Antileprotic drugs

PREPARED BY: JEGAN.S. NADAR
ANTILEPROTIC DRUGS

LEPROSY
● A contagious disease that affects the skin, mucous membranes, and nerves,
causing discoloration and lumps on the skin and, in severe cases, disfigurement
and deformities
● Leprosy is caused by Mycobacterium leprae
● It has been considered incurable since ages and bears a social stigma.
● Due to availability of effective antileprotic drugs now, it is entirely curable, but
deformities/defects already incurred may not reverse.
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Dapsone (DDS)
● It is diamino diphenyl sulfone (DDS), the simplest, oldest, cheapest, most active
and most commonly used member of its class
● It is bacteriostatic for M. leprae

Dapsone
● Dapsone is structurally related to the sulfonamides and similarly inhibits
dihydropteroate synthetase in the folate synthesis pathway.
● Dapsone-resistance among M. leprae has been reported which necessitated the use of
multidrug therapy
● When dapsone resistance is encountered in an untreated patient, it is called ‘primary’,
and indicates that the infection was contacted from a patient harbouring resistant bacilli
● Resistance which develops during monotherapy in an individual patient with dapsone is
called ‘secondary’
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Dapsone
● Dapsone is completely absorbed after oral administration and is widely
distributed in the body
● It is 70% plasma protein bound, but more importantly it is 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 urine.
● The plasma t½ of dapsone is variable, though often > 24 hrs
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Dapsone
● 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 are frequent in the beginning but decreases
later.
● 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 Jegan Nadar

● Sulfone syndrome: It is the reaction which develops 4–6 weeks after starting
dapsone treatment
● Symptoms consists of fever, malaise, lymph node enlargement, desquamation of
skin, jaundice and anaemia.
● It is generally seen in malnourished patients, and has become more frequent
after the introduction of MDT.
● Dapsone should not be used in patients with severe anaemia (Hb < 7 g/dl), G-6-
PD deficiency and in those showing hypersensitivity reactions.
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Clofazimine
● It is a dye with leprostatic and antiinflammatory properties.
● The putative mechanisms of antileprotic action of clofazimine are:
 Interference with template function of DNA in M.leprae
 Alteration of membrane stucture and its transport function.
 Disruption of mitochondrial electron transport chain.
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Clofazimine
● When used alone, the clinical response to clofazimine is slower than that to
dapsone, and resistance develops in 1–3 years.
● Dapsone resistant M. leprae respond to clofazimine, but apparently after a lag
period of about 2 months.
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Clofazimine
● Clofazimine is orally active (40–70% absorbed).
● It accumulates in macrophages and gets deposited in many tissues including
subcutaneous fat, as needle-shaped crystals.
● However, entry in CSF is poor.
● The t½ is 70 days so that intermittent therapy is possible.

Clofazimine
● In the doses employed for MDT, clofazimine is well tolerated
● Skin : The major disadvantage is reddish-black discolouration of skin, especially
on exposed parts. Dryness of skin and itching is often troublesome
● GI symptoms: Nausea, anorexia, abdominal pain, weight loss and enteritis with
intermittent loose stools can occur, particularly when higher doses are used to
control lepra reaction
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Rifampin (Rifampicin, R)
● It is a semisynthetic derivative of rifamycin B obtained from Streptomyces
mediterranei.
● Rifampin is bactericidal
● M. leprae is highly sensitive to Rifampin
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Rifampin
● It is well absorbed orally, (bioavailability is ~ 70%), but food decreases
absorption; rifampin is to be taken in empty stomach.
● It is widely distributed in the body: penetrates intracellularly, enters tubercular
cavities, caseous masses and placenta.
● Though it crosses meninges, it is largely pumped out from CNS by P-
glycoprotein.
● It is metabolized in liver to an active deacetylated metabolite
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Rifampin
● Rifampin is a microsomal enzyme inducer—increases several CYP450
isoenzymes, including CYP3A4, CYP2D6, CYP1A2 and CYP2C subfamily.
● It thus enhances its own metabolism as well as that of many drugs including
warfarin, oral contraceptives, corticosteroids, sulfonylureas, steroids, HIV
protease inhibitors, NNRTIs, theophylline, metoprolol, fluconazole,
ketoconazole, clarithromycin, phenytoin, etc.
● Contraceptive failures have occurred
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Rifampin
● Hepatitis, a major adverse effect, generally occurs in patients with preexisting
liver disease and is dose-related
● Minor reactions, usually not requiring drug withdrawal and more common with
intermittent regimens, are:
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Rifampin
● Cutaneous syndrome: flushing, pruritus + rash (especially on face and scalp),
redness and watering of eyes.
● Flu syndrome: with chills, fever, headache,malaise and bone pain.
● Abdominal syndrome: nausea, vomiting, abdominal cramps with or without
diarrhoea.
● Urine and secretions may become orange-red—but this is harmless.
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