Anti leprotic drugs Pharma 2nd mbbs

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Anti-Leprotic Drugs (Pharmacology - 2nd MBBS)

Causative Organism

Leprosy (Hansen's disease) is caused by Mycobacterium leprae, an obligate intracellular pathogen with a very long doubling time (14 days). It cannot be cultured on synthetic media, and animal models (mouse footpad) are used to evaluate drugs.

Classification of Leprosy (Clinically Relevant for Drug Choice)

Type	Bacterial Burden	Classification
Tuberculoid	Low (skin smear negative)	Paucibacillary (PB)
Borderline tuberculoid	Low-moderate	PB
Borderline lepromatous	Moderate-high	Multibacillary (MB)
Lepromatous	High (skin smear positive)	MB

WHO Multidrug Therapy (MDT) Regimens

MDT was introduced because dapsone monotherapy led to widespread drug resistance.

Paucibacillary Leprosy (2 drugs, 6 months)

Drug	Dose	Frequency
Rifampicin	600 mg	Once monthly (supervised)
Dapsone	100 mg	Daily (self-administered)

Duration: 6 months

Multibacillary Leprosy (3 drugs, 12 months)

Drug	Dose	Frequency
Rifampicin	600 mg	Once monthly (supervised)
Clofazimine	300 mg monthly + 50 mg daily	Monthly dose supervised; daily self-administered
Dapsone	100 mg	Daily (self-administered)

Duration: 12 months

Individual Drug Profiles

1. DAPSONE (Diaminodiphenylsulfone / DDS)

Drug class: Sulfone

Mechanism of Action:

Structural analogue of PABA
Competitively inhibits dihydropteroate synthase (same enzyme inhibited by sulfonamides) - blocks folate synthesis in M. leprae
Also has anti-inflammatory effects: inhibits neutrophil myeloperoxidase, scavenges free radicals, and inhibits neutrophil migration

Effect on M. leprae: Primarily bacteriostatic (MIC: 1-10 mg/L)

Pharmacokinetics:

Oral absorption: Complete
Widely distributed; concentrates in skin, muscle, liver, kidney
t½: 20-30 hours (retained in tissues up to 3 weeks)
Hepatic metabolism: N-acetylation (NAT2) - slow vs. fast acetylators relevant
N-oxidation to dapsone hydroxylamine (via CYP2E1) - responsible for methemoglobin formation
Excreted in bile and reabsorbed (enterohepatic circulation); urine excretion variable
Dose: 100 mg/day orally (adults)

Adverse Effects (High-Yield):

Adverse Effect	Notes
Hemolytic anemia	Most common; exaggerated in G6PD deficiency
Methemoglobinemia	Common but usually subclinical
Gastrointestinal intolerance	Nausea, vomiting
Peripheral neuropathy	Less common
Rash, fever, pruritus	Hypersensitivity
Dapsone syndrome	Fever, rash, lymphadenopathy, hepatitis - at 6 weeks
Erythema nodosum leprosum (ENL)	During treatment of lepromatous leprosy - immune-mediated reaction (not direct drug toxicity)

Other Uses of Dapsone:

Prophylaxis and treatment of Pneumocystis jirovecii pneumonia (PCP) in AIDS patients
Dermatitis herpetiformis
Active against Plasmodium falciparum (used in combination - Lapdap)
Toxoplasma gondii prophylaxis

Drug Resistance: Due to mutations in dihydropteroate synthase gene

2. RIFAMPICIN (Rifampin)

Drug class: Rifamycin antibiotic

Mechanism of Action:

Inhibits bacterial DNA-dependent RNA polymerase - bactericidal
Most bactericidal drug in the leprosy MDT regimen - achieves the highest kill rate

Note: Because rifampicin kills bacteria so rapidly, it causes massive release of bacterial antigens. This can precipitate or worsen reversal reactions and ENL - so rifampicin is often withheld during these reactions.

Dose: 600 mg once monthly (WHO MDT) or 600 mg daily (US regimen)

Key Adverse Effects:

Orange/red discoloration of urine, tears, sweat
Hepatotoxicity
Flu-like syndrome (intermittent dosing)
Powerful CYP450 inducer - reduces levels of many drugs (OCP, warfarin, etc.)

3. CLOFAZIMINE

Drug class: Phenazine dye

Mechanism of Action:

Not clearly established
Proposed: Binds to mycobacterial DNA (guanine-preferring)
Redox cycling generates cytotoxic reactive oxygen species (ROS) toxic to bacteria
Also has direct anti-inflammatory and immunosuppressive effects (inhibits T-lymphocyte proliferation)

Effect on M. leprae: Bacteriostatic (Note: Lippincott considers it bactericidal)

Pharmacokinetics:

Oral absorption variable; accumulates extensively in adipose tissue and reticuloendothelial cells
Crystals visible inside phagocytic cells
Extremely long t½: ~70 days (up to 2 months)
Does not enter CNS
Excreted mainly in feces

Dose: 50 mg daily + 300 mg once monthly (in MDT)

Adverse Effects (High-Yield):

Adverse Effect	Notes
Skin discoloration	Pink to brownish-black pigmentation; reversible but takes months to clear
Ichthyosis/dry skin	Due to drug deposition in skin
GI intolerance	Nausea, abdominal pain
Eosinophilic enteritis	Rare; crystal deposition in intestinal mucosa; may require surgery
Reduced sweating

Special advantage: Because clofazimine has anti-inflammatory properties, ENL (erythema nodosum leprosum) may NOT develop in patients treated with it.

Lepra Reactions and Their Management

These are immunological reactions that occur during the course of leprosy treatment:

Type 1 Reaction (Reversal Reaction)

Occurs in borderline leprosy
Cell-mediated immunity (delayed hypersensitivity)
Treatment: Prednisolone (corticosteroids)

Type 2 Reaction (Erythema Nodosum Leprosum - ENL)

Occurs in lepromatous/borderline lepromatous leprosy
Immune complex deposition (Type III hypersensitivity)
Treatment options:
- Thalidomide (drug of choice for ENL; inhibits TNF-alpha) - contraindicated in pregnancy (teratogenic)
- Clofazimine (also suppresses ENL)
- Corticosteroids (for acute severe episodes)

Secondary / Reserve Anti-Leprotic Drugs

Drug	Role
Minocycline	Active against M. leprae; used in rifampicin-intolerant patients
Ofloxacin	Fluoroquinolone; bactericidal against M. leprae
Clarithromycin	Macrolide; used in combination for resistance cases

Thalidomide - Special Notes

Mechanism: Inhibits TNF-alpha synthesis
Use: ENL (Type 2 lepra reaction) - very effective
Contraindicated in pregnancy - causes severe teratogenicity (phocomelia - flipper-like limb deformities)
Also used in multiple myeloma

Quick Exam Summary Table

Drug	MOA	Effect	Key ADR
Dapsone	Inhibits dihydropteroate synthase (anti-folate)	Bacteriostatic	Hemolysis, met-Hb, G6PD-sensitive
Rifampicin	Inhibits RNA polymerase	Bactericidal (most potent)	Orange urine, hepatotoxicity, CYP inducer
Clofazimine	DNA binding + ROS generation	Bacteriostatic	Skin pigmentation (brown-black), dry skin
Thalidomide	TNF-alpha inhibition	Anti-inflammatory	Teratogenicity, neuropathy

High-Yield Points for Exam

Most bactericidal drug in leprosy MDT = Rifampicin
Drug of choice for ENL (Type 2 reaction) = Thalidomide (contraindicated in pregnancy)
Dapsone resistance - due to mutations in dihydropteroate synthase
Dapsone is contraindicated in G6PD deficiency (severe hemolysis)
Clofazimine t½ = ~70 days (longest among anti-leprotics)
Clofazimine ADR = brownish-black skin discoloration (commonly asked MCQ)
Dapsone is also used in PCP prophylaxis in HIV/AIDS patients
Leprosy treatment must never be stopped during pregnancy (except thalidomide)
The WHO provides MDT free of charge globally - prevalence reduced by >90% since 1985
Dapsone hydroxylamine (toxic metabolite) = responsible for methemoglobinemia

Sources: Goodman & Gilman's Pharmacological Basis of Therapeutics; Katzung's Basic & Clinical Pharmacology 16e; Lippincott Illustrated Reviews Pharmacology

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