General Description
White powder. Sublimes from 318°F.
Reactivity Profile
PYRAZINAMIDE(98-96-4) is a carbamate ester. Incompatible with strong acids and bases, and especially incompatible with strong reducing agents such as hydrides. May react with active metals or nitrides to produce flammable gaseous hydrogen. Incompatible with strongly oxidizing acids, peroxides, and hydroperoxides.
Air & Water Reactions
Water soluble.
Description
Pyrazinamide was synthesized in 1952, and it is the nitrogen-analog of nicotinamide. It
exhibits hepatotoxicity. Synonyms of this drug are dexambutol, miambutol, esnbutol, ebutol, and others.
Chemical Properties
Crystalline Solid
Definition
ChEBI: Pyrazinecarboxamide is a monocarboxylic acid amide resulting from the formal condensation of the carboxy group of pyrazinoic acid (pyrazine-2-carboxylic acid) with ammonia. A prodrug for pyrazinoic acid, pyrazinecarboxamide is used as part of multidrug regimens for the treatment of tuberculosis. It has a role as an antitubercular agent and a prodrug. It is a member of pyrazines, a N-acylammonia and a monocarboxylic acid amide.
Antimicrobial activity
It is principally active against actively metabolizing intracellular
bacilli and those in acidic, anoxic inflammatory lesions.
Activity against M. tuberculosis is highly pH dependent: at pH
5.6 the MIC is 8–16 mg/L, but it is almost inactive at neutral
pH. Other mycobacterial species, including M. bovis, are resistant.
Activity requires conversion to pyrazinoic acid by the
mycobacterial enzyme pyrazinamidase, encoded for by the
pncA gene, which is present in M. tuberculosis but not M. bovis.
A few resistant strains lack mutations in pncA, indicating alternative
mechanisms for resistance, including defects in transportation
of the agent into the bacterial cell.
Acquired resistance
Drug resistance is uncommon and cross-resistance to other
antituberculosis agents does not occur. Susceptibility testing
is technically demanding as it requires very careful control of
the pH of the medium, but molecular methods for detection
of resistance-conferring mutations are available.
Pharmaceutical Applications
Like isoniazid, pyrazinamide is a synthetic nicotinamide analog,
although its mode of action is quite distinct.
Biochem/physiol Actions
The active moiety of pyrazinamide is pyrazinoic acid (POA). POA is thought to disrupt membrane energetics and inhibit membrane transport function at acid pH in Mycobacterium tuberculosis. Iron enhances the antituberculous activity of pyrazinamide . Pyrazinamide and its analogs have been shown to inhibit the activity of purified FAS I.
Pharmacokinetics
Oral absorption: >90%
Cmax 20–22 mg/kg oral: 10–50 mg/L after 2 h
Plasma half-life: c. 9 h
Plasma protein binding: c. 50%
It readily crosses the blood–brain barrier, achieving CSF
concentrations similar to plasma levels. It is metabolized to
pyrazinoic acid in the liver and oxidized to inactive metabolites,
which are excreted in the urine, although about 70% of
an oral dose is excreted unchanged.
Pharmacology
Pyrazinamide is well absorbed from the GI tract and
is widely distributed throughout the body. It penetrates
tissues, macrophages, and tuberculous cavities and has
excellent activity on the intracellular organisms; its
plasma half-life is 9 to 10 hours in patients with normal
renal function. The drug and its metabolites are excreted
primarily by renal glomerular filtration.
Clinical Use
Pyrazinamide is an essential component of the multidrug
short-term therapy of tuberculosis. In combination
with isoniazid and rifampin, it is active against the
intracellular organisms that may cause relapse.
Clinical Use
Tuberculosis (a component of the early, intensive phase of short-course
therapy)
Side effects
Hepatotoxicity is the major concern in 15% of pyrazinamide
recipients. It also can inhibit excretion of urates,
resulting in hyperuricemia. Nearly all patients taking
pyrazinamide develop hyperuricemia and possibly acute
gouty arthritis. Other adverse effects include nausea,
vomiting, anorexia, drug fever, and malaise. Pyrazinamide
is not recommended for use during pregnancy.
Side effects
It is usually well tolerated. Moderate elevations of serum
transaminases occur early in treatment. Severe hepatotoxicity
is uncommon with standard dosage, except in patients with
pre-existing liver disease.
Its principal metabolite, pyrazinoic acid, inhibits renal
excretion of uric acid, but gout is extremely rare. An unrelated
arthralgia, notably of the shoulders and responsive to
analgesics, also occurs.
Other side effects include anorexia, nausea, mild flushing
of the skin and photosensitization.
Synthesis
Pyrazinamide, pyrazincarboxamide (34.1.11), is synthesized from quinoxaline (34.1.7) by reacting o-phenylendiamine with glyoxal. Oxidation of this compound
with sodium permanganate gives pyrazin-2,3-dicarboxylic acid (34.1.8). Decarboxylation
of the resulting product by heating gives pyrazin-2-carboxylic acid (34.1.9). Esterifying
the resulting acid with methanol in the presence of hydrogen chloride and further reaction
of this ester (34.1.10) with ammonia gives pyrazinamide.
Pyrazinamide was synthesized in 1952, and it is the nitrogen-analog of nicotinamide. It
exhibits hepatotoxicity. Synonyms of this drug are dexambutol, miambutol, esnbutol, ebutol, and others.
Metabolism
Pyrazinamide is metabolised mainly in the liver by
hydrolysis to the major active metabolite pyrazinoic acid,
which is subsequently hydroxylated to the major excretory
product 5-hydroxypyrazinoic acid.
It is excreted via the kidneys mainly by glomerular
filtration. About 70% of a dose appears in the urine
within 24 hours mainly as metabolites.
Purification Methods
The amide crystallises from water, EtOH or 1:1 hexane/EtOH in four modifications viz -form, -form, -form and form. [R. & S.rum Acta Cryst 28B 1677 1972, Beilstein 25 III/IV 772.]
