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Pharmacology: Pharmacodynamics: There are three main properties of antituberculosis drugs: bactericidal activity; sterilizing activity and the ability to prevent resistance. The essential antituberculosis drugs possess these properties to different extents. Isoniazid and rifampicin are the most powerful bactericidal drugs, active against all populations to TB bacilli. Rifampicin is the most potent sterilizing drug available.
Pharmacokinetics: Rifampicin: Rifampicin is readily absorbed from the GIT and peak plasma concentrations of about 7-10 mcg/mL have been reported 2-4 hrs after a dose of 600 mg, although there may be considerable interindividual variation. Food may reduce and delay absorption. Rifampicin is approximately 80% bound to plasma proteins. It is widely distributed in body tissues and fluids and diffusion into the CSF is increased when the meninges are inflamed. Rifampicin crosses the placenta and is distributed into breast milk. Half-lives for rifampicin have been reported to range initially from 2-5 hrs, the longest elimination times occurring after the largest doses. However, as rifampicin induces its own metabolism, elimination time may decrease by up to 40% during the first 2 weeks, resulting in t½ of about 1-3 hrs. The t½ is prolonged in patients with liver disease.
Rifampicin is rapidly metabolized in the liver mainly to active 25-O-deacetyrifampicin; rifampicin and deacetylrifampicin are excreted in the bile. Deacetylation diminishes intestinal reabsorption and increases fecal excretion, although significant enterohepatic circulation still takes place. About 60% of a dose eventually appears in the feces. The amount excreted in the urine increases with increasing doses and up to 30% of a dose of 900 mg may be excreted in the urine, about half of it within 24 hrs. The metabolite formylrifampicin is also excreted in the urine. In patients with impaired renal function, the t½ of rifampicin is not prolonged at doses of ≤600 mg.
Isoniazid: Isoniazid is readily absorbed from the GIT. Peak concentrations of about 3-8 mcg/mL appear in blood 1-2 hrs after a fasting dose of 300 mg orally. The rate and extent of absorption of isoniazid is reduced by food. Isoniazid is not considered to be bound appreciably to plasma proteins and diffuses into all body tissues and fluids, including the CSF. The plasma t½ for isoniazid ranges from about 1-6 hrs, those who are fast acetylators having shorter t½. The primary metabolic route is the acetylation of isoniazid to acetylisoniazid by N-acetyltransferase found in the liver and small intestine.
In patients with normal renal function, over 75% of a dose appears in the urine in 24 hrs, mainly as metabolites. Small amounts of drug are also excreted in the feces. Isoniazid is removed by dialysis.
Ethambutol: About 80% of an oral dose is absorbed from the GIT and the remainder appears in the feces unchanged. Absorption is not significantly impaired by food. After a single dose of 25 mg/kg body weight, peak plasma concentrations of up to 5 mcg/mL appear within 4 hrs and are <1 mcg/mL by 24 hrs.
Ethambutol is distributed to most tissues including the lungs, kidneys and erythrocytes. It diffuses into the CSF when the meninges are inflamed. It has been reported to cross the placenta and is distributed into breast milk. The elimination t½ following oral administration is about 3-4 hrs.
Ethambutol is partially metabolized in the liver to the aldehyde and dicarboxylic acid derivatives which are inactive and then excreted in the urine. Most of a dose appears in the urine within 24 hrs as unchanged drug and 8-15% as the inactive metabolites. About 20% of the dose is excreted unchanged in the feces.
Although the absorption of ethambutol is not generally regarded as being impaired by food, a study in 14 healthy subjects suggested that administration with a high fat meal or an antacid could delay absorption and reduce the maximum plasma concentration.
Fixcom 4: Pyrazinamide: Pyrazinamide is readily absorbed from the GIT. Peak serum concentrations occur about 2 hrs after a dose orally and have been reported to be about 35 mcg/mL after 1.5 g and 66 mcg/mL after 3 g. Pyrazinamide is widely distributed in the body fluids and tissues and diffuses into the CSF. The t½ has been reported to be about 9-10 hrs. It is metabolized primarily in the liver by hydrolysis to the major active metabolite pyrazinoic acid which is subsequently hydroxylated to the major excretory product 5-hydroxypyrazinoic acid. It is excreted through the kidney mainly by glomerular filtration. About 70% of the dose appears in the urine within 24 hrs mainly as metabolites and 4-14% as unchanged drug. Pyrazinamide is removed by dialysis.
Microbiology: Antimicrobial Actions: Rifampicin: Rifampicin is bactericidal against a wide range of microorganisms and interferes with their synthesis of nucleic acids by inhibiting DNA-dependent RNA polymerase. It has the ability to kill intracellular organisms. It is active against mycobacteria, including Mycobacterium tuberculosis and M. leprae and having high sterilizing activity against these organisms, it possesses the ability to eliminate semi-dormant or persisting organisms. Rifampicin is active against gram-positive bacteria, especially staphylococci, but less active against gram-negative organisms. The most sensitive gram-negative bacteria include Neisseria meningitides, N. gonorrhoeae, Haemophilus influenzae and Legionella spp. Rifampicin also has activity against Chlamydia trachomatis and some anaerobic bacteria. At high concentrations, it is active against some viruses. Rifampicin has no effect on fungi but has been reported to enhance the antifungal activity of amphotericin B. Minimum inhibitory concentrations (MICs) tend to vary with the medium used; MICs for the most sensitive organisms (Chlamydia, staphylococci) tend to range from about 0.01-0.02 mcg/mL, while the MIC for most susceptible mycobacteria ranges from 0.1-0.2 mcg/mL. The concomitant use of other antimicrobials may enhance or antagonize the bactericidal activity of rifampicin.
Strains of Mycobacterium tuberculosis, M. leprae and other usually susceptible bacteria gave demonstrated resistance, both initially and during treatment. Thus in tuberculosis and leprosy regiments, rifampicin is used in combination with other drugs to delay or prevent the development of rifampicin resistance.
Isoniazid: Isoniazid is highly active against Mycobacterium tuberculosis which it inhibits in vitro at concentrations of 0.02-0.2 mcg/mL. Isoniazid may have activity against some strains of other mycobacteria including M. kansasii.
Although it is rapidly bactericidal against actively dividing M. tuberculosis, it is considered to be only bacteriostatic against semi-dormant organisms and has less sterilizing activity than rifampicin or pyrazinamide.
Resistance to isoniazid develops rapidly if it is used alone in the treatment of clinical infection and may be due in some strains to loss of the gene for catalase production. Resistance is delayed or prevented by combination with other antimycobacterials and it appears to be highly effective in preventing emergence of resistance to other antituberculous drugs. Resistance does not appear to be a problem when isoniazid is used alone in prophylaxis, probably because the bacillary load is low.
Ethambutol: Ethambutol is bacteriostatic against Mycobacterium tuberculosis with an MIC of 0.5-0.8 mcg/mL; it is bactericidal at higher concentrations. It possesses little sterilizing activity. Resistant strains of M. tuberculosis are readily produced if ethambutol is used alone.
Fixcom 4: Pyrazinamide: Pyrazinamide has a bactericidal effect on Mycobacterium tuberculosis but appears to have no activity against other mycobacteria or microorganisms in vitro. The MIC for M. tuberculosis is <20 mcg/mL at pH 5.6; it is almost completely inactive at neutral pH. Pyrazinamide is effective against persisting tubercle bacilli within the acidic intracellular environment of the macrophages. The initial inflammatory response to chemotherapy increases the number of organisms in the acidic environment. As inflammation subsides and pH increase, the sterilizing activity of pyrazinamide decreases. This pH-dependent activity explains the clinical effectiveness of pyrazinamide as part of the initial 8-week phase in short-course treatment regimens.
