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Anti Leprosy Drugs

Introduction
• Mycobacterium leprae
• History
– Chaulmoogra Oil
– Antibiotic Era
Classification
1. Sulfone
– Dapsone { 4-4‘Diaminodiphenylsulfone}
2. Phenazine derivative
– Clofazimine
3. Antitubercular drugs
– Rifampin
– ethionamide
4. Other antibiotics
– Ofloxacin
– Minocycline
– Clarithromycin
Dapsone
• The simplest, oldest, cheapest, most active and
most commonly used member of the class
• Mechanism of action:
– Inhibits incorporation of PABA into folic acid
– Leprostatic
– Peak serum conc. after 100mg/day exceeds MIC for
M.leprae by 500 times and continues to be active
against even moderately resistant bacteria
Dapsone
• Pharmacokinetics
– Completely absorbed after oral admn.
– T1/2 is 20 -30 hrs, drug undergoes acetylation,
conjugation in liver, enterohepatic circulation and
finally excreted through urine
– Cumulative T ½ is very long{1-2weeks}
– Distributed throughout total body water and all
tissues, they tend to be retained in skin and
muscle and especially in liver and kidney
Dapsone
• Adverse effects
– Mild hemolytic anemia : oxidizing property, dose
dependent
– Severe hemolytic anemia : Glucose-6-phosphate
dehydrogenase deficiency, Erythrocyte and bone marrow
disorders
– Gastric intolerance : anorexia, nausea, vomiting
– Skin manifestations : allergic rashes, FDE, phototoxicity ,
hypermelanosis
– Others : headache, methemoglobinemia, hepatitis,
agranulocytosis
– Sulfone syndrome : develops 4 to 6 weeks of dapsone
treatment, fever, malaise, LN enlargement, jaundice,
anemia (Rx clofazimine)
Clofazimine
• It is a dye with antileprotic and anti-inflammatory
effects
• Mechanism of action
– (?) by interfering template function of DNA
– inhibit microbial K+ transport
• Pharmacokinetics
– Orally active (40-70% absorption)
– Accumulates in many tissues esp. fat
– Poor penetration into CSF
– T ½ ~70 days
Clofazimine
• Adverse effects
– Skin : reddish-black discoloration of skin esp. in
exposed body parts & lesions, dryness, pruritis, acne
form eruption, conjunctival pigmentation,
discoloration of hairs and body fluids
– GI symptoms :
• Early- anorexia, nausea, loose stools, abdominal pain,
weight loss, …….(Rx )
• Late- Eosinophilic enteritis
– To be avoided in early pregnancy, liver or kidney
diseases
Rifampin
• Bactericidal, kills upto 99.99% bacteria in 3-7 days
• Rapidly renders leprosy patients noncontagious
• Mechanism of action
– Inhibits DNA-dependent RNA polymerase of
mycobacterium
• Pharmacokinetics
– Orally active, enterohepatic circulation ( T 1/2 )
– Up to 30% of a dose of the drug is excreted in the urine
and 60% to 65% in the faeces
– Adjustment of dosage is not necessary in patients with
impaired renal function
Rifampin
• Adverse effects
– Very rare in doses taken for leprosy
– Includes rash, fever, nausea, vomiting
– To be avoided in pre-existing hepatic disorders
– No reduction in dosage required in renal
dysfunction
Other antibiotics
• Ofloxacin
– Bactericidal, and highly active
– Over 99.9% bacteria killed in 22 days
– Included in alternative treatment regimens, and
where rifampicin cannot be used
– Dosage – 400 mg/day
– Other fluoroquinolones that can be used are
sparfloxacin, pefloxacin
Other antibiotics
• Minocycline
– Highly active, bactericidal, 100mg/day achieves 10
to 20 times MIC
– being tried in alternative regimens
• Clarithromycin
– Less active than minocycline
– Monotherapy kills 99.9% bacteria in ~8 weeks
– Used in alternative regimens
– 500mg/ day dose
Classification of disease
• For operational purposes leprosy has been
divided into
– Paucibacillary leprosy (<5 lesions)
– Multibacillary leprosy (≥5 lesions, or demonstration
of even 1 bacteria on Split skin smear)
• Histopathologically, has many classifications eg.
Madrid classification, Ridley- Jopling, Indian
classification etc.
Effectiveness of multidrug therapy
• PB patients treated with MDT are cured within
six months
• MB patients treated with MDT are cured
within 12 months
• Patients are no longer infectious to others
after the first dose of MDT. In other words,
transmission of leprosy is interrupted
• No resistance of the bacillus to MDT has been
detected
WHO Treatment Regimen
Paucibacillary leprosy Multibacillary leprosy

Rifampin 600mg once per month 600mg once per month


Supervised supervised

Dapsone 100 mg per day 100 mg per day


Self administered Self administered

Clofazimine 300mg once per month -----


(S)
50 mg per day ( self)
Duration 24 months 6 months
• Government of India has adopted 12 month
regimen for MDT since 1999
• Long term efficiency not known at present
• Primary purpose of this program is to render
patients non-contagious so as to cut down
transmission
– WHO action program for elimination of leprosy or
NLEP India
Alternative regimens
• Used when it is impossible or inadvisable to
employ standard regimen
– Clofazimine 50 mg + any two of ofloxacin 400mg
per day / minocycline 100mg per day/
clarithromycin 500 mg per day……. For 6 MONTHS
Followed by
Clofazimine 50 mg per day + any of ofloxacin or
minocycline for 18 MONTHS
Reactions in leprosy
• Type 1 reaction (Reversal reaction or Down
grading reaction)
– 40-60 mg of prednisolone for atleast 3 months
– Clofazimine (200–300 mg/d) is of questionable benefit
but in any event is far less efficacious than
glucocorticoids
• Type 2 reaction (ENL)
– Depending upon severity antipyretics, short course
steroids(1-2 weeks)
– Those not responding to 2 course steroids..
Thalidomide 100 to 300 mg H.S