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.
Isoniazid is an antibiotic that acts as a prodrug, being converted by bacterial catalase-peroxidases to form isonicotinic acyl-NADH complex, which inhibits mycolic acid biosynthesis. It is effective against several species of Mycobacterium, including M. tuberculosis.
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.
For the treatment of all forms of tuberculosis in which organisms are susceptible.
antibacterial, tuberculostatic
Antibiotic for treatment of Mycobacterium tuberculosis, inhibits mycolic acid biosynthesis. Metabolized by hepatic N-acetyltransferase (NAT) and cytochrome P450 2E1 (CYP2E1) to form hepatotoxins. Sele
ctively induces expression of CYP2E1. Reversibly inhibits CYP2C19 and CYP3A4 activities, and mechanistically inactivates CYP1A2, CYP2A6, CYP2C19 and CYP3A4 at clinically relevant concentrations. Antib
acterial (tuberculostatic).
ChEBI: A carbohydrazide obtained by formal condensation between pyridine-4-carboxylic acid and hydrazine.
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.
4 parts of 4-cyanopyridine in 12 parts of water were reacted with 4 parts of
hydrazine hydrate in the presence of 0.08 part of sodium hydroxide at 100°C
under reflux for 7 hours. The product, after filtration and evaporation to
dryness, was crystallized from ethanol. The yield of isonicotinyl hydrazide
amounted to 3.27 parts which is 62% of the theoretical.
Inh (Novartis); Nydrazid (Bristol-Myers
Squibb); Nydrazid (Sandoz); Rimifon (Roche).
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.
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).
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.
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.
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.
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.
Isoniazid is combustible.
Pharmaceutical Applications
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.
Antibiotic for treatment of Mycobacterium tuberculosis, inhibits mycolic acid biosynthesis. Metabolized by hepatic N-acetyltransferase (NAT) and cytochrome P450 2E1 (CYP2E1) to form hepatotoxins. Selectively induces expression of CYP2E1. Reversibly inhibits CYP2C19 and CYP3A4 activities, and mechanistically inactivates CYP1A2, CYP2A6, CYP2C19 and CYP3A4 at clinically relevant concentrations.
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.
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.
Oral absorption: >95%
Cmax 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.
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.
Isoniazid is among the safest and most active mycobactericidal
agents. It is considered the primary drug for
use in all therapeutic and prophylactic regimens for susceptible
tuberculosis infections. It is also included in the
first-line drug combinations for use in all types of tuberculous
infections. Isoniazid is preferred as a single
agent in the treatment of latent tuberculosis infections
in high-risk persons having a positive tuberculin skin reaction
with no radiological or other clinical evidence of
tuberculosis. Mycobacterium kansasii is usually susceptible
to isoniazid, and it is included in the standard multidrug
treatment regimen.
Tuberculosis (intensive and continuation phases)
Prevention of primary tuberculosis in close contacts and reactivation
disease in infected but healthy persons (monotherapy)
Toxic effects are unusual on recommended doses and are
more frequent in slow acetylators. Many side effects are neurological,
including restlessness, insomnia, muscle twitching
and difficulty in starting micturition. More serious but less
common neurological side effects include peripheral neuropathy,
optic neuritis, encephalopathy and a range of psychiatric
disorders, including anxiety, depression and paranoia.
Neurotoxicity is usually preventable by giving pyridoxine
(vitamin B6) 10 mg per day. Pyridoxine should be given
to patients with liver disease, pregnant women, alcoholics,
renal dialysis patients, HIV-positive patients, the malnourished
and the elderly. Encephalopathy, which has been reported in
patients on renal dialysis, may not be prevented by, or respond
to, pyridoxine, but usually resolves on withdrawal of isoniazid.
Isoniazid-related hepatitis occurs in about 1% of patients
receiving standard short-course chemotherapy. The incidence
is unaffected by acetylator status. It is more common in those
aged over 35 years and preventive isoniazid monotherapy
should be used with care in older people.
Less common side effects include arthralgia, a ‘flu’-like
syndrome, hypersensitivity reactions with fever, rashes and,
rarely, eosinophilia, sideroblastic anemia, pellagra (which
responds to treatment with nicotinic acid) and hemolysis in
patients with glucose-6-phosphate dehydrogenase deficiency.
It exacerbates acute porphyria and induces antinuclear antibodies,
but overt systemic lupus erythematosus is rare.
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.
Isoniazid, isonicotinic acid hydrazide (34.1.1), is synthesized by reacting ethyl
ester of isonicotinic acid with hydrazine.
Veterinary Drugs and Treatments
Isoniazid (INH) is sometimes used for chemoprophylaxis in small
animals in households having a human with tuberculosis. It potentially
can be used in combination with other antimycobacterial
drugs to treat infections of M. bovis or M. tuberculosis in dogs or
cats. But because of the public health risks, particularly in the face of
increased populations of immunocompromised people, treatment
of mycobacterial (M. bovis, M. tuberculosis) infections in domestic
or captive animals is controversial. In addition, INH has a narrow
therapeutic index and toxicity is a concern (see Adverse Effects).
In humans, isoniazid (INH) is routinely used alone to treat latent
tuberculosis infections (positive tuberculin skin test) and in
combination with other antimycobacterial agents to treat active
disease.
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.
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.
Crystallise isoniazide from 95% EtOH and dry it in a vacuum. [Beilstein 22 III/IV 545, 22/2 V 219.]
Isoniazid causes toxicity by altering the metabolism of pyridoxine
and creating a functional deficiency. Pyridoxine is
needed for transamination, transketolization, decarboxylation,
and biotransformation reactions. This occurs through three processes: (1) isoniazid metabolites form complexes with pyridoxine
increasing its urinary excretion with increasing doses; (2)
isoniazid metabolites disrupt the conversion of pyridoxine to its
active form, pyridoxine-50-phosphokinase; and (3) metabolites
directly inactivate pyridoxal-50-phosphate.
Isoniazid-induced seizures are thought to be caused by the
depletion of gamma-aminobutyric acid (GABA). GABA is the
primary inhibitory neurotransmitter in the central nervous
system that requires the cofactor pyridoxal-50-phosphate for its
synthesis from glutamate. Prolonged seizures commonly result
in plasma lactic acid accumulation that can lead to an anion
gap metabolic acidosis. Isoniazid may worsen the severity of
acidosis by inhibiting the production of nicotinamideadensosine
dinucleotide (NAD), a cofactor necessary for the
conversion of lactate to pyruvate. Long-term exposure to
isoniazid therapy commonly causes peripheral neuropathy due
to pyridoxine deficiency, and may induce pellagra, a niacin
deficiency disorder. Niacin requires the cofactor pyridoxal-50-
phosphate for its production from tryptophan.
The exact mechanism of isoniazid-induced hepatotoxicity is
unknown. However, it is thought to involve an idiopathic
autoimmune mechanism or result from direct hepatic injury
from isoniazid or its metabolites. The metabolite thought to be
responsible is acetyl hydrazine, produced from isoniazid
hydrolysis via cytochrome P450 (CYP)2E1. Persons with the
CYP2E1c1/c1 genotype may be more susceptible to hepatotoxicity.
The role acetylator status plays in hepatotoxicity
continues to be debated, but it is currently thought that slow
acetylators are at greater risk. Other risk factors include
increasing age, chronic isoniazid overdose, comorbid conditions
such as malnutrition, pregnancy, diabetes, HIV, renal
dysfunction, hepatic dysfunction, alcoholism, and concomitant
use of enzyme inducing drugs.
Other enzymes inhibited by isoniazid include the cytochrome
P450 mixed function oxidases, monoamine oxidase,
glutamate decarboxylase, and histaminase. The consequences
of these extensive enzymatic disturbances are mood elevation,
decreased central nervous system GABA levels, depressed catecholamine
synthesis, defects in glucose and fatty acid oxidation,
and impaired metabolism of other drugs. Important drug
interactions include those with carbamazepine, phenytoin,
rifampin, theophylline, valproate, and warfarin. Isoniazid is
also a weak monoamine oxidase inhibitor, and serotonin
syndrome and tyramine reactions to foods causing flushing,
tachycardia, and hypertension are reported.
Isoniazid does cross the placenta and enters the fetal
compartment; however, it has been determined to not be
a human teratogen in studies. In acute toxicity, fetal deformities
have been reported.
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.
[1] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2015, vol. 54B, # 10, p. 1260 - 1274
[2] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 6, p. 1532 - 1537
[3] Patent: US2015/210679, 2015, A1. Location in patent: Paragraph 0091
[4] Patent: US2016/214969, 2016, A1. Location in patent: Paragraph 0076-0077
[5] Patent: CN105481765, 2016, A. Location in patent: Paragraph 0030; 0031; 0032
