Antituberculosis Drugs

Isoniazid

Isoniazid (INH, INAH, isonicotinic acid hydrazide) is selectively effective against Mycobacterium tuberculosis because it prevents the synthesis of components that are unique to mycobacterial cell walls. Hence it is bactericidal against actively multiplying bacilli (whether within macrophages or at extracellular sites) but is bacteriostatic against non-dividing bacilli; it has little or no activity against other bacteria. Isoniazid is well absorbed from the alimentary tract and is distributed throughout the body water, readily crossing tissue barriers and entering cells and cerebrospinal fluid. It should always be given in cases where there is special risk of meningitis (miliary tuberculosis and primary infection). Isoniazid is inactivated by conjugation with an acetyl group and the rate of the reaction is bimodally distributed (see Pharmacogenetics, p. 123). The t'/2 is 1 h in fast and 4 h in slow acetylators; steady-state plasma concentration in fast acetylators is less than half that in slow acetylators but standard oral doses (300 mg/d) on daily regimens give adequate tuberculocidal concentrations in both groups.

Adverse effects. Isoniazid is in general well tolerated. The most severe adverse effect is liver damage which may range from moderate elevation of hepatic enzymes to severe hepatitis and death. It is probably caused by a chemically reactive metabolite^), e.g. acetylhydrazine. Most cases develop within the first 8 weeks of therapy and liver function tests should be monitored monthly during this period at least.

Isoniazid is a structural analogue of pyridoxine and accelerates its excretion, the principal result of which is peripheral neuropathy with numbness and tingling of the feet, motor involvement being less common. Neuropathy is more frequent in slow acetylators, malnourished people, the elderly and those with HIV infection, liver disease and alcoholism. Such patients should receive pyridoxine 10mg/d by mouth, which prevents neuropathy and does not interfere with the therapeutic effect; some prefer simply to give pyridoxine to all patients. Other adverse effects include mental disturbances, incoordination, optic neuritis and convulsions.

Isoniazid inhibits the metabolism of phenytoin, carbamazepine and ethosuximide, increasing their effect.

Rifampicin

Rifampicin has bactericidal activity against the tubercle bacillus, comparable to that of isoniazid. It is also used in leprosy.

It acts by inhibiting RNA synthesis, bacteria being sensitive to this effect at much lower concentrations than mammalian cells; it is particularly effective against mycobacteria that lie semidormant within cells. Rifampicin has a wide range of antimicrobial activity. Other uses include leprosy, severe Legionnaires' disease (with erythromycin or ciprofloxacin), the chemoprophylaxis of meningococcal meningitis, and severe staphylococcal infection (with flucloxacillin or vancomycin).

Rifampicin is well absorbed from the gastrointestinal tract. It penetrates well into most tissues. Entry into the CSF when meninges are inflamed is sufficient to maintain therapeutic concentrations at normal oral doses but transfer is reduced as inflammation subsides in 1 or 2 months.

Enterohepatic recycling takes place, and eventually about 60% of a single dose is eliminated in the faeces; urinary excretion of unchanged drug also occurs. The tV2 is 4 h after initial doses, but shortens on repeated dosing because rifampicin is a very effective enzyme inducer and increases its own metabolism (as well as that of several other drugs, see below).

Adverse reactions. Rifampicin rarely causes any serious toxicity. Adverse reactions include flushing and itching with or without a rash, and thrombocytopenia. Rises in plasma bilirubin and hepatic enzymes may occur when treatment starts but are often transient and are not necessarily an indication for stopping the drug; fatal hepatitis, however, has occurred. Hepatic function should be checked before starting treatment and at least for the first few months of therapy. Intermittent dosing, i.e. less than twice weekly, either as part of a regimen or through poor compliance, promotes certain effects that probably have an immunological basis, namely, an influenza-like syndrome (malaise, headache and fever, shortness of breath and wheezing), acute haemolytic anaemia and thrombocytopenia and acute renal failure sometimes with haemolysis. Red discolouration of urine, tears and sputum is a useful indication that the patient is taking the drug. Rifampicin also causes an orange discolouration of soft contact lenses.

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).

Rifabutin (t'/2 36 h) has similar activity and adverse reactions, and is used for prophylaxis of Mycobacterium avium infection in patients with AIDS, and for treatment of tuberculous and nontuberculous mycobacterial infection in combination with other drugs.

Pyrazinamide

Pyrazinamide is a derivative of nicotinamide and is included in first-choice combination regimens because of its particular ability to kill intracellular persisters, i.e. mycobacteria that are dividing or semidormant, often within cells. Its action is dependent on the activity of intrabacterial pyrazinami-dase which converts pyrazinamide to the active pyrazinoic acid; this enzyme is most effective in an acidic environment such as the interior of cells. It is inactive against Mycobacterium bovis. Pyrazinamide is well absorbed from the gastrointestinal tract and metabolised in the liver, very little unchanged drug appearing in the urine (t'/2 9 h). CSF concentrations are almost identical to those in the blood, hence the drug is valuable in tuberculous meningitis. Experience in several countries indicates that pyrazinamide is safe to use in pregnancy.

Adverse effects include hyperuricaemia and arthralgia, which is relatively frequent with daily but less so with intermittent dosing and, unlike gout, affects both large and small joints. Pyrazinoic acid, the principal metabolite of pyrazinamide, inhibits renal tubular secretion of urate. Symptomatic treatment with an NSAID is usually sufficient and it is rarely necessary to discontinue pyrazinamide because of arthralgia. Hepatitis, which was particularly associated with high doses, is not a problem with modern short-course schedules. Sideroblastic anaemia and urticaria also occur.

Ethambutol

Ethambutol, being bacteriostatic, is used in conjunction with other antituberculosis drugs to delay or prevent the emergence of resistant bacilli. It is well absorbed from the gastrointestinal tract and effective concentrations occur in most body tissues including the lung; in tuberculous meningitis, sufficient may reach the CSF to inhibit mycobacterial growth but insignificant amounts cross into the CSF if the meninges are not inflamed. Excretion is mainly by the kidney, by tubular secretion as well as by glomerular filtration (t1/, 4 h); the dose should be reduced when renal function is impaired.

Adverse effects. In recommended oral doses (15 mg/kg per day) (taking account of reduced renal function), ethambutol is relatively nontoxic. The main problem is optic neuritis (unilateral or bilateral) causing loss of visual acuity, central scoto-mata, occasionally also peripheral vision loss and red-green colour blindness. The changes reverse if treatment is stopped promptly; if not, the patient may go blind. It is prudent to note any history of eye disease and to get baseline tests of vision before starting treatment with ethambutol. The drug should not be given to a patient whose vision is much reduced and who may not notice further minor deterioration. Patients should be told to make a point of reading small print in newspapers

(with each eye separately) and if there is any deterioration to stop the drug immediately and seek advice. Patients who cannot understand and comply (especially children) should be given alternative therapy, if possible. The need for repeated specialist ophthalmological monitoring is controversial. Peripheral neuritis occurs but is rare. Streptomycin: see page 225.

Thiacetazone

Thiacetazone is tuberculostatic and is used with isoniazid to inhibit the emergence of resistance to the latter drug. It is absorbed from the gastrointestinal tract, partly metabolised and partly excreted in the urine (tV213 h).

Adverse reactions include gastrointestinal symptoms, conjunctivitis and vertigo. More serious effects are erythema multiforme, haemolytic anaemia, agranulocytosis, cerebral oedema and hepatitis.

Alternative or reserve drugs are used where there are problems of drug intolerance and bacterial resistance. They are in this class because of either greater toxicity or of lesser efficacy and include: ethionamide (gastrointestinal irritation, allergic reactions), capreomycin (nephrotoxic), and cycloserine (effective but neurotoxic). Quinolone antibiotics such as ciprofloxacin and the more recently introduced macrolides such as clarithromycin and azithromycin also have useful activity against mycobacteria.

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