|Trade names||Hydra, Hyzyd, Isovit, other|
|by mouth, intramuscular, intravenous|
|ATC code||J04AC01 (WHO)|
|Protein binding||Very low (0-10%)|
|Metabolism||liver; CYP450: 2C19, 3A4 inhibitor|
|Biological half-life||0.5-1.6h (fast acetylators), 2-5h (slow acetylators)|
|Excretion||urine (primarily), feces|
|Synonyms||Isonicotinic Acid Hydrazide, Isonicotinyl hydrazine, INHA, INH|
|Chemical and physical data|
|Molar mass||137.139 g/mol|
|3D model (Jmol)||Interactive image|
Isoniazid, also known as isonicotinylhydrazide (INH), is an antibiotic used as a first-line agent for the prevention and treatment of both latent and active tuberculosis. It is effective against mycobacteria, particularly Mycobacterium tuberculosis. It is also active against some atypical types of mycobacteria, such as M. kansasii and M. xenopi. Isoniazid is an organic compound that is available in tablet, syrup, and injectable forms.
The most common side effect of isoniazid is an increase in blood levels of liver enzymes; however, it is usually harmless. Uncommon but more serious side effects include inflammation of nerves, which causes numbness in the arms or legs, and liver inflammation. Isoniazid blocks the formation of mycolic acids, which are essential parts of mycobacterial cell walls. Disruption of the mycobacterial cell wall results in cell death. Isoniazid acts on both intracellular and extracellular mycobacteria.
Isoniazid was first made in 1952. Three pharmaceutical companies unsuccessfully attempted to patent the drug at the same time, the most prominent one being Roche, which launched its version, Rimifon, in 1952. With the introduction of isoniazid, a cure for tuberculosis was first considered possible. It is available worldwide, is inexpensive, and is generally well tolerated. It is on the World Health Organization's List of Essential Medicines, a list of medicines that constitute the bare minimum for a basic health system.
Isoniazid is approved for latent and active tuberculous infections. For the latter, it must be used in combination with other tuberculosis medications to prevent the development of drug resistance.
Isoniazid has been approved as prophylactic therapy for the following populations:
- People with HIV infection and a PPD 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
It is recommended that women with active tuberculosis who are pregnant or breastfeeding take isoniazid. Preventive therapy should be delayed until after giving birth. 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. 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.
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.
Up to 20% of people taking isoniazid experience peripheral neuropathy when taking doses of 6 mg/kg of weight daily or higher. Gastrointestinal reactions include nausea and vomiting. 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. Hypersensitivity reactions are also common and can present with a maculopapular rash and fever.
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. 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. Symptoms suggestive of liver toxicity include nausea, vomiting, abdominal pain, dark urine, right upper quadrant pain, and loss of appetite. Black and Hispanic women are at higher risk for isoniazid-induced hepatotoxicity. When it happens, isoniazid-induced liver toxicity has been shown to occur in 50% of patients within the first 2 months of therapy.
Headache, poor concentration, weight gain, poor memory, insomnia, and depression have all been associated with isoniazid use. All patients and healthcare workers should be aware of these serious side effects, especially if suicidal ideation or behavior are suspected.
Isoniazid is associated with pyridoxine deficiency due to the 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.
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.
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.
Mechanism of action
Isoniazid is a prodrug and must be activated by a bacterial catalase-peroxidase enzyme in Mycobacterium tuberculosis called KatG. KatG couples the isonicotinic acyl with NADH to form isonicotinic acyl-NADH complex. This complex binds tightly to the enoyl-acyl carrier protein reductase known as 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, which has also been shown to be important in the action of another antimycobacterial prodrug pretomanid.
Isoniazid is bactericidal to rapidly dividing mycobacteria, but is bacteriostatic if the mycobacteria are slow-growing. It inhibits the cytochrome P450 system and hence acts as a source of free radicals.
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.
The drug was first tested at Many Farms, a Navajo community, 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.
In another method, isoniazid was claimed to have been made from citric acid starting material.
Isonicotinic acid hydrazide is also used in chromatography to differentiate between various degrees of conjugation in organic compounds barring the ketone functional group. The test works by forming a hydrazone which can be detected by its bathochromic shift.
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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
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