Pharmacology and pharmacokinetics of antileprotic drugs with ADRs, Treatment etc.

1. Dreamz College of Pharmacy
Pharmacokinetics and Pharmacology
of Anti-Leprotic Drugs
Mrinal
Assistant Professor
Pharmacology

2. Introduction
• Leprosy is caused by a slow-growing type of bacteria called
Mycobacterium leprae (M. leprae)
• Also known as Hansen's disease, after the scientist ho discovered M.
leprae in 1873
• It primarily affects the skin and the peripheral nerves
• Leprosy is slow communicable disease and incubation period is between
first exposure and appearance of signs of disease. Long Incubation period
(3 – 5 years)
• Live dormant in macrophages but alive
• Transmitted from person to person through nose, skin lesions of the
infected persons.

3. Classification

4. Dapsone (DDS)
• The simplest, oldest, cheapest
• MOA: Leprostatic even at low concentration Chemically
related to Sulfonamides – same mechanism – inhibition of
incorporation of PABA into folic acid (folic acid synthase)
Specificity to M. leprae – affinity for folate synthase
• Activity: Used alone – resistance – multidrug therapy
(MDT) needed
• Resistance – Primary and Secondary (mutation of folate
synthase – lower affinity). However, 100 mg/day – high MIC
-500 times and continued to be effective to low and
moderately resistant Bacilli (low % of resistant patient)
Persisters. Also has antiprotozoal action (Falciparum and T.
gondii)

5. Dapsone (DDS)
• Pharmacokinetics: Complete oral absorption and
high distribution (less CNS penetration). Half life
24-36 Hrs, but cumulative 70% bound to plasma
protein – concentrated in Skin, liver, muscle and
kidney. Acetylated and glucoronidated and sulfate
conjugated – enterohepatic circulation.
• ADRs: Generally Well tolerated drug. Haemolytic
anaemia (oxidizing property) - G-6-PD are more
susceptible. Gastric - intolerance, nausea,
gastritis. Methaemoglobinaemia, paresthesia,
allergic rashes, FDE, phototoxicity, exfoliative
dermatitis and hepatotoxicity etc.

6. Dapsone (DDS)
Active against protozoa
Combined with pyrimethamine alternative to sulfadoxine-
pyrimethamine for P. falciparum and toxoplasma gondii infection
Active against Pneumocystis jirovecii
Also has anti-inflammatory property
• Sulfone syndrome :- It is the reaction which developsn 4-6 weeks
after startning dapsone treatment.
Symptoms: Fever, malaise, lymph node enlargement, desquamation
of skin, jaundice and anemia.
More common with MDT Management
Its treatment consists of stopping dapsone and instituting
corticosteroid therapy a long with supportive measures.
• Dapsone contraindications: Severe anaemia and G-6- PD deficiency

7. Clofazimine (Clo)
• Phenazine dye – antileprotic, anti-inflammatory and
Bacteriostatic
• MOA: Interference with template function of DNA.
Alteration of membrane structure and transport.
Disruption of mitochondrial electron transport.
Monotherapy causes resistance in 1 – 3 years
• Dapsone resistantants M. leprae respond to
Clofazimine
• Kinetics: absorbed orally (70%) and gets deposited in
subcutaneous tissues – as crystals Half life – 70 days

8. Clofazimine (Clo)
• ADRs: well tolerated
Skin: Reddish-black discolouration of skin,
discolouration of hair and body secretions
Dryness of skin and troublesome itching,
phototoxicity, conjunctival pigmentation
GIT: Nausea, anorexia, abdominal pain and
loose stool (early and late) – dreaded enteritis
• Contraindication: Early pregnancy, liver and
kidney diseases

9. Rifampin (R)
• Rifampicin: Cidal. 99.99% killed in 3-7 days, skin
symptoms regress within 2 months
Included in multidrug therapy (MDT) to shorten the
duration of treatment and also to prevent resistance
No toxic dose as single dose only
Should not be used in 'erythema nodosum leprosum'
(ENL) and Reversal reaction
• Ofloxacin: all fluoroquinolones except ciprofloxacin are
active. Used as alternative to Rifampicin
• Minocycline: Lipophillic - enters M. leprae Less marked
effect than Rifampicin

10. Ethionamide
• Anti leprotic and anti tubercular
• It is a fast acting drug than dapsone but, it is
more expensive and more toxic
• It is orally effective and it is administered daily
• Poorly tolerated –hepatotoxicity 250mg/day

11. Clarithromycin
• Only macrolide with activity against M. leprae
• Less bactericidal than rifampin
• Monotherapy- 500mg daily/ 8wks- 99.9%
killing Synergistic action with Minocycline
used in alternative multidrug therapy (MDT)
regimen
• MINOCYCLINE High lipophilicity –penetrates
into M. leprae 100mg/day Antileprotic activity
rif>mino >Clari 8 wks treatment

12. LEPRA REACTION
• The acute exacerbation which occurs during the course of
leprosy is called as Lepra reaction
• It occursin Lepromatous (LL) type- after starting with
chemotherapy and intercurrent infections
• Jerish Hexheimer (Arthus) type reaction due to release of
antigens from killed bacilli
• May be mild severe or life threatening ENL- erythema Nodosum
Leprosum
• Treatment- Clofazimine -200mg
Dapsone temporary withdrawal
Severe reaction- prednisone-40-60 mg.. Tapered in 2-3 months
Thalidomide –alternative to prednisolone in ENL

13. REVERSAL REACTION
Tuberculoid (TT) and Borderline lepromatous
(BL) cases
Manisfestation of delayed hypersensitivity to
M. leprae antigens
Cutaneous ulceration, multiple nerve
involvement with tender nerves
Treatment-Clofazimine/ corticosteroids

14. Classification of leprosy
by Ridley and Jopling ( l 966)
• Lepromatous -LL
• Borderline lepromatous –BL
• Borderline tubercular-BT
• Tuberculoid TT

15. WHO divided leprosy
• For operational purposes:
Paucibacillary: few bacilli and non-infectious – TT and BT
Multibacillary: large bacilli load and infectious – LL, BL and
BB types
WHO reclassified leprosy in 1998
• Single lesion paucibacil/a,y leprosy (SLPB): With a solitary
cutaneous lesion.
• Paucibacillary leprosy (PB): With 2-5 skin lesions. Both SLPB
and PB cases are skin smear negative for M. leprae.
• Multibacil/my leprosy (MB) : With ≥6 skin lesions, as well as
all smear positive cases.

16. Classification being followed by NLEP since
2009

17. Multidrug therapy (MDT) of leprosy

18. Alternative regimens
• Intermittent ROM: Rifampin 600 mg + ofloxacin 400 mg +
minocycline 00 mg arr given once a month for 3-6 month
for PBL and for 12 or 24 month for MBL cases, without any
drug in between.
• CloflaLimine 50 mg + any two of ofloxacin 400 mg/
minocycline 100 mg/clarithromycin 500 mg dai ly for 6
month, followed by clofazimine 50 mg + any one of
ofloxacin 400 mg/minocycline I 00 mg daily for additional
18 months.
• Four drug regimen of rifampin 600 mg + sparfloxacin 200
mg + clarithromycin 500 mg + minocycline 100 mg daily for
12 weeks has yielded equivalent clinical improvement in
MBL cases to standard 12 month MDT.