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

pyrazinamide was administered for durations much longer than the
current 2 months. Elevations of plasma alanine/aspartate aminotransferases
are the earliest abnormalities produced by the drug.
Regimens employed currently (15-30 mg/kg/day) are much safer.
Prior to pyrazinamide administration, all patients should undergo
studies of hepatic function, and these studies should be repeated at
frequent intervals during the entire period of treatment. If evidence
of significant hepatic damage becomes apparent, therapy must be
stopped. Pyrazinamide should not be given to individuals with
hepatic dysfunction unless this is absolutely unavoidable.
Pyrazinamide inhibits excretion of urate, resulting in hyperuricemia
in nearly all patients, and may cause acute episodes of gout.
Other untoward effects observed with pyrazinamide include arthralgias,
anorexia, nausea and vomiting, dysuria, malaise, and fever. In
the U.S., the use of pyrazinamide is not approved during pregnancy
because of inadequate data on teratogenicity.
There are minimal data on pyrazinamide overdose, and no
antidote has been studied.
Isoniazid
Isoniazid (NYDRAZID, others) is a primary drug for the
chemotherapy of tuberculosis. All patients infected with
isoniazid-sensitive strains of the tubercle bacillus
should receive the drug if they can tolerate it. The use
of combination therapy (isoniazid + pyrazinamide +
O
Isoniazid
(pro-drug)
C
N
H
N
In host
In bacillus
KatG
NH 2
AcCoA
NAT2
O C R
CoA
rifampin) provides the basis for “short-course” therapy
and improved remission rates.
Chemistry. Isoniazid (Isonicotinic acid hydrazide), also called INH,
is a small water-soluble molecule (MW = 137) that is structurally
related to pyrazinamide (see Figure 56–3).
Mechanism of Action. Isoniazid enters bacilli by passive
diffusion. The drug is not directly toxic to the
bacillus but must be activated to its toxic form within
the bacillus by KatG, a multifunctional catalaseperoxidase.
KatG catalyzes the production from isoniazid
of an isonicotinoyl radical that subsequently
interacts with mycobacterial NAD and NAPD to produce
a dozen adducts (Argyrou et al., 2007). One of
these, a nicotinoyl-NAD isomer, inhibits the activities
of enoyl acyl carrier protein reductase (InhA) and
β-ketoacyl acyl carrier protein synthase (KasA).
Inhibition of these enzymes inhibits synthesis of
mycolic acid, an essential component of the mycobacterial
cell wall, leading to bacterial cell death. Another
adduct, a nicotinoyl-NADP isomer, potently inhibits
(K i
<1nM) mycobacterial dihydrofolate reductase,
thereby interfering with nucleic acid synthesis (Argyrou
et al., 2006). See Figure 56–3.
N-acetyl isoniazid
(major metabolite)
O
C
N
H
N
N
H
O
C
CH 3
Renal excretion
R
N
C
O
1555
CHAPTER 56
CHEMOTHERAPY OF TUBERCULOSIS, MYCOBACTERIUM AVIUM COMPLEX DISEASE, AND LEPROSY
N
spontaneous
C
O
NH 2
N
Nicotinoyl radical
(“activated” drug)
C
NAD +
NADP +
O
NH 2
N
Nicotinoyl-NAD adduct
(inhibitor of InhA)
Nicotinoyl-NADP adduct
(inhibitor of DHFR)
Figure 56–3. Metabolism and activation of isoniazid. The pro-drug isoniazid is metabolized in humans by NAT2 isoforms to its principal
metabolite, N-acetyl isoniazid, which is excreted by the kidney. Isoniazid diffuses into mycoplasma where it is “activated” by
KatG (oxidase/peroxidase) to the nicotinoyl radical, which reacts spontaneously with NAD + or NADP + to produce adducts that inhibit
important enzymes in cell-wall and nucleic acid synthesis. DHFR, dihydrofolate reductase.