Which
of the following antituberculars can cause hyperuricemia as a side effect?
1. Isoniazid
2. Ethambutol
3. Rifampicin
4. Pyrazinamide
Ø
Mechanism of Action
o
Pyrazinamide's antimycobacterial activity is
essentially limited to M. tuberculosis.
o
more active against slowly replicating organisms
than against actively replicating organisms.
o
Pyrazinamide is a prodrug that is converted by
the mycobacterial pyrimidase to the active form, pyrazinoic acid (POA).
o
This agent is active only in acidic environments pH <6 span="">6>
o
as are found within phagocytes or granulomas.
o
The exact mechanism of action of POA is unclear,
but fatty acid synthetase I may be the primary target in M. tuberculosis.
Ø
METABOLISM
o
Pyrazinamide is well absorbed after oral
administration,
o
It distributes well to various body
compartments, including CSF, and is an important component of treatment for
tuberculous meningitis.
o
Pyrazinamide is metabolized in the liver to POA,
5-hydroxypyrazinamide, and 5-hydroxy-POA. A high proportion of pyrazinamide and
its metabolites (70%) is excreted in the urine.
o
The dosage must be adjusted according to the
level of renal function in patients with reduced creatinine clearance.
Ø
Adverse Effects
o
At the higher dosages used previously,
hepatotoxicity was seen in as many as 15% of patients treated with
pyrazinamide.
o
However, at the currently recommended dosages,
hepatotoxicity now occurs less commonly when this drug is administered with isoniazid
and rifampin during the treatment of TB.
o
Older age, active liver disease, HIV infection,
and low albumin levels may increase the risk of hepatotoxicity.
o
The use of pyrazinamide with rifampin for the
treatment of LTBI is no longer recommended because of unacceptable rates of
hepatotoxicity and death in this setting.
o
Hyperuricemia is a common adverse effect of
pyrazinamide therapy that usually can be managed conservatively.
§
Clinical gout is rare.
Ø
Although pyrazinamide is recommended by
international tuberculosis organizations for routine use in pregnancy, it is
not recommended in the United States because of inadequate teratogenicity data.
Ø
Resistance
Ø
The basis of pyrazinamide resistance in M.
tuberculosis is a mutation in the pncA gene coding for pyrazinamidase, the
enzyme that converts the prodrug to active POA. Resistance to pyrazinamide is
associated with loss of pyrazinamidase activity, which prevents conversion of
pyrazinamide to POA. Of pyrazinamide-resistant M. tuberculosis isolates, 72–98%
have mutations in pncA. Conventional methods of testing for susceptibility to
pyrazinamide may produce both false-negative and false-positive results because
the high-acidity environment required for the drug's activation also inhibits
the growth of M. tuberculosis. There is some controversy as to the clinical
significance of in vitro pyrazinamide resistance.
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