  1. Agranulocytosis (at 2-12 weeks, recovers within 1-2 weeks +/- granulocyte colony stimulating factor) 
  2. Leukopenia
  3. Cutanoeus: Dapsone hypersensitivity syndrome (2-7 weeks), exfoliative dermatitis, toxic epidermal necrolysis, morbilliform eruption, fixed drug eruption 
  4. Hepatic/Gastrointestinal: Hepatitis, cholestasis, pancreatitis
  5. Neuropathy: Distal motor +/- sensory, with higher doses & cumulative dose dependent, reversible after 1-2 years
  6. Others: Psychosis, retinal damage with overdose, phototoxicity, weak carcinogen

Decrease Dapsone

1. Absorption

  • Antacids
  • Antiretrovirals

2. Cytochrome-P450

  • Rifampin
  • Griseofulvin
  • Nucleoside reverse transcriptase inhibitors
  • Aromatic anticonvulsants

Increase Dapsone

  • Aprepitant
  • Probenecid

Increase Hematologic toxicity

  • Methotrexate
  • Trimetrexate
  • Trimethoprim-sulfamethoxazole
  • Pyrimethamine

Increase Oxidative stress

  • Antimalarials
  • Some antibiotics
  • Nitroprusside
  • Local anesthetics

Baseline

  • Complete blood count, chemistry profile, liver function tests, urinalysis, Glucose-6-phosphate dehydrogenase (G6PD)

Follow-up

  • Complete blood count weekly x4 weeks, then every 2weeks x8 weeks, then every 3months
  • Liver function tests & renal every 3months
  • Reticulocyte count & MgHb as indicated

Agranulocytosis

  • If fever, sore throat or any infectious symptoms, patient must discontinue Dapsone & seek medical care

Methemoglobenemia

  • Worsening or unmasking noted with local amide anesthetic & general anesthesia)
  • Treatment of acute Methemoglobenemia:
    1. Methylene blue (100-300mg daily)
    2. If contraindicated, or not responding or Glucose-6-phosphate dehydrogenase (G6PD) deficient: Plasma exchange 
    3. If due to general anesthesia or local anesthetic containing amide: Ascorbic acid 
  • Decrease Methemoglobenemia (MgHb):
    1. Vitamin E (800 IU daily) 
    2. Ascorbic acid (Vitamin C)
    3. Cimetidine (400 mg three times daily)