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

appear during the use of this drug, including euphoria, transient
impairment of memory, separation of ideas and reality, loss of selfcontrol,
and florid psychoses. The prophylactic administration of
pyridoxine prevents the development not only of peripheral neuritis,
as well as most other nervous system disorders in practically all
instances, even when therapy lasts as long as 2 years.
Patients may develop hypersensitivity to isoniazid. Hematological
reactions also may occur. Vasculitis associated with antinuclear
antibodies may appear during treatment but disappears when
the drug is stopped. Arthritic symptoms (back pain; bilateral proximal
interphalangeal joint involvement; arthralgia of the knees,
elbows, and wrists; and the “shoulder-hand” syndrome) have been
attributed to this agent.
Miscellaneous reactions associated with isoniazid therapy
include dryness of the mouth, epigastric distress, methemoglobinemia,
tinnitus, and urinary retention. In persons predisposed to pyridoxine-deficiency
anemia, the administration of isoniazid may result
in dramatic anemia. Treatment of the anemia with large doses of
vitamin B 6
gradually returns the blood count to normal. A druginduced
syndrome resembling systemic lupus erythematosus has
also been reported.
Isoniazid Overdose. Intentional isoniazid overdose occurs most
often in young women with concomitant psychiatric problems prescribed
isoniazid for latent TB (Sullivan et al., 1998). As little as 1.5 g
can be toxic. Isoniazid overdose has been associated with the clinical
triad of:
• seizures refractory to treatment with phenytoin and barbiturates
• metabolic acidosis with an anion gap that is resistant to treatment
with sodium bicarbonate
• coma
The common early symptoms appear within 0.5-3 hours of
ingestion and include ataxia, peripheral neuropathy, dizziness, and
slurred speech. The most dangerous are grand mal seizures and
coma, encountered when patients ingests ≥30 mg/kg of the drug.
Mortality in these circumstances is as high as 20%. Intravenous pyridoxine
is administered over 5-15 minutes on a gram-to-gram basis
with the ingested isoniazid. If the dose of ingested isoniazid is
unknown, then a pyridoxine dose of 70 mg/kg should be used. In
patients with seizures, benzodiazepines are utilized.
Isoniazid’s toxicity may be interpreted in terms of effects on
pyridoxine metabolism. Isoniazid binds to pyridoxal 5′-phosphate
to form isoniazid-pyridoxal hydrazones, thereby depleting neuronal
pyridoxal 5′-phosphate and interfering with pyridoxal phosphaterequiring
reactions, including the synthesis of the inhibitory neurotransmitter,
GABA. Decreased levels of GABA lead to cerebral
overexcitability and lowered seizure threshold. The antidote is
replenishment of pyridoxal 5′-phosphate.
Drug Interactions. Isoniazid is a potent inhibitor of CYP2C19,
CYP3A, and a weak inhibitor of CYP2D6 (Desta et al., 2001).
However, isoniazid induces CYP2E1. Drugs that are metabolized by
these enzymes will potentially be affected. Table 56–4, based on
work by Desta et al. (2001), is a summary of drugs that interact with
isoniazid via these mechanisms.
Ethambutol
Ethambutol hydrochloride (MYAMBUTOL) is a watersoluble
and heat-stable compound:
ETHAMBUTOL
Mechanism of Action. Ethambutol inhibits arabinosyl transferase
III, thereby disrupting the transfer of arabinose into arabinogalactan
biosynthesis, which in turn disrupts the assembly of mycobacterial
cell wall (Lewis, 1999). The arabinosyl transferases are encoded by
embAB genes.
Antibacterial Activity. Ethambutol has activity against a wide range
of mycobacteria but has no activity against any other genus. Ethambutol
MICs are 0.5-2 mg/L in clinical isolates of M. tuberculosis, ~0.8 mg/L
for M. kansasii, and 2-7.5 mg/L for M. avium (Heifets, 1991;
Table 56–4
Isoniazid-Drug Interactions via Inhibition and Induction of CYPs
CO-ADMINISTERED DRUG CYP ISOFORM ADVERSE EFFECTS
Acetaminophen CYP2E1 inhibition-induction Hepatotoxicity
Carbamazepine CYP3A inhibition Neurological toxicity
Diazepam CYP3A and CYP2C19 inhibition Sedation and respiratory depression
Ethosuximide CYP3A inhibition Psychotic behavior
Isoflurane and enflurane CYP2E1 induction Decreased effectiveness
Phenytoin CYP2C19 inhibition Neurological toxicity
Theophylline CYP3A inhibition Seizures, palpitation, nausea
Vincristine CYP3A inhibition Limb weakness and tingling
Warfarin CYP2C9 inhibition Possibility of increased bleeding
(single case reported)