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Drugs for leprosy

The document outlines the classification, mechanisms of action, pharmacokinetics, adverse effects, and treatment strategies for anti-leprosy drugs, including dapsone, clofazimine, rifampicin, fluoroquinolones, and macrolides. It details the treatment for different types of leprosy and lepra reactions, emphasizing multidrug therapy (MDT) and alternative regimens. The document also discusses the management of adverse effects and the implications of drug resistance.

Health & Medicine◦
Download as PDF, PPTX
Dr Naser Ashraf Tadvi
Objectives • Classify anti-leprosy drugs • Discuss the Mechanism of action, relevant pharmacokinetics, adverse effects and contraindications of antileprosy drugs • Describe the treatment of Paucibacillary and multibacillary leprosy • Describe the treatment of type 1 and 2 lepra reaction
Leprosy
• Dapsone SULFONES • Clofazimine PHENAZINE DERIVATIVES • Rifampicin ANTITUBERCULAR DRUGS • FLUOROQUINOLONES : Ofloxacin, Moxifloxacin • MACROLIDES : Clarithromycin • TETRACYCLINES : Minocycline OTHER ANTIBIOTICS :
• Chemically related to sulfonamides & shares a common mechanism of action • Leprostatic at very low concentration • Not used for other pyogenic infections • Not used alone always used with rifampicin and/or clofazimine in MDT for leprosy Dapsone's chemical name is 4,4'-diamino diphenyl sulfone
• Slowly and completely absorbed from GIT • 70% plasma protein bound • Produces ten times more concentration in diseased skin than in normal skin • t ½ - 24 hrs • 70-80% excreted in urine • Drug is excreted in milk PharmacokineticsDAPSONE
• Act as competitive inhibitor of the enzyme DIHYDROPTEROATE SYNTHETASE (DHPS). Mechanism of ActionDAPSONE
Mechanism of Action • Folate is necessary for the cell to synthesize nucleic acids and in its absence cells will be unable to divide. • Hence the sulfonamide antibacterial exhibit a bacteriostatic effect • Folate is not synthesized in mammalian cells, but is instead a dietary requirement. This explains the selective toxicity to bacterial cells of these drugs. DAPSONE
Resistance ❑ Secondary resistance usually is seen in lepromatous (multibacillary) patients treated with a single drug. RESISTANCE PRIMARY Untreated Patients SECONDARY Patients on treatment ❑ mutation in folP1 of M. leprae DAPSONE
• Mild hemolytic anemia in G6PD deficiency • Methemoglobinemia Adverse effectDAPSONE Dapsone to be avoided if Hb is < 7 gm/dl
• Gastric intolerance: nausea , vomiting anorexia. • Cutaneous reactions: • Hepatitis & agranulocytosis • CNS : headache parasthesia, tinnitus • Fever • Sulfone (Dapsone) syndrome Adverse EffectsDAPSONE
• Severe anemia • G6PD deficiency • Hypersensitivity reactions ContraindicationsDAPSONE
• Leprosy • With pyrimethamine – Resistant Falciparum malaria – P Jirovecii Infection – Toxoplasmosis IndicationsDAPSONE
• Phenazine dye • Leprostatic • Anti-inflammatory action: – Major advantage used in ENL • BIOLOGICAL LAG 6-7 weeks • Clinical improvement visible by 6th month CLOFAZIMINE
Mechanism of ActionCLOFAZIMINE • Preferentialy binds to mycobacterial DNA • Interferes with template function of the DNA • Alteration of membrane structure and transport function
PharmacokineticsCLOFAZIMINE ▪ Absorption : 40-70% ▪ Lipophilic taken up by macrophages ▪ t 1/2 – 70 days
Adverse EffectsCLOFAZIMINE • Reddish black discoloration of nonexposed skin • Discoloration of hair and body secretions • Dryness of skin, itching & scaling • Abdominal pain SMALL BOWEL SYNDROME Persistent diarrhea Abdominal pain Weight loss
1. Pregnancy 2. Liver and kidney disease 3. GI symptoms ContraindicationsCLOFAZIMINE
• Most potent cidal drug for M Leprae • Rifampicin kills 99.99 % of organisms in 3-7 days • Free from cross resistance from other organisms. • The drug has a particular effect in relieving nasal symptoms and healing of foot ulcers • Dose – 600 mg once a month
FLUOROQUINOLONES • Ofloxacin, Pefloxacin, Sparfloxacin, Moxifloxacin • BACTERICIDAL & highly effective • 22 doses of Ofloxacin ( 400mg/day) - killed 99.99% • Used as an alternate drug
• Only macrolide having significant activity against M. Leprae • Clarithromycin is less BACTERICIDAL than Rifampicin. • 500mg /day in Lepromatous Leprosy patients killed 99.9% bacteria in 8 WEEKS • Included in alternative regimens CLARITHROMYCINCLARITHROMYCIN
• Semisynthetic derivative of tetracycline • High lipophilicity • Bactericidal MINOCYCLINE BACTERICIDAL ACTION Rifampicin > Minocycline > Clarithromycin
Classification of Leprosy Tuberculoid leprosy • Anaesthetic patch • CMI is normal • Lepromin test positive • Bacilli rarely found in biopsies • Prolonged remissions with periodic exacerbation Lepromatous leprosy • Diffuse skin & mucus membrane infiltration & nodules • Deficient • Negative • Skin & mucus membrane lesions bacilli + • Progresses to anesthesia of distal parts, atrophy, ulceration, absorption of digits
Classification of Leprosy Paucibacillary leprosy • 1-5 skin lesions • No nerve or only 1 nerve involvement • Skin smear is negative at all sites • TT & BT Multibacillary leprosy • 6 or more skin lesions • > 1 nerve involvement • Negative • Skin smear positive at any one site • LL, BL, BB
Multidrug therapy for leprosy Multibacillary Paucibacillary Rifampicin 600 mg once monthly supervised 600 mg once monthly supervised Dapsone 100 mg daily supervised 100 mg daily supervised Clofazimine 300 mg/ month supervised + 50 mg daily supervised - Duration 12 months 6 months
Alternative regimens for leprosy • Intermittent ROM • Intermittent RMMx • Ofloxacin or minocycline can be used in place of clofazimine (if pt refuses Clofazimine) • 4 drug therapy – Rifampicin 600 mg + sparfloxacin 200 mg + clarithromycin 500 mg + Minocycline 100 mg daily for 12 weeks
Treatment : Corticosteroids Cutaneous ulcerations,multiple nerve involvement Type IV Hypersensitivity (Delayed hypersensitivity response) TYPE 1 / REVERSAL REACTIONS Treatment : Clofazamine,corticosteroids, Thalidomide Existing lesions enlarge , become red, inflamed and painful Type III Hypersensitivity (Humoral antibody response) TYPE2 / ERYTHEMA NODOSUM LEPROSUM LEPRA REACTIONS Lepra ReactionsDAPSONE
REACTION PREDNISOLONE CLOFAZAMINE THALIDOMIDE Reversal reaction (Type 1) up to 1 mg/kg/d then gradually reduced Erythema Nodosum Leprosum (Type 2) up to 1 mg/kg/d then gradually reduced up to 300 mg up to 400 mg • Maximum daily dose is shown when single use • Combination therapy is recommended in ENL Treatment of Lepra ReactionsDAPSONE
Drugs used for the Management of Reactions • Thalidomide • Corticosteroids • Chloroquine • Clofazamine • NSAIDS
Summary • Drugs for leprosy • MDT for leprosy • Type 1 lepra reaction • Type 2 lepra reaction