ANTILEPROSY DRUGS (Hansen's Disease)
Outline

The Therapeutic Problem

Importance -- [AMADE 90, 1:22]

• Estimated 12 million cases per year world-wide
• 62% Asia (India 3.2 million!), 34% Africa
• Estimated 4,000 cases in U.S.
• Seldom kills, but extremely disabling

Etiology

• Mycobacterium leprae
• 12-13 days -- Longest generation time known for bacteria

Drugs

• Dapsone
• Rifampin -- See antituberculosis notes
• Clofazimine

Sulfones -- Dapsone

• Analog of p-aminobenzoic acid (like sulfonamides)
• Spectrum
  • Bacteriostatic primarily
  • Mycobacteria -- especially M. leprae
  • Drug of choice for dapsone sensitive M. leprae
  • Also some protozoans
  • Sometimes listed among antifungals**

Mechanism

• Presumably like sulfonamides

Pharmacokinetics

• Oral administration, F=100%
• Half-life extremely variable
  • 10-50 hr
• Biotransformed
  • Conjugate -- N-glucuronide or N-sulfamate -- 70-80%
  • Acetylation -- resembles isoniazid

Adverse Effects

• Usually mild and infrequent
• Dose dependent hemolytic anemia
  • Worse if Glucose-6-phosphate dehydrogenase deficiency
• Methemoglobinemia
  • Worse if NADH dependent methemoglobin reductase deficiency

Clofazimine (Lamprene^R)

• Active against M. avium isolates -- and, therefore, is used in combination with up to 5 other antimycobacterial agents in treatment of atypical mycobacterial infections (associated with Mycobacterium avium-intracellulare) in patients with AIDS. Despite high in vitro activity, has often been clinically ineffective. [USPDI94]
• Resistance is rare
• See references for more information

REFERENCES

• [AMADExx,n:n] -- American Medical Association Drug Evaluations Subscription. xx = year, n:n = section:page
• [USPDI94] United States Pharmacopeia Drug Information ,1994. Volume I, Drug Information for the Health Professional. Revised and published annually by the Unites States Pharmacopeia Convention of the US.
• [GG8th90] Mandell, G.L., and Sande, M.A. 1990. Antimicrobial Agents: Drugs Used in the Chemotherapy of Tuberculosis and Leprosy. Chapter 49, pp 1146-1164. in Goodman and Gilman's The Pharmacological Basis of Therapeutics. eds. A.G. Gilman, T.W. Rall, A.S. Nies, and P.Taylor, Pergamon Press, NY.