Isoniazid

Last updated
Isoniazid
Isoniazid skeletal.svg
Isoniazid 3d.png
Clinical data
Trade names Hydra, Hyzyd, Isovit, other
Other namesisonicotinic acid hydrazide, isonicotinyl hydrazine, INHA
AHFS/Drugs.com Monograph
MedlinePlus a682401
Pregnancy
category
  • US: C (Risk not ruled out) [1]
    Routes of
    administration
    by mouth, intramuscular, intravenous
    ATC code
    Legal status
    Legal status
    Pharmacokinetic data
    Protein binding Very low (0–10%)
    Metabolism liver; CYP450: 2C19, 3A4 inhibitor
    Elimination half-life 0.5–1.6h (fast acetylators), 2-5h (slow acetylators)
    Excretion urine (primarily), feces
    Identifiers
    CAS Number
    PubChem CID
    DrugBank
    ChemSpider
    UNII
    KEGG
    ChEBI
    ChEMBL
    NIAID ChemDB
    CompTox Dashboard (EPA)
    ECHA InfoCard 100.000.195 OOjs UI icon edit-ltr-progressive.svg
    Chemical and physical data
    Formula C6H7N3O
    Molar mass 137.139 g/mol g·mol−1
    3D model (JSmol)
       (verify)

    Isoniazid, also known as isonicotinylhydrazide (INH), is an antibiotic used for the treatment of tuberculosis. [1] For active tuberculosis it is often used together with rifampicin, pyrazinamide, and either streptomycin or ethambutol. [2] For latent tuberculosis it is often used by itself. [1] It may also be used for atypical types of mycobacteria, such as M. avium , M. kansasii , and M. xenopi . [1] It is usually taken by mouth but may be used by injection into muscle. [1]

    Contents

    Common side effect include increased blood levels of liver enzymes and numbness in the hands and feet. [1] Serious side effects may include liver inflammation. [1] It is unclear if use during pregnancy is safe for the baby. [3] Use during breastfeeding is likely safe. [3] Pyridoxine may be given to reduce the risk of side effects. [4] Isoniazid works in part by disrupting the formation of the bacteria's cell wall which results in cell death. [1]

    Isoniazid was first made in 1952. [5] It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system. [6] Isoniazid is available as a generic medication. [1] The wholesale cost in the developing world is about US$0.60–4.75 per month. [7] In the United States a month of treatment costs less than $25. [4]

    Medical uses

    Tuberculosis

    Isoniazid is often used to treat latent and active tuberculosis infections. In persons with isoniazid-sensitive Mycobacterium tuberculosis infection, drug regimens based on isoniazid are usually effective when persons adhere to the prescribed treatment. However, in persons with isoniazid-resistant Mycobacterium tuberculosis infection, drug regimens based on isoniazid have a high rate of failure. [8]

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

    Non-tuberculous mycobacteria

    Isoniazid was widely used in the treatment of Mycobacterium avium complex as part of a regimen including rifampicin and ethambutol. [11] Evidence suggests that isoniazid prevents mycolic acid synthesis in M. avium complex as in M. tuberculosis [12] and although this is not bactericidal to M. avium complex, it greatly potentiates the effect of rifampicin. The introduction of macrolides led to this use greatly decreasing. However, since rifampicin is broadly underdosed in M. avium complex treatment this effect may be worth re-investigating. [13]

    Special populations

    It is recommended that women with active tuberculosis who are pregnant or breastfeeding take isoniazid. Preventive therapy should be delayed until after giving birth. [14] 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 take vitamin B6 in its pyridoxine form to minimize the risk of peripheral nerve damage. [15] 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. [16]

    People with liver dysfunction are at a higher risk for hepatitis caused by INH, and may need a lower dose. [14]

    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. [14] [17]

    Side effects

    Up to 20% of people taking isoniazid experience peripheral neuropathy when taking doses of 6 mg/kg of weight daily or higher. [18] Gastrointestinal reactions include nausea and vomiting. [9] Aplastic anemia, thrombocytopenia, and agranulocytosis due to lack of production of red blood cells, platelets, and white blood cells by the bone marrow respectively, can also occur. [9] Hypersensitivity reactions are also common and can present with a maculopapular rash and fever. [9]

    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. [19] 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. [9] [20] Symptoms suggestive of liver toxicity include nausea, vomiting, abdominal pain, dark urine, right upper quadrant pain, and loss of appetite. [9] Black and Hispanic women are at higher risk for isoniazid-induced hepatotoxicity. [9] When it happens, isoniazid-induced liver toxicity has been shown to occur in 50% of patients within the first 2 months of therapy. [21]

    Some recommend that liver function should be monitored carefully in all people receiving it, [22] but others recommend monitoring only in certain populations. [19] [23] [24]

    Headache, poor concentration, weight gain, poor memory, insomnia, and depression have all been associated with isoniazid use. [25] All patients and healthcare workers should be aware of these serious side effects, especially if suicidal ideation or behavior are suspected. [25] [26] [27]

    Isoniazid is associated with pyridoxine (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 d-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 to sideroblastic anemia. [16]

    Drug interactions

    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. [28] [29]

    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. [30]

    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. [31]

    Isoniazid may increase the amount of phenytoin in the body. The doses of phenytoin may need to be adjusted when given with isoniazid. [32] [33]

    Isoniazid may increase the plasma levels of theophylline. There are some cases of theophylline slowing down isoniazid elimination. Both theophylline and isoniazid levels should be monitored. [34]

    Valproate levels may increase when taken with isoniazid. Valproate levels should be monitored and its dose adjusted if necessary. [32]

    Mechanism of action

    Isoniazid is a prodrug that inhibits the formation of the mycobacterial cell wall. Isoniazid must be activated by KatG, a bacterial catalase-peroxidase enzyme in Mycobacterium tuberculosis . [35] KatG catalyzes the formation of the isonicotinic acyl radical, which spontaneously couples with NADH to form the nicotinoyl-NAD adduct. This complex binds tightly to the enoyl-acyl carrier protein reductase InhA, thereby blocking the natural enoyl-AcpM substrate and the action of fatty acid synthase. This process inhibits the synthesis of mycolic acids, which are required components of the mycobacterial cell wall. A range of radicals are produced by KatG activation of isoniazid, including nitric oxide, [36] which has also been shown to be important in the action of another antimycobacterial prodrug pretomanid. [37]

    Activation of isoniazid with NAD.jpg

    Isoniazid is bactericidal to rapidly dividing mycobacteria, but is bacteriostatic if the mycobacteria are slow-growing. [38] It inhibits the cytochrome P450 system and hence acts as a source of free radicals. [39]

    Isoniazid is a mild monoamine oxidase inhibitor(MAO-I). [40]

    Metabolism

    Isoniazid reaches therapeutic concentrations in serum, cerebrospinal fluid, and within caseous granulomas. It is metabolized in the liver via acetylation into acetylhydrazine. Two forms of the enzyme are responsible for acetylation, so some patients metabolize the drug more quickly than others. Hence, the half-life is bimodal, 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 of renal failure.

    History

    Three pharmaceutical companies unsuccessfully attempted to patent the drug at the same time, [41] the most prominent one being Roche, which launched its version, Rimifon, in 1952. [42] With the introduction of isoniazid, a cure for tuberculosis was first considered possible.

    The drug was first tested at Many Farms, a Navajo community in Arizona, due to the Navajo reservation's tuberculosis problem and because the population had not previously been treated with streptomycin, the main tuberculosis treatment at the time. [43]

    Isoniazid and a related drug, iproniazid, were among the first drugs to be referred to as antidepressants. [44]

    Preparation

    Isoniazid is an isonicotinic acid derivative. It is manufactured using 4-cyanopyridine and hydrazine hydrate. [45] In another method, isoniazid was claimed to have been made from citric acid starting material. [46]

    Brand names

    Hydra, Hyzyd, Isovit, Laniazid, Nydrazid, Rimifon, and Stanozide. [47]

    Other uses

    Chromatography

    Isonicotinic acid hydrazide is also used in chromatography to differentiate between various degrees of conjugation in organic compounds barring the ketone functional group. [48] The test works by forming a hydrazone which can be detected by its bathochromic shift.

    Dogs

    Isoniazid may be used for dogs, but there have been concerns it can cause seizures. [49]

    Related Research Articles

    Tuberculosis Infectious disease caused by the bacterium Mycobacterium tuberculosis

    Tuberculosis (TB) is an infectious disease usually caused by Mycobacterium tuberculosis (MTB) bacteria. Tuberculosis generally affects the lungs, but can also affect other parts of the body. Most infections do not have symptoms, in which case it is known as latent tuberculosis. About 10% of latent infections progress to active disease which, if left untreated, kills about half of those affected. The classic symptoms of active TB are a chronic cough with blood-containing mucus, fever, night sweats, and weight loss. It was historically called "consumption" due to the weight loss. Infection of other organs can cause a wide range of symptoms.

    Mantoux test immunological method

    The Mantoux test or Mendel–Mantoux test is a tool for screening for tuberculosis (TB) and for tuberculosis diagnosis. It is one of the major tuberculin skin tests used around the world, largely replacing multiple-puncture tests such as the tine test. The Heaf test, a form of tine test, was used until 2005 in the UK, when it was replaced by the Mantoux test. The Mantoux test is endorsed by the American Thoracic Society and Centers for Disease Control and Prevention. It was also used in the USSR and is now prevalent in most of the post-Soviet states.

    ATC code J04Antimycobacterials is a therapeutic subgroup of the Anatomical Therapeutic Chemical Classification System, a system of alphanumeric codes developed by the WHO for the classification of drugs and other medical products. Subgroup J04 is part of the anatomical group J Antiinfectives for systemic use.

    Rifampicin pharmaceutical drug

    Rifampicin, also known as rifampin, is an antibiotic used to treat several types of bacterial infections, including tuberculosis, Mycobacterium avium complex, leprosy, and Legionnaires’ disease. It is almost always used together with other antibiotics, except when given to prevent Haemophilus influenzae type b and meningococcal disease in people who have been exposed to those bacteria. Before treating a person for a long period of time, measurements of liver enzymes and blood counts are recommended. Rifampicin may be given either by mouth or intravenously.

    Tuberculosis management medical treatment of the infectious disease tuberculosis

    Tuberculosis management refers to the medical treatment of the infectious disease tuberculosis (TB).

    Pyrazinamide Medication

    Pyrazinamide is a medication used to treat tuberculosis. For active tuberculosis, it is often used with rifampicin, isoniazid, and either streptomycin or ethambutol. It is not generally recommended for the treatment of latent tuberculosis. It is taken by mouth.

    Ethambutol chemical compound

    Ethambutol is a medication primarily used to treat tuberculosis. It is usually given in combination with other tuberculosis medications, such as isoniazid, rifampicin and pyrazinamide. It may also be used to treat Mycobacterium avium complex, and Mycobacterium kansasii. It is taken by mouth.

    4-Aminosalicylic acid chemical compound

    4-Aminosalicylic acid, also known as para-aminosalicylic acid (PAS) is an antibiotic primarily used to treat tuberculosis. Specifically it is used to treat active drug resistant tuberculosis together with other antituberculosis medications. It has also been used as a second line agent to sulfasalazine in people with inflammatory bowel disease such as ulcerative colitis and Crohn's disease. It is typically taken by mouth.

    Iproniazid chemical compound

    Iproniazid is a non-selective, irreversible monoamine oxidase inhibitor (MAOI) of the hydrazine class. It is a xenobiotic that was originally designed to treat tuberculosis, but was later most prominently used as an antidepressant drug. However, it was withdrawn from the market because of its hepatotoxicity. The medical use of iproniazid was discontinued in most of the world in the 1960s, but remained in use in France until fairly recently.

    <i>Mycobacterium avium-intracellulare</i> infection Human disease

    Mycobacterium avium-intracellulare infection (MAI) is an atypical mycobacterial infection, i.e. one with nontuberculous mycobacteria or NTM, caused by Mycobacterium avium complex ("MAC"), which is made of two mycobacteria species, M. avium and M. intracellulare. This infection causes respiratory illness in birds, pigs, and humans, especially in immunocompromised people. In the later stages of AIDS it can be very severe. It usually first presents as a persistent cough. It is typically treated with a series of three antibiotics for a period of at least six months.

    Rifabutin chemical compound

    Rifabutin (Rfb) is an antibiotic used to treat tuberculosis and prevent and treat Mycobacterium avium complex. It is typically only used in those who cannot tolerate rifampin such as people with HIV/AIDS on antiretrovirals. For active tuberculosis it is used with other antimycobacterial medications. For latent tuberculosis it may be used by itself when the exposure was with drug-resistant TB.

    Rifapentine chemical compound

    Rifapentine (RPT), sold under the brand name Priftin, is an antibiotic used in the treatment of tuberculosis. In active tuberculosis it is used together with other antituberculosis medications. In latent tuberculosis it is typically used with isoniazid. It is taken by mouth.

    Latent tuberculosis (LTB), also called latent tuberculosis infection (LTBI) is when a person is infected with Mycobacterium tuberculosis, but does not have active tuberculosis. Active tuberculosis can be contagious while latent tuberculosis is not, and it is therefore not possible to get TB from someone with latent tuberculosis. The main risk is that approximately 10% of these people will go on to develop active tuberculosis. This is particularly true, and there is added risk, in particular situations such as medication that suppresses the immune system or advancing age.

    Ethionamide chemical compound

    Ethionamide is an antibiotic used to treat tuberculosis. Specifically it is used, along with other antituberculosis medications, to treat active multidrug-resistant tuberculosis. It is no longer recommended for leprosy. It is taken by mouth.

    Mycobacterium avium complex is a group of mycobacteria comprising Mycobacterium intracellulare and Mycobacterium avium that are commonly grouped together because they infect humans together; this group, in turn, is part of the group of nontuberculous mycobacteria. These bacteria cause disease in humans called Mycobacterium avium-intracellulare infection or Mycobacterium avium complex infection. This group should not be confused with Mycobacterium tuberculosis complex.

    Multi-drug-resistant tuberculosis tuberculosis that is resistant to isoniazid and rifampicin, the two most powerful first-line anti-TB drugs

    Multi-drug-resistant tuberculosis (MDR-TB) is a form of tuberculosis (TB) infection caused by bacteria that are resistant to treatment with at least two of the most powerful first-line anti-TB medications (drugs), isoniazid and rifampin. Some forms of TB are also resistant to second-line medications, and are called extensively drug-resistant TB (XDR-TB).

    Mycobacterium scrofulaceum is a species of Mycobacterium.

    Delamanid, sold under the brand name Deltyba, is a medication used to treat tuberculosis. Specifically it is used, along with other antituberculosis medications, for active multidrug-resistant tuberculosis. It is taken by mouth.

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    See Chapter 6, Treatment of LTBI Regimens – Isoniazid::
    See Chapter 7 – Treatment of TB Disease Monitoring – Adverse Reactions to First-line TB Drugs – Isoniazid::
    See Table 5 First-Line Anti-TB Medications