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Isoniazid
 
 
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Isoniazid (also called isonicotinyl hydrazine or INH) is an organic compound
Organic compound

An organic compound is any member of a large class of chemical compounds whose molecules contain carbon. For historical reasons discussed below, a few types of compounds such as carbonates, simple oxides of carbon and cyanides, as well as the allotropes of carbon, are considered Inorganic compound....
 that is the first-line antituberculosis
Tuberculosis

Tuberculosis is a common and often deadly infectious disease caused by mycobacterium, mainly Mycobacterium tuberculosis . Tuberculosis usually attacks the lungs but can also affect the central nervous system, the lymphatic system, the circulatory system, the genitourinary system, the gastrointestinal system, bones, joints, and even the...
 medication in prevention and treatment. Isoniazid is never used on its own to treat active tuberculosis because resistance quickly develops.

Isoniazid is used in the treatment of mycobacterial
Mycobacterium

Mycobacterium is a genus of Actinobacteria, given its own family, the Mycobacteriaceae. The genus includes pathogens known to cause serious diseases in mammals, including tuberculosis and leprosy....
 infection. It was reported in 1952 by Roche (trademarked as ), when for the first time, a cure for tuberculosis was considered reasonable.






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Isoniazid (also called isonicotinyl hydrazine or INH) is an organic compound
Organic compound

An organic compound is any member of a large class of chemical compounds whose molecules contain carbon. For historical reasons discussed below, a few types of compounds such as carbonates, simple oxides of carbon and cyanides, as well as the allotropes of carbon, are considered Inorganic compound....
 that is the first-line antituberculosis
Tuberculosis

Tuberculosis is a common and often deadly infectious disease caused by mycobacterium, mainly Mycobacterium tuberculosis . Tuberculosis usually attacks the lungs but can also affect the central nervous system, the lymphatic system, the circulatory system, the genitourinary system, the gastrointestinal system, bones, joints, and even the...
 medication in prevention and treatment. Isoniazid is never used on its own to treat active tuberculosis because resistance quickly develops.

Isoniazid is used in the treatment of mycobacterial
Mycobacterium

Mycobacterium is a genus of Actinobacteria, given its own family, the Mycobacteriaceae. The genus includes pathogens known to cause serious diseases in mammals, including tuberculosis and leprosy....
 infection. It was reported in 1952 by Roche (trademarked as ), when for the first time, a cure for tuberculosis was considered reasonable. It is available in tablet, syrup, and injectable forms (given intramuscularly or intravenously). Isoniazid is available worldwide, is inexpensive and is generally well tolerated. It is manufactured from isonicotinic acid, which is produced from 4-methylpyridine
4-Methylpyridine

4-Methylpyridine is the organic compound with the chemical formula CH3C5H4N. This colourless pungent liquid is a building block for the synthesis of other heterocyclic compounds....
.

Mechanism of action

Isoniazid is a prodrug
Prodrug

A prodrug is a Pharmacology substance that is administered in an inactive form. Once administered, the prodrug is drug metabolism in vivo into an active metabolite....
 and must be activated by bacterial catalase. It is activated by catalase-peroxidase enzyme KatG which couples the isonicotinic acyl with NADH to form isonicotinic acyl-NADH complex. This complex binds tightly to ketoenoylreductase known as InhA, thereby blocking the natural enoyl-AcpM substrate. This process inhibits the synthesis of mycolic acid
Mycolic acid

Mycolic acids are long fatty acids found in the cell walls of the Mycobacterium taxon, a group of bacteria that includes Mycobacterium tuberculosis, the causative agent of the disease tuberculosis....
 required for the mycobacterial
Mycobacterium

Mycobacterium is a genus of Actinobacteria, given its own family, the Mycobacteriaceae. The genus includes pathogens known to cause serious diseases in mammals, including tuberculosis and leprosy....
 cell wall.

Isoniazid reaches therapeutic concentrations in serum, cerebrospinal fluid
Cerebrospinal fluid

Cerebrospinal fluid , Liquor cerebrospinalis, is a clear bodily fluid that occupies the subarachnoid space and the ventricular system around and inside the brain....
 (CSF), and within caseous granulomas. Isoniazid is metabolized in the liver via acetylation
Acetylation

Acetylation describes a reaction that introduces an acetyl functional group into an organic compound. Deacetylation is the removal of the acetyl group....
. There are two forms of the enzyme responsible for acetylation, so that some patients metabolize the drug more quickly than others. Hence, the half-life
Half-life

The half-life of a quantity whose value decreases with time is the interval required for the quantity to decay to half of its initial value. The concept originated in describing how long it takes atoms to undergo radioactive decay but also applies in a wide variety of other situations....
 is bimodal
Bimodal distribution

In statistics, a bimodal distribution is a continuous probability distribution with two different mode s. These appear as distinct peaks in the probability density function, as shown in Figure 1....
 with peaks at 1 hour and 3 hours in the US population. The metabolites are excreted in the urine. Doses do not usually have to be adjusted in case of renal failure
Renal failure

Renal failure or kidney failure is a situation in which the kidneys fail to function adequately. It is divided in acute and chronic forms; either form may be due to a large number of other medical problems....
.

Isoniazid is bactericidal to rapidly-dividing mycobacteria
Mycobacterium

Mycobacterium is a genus of Actinobacteria, given its own family, the Mycobacteriaceae. The genus includes pathogens known to cause serious diseases in mammals, including tuberculosis and leprosy....
 but is bacteriostatic if the mycobacterium is slow-growing.

Dosing

The standard dose of isoniazid in adults is 5mg/kg/day (max 300mg daily). When prescribed intermittently (twice or thrice weekly) the dose is 15mg/kg (max 900mg daily). Patients with slow clearance of the drug (via acetylation as described above) may require reduced dosages to avoid toxicity
Toxicity

Toxicity is the degree to which a substance is able to damage an exposed organism. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a substructure of the organism, such as a cell or an organ , such as the liver ....
.

Side effects

Adverse reactions include rash
Rash

A rash is a change of the skin which affects its color, appearance, or texture. A rash may be localized in one part of the body, or affect all the skin....
, abnormal liver function tests
Liver function tests

Liver function tests , which include liver enzymes, are groups of clinical biochemistry laboratory blood assays designed to give information about the state of a patient's liver....
, hepatitis
Hepatitis

Hepatitis implies injury to the liver characterized by the presence of inflammatory cell s in the Tissue of the organ. The name is from ancient Greek hepar , the root being hepat- , meaning liver, and suffix -itis, meaning "inflammation" ....
, sideroblastic anemia
Sideroblastic anemia

Sideroblastic anemia is caused by abnormal production of red blood cells , usually as part of myelodysplastic syndrome, which can evolve into hematological malignancy ....
, peripheral neuropathy
Peripheral neuropathy

Peripheral neuropathy is the term for damage to nerves of the peripheral nervous system, which may be caused either by diseases of the nerve or from the Adverse effect of systemic illness....
, mild central nervous system
Central nervous system

The central nervous system is the part of the nervous system that functions to coordinate the activity of all parts of the bodies of multicellular organisms....
 (CNS) effects, drug interaction
Interaction

Interaction is a kind of action that occurs as two or more objects have an effect upon one another. The idea of a two-way effect is essential in the concept of interaction, as opposed to a one-way causal effect....
s resulting in increased phenytoin
Phenytoin

Phenytoin sodium is a commonly used antiepileptic. Phenytoin acts to dampen the unwanted, runaway brain activity seen in seizure by reducing electrical conductance among brain cells by stabilizing the inactive state of voltage gated sodium channels....
 (Dilantin) or disulfiram
Disulfiram

Disulfiram is a medication used to support the treatment of chronic alcoholism by producing an acute sensitivity to ethanol. Trade names for disulfiram in different countries are Antabuse and Antabus manufactured by Odyssey Pharmaceuticals....
 (Antabuse) levels and intractable seizures (status epilepticus
Status epilepticus

Status epilepticus refers to a life-threatening condition in which the brain is in a state of persistent seizure. Definitions vary, but traditionally it is defined as one continuous unremitting seizure lasting longer than 30 minutes , or recurrent seizures without regaining consciousness between seizures for greater than 30 minutes....
).

Peripheral neuropathy
Peripheral neuropathy

Peripheral neuropathy is the term for damage to nerves of the peripheral nervous system, which may be caused either by diseases of the nerve or from the Adverse effect of systemic illness....
 and CNS
Central nervous system

The central nervous system is the part of the nervous system that functions to coordinate the activity of all parts of the bodies of multicellular organisms....
 effects are associated with the use of isoniazid and are due to pyridoxine
Pyridoxine

Pyridoxine is one of the compounds that can be called vitamin B6, along with Pyridoxal and Pyridoxamine. It differs from pyridoxamine by the substituent at the '4' position....
 (vitamin B6) depletion, but are uncommon at doses of 5 mg/kg. Persons with conditions in which neuropathy is common (e.g., diabetes, uremia
Uremia

Uremia is a term used to loosely describe the illness accompanying renal failure , in particular the nitrogenous waste products associated with the failure of this organ....
, alcoholism
Alcoholism

Alcoholism is a term with multiple and sometimes conflicting definitions to describe the detrimental effects of alcohol intake.In common and historic usage, alcoholism refers to any condition that results in the continued consumption of alcoholic beverages despite health problems and negative social consequences....
, malnutrition
Malnutrition

Malnutrition is a general term for a medical condition caused by an improper or inadequate diet and nutrition.According to the World Health Organization, hunger and malnutrition are the single gravest threats to the world's public health and malnutrition is by far the biggest contributor to child mortality, present in half of all cases....
, HIV
HIV

Human immunodeficiency virus is a lentivirus that can lead to AIDS , a condition in humans in which the immune system begins to fail, leading to life-threatening opportunistic infections....
-infection), as well as pregnant women and persons with a seizure
Seizure

An epileptic seizure is a transient symptom of abnormal, excessive or synchronous neuronal activity in the brain. It can manifest as an alteration in mental state, tonic or clonic movements, convulsions, and various other psychic symptoms ....
 disorder, may be given pyridoxine
Pyridoxine

Pyridoxine is one of the compounds that can be called vitamin B6, along with Pyridoxal and Pyridoxamine. It differs from pyridoxamine by the substituent at the '4' position....
 (vitamin B6) (10-50 mg/day) with isoniazid.

Hepatotoxicity can be avoided with close clinical monitoring of the patient, specifically nausea, vomiting, abdominal pain and appetite. Isoniazid is metabolized by the liver mainly by acetylation
Acetylation

Acetylation describes a reaction that introduces an acetyl functional group into an organic compound. Deacetylation is the removal of the acetyl group....
 and dehydrazination. The N-acetylhydrazine metabolite is believed to be responsible for the hepatotoxic effects seen in patients treated with isoniazid. The rate of acetylation is genetically determined. Approximately 50% of blacks and Caucasians are slow inactivators; the majority of Inuit and Asians are rapid inactivators. The half-life in fast acetylators is 1 to 2 hours while in slow acetylators it is 2 to 5 hours. Elimination is largely independent of renal function, however the half-life may be prolonged in liver disease. The rate of acetylation has not been shown to significantly alter the effectiveness of isoniazid. However, slow acetylation may lead to higher blood concentrations with chronic administration of the drug, with an increased risk of toxicity. Isoniazid and its metabolites are excreted in the urine with 75 to 95% of the dose excreted in 24 hours. Small amounts are also excreted in saliva, sputum and feces. Isoniazid is removed by hemodialysis and peritoneal dialysis. Headache, poor concentration, poor memory and depression have all been associated with isoniazid use. The frequency of these side effects is not known, and the association with isoniazid is not well validated. The presence of these symptoms is not frequently disabling and is certainly not a reason to stop treatment with isoniazid; the patient should be strongly encouraged to continue treatment despite these symptoms. It must be explained to the patient that the harm done from not taking isoniazid far outweighs the problems arising from these symptoms.

INH therapy will decrease the efficacy of hormonal birth control when combined with Rifampin.

Synonyms and abbreviations

  • Isonicotinyl hydrazine
  • Isonicotinic acid hydrazide
  • INH
  • H (for "hydrazide", and also the WHO standard abbreviation)


See also

  • Tuberculosis treatment
    Tuberculosis treatment

    Active tuberculosis will kill about two of every three people affected if left untreated. Treated tuberculosis has a mortality rate of less than 5%....
  • Tuberculosis
    Tuberculosis

    Tuberculosis is a common and often deadly infectious disease caused by mycobacterium, mainly Mycobacterium tuberculosis . Tuberculosis usually attacks the lungs but can also affect the central nervous system, the lymphatic system, the circulatory system, the genitourinary system, the gastrointestinal system, bones, joints, and even the...
  • Mycobacterium tuberculosis
    Mycobacterium tuberculosis

    Mycobacterium tuberculosis is a pathogenic bacterial species in the genus Mycobacterium and the causative agent of most cases of tuberculosis....