Leprosy & Anti-Leprotic Drugs

Clinical Features of Leprosy and Pharmacology of Anti-leprosy drugs

1. Pharmacology Anti-Leprotic Drugs Nem Kumar Jain MS (Pharm.) Pharmacology & Toxicology Assistant Professor, School of Pharmacy ITM University Gwalior

2. Leprosy Leprosy ( Hansen’s disease ) is a chronic, systemic infectious disease. Chronic granulomatous inflammation caused by Acid Fast Mycobacterium leprae Which cannot be grown on culture media affecting primarily the peripheral nerves and secondarily the skin , mucous membranes, the eyes, bones, lymph nodes and viscera. nine - banded armadillo is considered as its primary reservoir Replicate very slow (every 12 days once). Has an affinity for macrophages & Schwann cell. It grows best at 27-30 C, hence its predilection for cooler areas of the body. Skin, peripheral nerves, anterior chamber of the eye, upper respiratory tract & testes.

3. Leprosy Mode of Transmission: The disease is believed to be spread through droplets from the nose or mouth of a patient to the skin and respiratory tract of another person, require prolonged/ frequent contact The bacteria multiply very slowly and therefore leprosy is not highly infectious About 95% of people have natural immunity against leprosy Incubation period: This ranges from 9 months to 20 years. Epidemiology: Males are more prone to develop leprosy than female Children too are more susceptible According to WHO: India, Brazil, Indonesia, Myanmar and Nigeria are with most cases. Risk factors: Living in abovementioned endemic regions, low socioeconomic class

4. Leprosy Classification: based on clinical forms Tuberculoid type (TT) Lepromatous type (LL) Borderline (BB) Borderline lepromatous (BL) Borderline tuberculoid (BT) Indeterminate (I) WHO: Operational Classification Paucibacillary leprosy (PB) (Non-infectious): This includes TT, BT, I and polyneuritic . Multibacillary leprosy (MB) (Infectious): This includes LL, BL and BB. PB Case: A case of leprosy with 1 to 5 skin lesions and without demonstrated presence of bacilli in a skin smear. MB Case: A case of leprosy with 6 or more skin lesions; or with nerve involvement; or with demonstrated presence of bacilli in a slit skin smear irrespective of the number of skin lesions.

5. Leprosy At least one of the following CARDINAL SIGNS must be present to diagnose leprosy: 1. Hypo-pigmented or reddish skin lesion (s) with definite sensory deficit 2. Involvement of the peripheral nerves, as demonstrated by definite thickening with loss of sensation and/or weakness of muscles of the corresponding nerve: lead to organ deformity 3. Demonstration of Mycobacterium leprae (M leprae) in the lesions. The first two cardinal signs can be identified by clinical examination alone while the third can be identified by microscopic examination of the slit skin smear. PB MB Nerve enlargement

6. Anti-Leprotic Drugs Classification: Sulfone: Dapsone (DDS) Phenazine derivative: Clofazimine Anti-tubercular Drugs: Rifampin, Ethionamide Other antibiotics: Ofloxacine , Moxifloxacine , Minocycline, Clarithromycin Dapsone: It is diamino diphenyl sulfone (DDS), the simplest, oldest, cheapest, most active and most commonly used member of its class. Activity and mechanism : Dapsone is chemically related to sulfonamides and has the same mechanism of action, i.e. inhibition of PABA incorporation into folic acid; its antibacterial action is antagonized by PABA. It is leprostatic at low concentrations Specificity for M. leprae may be due to difference in the affinity of its folate synthase

7. Anti-Leprotic Drugs Dapsone-resistance among M. leprae, first noted in 1964 Primary-in untreated patients, i.e. they have acquired infection from a patient harbouring resistant bacilli Secondary-which develops during therapy in an individual patient with a single drug The incidence of primary dapsone resistance varied from 2.5% to 40%. Warrants use of Multi-Drug Therapy (MDT) Pharmacokinetics: completely absorbed after oral administration and is widely distributed in the body, though penetration in CSF is poor penetration in CSF is poor. It is 70% plasma protein bound, but more importantly concentrated in skin (especially lepromatous skin), muscle, liver and kidney Dapsone is acetylated as well as glucuronide and sulfate conjugated in liver Metabolites are excreted in bile and reabsorbed from intestine, so that ultimate excretion occurs mostly in urine

8. Anti-Leprotic Drugs Adverse effects : Dapsone is generally well tolerated at doses 100 mg/ day or less Mild haemolytic anaemia is common Patients with G-6-PD deficiency are more susceptible Gastric intolerance-nausea and anorexia Other side effects are methaemoglobinaemia , headache, paresthesias , mental symptoms and drug fever. Cutaneous reactions include allergic rashes, fixed drug eruption, hypermelanosis , phototoxicity and rarely exfoliative dermatitis. Hepatitis and agranulocytosis are other rare complications. Lepra reaction and sulfone syndrome Contraindications: Dapsone should not be used in patients with severe anaemia with Hb < 7g%, G-6-PD deficiency and in those showing hypersensitivity reactions. Other use In combination with pyrimethamine, dapsone can be used for chloroquine-resistant malaria.

9. Anti-Leprotic Drugs Clofazimine: It is a dye with leprostatic and antiinflammatory properties; acts probably by interfering with template function of DNA in M. leprae . When used alone, resistance to clofazimine develops in 1-3 years . Clofazimine is used as a component of multidrug therapy of leprosy. Because of its antiinflammatory property, it is valuable in lepra reaction. Adverse effects: reddish-black discolouration of skin Enteritis with intermittent loose stool, nausea, abdominal pain, anorexia and weight loss can occur Avoid during pregnancy and liver and kidney patients Rifampin: an important antitubercular drug; also bactericidal toM . leprae; rapidly renders leprosy patients noncontagious Up to 99.99% M. leprae are killed in 3-7 days. The 600 mg monthly dose used in leprosy is ;- elatively nontoxic and does not induce metabolism of other drugs. It should not be given to patients with hepatic or renal dysfunction Ethionamide: hepatotoxic, only when clofazimine cant be used or absolut necessary

10. Multidrug therapy

11. Reactions in leprosy Lepra reaction : These occur in LL, usually with institution of chemotherapy and/ or intercurrent infection. It is a Jarish Herxheimer ( Arthus ) type of reaction due to release of antigens from the killed bacilli. It may be mild, severe or life threatening (erythema nodosum leprosum ).

12. Reactions in leprosy Sulfone syndrome It is the reaction which develops 4-6 weeks after dapsone treatment: consists of fever, malaise, lymph node enlargement, desquamation of skin, jaundice and anaemia . It is generally seen in malnourished patients. Reversal Reaction: This is seen in TT- is a manifestation of delayed hypersensitivity to M leprae antigens. Cutaneous ulceration, multiple nerve involvement with pain and tenderness occur suddenly even after completion of therapy. It is treated with clofazimine or corticosteroids.