Antileprotic Drugs Chapter 56 Leprosy, caused by Mycobacterium leprae, has Activity and mechanism Dapsone is che- been considered incurable since ages and bears mically related to sulfonamides and has the same a social stigma. Due to availability of effective mechanism of action, i.e. inhibition of PABA antileprotic drugs now, it is entirely curable, but incorporation into folic acid by folate synthase. deformities/defects already incurred may not The antibacterial action of dapsone is antagonized reverse. by PABA. It is leprostatic at very low concentra- tions, while growth of many other bacteria Chaulmoogra oil with weak antileprotic property was used in Indian medicine for centuries. Shortly after the sensitive to sulfonamides is arrested at relatively demonstration of antibacterial property of sulfonamides, higher concentrations. Specificity for M. leprae congeners were tested and dapsone, the parent sulfone, was may be due to difference in the affinity of its found to be an active antileprotic. Demonstration of its folate synthase. Doses of dapsone needed for efficacy in experimental tuberculosis and leprosy led to clinical trials in the 1940s, and since then it is the sheet-anchor of treatment of acute pyogenic bacterial infections treatment of leprosy. Few other sulfones were added, but none are too toxic, so not used. could excel dapsone. Clofazimine was inducted in the early Dapsone-resistance among M. leprae, first 1960s as a useful adjunct, and soon rifampin, developed for noted in 1964, has spread and has necessitated TB, was found to be a rapidly acting cidal drug for M.leprae as well. Lately good antileprotic activity has been detected the use of multidrug therapy (MDT). When in some fluoroquinolones, macrolides and minocycline. dapsone resistance is encountered in an untreated patient, it is called ‘primary’, and indicates that CLASSIFICATION the infection was contacted from a patient harbouring resistant bacilli. Resistance which 1. Sulfone Dapsone (DDS) develops during monotherapy in an individual 2. Phenazine derivative Clofazimine patient with dapsone is called ‘secondary’.The 3. Antitubercular drugs Rifampin, incidence of primary dapsone resistance reported Ethionamide from different parts of the world, from time- 4. Other antibiotics Ofloxacin, to-time, has been variable; whereas secondary Moxifloxacin, dapsone resistance occurred in upto 20% patients Minocycline, treated with monotherapy. The mechanism of Clarithromycin secondary resistance appears to be the same as for M. tuberculosis, i.e. selective propagation Dapsone (DDS) of resistant bacilli over time. Dapsone resistant It is diamino diphenyl sulfone (DDS), the M. leprae have mutated folate synthase which simplest, oldest, cheapest, most active and most has lower affinity for dapsone. However, the peak commonly used member of its class. All other serum concentration of dapsone after 100 mg/ sulfones have become obsolete. day dose exceeds MIC for M. leprae by nearly 500 times; it continues to be active against low to moderately resistant bacilli, and the risk of relapse due to dapsone resistance is reported to be 2–3%. In addition to resistance, there is the problem of ‘persisters’, that are drug ANTILEPROTIC DRUGS 781 sensitive bacilli which become dormant, hide in treatment: consists of fever, malaise, lymph node some tissues and are not affected by any drug. enlargement, desquamation of skin, jaundice and They may stage a comeback after the drug is anaemia. It is generally seen in malnourished withdrawn. patients, and has become more frequent after the Dapsone is active against certain protozoa introduction of MDT. Some or all of the above as well. Combined with pyrimethamine, it is an symptoms may occur. Its treatment consists of alternative to sulfadoxine-pyrimethamine for stopping dapsone and instituting corticosteroid P. falciparum and Toxoplasma gondii infections, therapy along with supportive measures. as well as for the fungus Pneumocystis jirovecii. Contraindications Dapsone should not be used CHAPTER 56 Antiinflammatory property has been detected in in patients with severe anaemia (Hb < 7 g/dl), dapsone. G-6-PD deficiency and in those showing hyper- Pharmacokinetics Dapsone is completely sensitivity reactions. absorbed after oral administration and is widely Other use In combination with pyrimethamine, distributed in the body, though penetration in CSF is poor. It is 70% plasma protein bound, but more dapsone can be used for chloroquine-resistant importantly it is concentrated in skin (especially malaria, toxoplasmosis and P. jirovecii infection. lepromatous skin), muscle, liver and kidney. Dapsone is acetylated as well as glucuronide Clofazimine (Clo) and sulfate conjugated in liver. Metabolites are It is a dye with leprostatic and antiinflammatory excreted in bile and reabsorbed from intestine, properties. The putative mechanisms of anti- so that ultimate excretion occurs mostly in urine. leprotic action of clofazimine are: The plasma t½ of dapsone is variable, though • Interference with template function of DNA often > 24 hrs. The drug is cumulative due to in M.leprae retention in tissues and enterohepatic circulation. • Alteration of membrane stucture and its Elimination takes 1–2 weeks or longer. transport function. DAPSONE 25, 50, 100 mg tab. • Disruption of mitochondrial electron trans- Adverse effects Dapsone is generally well port chain. tolerated at doses 100 mg/day or less. When used alone, the clinical response to Mild haemolytic anaemia is common. It is a dose- clofazimine is slower than that to dapsone, and related toxicity—reflects oxidising property of resistance develops in 1–3 years. Dapsone- the drug. Patients with G-6-PD deficiency are resistant M. leprae respond to clofazimine, but more susceptible; doses > 50 mg/day produce apparently after a lag period of about 2 months. haemolysis in such subjects. Clofazimine is orally active (40–70% absor- Gastric intolerance—nausea and anorexia are bed). It accumulates in macrophages and gets frequent in the beginning, decrease later. deposited in many tissues including subcuta- Other side effects are methaemoglobinaemia, neous fat, as needle-shaped crystals. However, headache, paresthesias, mental symptoms and entry in CSF is poor. The t½ is 70 days so that drug fever. intermittent therapy is possible. Cutaneous reactions include allergic rashes, CLOFOZINE, HANSEPRAN 50, 100 mg cap. fixed drug eruption, hypermelanosis, photo- Clofazimine is used as a component of toxicity and rarely exfoliative dermatitis. multidrug therapy (MDT) of leprosy. Because Hepatitis and agranulocytosis are rare complica- of its antiinflammatory property, it is valuable tions. in lepra reaction. Sulfone syndrome It is the reaction which Occasionally, it is used as a component of develops 4–6 weeks after starting dapsone MDT for MAC infection. 782 ANTIMICROBIAL DRUGS Adverse effects In the doses employed for nontoxic and does not cause enzyme induction MDT, clofazimine is well tolerated. to affect metabolism of other drugs. However, it should not be given to patients with hepatic Skin The major disadvantage is reddish-black or renal dysfunction, as well as during ‘erythema discolouration of skin, especially on exposed nodosum leprosum’ (ENL) and ‘reversal parts. Discolouration of hair and body secretions reaction’ in leprosy patients, because it can may also occur. Dryness of skin and itching is release large quantities of mycobacterial often troublesome. Acneform eruptions and antigens by inducing rapid bacillary killing. phototoxicity have been noted. Conjunctival pigmentation may create cosmetic problem. Ethionamide This antitubercular drug has significant antileprotic activity, but is poorly tolerated and causes GI symptoms Nausea, anorexia, abdominal hepatotoxicity in ~ 10% patients. It has been used as an pain, weight loss and enteritis with intermittent alternative to clofazimine, but other substitutes are preferred. loose stools can occur, particularly when higher Ethionamide 250 mg/day may be used only when absolutely doses are used to control lepra reaction. The necessary. SECTION 12 early syndrome is a reflection of irritant effect Ofloxacin of the drug—subsides with dose adjustment and by taking the drug with meals. A late syndrome Many fluoroquinolones like ofloxacin, pefloxa- occurring after few months of therapy—is due cin, moxifloxacin, sparfloxacin are highly active to deposition of clofazimine crystals in the against M.leprae, but ciprofloxacin has poor intestinal submucosa. activity. Clinically, ofloxacin has been used to Clofazimine is to be avoided during early the largest extent. As a component of MDT, it pregnancy and in patients with liver or kidney has been found to hasten the bacteriological and damage. clinical response. It is cidal to M.leprae, and in one study, over 99.9% bacilli were found to Rifampin (R) be killed by 22 daily doses of ofloxacin monotherapy. However, it is not yet included in This important tuberculocidal drug is also the the standard treatment protocols, but can be used most potent cidal drug for M.leprae; rapidly in alternative regimens in case rifampin cannot renders leprosy patients noncontagious. Upto be used, or to shorten the duration of treatment 99.99% M.leprae are killed in 3–7 days by 600 and reduce chances of drug resistance. Its safety mg/day dose. Clinical effects of rifampin are during long-term use is not well documented. very rapid; nasal symptoms in lepromatous Dose: 400 mg/day. leprosy subside within 2–3 weeks and skin Moxifloxacin