DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

1562 acid synthase II (Larsen et al., 2002). This is the same enzyme that
activated isoniazid inhibits. Although the exact mechanisms of inhibition
may differ, the results are the same: inhibition of mycolic acid
biosynthesis and consequent impairment of cell-wall synthesis.
Antibacterial Activity. The multiplication of M. tuberculosis is suppressed
by concentrations of ethionamide ranging from 0.6-2.5 mg/L.
A concentration of ≤10 mg/L will inhibit ~75% of photochromogenic
mycobacteria; the scotochromogens are more resistant.
Bacterial Resistance. Resistance occurs mainly via changes in the
enzyme that activates ethionamide, and mutations are encountered in
a transcriptional repressor gene that controls its expression, etaR.
Mutations in inhA gene lead to resistance to both ethionamide and
isoniazid.
Absorption, Distribution, and Excretion. The oral bioavailability
of ethionamide approaches 100%. The pharmacokinetics are adequately
explained by a one-compartment model with first-order
absorption and elimination (Zhu et al., 2002); see PK values in Table
56–2. After oral administration of 500 mg of ethionamide, a C max
of
1.4 mg/L is achieved in 2 hours. The t 1/2
is ~2 hours. The concentrations
in the blood and various organs are approximately equal.
Ethionamide is cleared by hepatic metabolism; six metabolites have
been identified. Metabolites are eliminated in the urine, with <1% of
ethionamide excreted in an active form.
SECTION VII
CHEMOTHERAPY OF MICROBIAL DISEASES
Therapeutic Uses. Ethionamide is administered only orally. The initial
dosage for adults is 250 mg twice daily; it is increased by 125 mg/day
every 5 days until a dose of 15-20 mg/kg/day is achieved. The maximal
dose is 1 g daily. The drug is best taken with meals in divided
doses to minimize gastric irritation. Children should receive 10-20
mg/kg/day in two divided doses, not to exceed 1 g/day.
Untoward effects. Approximately 50% of patients are unable to tolerate
a single dose larger than 500 mg because of GI upset. The most
common reactions are anorexia, nausea and vomiting, gastric irritation,
and a variety of neurologic symptoms. Severe postural hypotension,
mental depression, drowsiness, and asthenia are common.
Convulsions and peripheral neuropathy are rare. Other reactions
referable to the nervous system include olfactory disturbances,
blurred vision, diplopia, dizziness, paresthesias, headache, restlessness,
and tremors. Pyridoxine (vitamin B 6
) relieves the neurologic
symptoms, and its concomitant administration is recommended.
Severe allergic skin rashes, purpura, stomatitis, gynecomastia, impotence,
menorrhagia, acne, and alopecia have also been observed. A
metallic taste also may be noted. Hepatitis has been associated with
the use of the ethionamide in ~5% of cases. Hepatic function should
be assessed at regular intervals in patients receiving the drug.
Para-Aminosalicylic Acid
Para-aminosalicylic acid (PAS), discovered by Lehman
in 1943, was the first effective treatment for TB.
AMINOSALICYLIC ACID
Mechanism of Action. PAS is a structural analog of para-aminobenzoic
acid, the substrate of dihydropteroate synthase (folP1/P2). As a
result, PAS is thought to be a competitive inhibitor folP1. However,
in vitro the inhibitory activity against folP1 is very poor. However,
mutation of the thymidylate synthase gene (thyA) results in resistance
to PAS, but only 37% of the PAS-resistant clinical isolates or
spontaneous mutants encode a mutation in thyA gene, or in any genes
encoding enzymes in the folate pathway or biosynthesis of thymine
nucleotides (Mathys et al., 2009). Unidentified actions of PAS likely
play more important roles in its anti-TB effects.
Antibacterial Activity. PAS is bacteriostatic. In vitro, most strains
of M. tuberculosis are sensitive to a concentration of 1 mg/L. It has
no activity against other bacteria.
Bacterial Resistance. Mutations in thyA gene lead to drug resistance
in a minority of drug-resistant isolates.
Absorption, Distribution, and Excretion. PAS oral bioavailability
is >90%. PAS pharmacokinetics are described by a one-compartment
model (Peloquin et al., 2001); see the PK values in Table 56–2. The
C max
increases 1.5-fold and AUC 1.7-fold with food compared to
fasting (Peloquin et al., 2001). These results mean that PAS should
be administered with food, which also greatly reduces gastric irritation.
Protein binding is 50-60%. PAS is N-acetylated in the liver to
N-acetyl PAS, a potential hepatotoxin. Over 80% of the drug is
excreted in the urine; >50% is in the form of the acetylated compound.
Excretion of PAS acid is reduced by renal dysfunction; thus the dose
must be reduced in renal dysfunction.
Therapeutic Uses. PAS is administered orally in a daily dose of 12 g.
The drug is best administered after meals, with the daily dose divided
into three equal portions. Children should receive 150-300 mg/kg/day
in 3-4 divided doses.
Untoward Effects. The incidence of untoward effects associated
with the use of PAS is ~10-30%. GI problems predominate and often
limit patient adherence. Hypersensitivity reactions to PAS are seen
in 5-10% of patients and manifest as skin eruptions, fever,
eosinophilia, and other hematological abnormalities.
Cycloserine
Cycloserine (SEROMYCIN) is D-4-amino-3-isoxazolidone. It
is a broad-spectrum antibiotic produced by Streptococcus
orchidaceous.
CYCLOSERINE
Mechanism of Action. Cycloserine and d-alanine are structural
analogs; thus cycloserine inhibits alanine racemase which converts
L-alanine to d-alanine and d-alanine: d-alanine ligase, stopping reactions
in which d-alanine is incorporated into bacterial cell-wall synthesis
(Anonymous, 2008b).
Antibacterial Activity. Cycloserine is a broad-spectrum antibiotic.
It inhibits M. tuberculosis at concentrations of 5-20 mg/L. It has
good activity against MAC, enterococci, E. coli, S. aureus, Nocardia
species, and Chlamydia.