DRUG THERAPY OF HANSEN’S DISEASE

ANTI-LEPROTIC DRUGS

Dr.C.Adithan

HISTORICAL ASPECTOldest and most dreaded disease known to

mankindIn 600 BC: described in India as Kushtha

Roga & attributed to punishment of GODWord leper comes from Greek word “Scaling”M.Leprae was discovered by Dr.Hansen in

1873 in Norway (Hansen’s disease)Dapsone was used for several years as

monotherapy for 5 or more years duration.Now MDT is the main tool against leprosy

Introduction Nonfatal, chronic infectious skin disease Confined to the skin, peripheral nervous

system, upper respiratory tract, eyes, and testes

Causative agent – Mycobacterium leprae Acid fast obligate intracellular bacilli, slow

multiplying Do not grow on artificial media. They

multiply in mice footpads and armadillo, which are used to evaluate antimicrobial agents and screen vaccines

Continued…The route of transmission - nasal droplets,

contact with infected soil, and even insect vectors have been considered

Skin-to-skin contact is not an important route of transmission.

Social stigma is associated with the disease

Completely curable

Skin lesion (hypoesthetic) of leprosy

Nodular lesions of leprosy

Types of leprosy

Leprosy can manifest as Lepromatous (LL) Borderline Lepromatous (BL) Borderline (BB) Borderline Tuberculoid (BT) Tuberculoid (TT)

Less bacterial loadGood immunity

Greater bacterial loadPoorer immunity

Host defence is crucial for : Clinical presentation and bacillary load

TUBERCULOID LEPROSY■Anesthetic patch

■CMI – normal■Lepromin test –

positive■Bacilli rare – in biopsy■Prolonged remission

LEPROMATOUS LEPROSY

■Diffuse skin & mucous membrane infiltration

■CMI – absent■Lepromin test – negative■Plenty of bacilli■Atrophy & ulceration of

digits

Classification■SULFONE DAPSONE

(DDS)

■PHENAZINE DERIVATIVE CLOFAZIMINE

■ANTI-TB DRUGS : RIFAMPICIN, ETHIONAMIDE

OTHERS OFLOXACINMOXIFLOXACINMINOCYCLINECLARITHROMYCIN

Dapsone [Diamino - Diphenyl Sulfone, DDS ]

■Related to sulfonamides■Inhibition of folic acid synthesis■Leprostatic ■Persisters ????■Complete oral absorption, wide distribution, poor

CSF level■Concentrated in skin (especially lepromatous skin )■Glucuronide and sulfate conjugation■Cumulative – due to enterohepatic circulation

Dapsone - MOA

Dapsone [Diamino - Diphenyl Sulfone, DDS ]

Other Uses■ DDS + Pyrimethamine

Chloroquine resistant malaria Toxoplasmosis (T.gondii, asymptomatic but a problem for immunocompromised patients) Pneumocystis jirovecii (previously P. carinii, a

yeast like fungus)

■Acne: used as 5% topical gel

Dapsone : Adverse effects

■Hemolytic anaemia (dose related , 20%) more in G6PD deficient individuals

■Gastric intolerance (nausea, anorexia)

■Meth-hemoglobinemia■Fixed Drug Eruption■Phototoxicity, ■Agranulocytosis, aplastic anemia (rare)■Hepatitis

Sulfone reaction Develops 4-6 weeks after starting dapsone

treatment Fever, malaise, lymph node enlargement,

desquamation of skin, jaundice and anemia. Temporary discontinuation of dapsone only in

severe cases. Clofazimine is highly effective in controlling this

reaction (200mg daily)

■Severe anemia (Hb less than 7%)

■G6PD deficiency

■Hypersensitive individuals

Contraindications

CLOFAZIMINE■ a dye with leprostatic and anti-inflammatory■40-70% oral absorption, poor CSF level■Accumulates in macrophages, subcutaneous

fat■Long half life – 70 days■Used as a component of MDT■Used in lepra reaction

CLOFAZIMINE - MOA

■Interferes template function of DNA

■Alteration of membrane structure and its transport function

■Disruption of mitochondrial electron transport chain

Adverse Effects■Skin: produces pink to brownish skin

pigmentation in 75 – 100 % patients within few weeks, most body fluids and secretions also, conjunctival pigmentation

Reversible (months to years)■GI symptoms: Nausea, anorexia, abdominal

pain, weight loss, enteritis (early syndrome and late syndrome - after few months of therapy due crystal deposition)

■Avoid – pregnancy , hepatic & renal dysfunction

RIFAMPICIN■Bactericidal■Kills 99.9 % in 3-7 days■Shortens duration of treatment■Low monthly dose:

non toxic, do not induce enzymes

■NOT used in – hepatic or renal

dysfunctionENLreversal reaction

Other drugsFluoroquinolones:■Ofloxacin (400 mg/day)■Moxifloxacin – most potent quinolone■SparfloxacinMinocycline: lesser than R but greater than Clarithromycin, side effect – vertigoClarithromycin : only macrolide active against M. LepraeEthionamide – hepatotoxic (10%), used as an alternative to clofazimine

Leprosy ■Types

Lepromatous (LL)Borderline Lepromatous (BL)Borderline (BB)Borderline Tuberculoid (BT)Tuberculoid (TT)

For operational purpose WHO classification (1998)■Single lesion paucibacillary leprosy (SL PB) –

Solitary cutaneous lesion

■Paucibacillary Leprosy (PB) – 2-5 skin lesions Both SL PB and PB cases are smear negative

■Multibacillary Leprosy (MB) – More than 6 lesions as well as all smear

positive cases

Followed by NLEP from 2009

Single drug therapy not effective:

long duration, relapse, resistance develop

MULTIDRUG THERAPY• Highly successful in both MBL & PBL• Effective in dapsone resistant cases• No resistance to rifampicin & clofazimine• Safe and acceptable• HIV +ve case treated same• Reduces total duration of therapy• Quick symptomatic relief

MDT regimenMULTIBACILLARY: LL, BL, BB

■RIFAMPICIN - 600mg once a month■DAPSONE - 100mg daily■CLOFAZIMINE

300mg once a month50mg daily

■12MONTHS

MDT regimenPAUCIBACILLARY: TT, BT

■RIFAMPICIN - 600mg once a month

■DAPSONE - 100mg daily

■6 MONTHS

Alternative regimens■Clofazimine + ANY 2 of Ofloxacin

/Clarithromycin /Minocycline daily for 6 months followed by Clofazimine + ANY ONE for 18 months■R (600)+ spar (200) + Clar (500) +Mino (100

mg) -12 weeks – 4 drug regimen■Solitary lesion (PBL) – Single dose ROM

regimen■ Intermitt ROM - once a month – 3-6 months for PBL

12 – 24 months – MBL

■ Intermittent RMMx: once a month, 6 for PBL, 12 for MBL

ROM: R, Ofl, Mino; RMM: R, Mino, Moxi

Lepra reactions TYPE 1 LEPRA REACTION (Reversal) delayed type IV Hypersenstivity, cell mediated

reaction, Occur suddenly even after completion of therapy

Patients with TT and BL Manifestations – fever, cutaneous ulceration &

multiple nerve involved (neuritis), swollen and painful nerves

Most commonly involved - ulnar nerve. Irreversible nerve damage may result in as little as 24 h.

Foot drop - occurs when the peroneal nerve is involved.

Type 1 lepra reactions – treatment

Glucocorticoids (Prednisone, initially at doses of 40 to 60 mg/d). As the inflammation subsides, the glucocorticoid dose can be tapered, but steroid therapy must be continued for at least 3 months lest recurrence supervene.

Strictly limited to lesions whose intense inflammation poses a threat of ulceration. Mild to moderate lepra reactions that do not meet these criteria should be tolerated and glucocorticoid treatment withheld.

Thalidomide is ineffective clofazimine (200 to 300 mg/d) is of questionable

benefit; far less efficacious than glucocorticoids.

TYPE 2 LEPRA REACTION (ERYTHEMA NODOSUM LEPROTICUM, ENL)

Occurs exclusively in patients with LL Jarisch Herxheimer (Arthus) type of reaction due to release of

antigen from killed bacilli Usually coincides with initiation of chemotherapy and / or

intercurrent infection Crops of painful erythematous papules, malaise, fever,

neuritis, lymphadenitis, uveitis, orchitis, and glomerulonephritis.

May develop anemia, leukocytosis, and abnormal liver function tests, particularly increased aminotransferase levels. In rare instances, ENL results in death.

Lepra reactions – treatmentType 2 lepra reactions If ENL is mild: antipyretics only In cases with many skin lesions, fever, malaise,

and other tissue involvement - Glucocorticoids (initially 40 to 60 mg/d for 1 to 2 weeks) are often effective.

If, despite two courses of glucocorticoid therapy, ENL appears to be recurring and persisting, treatment with thalidomide (100 to 300 mg nightly) should be initiated

Continued…

Mechanism of thalidomide's action - reduction of TNF levels and IgM synthesis and its slowing of polymorphonuclear leukocyte migration.

After the reaction is controlled, lower doses of thalidomide (50 to 200 mg at night) are effective in preventing relapses of ENL.

Clofazimine in high doses (300 mg nightly) has some efficacy against ENL.

Lepra reactions – cont… LUCIO'S PHENOMENON This unusual reaction is seen exclusively in patients

from the Caribbean and Mexico who have the diffuse lepromatosis form of lepromatous leprosy.

Develop recurrent crops of large ulcerative lesions — frequently fatal as a result of secondary infection and septic bacteremia.

Mediated by the immune complex. Glucocorticoids and thalidomide: Ineffective Optimal wound care and therapy for bacteremia are

indicated. Ulcers tend to be chronic and heal poorly. In severe

cases, exchange transfusion may prove useful.

Points to be remembered…….■Mechanism of dapsone & its adverse

effects■Mechanism of clofazimine & its

adverse effects■Treatment regimen for multibacillary

& paucibacillary leprosy■Types of lepra reaction & its

treatment

Thank you

Lepra reaction■Type I (REVERSAL) – delayed type IV HS

cell mediated reaction, cutaneous ulceration & multiple nerve involved

CorticosteroidsType II – humoral - type III HS immune

complex mediated

■Erythema Nodosum Leprosum (ENL)lesions enlarge, red, inflammed & painful

Corticosteroids/Clofazimine

/Chloroquine/Thalidomide