CHEMOTHERAPY OF LEPROSYCHEMOTHERAPY OF LEPROSY

EPIDEMIOLOGY OF LEPROSY• Leprosy is a chronic granulomatous infection• Agent– Mycobacterium Leprae -1873-Armauer

• Large number of person may be infected but only few suffer chemically

• Source of Infection– Nasal secretion– Discharged from superficial ulcers

Clinical Manifestation

Cardinal features… – Hypo pigmented patches (T)– Loss of coetaneous sensation in affected areas.– Thickened nerves – M. Leprae in skin or nasal passage.

Signs of advanced disease… – Nodules / lumps in skin of face & ears.– Planter ulcers – Loss of fingers / toes– Nasal depression – Foot drop – Claw hand and toes.

BACTERIOLOGICAL CLASSIFICATION

PAUCIBACILLARY

• NON INFECTIOUS

• TUBERCULOID

• Incubation period 2-5yr

• < 5 LESIONS

• NORMAL CMI/ partially deficient

• +ve LEPROMIN

• FEW BACILLI

MULTIBACILLARY

• INFECTIOUS

• LEPROMATOUS

• Incubation period 8-12y

• > 5 LESIONS

• DEFICIENT CMI

• -ve LEPROMIN

• NUMEROUS BACILLI

Classification of Leprosy

– Indeterminate Type/Borderline Type

– Which ultimately progresses to either

tuberculoid or lepromatous

ANTILEPROTIC DRUGS

– SULFONE : DAPSONE, SULFOXONE, ACEDAPSONE

– PHENAZINE : CLOFAZIMINE

– ANTITUBERCULAR : RIFAMPIN

– ANTIBIOTICS : FQ: OFLOXACIN Tetra: MINOCYCLIN Macrolids:

CLARITHROMYCIN

DAPSONE

– Diamino Diphenyl Sulfone (DDS) -1940

– Oldest, cheapest, most active, most commonly used

MOA :Inhibition of PABAInhibit Bacterial Folic Acid SynthesisLeprostatic

RESISTANCE : 1964 – More in lepromatous leprosy patients if used monotherapy– Primary- harbouring from resistant bacilli– Secondary- during treatment – Combined with Rifampicin

Pharmacokinetics of DAPSONE

– p. o. absorbed

– Distributed to all body compartment

– Retains in skin & organs upto 3 wks.

– Metabolised by – acetylation– glucuronid conjugation

– half life > 24 hrs.

– Dose is cumulative

– excretion through kidney (1-2 wks)

ADVERSE EFFECTS OF DAPSONE

– HAEMOLYTIC ANAEMIA

– METHAEMOGLOBINEMIA

– GASTRIC INTOLERANCE –decrease later

– CUTANEOUS REACTIONS– ALLERGIC RASHES– FIXED DRUG ERUPTION– HYPERMELANOSIS– PHOTOTOXICITY

– LEPRA REACTIONS

– SULFONE SYNDROME

ADVERSE EFFECTS OF DAPSONE

Type 1

• Delayed hypersensitivity

• IV

• Reversal reaction

• Reactions to M. Leprae antigens

• Characterized by cutanoeus

ulceration, multiple nerve

involvement

• Prevented by corticosteroids

Type 2

• Erythema nodosum leprosum

• Humoral antibody response

• III

• Response to dead bacteria

• Characterized lesions enlarge,

become red, inflamed, painful

• Treated by

clofazamine/corticosteriods

SULFONE SYNDROME• If lepra reactions develops after 1-2months c/s sulfone syndrome • Characterized by

– Fever– Lymphnode enlargement – general malaise– Jaundice – anaemia

INDICATIONS OF DAPSONE

– WELL TOLERATED

– CHEAP

– TABLET : 100 mg OD

– I.M. DEPOT : Acedapsone

– BOTH TYPE OF LEPROSY

– CI in Hb% below 7g

– OTHER –

– PNEUMOCYSTIS CARINII PNEUMONIA(100mg)

– DERMATITIS HERPETIFORMIS (first 50mg, slow 300mg)

CLOFAZIMINE

• MOA :

– BINDS TO DNA

INTERFERES TEMPLATE FUNCTION of DNA

INHIBITS GROWTH

– LEPROSTATIC

– ANTI-INFLAMMATORY

KINETICS OF CLOFAZIMINE

– P. O. INCOMPLETE ABSORPTION

– WIDELY DISTRIBUTED IN TISSUES : PHAGOCYTES

– HALF LIFE : 60 – 70 hrs.

– Elimination through FAECES

ADVERSE EFFECTS OF CLOFAZIMINE

– REDDISH-BROWN DISCOLORATION• SKIN ; HAIR ; SECRETIONS

– CONJUNCTIVAL PIGMENTATION

– ACNEFORM ERRUPTIONS

– PHOTOTOXICITY

– GASTRIC INTOLERANCE• ABDOMINAL PAIN• LOOSE STOOL

PRECAUTION : PREGNANCY/Liver/Kidney damage

INDICATIONS OF CLOFAZIMINE

– DAPSONE RESISTANT LEPROSY

– PREFERED IN MDT OF LEPROSY

– LEPRA REACTION

– ULCERATIVE LESIONS : M. ulcerans

RIFAMPIN

– INHIBIT DNA DEPENDENT RNA SYNTHESIS

– BACTERIOCIDAL

– KILLS 99.9 % M. leprae : NONCONTAGIOUS

– RESISTANCE : MONOTHERAPY

– USE IN MDT : DURATION OF T/t

– DOSE 600 mg MONTHLY

OFLOXACIN

– KILLS 99.9 % BACILLI : 22 Day MONOTHERAPY

– HASTEN BACTERIOLOGICAL & CLINICAL RESPONSE

– SHORTEN DURATION OF THERAPY

– ALTERNATIVE DRUG– RIFAMPIN INTOLERANCE / RESISTANCE

– DOSE : 400 mg/day

CLARITHROMYCIN

– MACROLIDE ANTIBIOTIC

– BACTERICIDAL < RIFAMPIN

– KILLS 99.9 % BACILLI IN 8 wks

– DOSE : 500 mg/day

– ALTERNATIVE DRUG

MINOCYCLINE

– TETRACYCLIN

– RIFAMPIN > MINOCYCLINE >

CLARITHROMYCIN

– ALTERNATIVE TO CLOFAZIMINE

– DOSE : 100 mg/day

WHO REGIMEN

• PAUCIBACILLARY LEPROSYDAPSONE 100 mg ODRIFAMPIN 600 mg MONTHLYDURATION 6 MONTHS

• MULTIBACILLARY LEPROSYDAPSONE 100 mg ODRIFAMPIN 600 mg MONTHLYCLOFAZIMINE 300 mg MONTHLY

50 mg DAILYDURATION 2 YEARS