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

1554 Rifamycin Overdose. Rifampin overdose is uncommon and has
been poorly studied. Doses of up to 12 g have produced serum
rifampin concentrations of 400 mg/L with no change in the serum
elimination rate. The most prominent symptoms are the orange
discoloration of skin, fluids, and mucosal surfaces, leading to the
term red-man syndrome. Overdose can be life-threatening; treatment
consists of supportive measures; there is no antidote.
Drug Interactions. Because rifampin potently induces CYPs 1A2,
2C9, 2C19, and 3A4, its administration results in a decreased t 1/2
for a
number of compounds, including HIV protease and non-nucleoside
reverse transcriptase inhibitors, digitoxin, digoxin, quinidine, disopyramide,
mexiletine, tocainide, ketoconazole, propranolol, metoprolol,
clofibrate, verapamil, methadone, cyclosporine, corticosteroids,
coumarin anticoagulants, theophylline, barbiturates, oral contraceptives,
halothane, fluconazole, and the sulfonylureas. It leads to therapeutic
failure of these agents, with potentially catastrophic
consequences. Prior to putting a patient on rifampin, therefore, all
the patient’s medications should be examined for potential interactions.
Rifabutin is a less potent inducer of CYPs than rifampin,
both in terms of potency and number of CYP enzymes involved;
however, rifabutin does induce hepatic microsomal enzymes and
decreases the t 1/2
of zidovudine, prednisone, digitoxin, quinidine, ketoconazole,
propranolol, phenytoin, sulfonylureas, and warfarin. It
has less effect than rifampin on serum levels of indinavir and nelfinavir.
Compared to rifabutin and rifampin, the CYP-inducing
effects of rifapentine are intermediate.
SECTION VII
CHEMOTHERAPY OF MICROBIAL DISEASES
Pyrazinamide
Pyrazinamide is the synthetic pyrazine analog of nicotinamide.
Pyrazinamide is also known as pyrazinoic acid
amide, pyrazine carboxylamide, and pyrazinecarboxamide.
PYRAZINAMIDE
Mechanism of Action. Pyrazinamide is “activated” by acidic conditions.
Initially it was assumed that the acidic conditions under which
pyrazinamide works were inside macrophage phagosomes. However,
pyrazinamide may not be very effective within macrophages; rather,
the acidic conditions for activation may be at the edges of necrotic
TB cavities where inflammatory cells produce lactic acid (Blumberg
et al., 2003).
Mycobacterium tuberculosis nicotinamidase, or pyrazinaminidase
deaminates pyrazinamide to pyrazinoic acid (POA - ),
which is then transported to the extracellular milieu by an efflux
pump (Zhang et al., 1999). In an acidic extracellular milieu, a fraction
of POA − is protonated to POAH, a more lipid-soluble form that
enters the bacillus. The Henderson-Hasselbalch equilibrium
(Chapter 2) progressively favors the formation of POAH and its equilibration
across membrances as the pH of the extracellular medium
declines toward the pK a
of pyrazinoic acid, 2.9, a condition that also
enhances microbial killing (Zhang et al., 2002). Although the actual
mechanism of microbial kill is still unclear, three mechanisms have
been proposed (Zhang et al., 2003; Zimhony et al., 2000):
• inhibition of fatty acid synthase type I leading to interference
with mycolic acid synthesis
• reduction of intracellular pH
• disruption of membrane transport by HPOA
Antibacterial Activity. Pyrazinamide exhibits antimicrobial activity
in vitro only at acidic pH. At pH of 5.8-5.95, 80-90% of clinical
isolates have an MIC of ≤100 mg/L (Salfinger and Heifets,
1988).
Mechanisms of Resistance. Pyrazinamide-resistant M. tuberculosis
have pyrazinamidase with reduced affinity for pyrazinamide. This
reduced affinity decreases the conversion of pyrazinamide to POA.
Single point mutations in the pncA gene are encountered in up to
70% of resistant clinical isolates. The mechanisms contributing to
resistance in 30% of resistant clinical isolates is unclear.
Absorption, Distribution, and Excretion. Pyrazinamide oral
bioavailability is >90%. Pharmacokinetics are best described by a
one-compartment model. GI absorption segregates patients into two
groups: fast absorbers (56%) with an absorption rate constant of
3.56/hour and slow absorbers (44%) with an absorption rate of
1.25/hour (Wilkins et al., 2006). The drug is concentrated 20-fold in
lung epithelial lining fluid (Conte et al., 2000). Pyrazinamide is
metabolized by microsomal deamidase to POA and subsequently
hydroxylated to 5-hydroxy-POA, which is then excreted by the kidneys.
CL (clearance) and V d
(volume of distribution) increase with
patient mass (0.5 L/hour and 4.3 L for every 10 kg above 50 kg),
and V d
is larger in males (by 4.5 L) (see Table 56–2) This has several
implications: The t 1/2
of pyrazinamide will vary considerably
based on weight and gender, and the AUC 0-24
will decrease with
increase in weight for the same dose (same mg drug/kg body
weight). Pyrazinamide clearance is reduced in renal failure; therefore,
the dosing frequency is reduced to three times a week at low
glomerular filtration rates. Hemodialysis removes pyrazinamide;
therefore, the drug needs to be re-dosed after each session of
hemodialysis (Malone et al., 1999b).
Microbial Pharmacokinetics-Pharmacodynamics. Pyrazinamide’s
sterilizing effect is closely linked to AUC 0-24
/MIC (Gumbo et al.,
2008). However, resistance suppression is linked to the fraction of
time that C P
persists above MIC (T > MIC). Because patient weight
impacts both SCL and volume, both AUC and t 1/2
will be impacted
by high weight. Clinical trial simulations that account for patient
weight reveal that optimal AUC 0-24
/MIC and T > MIC are likely to
be achieved only by doses much higher than the currently recommended
15-30 mg/kg/day (Gumbo et al., 2008). The safety of such
higher doses in actual patients is unclear.
Therapeutic Uses. The co-administration of pyrazinamide with isoniazid
or rifampin has led to a one-third reduction in the duration of
anti-TB therapy, and a two-thirds reduction in TB relapse. This led
to reduction in length of therapy to 6 months, producing the current
“short course” chemotherapy. Pyrazinamide is administered at an
oral dose of 15-30 mg/kg/day.
Untoward Effects. Injury to the liver is the most serious side effect
of pyrazinamide. When a dose of 40-50 mg/kg is administered orally,
signs and symptoms of hepatic disease appear in ~15% of patients,
with jaundice in 2-3% and death due to hepatic necrosis in rare
instances. However, these rates were determined in an era when