Page 858 - Basic _ Clinical Pharmacology ( PDFDrive )

844 SECTION VIII Chemotherapeutic Drugs

TABLE 47–2 Recommended treatment for drug-susceptible tuberculosis.

Intensive Phase Continuation Phase
Regimen (min duration = 8 weeks) (min duration = 18 weeks) 1
(in order of
preference) Drugs Dosing Interval Drugs Dosing Interval Comments
1 INH 7 days per week 2 INH 7 days per week 2 Preferred regimen.
RIF RIF
PZA
EMB
2 INH 7 days per week 2 INH 3 days per week Preferred alternative if less frequent DOT is
RIF RIF needed.
PZA
EMB
3 INH 3 days per week INH 3 days per week Caution in patients with HIV and/or cavitary
RIF RIF disease due to concerns for treatment
failure, relapse, drug resistance.
PZA
EMB
4 INH 7 days per week × INH 2 days per week Avoid in patients with HIV or those with
RIF 2 weeks, then RIF smear-positive and/ or cavitary disease.
PZA 2 days per week ×
EMB 6 weeks
1
Experts recommend prolonged continuation phase (31 weeks) for patients with cavitation on initial chest radiograph and positive cultures at the end of the intensive
treatment phase.
2
May consider 5 days per week if needed for DOT. No studies compare 5 versus 7 doses per week, but extensive experience suggests efficacy of this regimen.
DOT, directly observed therapy; EMB, ethambutol; HIV, human immunodeficiency virus; INH, isoniazid; PZA, pyrazinamide; RIF, rifampin.

preexisting hepatic insufficiency and should be guided by serum A. Immunologic Reactions
concentrations if a reduction in dose is contemplated. Isoniazid Fever and skin rashes are occasionally seen. Drug-induced sys-
inhibits several cytochrome P450 enzymes, leading to increased temic lupus erythematosus has been reported.
concentrations of such medications as phenytoin, carbamazepine,
and benzodiazepines. However, when used in combination with B. Direct Toxicity
rifampin, a potent CYP enzyme inducer, the concentrations of Isoniazid-induced hepatitis is the most common major toxic effect.
these medications are usually decreased.
This is distinct from the minor increases in liver aminotransferases
(up to three or four times normal), which do not require cessa-
Clinical Uses tion of the drug and which are seen in 10–20% of patients, who

The typical dosage of isoniazid is 5 mg/kg/d; a typical adult dose is usually are asymptomatic. Clinical hepatitis with loss of appetite,
300 mg given once daily. Up to 10 mg/kg/d may be used for seri- nausea, vomiting, jaundice, and right upper quadrant pain occurs
ous infections or if malabsorption is a problem. A 15-mg/kg dose, in 1% of isoniazid recipients and can be fatal, particularly if the
or 900 mg, may be used in a twice to three times-weekly dosing drug is not discontinued promptly. There is histologic evidence of
regimen in combination with a second antituberculous agent (eg, hepatocellular damage and necrosis. The risk of hepatitis depends
rifampin, 600 mg). Pyridoxine, 25–50 mg/d, is recommended on age. It occurs rarely under age 20, in 0.3% of those age 21–35,
for those with conditions predisposing to neuropathy, an adverse 1.2% of those age 36–50, and 2.3% for those age 50 and above.
effect of isoniazid. Isoniazid is usually given by mouth but can be The risk of hepatitis is greater in individuals with alcohol depen-
given parenterally in the same dosage. dence and possibly during pregnancy and the postpartum period.
Isoniazid as a single agent is also indicated for treatment Development of isoniazid hepatitis contraindicates further use of
of latent tuberculosis. The dosage is 300 mg/d (5 mg/kg/d) or the drug.
900 mg twice weekly, and the duration is usually 9 months. Peripheral neuropathy is observed in 10–20% of patients given
dosages greater than 5 mg/kg/d, but it is infrequently seen with
the standard 300-mg adult dose. Peripheral neuropathy is more
Adverse Reactions likely to occur in slow acetylators and patients with predisposing

The incidence and severity of untoward reactions to isoniazid are conditions such as malnutrition, alcoholism, diabetes, AIDS, and
related to dosage and duration of administration. uremia. Neuropathy is due to a relative pyridoxine deficiency.