Rifampicin Dapsone

PABA) incorporation into folic acid (inhibition of folate synthesis). In large proportion of Mycobacterium leprae infections e.g. in lepromatous leprosy, resistance can develop, so combination of dapsone, rifampicin and clofazimine is used in initial therapy. 

Alycobocteriiim leprae (leprosy) Actinomycetes dapsone + rifampicin clofazimine ethionamide or cycloserine... 

When thionamides are used in combination with rifam-picin, hepatotoxicity is more common and severe (18,19). There was a 13% incidence of hepatotoxicity in patients with multibaciUary leprosy treated with dap-sone, rifampicin, and protionamide 10 mg/kg/day, and a 17% incidence in 110 patients treated with dapsone, rifampicin, and protionamide 5 mg/kg/day however, although the lower dose of protionamide did not reduce the incidence of hepatotoxicity, it did reduce its severity (20). Protionamide does not affect the pharmacokinetics of rifampicin (21). 

Rifampicin and rifabutin increase the metabolism and clearance of dapsone. Rifampicin also increases the blood levels of the toxic hydroxylamine metabolite of dapsone. Similarly, rifabutin increased the formation of this metabolite, although increases in the AUC were not seen. 

Goulart IM, Reis AC, De Rezende TM, Borges AS, Ferreira MS, Nishioka SA. Aplastic anaemia associated with multidrug therapy (dapsone, rifampicin and clofazimine) in a patient with lepromatous leprosy. Lepr Rev 2005 76 167-9. 

Dapsone (diaminodiphenylsulphone Fig. 5.16F) is used specifically in the treatment of leprosy. However, because resistance to dapsone is unfortunately now well known, it is recommended that dapsone be used in conjunction with rifampicin and clofazimine. 

Clofazimine is a substituted iminophenazine that was first proposed for treating leprosy in 1962 however, it entered into medical practice toward the end of the 1980s. The mechanisms of its action is not definitively known, although there is the assumption that it can inhibit the formation of matrixes with DNA, which leads to a delay in the growth of mycobacteria. Clofazimine exhibits a bactericidal effect between that of dapsone and rifampicin. Synonym of this drug is lamprene. 

Rifampicin, a semisynthetic derivative of the antimicrobial agent rifamycin B obtained from Strep-tomyces mediterranei, is bactericidal for intra- and extracellular bacteria. Bacterial RNA synthesis is inhibited by binding to the beta-subunit of DNA-dependent RNA polymerase. Human polymerases are not affected. It has activity against gram-positive and gram-negative cocci, chlamydia as well as mycobacteria. It is used in combination with dapsone for leprosy. 

Rifampicin (see Section III.a.2) has bactericidal activity against Mycobacterium lepra and is employed in combination with clofazamine and dapsone. 

Clofazimine is phenazine dye and used as alternative to dapsone in dapsone intolerant/resistant cases and in combination with dapsone and rifampicin in the multidrug treatment of leprosy. It s probable mechanism of action is its involvement in DNA binding, it may interfere with template function of DNA. 

Choice of antimicrobial follows automatically from the clinical diagnosis because the causative organism is always the same, and is virtually always sensitive to the same drug, e.g. meningococcal septicaemia (benzylpenicillin), some haemolytic streptococcal infections, e.g. scarlet fever, erysipelas (benzylpenicillin), typhus (tetracycline), leprosy (dapsone with rifampicin). 

Interactions. Rifampicin is a powerful enzyme inducer and speeds the metabolism of numerous drugs, including warfarin, steroid contraceptives, narcotic analgesics, oral antidiabetic agents, phenytoin and dapsone. Appropriate increase in dosage, and alternative methods of contraception, are required to compensate for increased drug metabolism (see also paracetamol overdose, p. 287). 

When rifampicin was given, dapsone blood concentrations were lowered and urinary excretion was increased during the first 2 days however, blood concentrations remained in the therapeutic range (47). 

Mathur A, Venkatesan K, Girdhar BK, Bharadwaj VP, Girdhar A, Bagga AK. A study of drug interactions in leprosy—1. Effect of simultaneous administration of prothionamide on metabolic disposition of rifampicin and dapsone. Lepr Rev 1986 57(l) 33-7. 

A 46-year-old woman died of severe disseminated intravascular coagulation after her third monthly dose of rifampicin, given with daily dapsone for the treatment of leprosy (41). 

Hepatotoxicity of combined therapy for leprosy has been reported in 39 patients treated with dapsone, pro-tionamide, and rifampicin. There were similar findings in 50 patients treated with dapsone, clofazimine, rifampicin, and protionamide. Deaths probably related to the drngs occurred in both groups after 3-4 months of treatment... 

The interaction of rifampicin with dapsone has been reviewed (105). In seven patients with leprosy, rifampicin shortened the half-hfe of dapsone by 50% (116). 

Lau G. A fatal case of drug-induced multi-organ damage in a patient with Hansen s disease dapsone syndrome or rifampicin toxicity Forensic science international. 1995 May 22 73(2) 109-15. 

The occurence of drug interactions involving clofazimine have also been investigated. Most of the studies show that clofazimine does not exert any effect on dapsone excretion in leprosy patients (Balakrishnan and Seshadri, 1981 Zuidema et al., 1986). Clofazimine has been shown to significantly reduce the absorption of simultaneously administered rifampicin, resulting in delayed time to reach peak serum concentration and increased t j. No significant changes were seen in Cmax or AUC (Mehta et al., 1986). 

Antimycobacterials and related drugs Aminosalicylic acid (PAS), Capreomycin, Clofazimine, Cycloserine, Dapsone, Ethambutol, Ethionamide, Isoniazid, Methaniazide, Protionamide, Pyrazinamide, Rifabutin, Rifampicin (Rifampin), Rifamycin, Rihipentine, Rihiximin... 

The interaction between dapsone and rifampicin is established but of uncertain clinical importance. Concurrent use should be well monitored to confirm that treatment is effective. It may be necessary to raise the dosage of dapsone. It has been pointed out that there is the risk of treatment failures for Pneumocystis pneumonia as well as for leprosy. Also be alert for any evidence of methaemoglobinaemia. 

Although there is less information, rifabutin appears to interact similarly to rifampicin. When dapsone is given with rifabutin, the dosage of dapsone may need to be increased, but this may increase exposure to the potentially toxic hydroxylamine metabolite. ... 

Kriduia DR, Appa Rao AVN, Ramanakar TV, Pmbhakar MC. Pharmacdcinetic interaction between dapsone and rifampicin in leprosy patients. Drug Dev Ind Pharm (1986) 12,443-59. 

Pieters FAJM, Woonink F, Zuidema J. Influence of once-monthly rifampicin and daily clofazimine on the pharmacokinetics of dapsone in leprosy patients in Nigeria. EurJ CUn Pharmacol (1988) 34,73-6. 

Rifampicin increases the urinary excretion of dapsone, lowers its serum ieveis and increases the risk of toxicity (methaemoglobinaemia). Simiiariy, rifabutin increases the clearance of dapsone, and may also increase its toxicity. 

A study in 7 patients with leprosy given single doses of dapsone 100 mg and rifampici n 600 mg, alone or together, found that while the pharmacokinetics of rifampicin were not significantly changed, the half-life of the dapsone was roughly halved and the AUC was reduced hy about 20%. ... 

Jaundice, liver damage and deaths have occurred in other leprosy patients given rifampicin and protionamide or ethionamide. Protionamide does not affect the pharmacokinetics of either dapsone or rifampicin. ... 

Clofazimine 100 mg daily, given to 15 patients with leprosy taking ri-fampiein 600 mg daily and dapsone 100 mg daily, had no effect on the pharmaeokineties of rifampiein. A single-dose study similarly found that the bioavailability of elofazimine remained unaltered when rifampicin was given, although a reduction in the rate of absorption was seen4 No special precautions would seem to be necessary on concurrent use. 

Venkatesan K, Mathur Girdhar BK, Bharadwaj VP. The effect of clofazimine on the pharmacokinetics of rifampicin and dapsone in leprosy. JAntimicrob Chemother (1986) 18, 715-18. 

Mehta J, Gandhi IS, Sane SB, Wamburkar MN. Effect of clofazimine and dapsone on rifampicin (Lositril) pharmacokinetics inmultibacillary andpaucibacillary leprosy cases. Indian JLepr( 9S5)57, 297-310. 

Rifampicin toxicity is becoming of greater importance in the treatment of leprosy. Several studies have recently been reported in which rifampicin was used in combination with Isoprodian, a combination of dapsone, isoniazid and prothionamide. The commonest adverse effects observed on this combination are gastrointestinal disturbances and mild hepatitis, manifested either as abnormalities in biochemical parameters or clinically by jaundice. One case of exfoliative dermatitis was reported from a trial carried out in South India (35 ). 

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