Antituberculous and Antileproitc drugs

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Prescribing Notes

Tuberculosis

Rifampicin, rifabutin, isoniazid, ethambutol and pyrazinamide are commonly used drugs for the treatment of tuberculosis. They are used in a variety of combination regimens depending upon the disease site and whether the organism is likely to be resistant. Short-course combination regimens are recommended to aid patient compliance and reduce the risk of resistance developing.

Treatment is divided into two phases, an initial phase and a continuation phase. The initial phase of isoniazid plus rifampicin plus pyrazinamide taken daily or 2 months rapidly reduces the number of bacteria and minimises the risk of resistance. Treatment should be continued for a further 4 months (longer if non-pulmonary sites or if resistance) using a dual treatment regimen of isoniazid plus rifampicin daily.

In patients who are likely to be non-compliant, a supervised three times per week regimen should be followed. Rifampicin is highly active against Mycobacterium tuberculosis. It can be administered orally, attaining high and well sustained blood levels. It is a potent inducer of liver enzymes and interacts with many drugs the most important being warfarin, oral contraceptives, steroids, oral hypoglycaemics and some digitalis preparations. Side effects include flu-like symptoms, skin reactions. GI disturbances and transient disturbance of liver function. Patients should be warned that it causes an orange discolouration of urine and secretions. Rifabutin is highly active against most mycobacterlal species including a number of rifampicin resistant strains. It is indicated for prophylaxis in the immunocompromised and as adjunctive therapy. To reduce the risk of drug-induced uveitis, the dose of rifabutin should be reduced when co-prescribing with either macrolide ant ibioiics or triazole antifungals.

Isoniazid is bactericidal against M. tuberculosis. It is readily absorbed orally, and is distributed throughout the body including the CSF. Side effects are frequently seen among slow acetylators when large doses are used. These include insomnia. restlessness and muscle twitching. more serious effects are peripheral neuritis, psychotic disturbances, SLE-like symptoms and rheumatic syndrome. The incidence of toxic effects can be reduced by concomitant pyridoxine administration. Hepatitis is a potentially serious side effect of isoniazid, the incidence of which increases with age.

Pyrazinamide is an established component of many short course regimens. Hepatitis is a recognized side effect but is minimised by keeping the daily dose to 30mg/kg.

Capreomycin is a peptide antituberculous agent reserved for cases resistant to first-line drugs. It is given by injection and causes nephrotoxicity and ototoxicity. Other reactions include hepatic damage hypersensitivity and haematological changes especially eosinophllla.

Antimalarials

Prescribing Notes

The 4-AMINOOUINOLINE derivative chloroquine prevents nucleic acid synthesis in actively dividing erythrocytic schizonts and gametocytes of the malarial parasites by intercalating between the stacked base pairs of the DNA double helix. The parasitised erythrocyte selectively accumulates the drug which accounts for its selective toxicity. Chloroquine is used for treatment and prophylaxis of malaria. In many areas where malaria is endemic the malarial parasite is chloroquine resistant. another class of antimalarial should be used. Mefloquine appears to interfere with lysosomal degradation of the haemoglobin within the erythrocyte, lethally damaging the plasmodial membrane. It has been shown to be effective in the treatment and prophylaxis of chloroquine-resistant and multi-resistant P. falciparummalaria.

BIGUANIDE drugs such as proguanil are metabolised to an active metabolite . cycloguanil. This inhibits the dihydrofolate reductase enzyme in plasmodial cells thus blocking the production of tetrahydrofolic acid and consequently DNA synthesis. Mammalian cells remain protected because unlike parasital cells they can utilise tetrahydrofolic acid from external sources. Proguanil is only used in malaria prophylaxis. Proguanil in a fixed dose combination with atovaquone may be used in acute uncomplicated Plasmodium falciparum malaria showing resistance to other antlmalarials.

DIAMINOPYRIMIDINES which include pyrimethamine have a similar mode of action to proguanil. Pyrimethamine is given as a weeklydose. However, because of the spread of resistance, the drug is considered suitable for use only in residents of areas where pyrimethamine is known to be effective. It is no longer recommended as a prophylactic fortravellers.

SULPHONAMIDES and SULPHONES, eg sulfadoxine and dapsone, compete with p-aminobenzoic acid in the synthesis of folic acid. They are only weak antimalarials and should not be used alone. If combined with a dihydrofolate reduciase inhibitor they become more effective, eg sulfadoxine and pyrimethamine (Fansidar) or pyrimethamine and dapsone are useful for malaria prophylasix even in chloroquine resistant areas.

Sulfadoxine and pyrimethamine may be used for treatment of chloroquine resistant malaria. NB: Doses must be given on a weekly NOT daily basis. Doxycycline is used for prophylaxis in areas of mefloquine-resistant falciparum malaria in SE Asia. and as an alternative for travellers visiting high risk areas who are unable to take chloroquine or mefloquine. The recommended dose is 100 mg daily. It should not be taken for more than 3 months, and is unsuitable for use in children and during pregnancy. It may cause photosensitivity, so patients should be advised to avoid prolonged exposure to the sun. Due to the complex picture of developing resistance to the antimalarial drugs, prescribers should contact one of the malarial reference centres for detailed advice on appropriate prophylactic therapy for travellers.

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