Page 860 - Basic _ Clinical Pharmacology ( PDFDrive )

846 SECTION VIII Chemotherapeutic Drugs

Mechanism of Action & Clinical Uses O
N
Ethambutol inhibits mycobacterial arabinosyl transferases, which C NH 2
are encoded by the embCAB operon. Arabinosyl transferases are
involved in the polymerization reaction of arabinoglycan, an
essential component of the mycobacterial cell wall. Resistance to N
ethambutol is due to mutations resulting in overexpression of emb Pyrazinamide (PZA)
gene products or within the embB structural gene. Susceptible
strains of Mycobacterium tuberculosis and other mycobacteria are Mechanism of Action & Clinical Uses
inhibited in vitro by ethambutol, 1–5 mcg/mL. Pyrazinamide is converted to pyrazinoic acid—the active form of
Ethambutol is well absorbed from the gut. After ingestion the drug—by mycobacterial pyrazinamidase, which is encoded
of 25 mg/kg, a blood level peak of 2–5 mcg/mL is reached in by pncA. Pyrazinoic acid disrupts mycobacterial cell membrane
2–4 hours. About 20% of the drug is excreted in feces and 50% in metabolism and transport functions. Resistance may be due
urine in unchanged form. Ethambutol accumulates in renal failure, to impaired uptake of pyrazinamide or mutations in pncA that
and the dose should be reduced to three times weekly if creatinine impair conversion of PZA to its active form.
clearance is less than 30 mL/min. Ethambutol crosses the blood- Serum concentrations of 30–50 mcg/mL at 1–2 hours after
brain barrier only when the meninges are inflamed. Concentrations oral administration are achieved with dosages of 25 mg/kg/d.
in cerebrospinal fluid are highly variable, ranging from 4% to 64% Pyrazinamide is well absorbed from the gastrointestinal tract and
of serum levels in the setting of meningeal inflammation. widely distributed in body tissues, including inflamed meninges.
As with all antituberculous drugs, resistance to ethambutol The half-life is 8–11 hours. The parent compound is metabolized
emerges rapidly when the drug is used alone. Therefore, etham- by the liver, but metabolites are renally cleared; therefore, PZA
butol is always given in combination with other antituberculous should be administered at 25–35 mg/kg three times weekly (not
drugs. Ethambutol hydrochloride, 15–25 mg/kg, is usually given daily) in hemodialysis patients and those in whom the creatinine
as a single daily dose in combination with isoniazid, rifampin, and clearance is less than 30 mL/min. In patients with normal renal
pyrazinamide during the initial intensive phase of active tuber- function, a dose of 30–50 mg/kg is used for thrice-weekly or
culosis treatment. The higher dose may be used for treatment of twice-weekly treatment regimens.
tuberculous meningitis. Higher doses have been used with inter- Pyrazinamide is an important front-line drug used in conjunc-
mittent dosing regimens for directly observed therapy; for example, tion with isoniazid and rifampin in short-course (ie, 6-month)
25–30 mg/kg three times weekly or 50 mg/kg administered twice regimens as a “sterilizing” agent active against residual intracellular
weekly. Ethambutol is also used in combination with other agents organisms that may cause relapse. Tubercle bacilli develop resis-
for the treatment of nontuberculous mycobacterial infections, such tance to pyrazinamide fairly readily, but there is no cross-resistance
as Mycobacterium avium complex (MAC) or M. kansasii; the typical with isoniazid or other antimycobacterial drugs.
dose for these infections is 15 mg/kg once daily.
Adverse Reactions
Adverse Reactions
Major adverse effects of PZA include hepatotoxicity (in 1–5%
Hypersensitivity to ethambutol is rare. The most common serious of patients), nausea, vomiting, drug fever, photosensitivity, and
adverse event is retrobulbar neuritis, resulting in loss of visual acu- hyperuricemia. The latter occurs uniformly and is not a reason to
ity and red-green color blindness. This dose-related adverse effect halt therapy if patients are asymptomatic.
is more likely to occur at dosages of 25 mg/kg/d continued for
several months. At 15 mg/kg/d or less, visual disturbances occur in
approximately 2% of patients, typically after at least one month of SECOND-LINE DRUGS FOR
treatment. Experts recommend baseline and monthly visual acu- TUBERCULOSIS
ity and color discrimination testing, with particular attention to
patients on higher doses or with impaired renal function. Etham- The alternative drugs listed below are usually considered only (1)
butol is relatively contraindicated in children too young to permit in case of resistance to first-line agents; (2) in case of failure of
assessment of visual acuity and red-green color discrimination. clinical response to conventional therapy; and (3) in case of serious
treatment-limiting adverse drug reactions. Expert guidance is desir-
able in dealing with the toxic effects of these second-line drugs. For
PYRAZINAMIDE many drugs listed in the following text, the dosage, emergence of
resistance, and long-term toxicity have not been fully established.
Pyrazinamide (PZA) is a relative of nicotinamide, and it is used
only for treatment of tuberculosis. It is stable and slightly soluble in
water. It is inactive at neutral pH, but at pH 5.5 it inhibits tubercle Streptomycin
bacilli at concentrations of approximately 20 mcg/mL. The drug is The mechanism of action and other pharmacologic features of
taken up by macrophages and exerts its activity against mycobacte- streptomycin, an aminoglycoside, are discussed in Chapter 45.
ria residing within the acidic environment of lysosomes. The typical adult dosage is 1 g/d (15 mg/kg/d). If the creatinine