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Isoniazid

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Isoniazid
Clinical data
Trade namesHydra, Hyzyd, Isovit, others
Other namesisonicotinic acid hydrazide, isonicotinyl hydrazine, INH, INAH, INHA
AHFS/Drugs.comMonograph
MedlinePlusa682401
License data
Pregnancy
category
Routes of
administration		By mouth,intramuscular,intravenous
ATC code
Legal status
Legal status
Pharmacokineticdata
Protein bindingVery low (0–10%)
Metabolismliver; CYP450: 2C19, 3A4 inhibitor
Eliminationhalf-life0.5–1.6h (fast acetylators), 2-5h (slow acetylators)
Excretionurine (primarily), feces
Identifiers
  • Pyridine-4-carbohydrazide
CAS Number
PubChemCID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
NIAID ChemDB
CompTox Dashboard(EPA)
ECHA InfoCard100.000.195Edit this at Wikidata
Chemical and physical data
FormulaC6H7N3O
Molar mass137.142g·mol−1
3D model (JSmol)
  • C1=CN=CC=C1C(=O)NN
  • InChI=1S/C6H7N3O/c7-9-6(10)5-1-3-8-4-2-5/h1-4H,7H2,(H,9,10)checkY
  • Key:QRXWMOHMRWLFEY-UHFFFAOYSA-NcheckY
(verify)

Isoniazid,also known asisonicotinic acid hydrazide(INH), is anantibioticused for thetreatment of tuberculosis.[4]For active tuberculosis, it is often used together withrifampicin,pyrazinamide,and eitherstreptomycinorethambutol.[5]For latent tuberculosis, it is often used alone.[4]It may also be used foratypical types of mycobacteria,such asM. avium,M. kansasii,andM. xenopi.[4]It is usually taken by mouth, but may be used byinjection into muscle.[4]

History

[edit]

First synthesis was described in 1912.[6]A. Kachugin invented the drug against tuberculosis under name Tubazid in 1949. Three pharmaceutical companies unsuccessfully attempted to patent the drug at the same time,[7]the most prominent one being Roche, which launched its version, Rimifon, in 1952.[8]

The drug was first tested atMany Farms,aNavajocommunity inArizona,due to the Navajo reservation's tuberculosis problem and because the population had not previously been treated withstreptomycin,the main tuberculosis treatment at the time.[9]The research was led byWalsh McDermott,an infectious disease researcher with an interest in public health, who had previously taken isoniazid to treat his own tuberculosis.[10]

Isoniazid and a related drug,iproniazid,were among the first drugs to be referred to asantidepressants.[11]Psychiatric use stopped in 1961 following reports of hepatotoxicity. Use against tuberculosis continued, as isoniazid's effectiveness against the disease outweighs its risks.[12]

It is on theWorld Health Organization's List of Essential Medicines.[13]The World Health Organization classifies isoniazid as critically important for human medicine.[14]Isoniazid is available as ageneric medication.[4]

Medical uses

[edit]

Tuberculosis

[edit]

Isoniazid is often used to treat latent and active tuberculosis infections. In persons with isoniazid-sensitiveMycobacterium tuberculosisinfection, drug regimens based on isoniazid are usually effective when persons adhere to the prescribed treatment. However, in persons with isoniazid-resistantMycobacterium tuberculosisinfection, drug regimens based on isoniazid have a high rate of failure.[15]

Isoniazid has been approved as prophylactic therapy for the following populations:

  • People with HIV infection and a PPD (purified protein derivative) reaction of at least 5 mm induration
  • Contacts of people with tuberculosis and who have a PPD reaction at least 5 mm induration
  • People whose PPD reactions convert from negative to positive in a two-year period – at least 10 mm induration for those up to 35 years of age, and at least 15 mm induration for those at least 35 years old
  • People with pulmonary damage on their chest X-ray that is likely to be due to healed tuberculosis and also have a PPD reaction at least 5 mm induration
  • Injection drug users whose HIV status is negative who have a PPD reaction at least 10 mm induration
  • People with a PPD of greater than or equal to 10 mm induration who are foreign-born from high prevalence geographical regions, low-income populations, and patients residing in long-term facilities[16][17]

Isoniazid can be used alone or in combination withRifampinfor treatment of latent tuberculosis, or as part of a four-drug regimen for treatment of active tuberculosis.[18]The drug regimen typically requires daily or weekly oral administration for a period of three to nine months, often underDirectly Observed Therapy(DOT) supervision.[18]

Non-tuberculous mycobacteria

[edit]

Isoniazid was widely used in the treatment ofMycobacterium aviumcomplexas part of a regimen including rifampicin and ethambutol.[19]Evidence suggests that isoniazid prevents mycolic acid synthesis inM. aviumcomplex as inM. tuberculosis[20]and although this is not bactericidal toM. aviumcomplex, it greatly potentiates the effect of rifampicin. The introduction of macrolides led to this use greatly decreasing. However, since rifampicin is broadly underdosed inM. aviumcomplex treatment, this effect may be worth re-investigating.[21]

Special populations

[edit]

It is recommended that women with active tuberculosis who are pregnant or breastfeeding take isoniazid. Preventive therapy should be delayed until after giving birth.[22]Nursing mothers excrete a relatively low and non-toxic concentration of INH in breast milk, and their babies are at low risk for side effects. Both pregnant women and infants being breastfed by mothers taking INH should takevitamin B6in itspyridoxineform to minimize the risk of peripheral nerve damage.[23] Vitamin B6 is used to prevent isoniazid-induced B6 deficiency and neuropathy in people with a risk factor, such as pregnancy, lactation, HIV infection, alcoholism, diabetes, kidney failure, or malnutrition.[24]

People with liver dysfunction are at a higher risk for hepatitis caused by INH, and may need a lower dose.[22]

Levels of liver enzymes in the bloodstream should be frequently checked in daily alcohol drinkers, pregnant women, IV drug users, people over 35, and those who have chronic liver disease, severe kidney dysfunction, peripheral neuropathy, or HIV infection since they are more likely to develop hepatitis from INH.[22][25]

Side effects

[edit]

Up to 20% of people taking isoniazid experienceperipheral neuropathywhen taking daily doses of 6 mg/kg of body weight or higher.[26]Gastrointestinal reactions include nausea and vomiting.[16]Aplastic anemia,thrombocytopenia,andagranulocytosisdue to lack of production of red blood cells, platelets, and white blood cells by the bone marrow respectively, can also occur.[16]Hypersensitivity reactions are also common and can present with amaculopapularrash and fever.[16]Gynecomastiamay occur.[18]

Asymptomatic elevation of serum liver enzyme concentrations occurs in 10% to 20% of people taking INH, and liver enzyme concentrations usually return to normal even when treatment is continued.[27]Isoniazid has a boxed warning for severe and sometimes fatal hepatitis, which is age-dependent at a rate of 0.3% in people 21 to 35 years old and over 2% in those over age 50.[16][28]Symptoms suggestive of liver toxicity include nausea, vomiting, abdominal pain, dark urine, right upper quadrant pain, and loss of appetite.[16]Black and Hispanic women are at higher risk for isoniazid-induced hepatotoxicity.[16]When it happens, isoniazid-induced liver toxicity has been shown to occur in 50% of patients within the first 2 months of therapy.[29]

Some recommend that liver function should be monitored carefully in all people receiving it,[22]but others recommend monitoring only in certain populations.[27][30][31]

Headache, poor concentration, weight gain, poor memory, insomnia, and depression have all been associated with isoniazid use.[32]All patients and healthcare workers should be aware of these serious side effects, especially if suicidal ideation or behavior are suspected.[32][33][34]

Isoniazid is associated withpyridoxine(vitamin B6) deficiency because of its similar structure. Isoniazid is also associated with increased excretion of pyridoxine. Pyridoxal phosphate (a derivative of pyridoxine) is required for δ-aminolevulinic acid synthase,the enzyme responsible for the rate-limiting step in heme synthesis. Therefore, isoniazid-induced pyridoxine deficiency causes insufficient heme formation in early red blood cells, leading tosideroblastic anemia.[24]

Isoniazid was found to significantly elevate the in vivo concentration ofGABAandhomocarnosinein a single subject viamagnetic resonance spectroscopy.[35]

Drug interactions

[edit]

People taking isoniazid and acetaminophen are at risk of acetaminophen toxicity. Isoniazid is thought to induce a liver enzyme which causes a larger amount of acetaminophen to be metabolized to a toxic form.[36][37]

Isoniazid decreases the metabolism of carbamazepine, thus slowing down its clearance from the body. People taking carbamazepine should have their carbamazepine levels monitored and, if necessary, have their dose adjusted accordingly.[38]

It is possible that isoniazid may decrease the serum levels of ketoconazole after long-term treatment. This is seen with the simultaneous use of rifampin, isoniazid, and ketoconazole.[39]

Isoniazid may increase the amount of phenytoin in the body. The doses of phenytoin may need to be adjusted when given with isoniazid.[40][41]

Isoniazid may increase the plasma levels oftheophylline.There are some cases of theophylline slowing down isoniazid elimination. Both theophylline and isoniazid levels should be monitored.[42]

Valproatelevels may increase when taken with isoniazid. Valproate levels should be monitored and its dose adjusted if necessary.[40]

Mechanism of action

[edit]

Isoniazid is aprodrugthat inhibits the formation of themycobacterialcell wall. Isoniazid must be activated by KatG, a bacterial catalase-peroxidase enzyme inMycobacterium tuberculosis.[43]KatG catalyzes the formation of the isonicotinic acyl radical, which spontaneously couples withNADHto form the nicotinoyl-NAD adduct. This complex binds tightly to theenoyl-acyl carrier protein reductaseInhA, thereby blocking the natural enoyl-AcpM substrate and the action offatty acid synthase.This process inhibits the synthesis ofmycolic acids,which are required components of themycobacterialcell wall. A range of radicals are produced by KatG activation of isoniazid, includingnitric oxide,[44]which has also been shown to be important in the action of another antimycobacterial prodrugpretomanid.[45]

Isoniazid (INH) is activated by KatG to the isonicotinic acyl radical, which subsequently reacts with NAD to form the isonicotinic acyl-NADH complex.

Isoniazid isbactericidalto rapidly dividingmycobacteria,but isbacteriostaticif the mycobacteria are slow-growing.[46]It inhibits thecytochrome P450 systemand hence acts as a source of free radicals.[47]

Isoniazid is a mild non-selectivemonoamine oxidase inhibitor(MAO-I).[48]It inhibitsdiamine oxidasemore strongly. These two actions are possible explanations for its antidepressant action[49]as well as its ability to cause mania.[12]

Metabolism

[edit]

Isoniazid reaches therapeutic concentrations in serum,cerebrospinal fluid,and withincaseous granulomas.It is metabolized in the liver viaacetylationinto acetylhydrazine. Two forms of the enzyme are responsible for acetylation, so some patients metabolize the drug more quickly than others. Hence, thehalf-lifeisbimodal,with "slow acetylators" and "fast acetylators". A graph of number of people versus time shows peaks at one and three hours. The height of the peaks depends on the ethnicities of the people being tested. The metabolites are excreted in the urine. Doses do not usually have to be adjusted in case ofrenal failure.[citation needed]


Preparation

[edit]

Isoniazid is anisonicotinic acidderivative.It is manufactured using4-cyanopyridineandhydrazine hydrate.[50]In another method, isoniazid was claimed to have been made fromcitric acidstarting material.[51]

It can in theory be made frommethyl isonicotinate,which is labelled asemiochemical.

Brand names

[edit]

Hydra, Hyzyd, Isovit, Laniazid, Nydrazid, Rimifon, and Stanozide.[52]

Other uses

[edit]

Chromatography

[edit]

Isonicotinic acid hydrazide is also used inchromatographyto differentiate between various degrees ofconjugationinorganic compoundsbarring theketonefunctional group.[53]The test works by forming ahydrazonewhich can be detected by itsbathochromic shift.[citation needed]

Dogs

[edit]

Isoniazid may be used for dogs, but there have been concerns it can cause seizures.[54]

References

[edit]
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Further reading

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