Classification of Antileprotic Drugs

ANTILEPROTIC DRUGS

Leprosy, caused by Mycobacterium leprae, 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.

Chaulmoogra oil with weak antileprotic property had been used in Indian medicine for centuries. Shortly after the demonstration of antibacterial property of sulfonamides, congeners were tested and dapsone, the parent sulfone, was found to be active antileprotic. Demonstration of its efficacy in experimental tuberculosis and leprosy led to clinical trials in the 1940s, and since then it is the sheet-anchor of treatment of leprosy. Few other sulfones were added, but none could excel dapsone. Some antitubercular drugs and clofazimine were subsequently found to be useful adjuncts. Recently good antileprotic activity has been detected in some fluoroquinolones, macrolides and minocycline.

Classification                                                                              

1. Sulfone: Dapsone (DDS)

2. Phenazine Derivative: Clofazimine

3. Antitubercular Drugs: Rifampin, Ethionamide

4. Other Antibiotics: Ofloxacin, Minocycline, Clarithromycin

Dapsone (DDS)

It is diamino diphenyl sulfone (DDS), the simplest, oldest, cheapest, most active and most commonly used member of its class. All other sulfones are converted in the body to DDS; many have been used, but none is superior.

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, and at relatively higher concentrations arrests the growth of many other bacteria sensitive to sulfonamides. Specificity for M. leprae may be due to difference in the affinity of its folate synthase. Doses of dapsone needed for the treatment of acute infections are too toxic, so not used.

Dapsone-resistance among M. leprae, first noted in 1964, has spread, and has necessitated the use of multidrug therapy (MDT). It may be primary—in untreated patients, i.e. they have acquired infection from a patient harbouring resistant bacilli, or secondary—which develops during therapy in an individual patient with a single drug. The incidence of primary dapsone resistance reported from different parts of the world, from time-to-time, has varied from 2.5% to 40%; whereas secondary dapsone resistance occurred in about 20% patients treated with monotherapy. The mechanism of secondary resistance appears to be the same as for M. tuberculosis . However, the peak serum concentration of dapsone after 100 mg/day dose exceeds MIC for M. leprae by nearly 500 times; it continues to be active against low to moderately resistant bacilli.

Pharmacokinetics

Dapsone is completely absorbed after oral administration and is widely distributed in the body, though 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. The plasma t½ of dapsone is variable, though often > 24 hrs. The drug is cumulative due to retention in tissues and enterohepatic circulation. Elimination takes 1–2 weeks or longer.

DAPSONE 25, 50, 100 mg tab.

Adverse Effects

Dapsone is generally well tolerated at doses 100 mg/day or less.

Mild haemolytic anaemia is common. It is a dose-related toxicity—reflects oxidising property of the drug. Patients with G6PD deficiency are more susceptible; doses > 50 mg/day produce haemolysis in them.

Gastric intolerance—nausea and anorexia are frequent in the beginning, decrease 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.

Hepatitis and agranulocytosis are other rare complications.

Lepra reaction and sulfone syndrome (see below).

Contraindications Dapsone should not be used in patients with severe anaemia with Hb < 7g%, G6PD deficiency and in those showing hypersensitivity reactions.

Other Use In combination with pyrimethamine, dapsone can be used for chloroquineresistant malaria.

Clofazimine (Clo)

It is a dye with leprostatic and anti-inflammatory properties; acts probably by interfering with template function of DNA in M. leprae. When used alone, resistance to clofazimine develops in 1–3 years. Dapsone resistant M. leprae respond to clofazimine, but apparently after a lag period of about 2 months.

Clofazimine is orally active (40–70% absorbed). It accumulates in many tissues, especially in fat, in crystalline form. However, entry in CSF is poor. The t½ is 70 days so that intermittent therapy is possible.

CLOFOZINE, HANSEPRAN 50, 100 mg cap.

Clofazimine is used as a component of multidrug therapy of leprosy. Because of its anti-inflammatory property, it is valuable in lepra reaction.

Occasionally, it is used as a component of MDT for MAC.

Adverse Effects In the doses employed for multidrug therapy (MDT), clofazimine is well tolerated.

Skin The major disadvantage is reddish-black discolouration of skin, especially on exposed parts. Discolouration of hair and body secretions may also occur. Dryness of skin and itching is often troublesome. Acneform eruptions and phototoxicity have been noted. Conjunctival pigmentation may create cosmetic problem.

GI Symptoms Enteritis with intermittent loose stools, nausea, abdominal pain, anorexia and weight loss can occur, particularly when higher doses are used to control lepra reaction. The early syndrome is a reflection of irritant effect of the drug—subsides with dose adjustment and by taking the drug with meals. A late syndrome occurring after few months of therapy—is due to deposition of clofazimine crystals in the intestinal submucosa.

Clofazimine is to be avoided during early pregnancy and in patients with liver or kidney damage.

Rifampin (R)

It is an important antitubercular drug; also bactericidal to M. leprae; rapidly renders leprosy patients noncontagious. Up to 99.99% M. leprae are killed in 3–7 days. However, it is not satisfactory if used alone—some bacilli persist even after prolonged treatment—resistance develops. It has been included in the multidrug therapy of leprosy: shortens duration of treatment. The 600 mg monthly dose used in leprosy is relatively nontoxic and does not induce metabolism of other drugs. It should not be given to patients with hepatic or renal dysfunction.

The rifampin congener rifabutin is also cidal against M. leprae, but not superior to rifampin.

Ethionamide

This antitubercular drug has significant antileprotic activity, but causes hepatotoxicity in ~ 10% patients. It has been used as an alternative to clofazimine, but other substitutes are preferred. It should be used (250 mg/day) only when absolutely necessary.

Other Antibiotics

Ciprofloxacin is not active against M. leprae, but ofloxacin, pefloxacin, gatifloxacin and sparfloxacin are highly active.

Ofloxacin

Many trials have evaluated ofloxacin as a component of MDT and found it to hasten the bacteriological and clinical response. Over 99.9% bacilli were found to be killed by 22 daily doses of ofloxacin monotherapy. However, it is not included in the standard treatment protocols, but can be used in alternative regimens in case rifampin cannot be used, or to shorten the duration of treatment. Dose: 400 mg/day.

Minocycline

Because of high lipophilicity, this tetracycline is active against M. leprae. A dose of 100 mg/day produces peak blood levels that exceed MIC against M. leprae by 10–20 times. Its antibacterial activity is much less than that of rifampin, but greater than that of clarithromycin. In one trial minocycline 100 mg daily monotherapy rendered all 8 patients of lepromatous leprosy negative for M. leprae after 8 weeks. It is being tried in alternative MDT regimens.

Clarithromycin

It is the only macrolide antibiotic with significant activity against M. leprae. However, it is less bactericidal than rifampin. Monotherapy with clarithromycin 500 mg daily caused 99.9% bacterial killing in 8 weeks. It is being included in alternative MDT regimens.