Pyridin-4-carbons?urehydrazid Chemische Eigenschaften,Einsatz,Produktion Methoden
ERSCHEINUNGSBILD
WEISSES KRISTALLINES PULVER.
CHEMISCHE GEFAHREN
Zersetzung beim Erhitzen und Verbrennen unter Bildung giftiger Rauche mit Stickstoffoxiden.
ARBEITSPLATZGRENZWERTE
TLV nicht festgelegt (ACGIH 2005).
MAK nicht festgelegt (DFG 2005).
AUFNAHMEWEGE
Aufnahme in den K?rper durch Verschlucken.
INHALATIONSGEFAHREN
Verdampfung bei 20°C vernachl?ssigbar; eine gesundheitssch?dliche Partikelkonzentration in der Luft kann jedoch beim Dispergieren schnell erreicht werden, vor allem als Pulver.
WIRKUNGEN BEI KURZZEITEXPOSITION
WIRKUNGEN BEI KURZZEITEXPOSITION: M?glich sind Auswirkungen auf Nervensystem und Nieren mit nachfolgendem Orientierungsverlust, Teilnahmslosigkeit, Koma, metabolischer Azidose. Exposition in hoher Konzentration kann zum Tod führen. Exposition kann zu Bewusstlosigkeit führen.
WIRKUNGEN NACH WIEDERHOLTER ODER LANGZEITEXPOSITION
M?glich sind Auswirkungen auf Zentralnervensystem und Leber. Führt zu Gewebesch?den und Funktionsst?rungen.
LECKAGE
Verschüttetes Material in abdichtbaren Beh?ltern sammeln; falls erforderlich durch Anfeuchten Staubentwicklung verhindern. Reste sorgf?ltig sammeln. An sicheren Ort bringen. Pers?nliche Schutzausrüstung: Atemschutzger?t, P2-Filter für sch?dliche Partikel.
R-S?tze Betriebsanweisung:
R22:Gesundheitssch?dlich beim Verschlucken.
R38:Reizt die Haut.
R40:Verdacht auf krebserzeugende Wirkung.
R36/37/38:Reizt die Augen, die Atmungsorgane und die Haut.
S-S?tze Betriebsanweisung:
S37:Geeignete Schutzhandschuhe tragen.
S36/37/39:Bei der Arbeit geeignete Schutzkleidung,Schutzhandschuhe und Schutzbrille/Gesichtsschutz tragen.
S26:Bei Berührung mit den Augen sofort gründlich mit Wasser abspülen und Arzt konsultieren.
Beschreibung
Isoniazid, the hydrazide of isonicotinic acid was introduced into medical practice for treating tuberculosis in 1953. Isoniazid exhibits bactericidal action on Mycobacterium tuberculosis. It inhibits the synthesis of mycolic acid, an important component of the cell
membrane of mycobacteria. Mycolic acid is specific only to mycobacteria, and it is the
cause of the selective toxicity of the drug with respect to these microorganisms.
Mutants that are resistant to isoniazid are rarely seen in nature, and in a spontaneously
growing population of tuberculous bacillus there is approximately one mutant in every
105
–106 organisms. Large populations of microorganisms of the order 109
–1010 bacilli in
the pulmonary cavities contain a significant number of resistant mutants. If only isoniazid
is taken during treatment, an increased number of mutants will be observed and they will
eventually become the dominant phenotype. The transformation from sensitive to nonsensitive microorganisms during treatment is called secondary or acquired resistance, which
can originate over the course of a few weeks. Isoniazid is the most important drug for treating pulmonary and nonpulmonary forms of tuberculosis. It is active against both intracellular and extracellular organisms. In order to prevent secondary resistance, isoniazid
should be used with other effective drugs (usually rifampin). Synonyms of this drug are
tubazid, andrazide, niazid, piridizin, and many others.
Chemische Eigenschaften
white crystalline powder
Verwenden
Isoniazid is an antimicrobial used for the prevention of
tuberculosis infection or used concurrently with another agent
for the treatment of tuberculosis infection. Rifampin, pyrazinamide,
or both of these agents are commonly used with
isoniazid. Isoniazid is the only Food and Drug Administration
approved drug to treat latent tuberculosis in order to prevent it
from becoming active.
Indications
Isoniazid (isonicotinic acid hydrazide, or INH) is the
most active drug for the treatment of tuberculosis
caused by susceptible strains. It is a synthetic agent with
a structural similarity to that of pyridoxine.
Definition
ChEBI: A carbohydrazide obtained by formal condensation between pyridine-4-carboxylic acid and hydrazine.
Biologische Funktion
Its action is bactericidal against replicating organisms, but it appears to be only bacteriostatic at best against semidormant and dormant populations. After treatment with INH, M . tuberculosis loses its acid fastness, which may be interpreted as indicating that the drug interferes with cell wall development.
Antimicrobial activity
Susceptibility to isoniazid is virtually restricted to the M. tuberculosis
complex (MIC 0.01–0.2 mg/L). It is highly bactericidal
against actively replicating M. tuberculosis. Other mycobacteria
are resistant, except for some strains of M. xenopi (MIC 0.2 mg/L)
and a few strains of M. kansasii (MIC 1 mg/L).
Acquired resistance
Mutations in the katG gene, the inhA gene or its promoter
region, and in the intergenic region of the oxyR–ahpC locus
confer resistance to isoniazid. The relative
proportions of such mutations vary geographically and
are related to the distribution of the various lineages or superfamilies
of M. tuberculosis.
Isoniazid resistance is the commonest form of drug resistance
worldwide and the great majority of strains resistant to
another agent are also resistant to isoniazid.
Allgemeine Beschreibung
Odorless colorless or white crystals or white crystalline powder. Taste is slightly sweet at first and then bitter. pH (1% aqueous solution) 5.5-6.5. pH (5% aqueous solution) 6-8.
Air & Water Reaktionen
Sensitive to air and light. Absorbs insignificant amounts of moisture at 77°F at relative humidities up to approximately 90%. Water soluble. Dust can be explosive when suspended in air at specific concentrations.
Reaktivit?t anzeigen
Isoniazid is incompatible with chloral, aldehydes, iodine, hypochlorites and ferric salts. Isoniazid is also incompatible with oxidizers. Isoniazid may react with sugars and ketones. Isoniazid can react as a weak acid or a weak base. Isoniazid can be decomposed by oxidative and reductive reactions.
Brandgefahr
Isoniazid is combustible.
Pharmazeutische Anwendungen
One of a number of nicotinamide analogs found to have antituberculosis
activity, following the observation that nicotinamide
inhibited the replication of M. tuberculosis. It is soluble
in water. The dry powder is stable if protected from light. It is
a prodrug requiring oxidative activation by KatG, a mycobacterial
catalase–peroxidase enzyme.
Mechanism of action
Isoniazid is active against susceptible bacteria only when
they are undergoing cell division. Susceptible bacteria
may continue to undergo one or two divisions before
multiplication is arrested. Isoniazid can inhibit the synthesis
of mycolic acids, which are essential components of
mycobacterial cell walls.The mycobacterial enzyme catalase–
peroxidase KatG activates the administered isoniazid
to its biologically active form.The target sites for the
activated isoniazid action are acyl carrier protein AcpM
and Kas A, a β-ketoaceyl carrier protein synthetase that
blocks mycolic acid synthesis. Isoniazid exerts its lethal
effects at the target sites by forming covalent complexes.
Pharmakokinetik
Oral absorption: >95%
C
max 300 mg oral: 3–5 mg/L after 1–2 h
Plasma half-life: 0.5–1.5 h (rapid acetylators)
:
2–4 h (slow acetylators)
Volume of distribution: 0.6–0.8 L/kg
Plasma protein binding: Very low
Absorption and distribution
Isoniazid is almost completely absorbed from the gut and is well distributed. Absorption is impaired by aluminum hydroxide. Therapeutic concentrations are achieved in sputum and CSF. It crosses the placenta and is found in breast milk.
Metabolism
Isoniazid is extensively metabolized to a variety of pharmacologically inactive derivatives, predominantly by acetylation. As a result of genetic polymorphism, patients are divisible into rapid and slow acetylators. About 50% of Caucasians and Blacks, but 80–90% of Chinese and Japanese, are rapid acetylators. Acetylation status does not affect the efficacy of daily administered therapy. The rate of acetylation is reduced in chronic renal failure.
Excretion
Nearly all the dose is excreted in the urine within 24 h, as unchanged drug and metabolic products.
Pharmakologie
Isoniazid is water soluble and is well absorbed when
administered either orally or parenterally. Oral absorption
is decreased by concurrent administration of
aluminum-containing antacids.
Isoniazid does not bind to serum proteins; it diffuses
readily into all body fluids and cells, including the
caseous tuberculous lesions. The drug is detectable in
significant quantities in pleural and ascitic fluids, as well
as in saliva and skin. The concentrations in the central
nervous system (CNS) and cerebrospinal fluid are generally
about 20% of plasma levels but may reach close
to 100% in the presence of meningeal inflammation.
Isoniazid is acetylated to acetyl isoniazid by N-acetyltransferase,
an enzyme in liver, bowel, and kidney.
Individuals who are genetically rapid acetylators will have
a higher ratio of acetyl isoniazid to isoniazid than will slow
acetylators. Rapid acetylators were once thought to be
more prone to hepatotoxicity, but this is not proved. The
slow or rapid acetylation of isoniazid is rarely important
clinically, although slow inactivators tend to develop peripheral
neuropathy more readily. Metabolites of isoniazid
and small amounts of unaltered drug are excreted in
the urine within 24 hours of administration.
Clinical Use
Isonicotinic acid hydrazide, isonicotinyl hydrazide, or INH(Nydrazid) occurs as a nearly colorless crystalline solid thatis very soluble in water. It is prepared by reacting the methylester of isonicotinic acid with hydrazine.
Isoniazid is a remarkably effective agent and continuesto be one of the primary drugs (along with rifampin, pyrazinamide,and ethambutol) for the treatment of tuberculosis.It is not, however, uniformly effective against all formsof the disease. The frequent emergence of strains of the tuberclebacillus resistant to isoniazid during therapy wasseen as the major shortcoming of the drug. This problemhas been largely, but not entirely, overcome with the use ofcombinations.
The activity of isoniazid is manifested on the growing tuberclebacilli and not on resting forms. Its action, which isconsidered bactericidal, is to cause the bacilli to lose lipidcontent by a mechanism that has not been fully elucidated.The most generally accepted theory suggests that the principaleffect of isoniazid is to inhibit the synthesis of mycolicacids, high–molecular-weight, branched β-hydroxyfatty acids that constitute important components of the cellwalls of mycobacteria.
Nebenwirkungen
The incidence and severity of adverse reactions to isoniazid
are related to dosage and duration of therapy.
Isoniazid-induced hepatitis and peripheral neuropathy
are two major untoward effects.
Environmental Fate
Isoniazid is a colorless, odorless, white crystalline powder that
is slowly oxidized by exposure to air. It undergoes degradation
upon prolonged exposure to light. Isoniazid has a solubility of
1 g per 8 ml water, 1 g per 50 ml ethanol, and it is slightly
soluble in chloroform and very slightly soluble in ether. A 10%
solution of isoniazid has a pH of 6.0–8.0.
Stoffwechsel
Isoniazid is extensively metabolized to inactive metabolites. The major metabolite is N-acetylisoniazid. The enzyme responsible for acetylation, cytosolic N-acetyltransferase, is produced under genetic control in an inherited autosomal fashion. Individuals who possess high concentrations of the enzyme are referred to as rapid acetylators, whereas those with low concentrations are slow acetylators. This may result in a need to adjust the dosage for fast acetylators. The N-acetyltransferase is located primarily in the liver and small intestine. Other metabolites include isonicotinic acid, which is found in the urine as a glycine conjugate, and hydrazine. Isonicotinic acid also may result from hydrolysis of acetylisoniazid, but in this case, the second product of hydrolysis is acetylhydrazine. Acetylhydrazine is acetylated by N-acetyltransferase to the inactive diacetyl product. This reaction occurs more rapidly in rapid acetylators. The formation of acetylhydrazine is significant in that this compound has been associated with the hepatotoxicity, which may occur during INH therapy.
l?uterung methode
Crystallise isoniazide from 95% EtOH and dry it in a vacuum. [Beilstein 22 III/IV 545, 22/2 V 219.]
Vorsichtsma?nahmen
High isoniazid plasma levels inhibit phenytoin metabolismand potentiate phenytoin toxicity when the twodrugs are coadministered. The serum concentrations ofphenytoin should be monitored, and the dose should beadjusted if necessary.
Pyridin-4-carbons?urehydrazid Upstream-Materialien And Downstream Produkte
Upstream-Materialien
Downstream Produkte
