Isoniazid
Encyclopedia
Isoniazid also known as isonicotinylhydrazine (INH), is an organic compound
that is the first-line antituberculosis
medication in prevention and treatment. It was first discovered in 1912, and later in 1951 it was found to be effective against tuberculosis by inhibiting its mycolic acid
(wax coat). Isoniazid is never used on its own to treat active tuberculosis because resistance quickly develops. Isoniazid also has an antidepressant
effect, and it was one of the first antidepressants discovered. Isoniazid can also be used in the treatment of a BCG-oma
.
The compound was first synthesised in the early 20th century, but its activity against tuberculosis was first reported in the early 1950s and three pharmaceutical companies attempted unsuccessfully to simultaneously patent the drug (the most prominent one being Roche, who launched their version, Rimifon, in 1952). With the introduction of isoniazid, a cure for tuberculosis was first considered reasonable.
Isoniazid 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
.
, followed by displacement of ammonia by hydrazine
:
and must be activated by a bacterial catalase-peroxidase enzyme that in M. tuberculosis is 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 acid
, required for 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 PA-824.
Isoniazid is bactericidal to rapidly-dividing mycobacteria
but is bacteriostatic if the mycobacterium is slow-growing.
Isoniazid inhibits the P450 system.
(CSF), and within caseous granulomas. Isoniazid is metabolized in the liver via acetylation
. 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
is bimodal
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
.
. The recommended dose for children is 8 to 12 mg/kg/day.
, abnormal liver function tests
, hepatitis
, sideroblastic anemia
, high anion gap metabolic acidosis
, peripheral neuropathy
, mild central nervous system
(CNS) effects, drug interaction
s resulting in increased phenytoin
(Dilantin) or disulfiram
(Antabuse) levels and intractable seizures (status epilepticus
).
Peripheral neuropathy
and CNS
effects are associated with the use of isoniazid and are due to pyridoxine
(vitamin B6) depletion, but are uncommon at doses of 5 mg/kg. Persons with conditions in which neuropathy is common (e.g., diabetes, uremia
, alcoholism
, malnutrition
, HIV
-infection), as well as pregnant women and persons with a seizure
disorder, may be given pyridoxine
(vitamin B6) (10–50 mg/day) with isoniazid.
Hepatotoxicity of INH is by nitrogen group in its chemical structure, as it is metabolized in the liver and gets converted in to an ammonium molecule, which causes hepatitis.
Hepatotoxicity can be avoided with close clinical monitoring of the patient, to be specific, nausea, vomiting, abdominal pain, and appetite. Isoniazid is metabolized by the liver mainly by acetylation
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. Fast acetylation leads to higher blood levels of the toxic metabolite acetylisoniazid and thus to an increase in toxic reactions - hepatitis which is 250 times more common than in slow acetylators. 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, weight-gain, poor memory, and depression have all been associated with isoniazid use. All patients and healthcare workers should be aware of these serious adverse effects, especially if suicidal thinking or behavior are suspected.
INH is known to reduce cytochrome P450 and in theory promote the efficacy of Contraceptives. Therapy is often combined with Rifampin. Rifampin increases the P450 enzyme and can reduce the efficacy of contraceptives. Alternative means of birth control should be used when taking these medications.
As p450 is required for porphyrin synthesis its deficiency leads to poor heme formation in early RBCs leads to sideroblastic anemia
.
Organic compound
An organic compound is any member of a large class of gaseous, liquid, or solid chemical compounds whose molecules contain carbon. For historical reasons discussed below, a few types of carbon-containing compounds such as carbides, carbonates, simple oxides of carbon, and cyanides, as well as the...
that is the first-line antituberculosis
Tuberculosis
Tuberculosis, MTB, or TB is a common, and in many cases lethal, infectious disease caused by various strains of mycobacteria, usually Mycobacterium tuberculosis. Tuberculosis usually attacks the lungs but can also affect other parts of the body...
medication in prevention and treatment. It was first discovered in 1912, and later in 1951 it was found to be effective against tuberculosis by inhibiting its mycolic acid
Mycolic acid
Mycolic acids are long fatty acids found in the cell walls of the mycolata taxon, a group of bacteria that includes Mycobacterium tuberculosis, the causative agent of the disease tuberculosis. They form the major component of the cell wall of mycolata species...
(wax coat). Isoniazid is never used on its own to treat active tuberculosis because resistance quickly develops. Isoniazid also has an antidepressant
Antidepressant
An antidepressant is a psychiatric medication used to alleviate mood disorders, such as major depression and dysthymia and anxiety disorders such as social anxiety disorder. According to Gelder, Mayou &*Geddes people with a depressive illness will experience a therapeutic effect to their mood;...
effect, and it was one of the first antidepressants discovered. Isoniazid can also be used in the treatment of a BCG-oma
BCG-oma
A BCG-oma is an abscess caused by the BCG strain of Mycobacterium bovis. It follows incorrect administration of BCG . It is treated as for any Mycobacterium bovis infection ....
.
The compound was first synthesised in the early 20th century, but its activity against tuberculosis was first reported in the early 1950s and three pharmaceutical companies attempted unsuccessfully to simultaneously patent the drug (the most prominent one being Roche, who launched their version, Rimifon, in 1952). With the introduction of isoniazid, a cure for tuberculosis was first considered reasonable.
Isoniazid 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 formula CH3C5H4N. It is one of the three isomers of methylpyridine. This colourless pungent liquid is a building block for the synthesis of other heterocyclic compounds...
.
Preparation
Isoniazid may be prepared by the base hydrolysis of 4-cyanopyridine to give the amideIsonicotinamide
Isonicotinamide is a chemical based on the nicotinamide structure, but in which the amide is in the 4-position and not the 3-position. It has the chemical formula C6H6N2O....
, followed by displacement of ammonia by hydrazine
Hydrazine
Hydrazine is an inorganic compound with the formula N2H4. It is a colourless flammable liquid with an ammonia-like odor. Hydrazine is highly toxic and dangerously unstable unless handled in solution. Approximately 260,000 tons are manufactured annually...
:
Mechanism of action
Isoniazid is a prodrugProdrug
A prodrug is a pharmacological substance administered in an inactive form. Once administered, the prodrug is metabolised in vivo into an active metabolite, a process termed bioactivation. The rationale behind the use of a prodrug is generally for absorption, distribution, metabolism, and...
and must be activated by a bacterial catalase-peroxidase enzyme that in M. tuberculosis is 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
Enoyl-acyl carrier protein reductase
Enoyl-acyl carrier protein reductase , is a key enzyme of the type II fatty acid synthesis system. ENR is an attractive target for narrow-spectrum antibacterial drug discovery because of its essential role in metabolism and its sequence conservation across many bacterial species...
known as InhA, thereby blocking the natural enoyl-AcpM substrate and the action of fatty acid synthase
Fatty acid synthase
Fatty acid synthase is an enzyme that in humans is encoded by the FASN gene.Fatty acid synthase is a multi-enzyme protein that catalyzes fatty acid synthesis...
. This process inhibits the synthesis of mycolic acid
Mycolic acid
Mycolic acids are long fatty acids found in the cell walls of the mycolata taxon, a group of bacteria that includes Mycobacterium tuberculosis, the causative agent of the disease tuberculosis. They form the major component of the cell wall of mycolata species...
, 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. A range of radicals are produced by KatG activation of Isoniazid, including nitric oxide
Nitric oxide
Nitric oxide, also known as nitrogen monoxide, is a diatomic molecule with chemical formula NO. It is a free radical and is an important intermediate in the chemical industry...
, which has also been shown to be important in the action of another antimycobacterial prodrug PA-824.
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.
Isoniazid inhibits the P450 system.
Metabolism
Isoniazid reaches therapeutic concentrations in serum, cerebrospinal fluidCerebrospinal fluid
Cerebrospinal fluid , Liquor cerebrospinalis, is a clear, colorless, bodily fluid, that occupies the subarachnoid space and the ventricular system around and inside the brain and spinal cord...
(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 a chemical compound...
. 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
Half-life, abbreviated t½, is the period of time it takes for the amount of a substance undergoing decay to decrease by half. The name was originally used to describe a characteristic of unstable atoms , but it may apply to any quantity which follows a set-rate decay.The original term, dating to...
is bimodal
Bimodal distribution
In statistics, a bimodal distribution is a continuous probability distribution with two different modes. 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 describes a medical condition in which the kidneys fail to adequately filter toxins and waste products from the blood...
.
Dosing
The standard dose of isoniazid in adults is 5 mg/kg/day (max 300 mg daily). When prescribed intermittently (twice or thrice weekly) the dose is 15 mg/kg (max 900 mg daily). Patients with slow clearance of the drug (via acetylation as described above) may require reduced dosages to avoid toxicityToxicity
Toxicity is the degree to which a substance can damage a living or non-living organisms. 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...
. The recommended dose for children is 8 to 12 mg/kg/day.
Side effects
Adverse reactions include rashRash
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. Rashes may cause the skin to change color, itch, become warm, bumpy, chapped, dry, cracked or blistered, swell and may be painful. The causes, and...
, abnormal liver function tests
Liver function tests
Liver function tests , are groups of clinical biochemistry laboratory blood assays designed to give information about the state of a patient's liver. The parameters measured include PT/INR, aPTT, albumin, billirubin and others...
, hepatitis
Hepatitis
Hepatitis is a medical condition defined by the inflammation of the liver and characterized by the presence of inflammatory cells in the tissue of the organ. The name is from the Greek hepar , the root being hepat- , meaning liver, and suffix -itis, meaning "inflammation"...
, sideroblastic anemia
Sideroblastic anemia
Sideroblastic anemia or sideroachrestic anemia is a disease in which the bone marrow produces ringed sideroblasts rather than healthy red blood cells . It may be caused either by a genetic disorder or indirectly as part of myelodysplastic syndrome, which can evolve into hematological malignancies...
, high anion gap metabolic acidosis
High anion gap metabolic acidosis
High anion gap metabolic acidosis is a form of metabolic acidosis characterized by a high anion gap.The list of agents that cause high anion gap metabolic acidosis is similar to but broader than the list of agents that cause a serum osmolal gap.-"Mudpiles":...
, 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 or trauma to the nerve or the side-effects of systemic illness....
, mild central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
(CNS) effects, drug interaction
Drug interaction
A drug interaction is a situation in which a substance affects the activity of a drug, i.e. the effects are increased or decreased, or they produce a new effect that neither produces on its own. Typically, interaction between drugs come to mind...
s resulting in increased phenytoin
Phenytoin
Phenytoin sodium is a commonly used antiepileptic. Phenytoin acts to suppress the abnormal 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 drug discovered in the 1920s and used to support the treatment of chronic alcoholism by producing an acute sensitivity to alcohol. 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 is 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 5 minutes, or recurrent seizures without regaining consciousness between seizures...
).
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 or trauma to the nerve or the side-effects of systemic illness....
and CNS
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
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. It is often used as 'pyridoxine hydrochloride'.-Chemistry:...
(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 or uraemia is a term used to loosely describe the illness accompanying kidney failure , in particular the nitrogenous waste products associated with the failure of this organ....
, alcoholism
Alcoholism
Alcoholism is a broad term for problems with alcohol, and is generally used to mean compulsive and uncontrolled consumption of alcoholic beverages, usually to the detriment of the drinker's health, personal relationships, and social standing...
, malnutrition
Malnutrition
Malnutrition is the condition that results from taking an unbalanced diet in which certain nutrients are lacking, in excess , or in the wrong proportions....
, HIV
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
-infection), as well as pregnant women and persons with a seizure
Seizure
An epileptic seizure, occasionally referred to as a fit, is defined as a transient symptom of "abnormal excessive or synchronous neuronal activity in the brain". The outward effect can be as dramatic as a wild thrashing movement or as mild as a brief loss of awareness...
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. It is often used as 'pyridoxine hydrochloride'.-Chemistry:...
(vitamin B6) (10–50 mg/day) with isoniazid.
Hepatotoxicity of INH is by nitrogen group in its chemical structure, as it is metabolized in the liver and gets converted in to an ammonium molecule, which causes hepatitis.
Hepatotoxicity can be avoided with close clinical monitoring of the patient, to be specific, 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 a chemical compound...
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. Fast acetylation leads to higher blood levels of the toxic metabolite acetylisoniazid and thus to an increase in toxic reactions - hepatitis which is 250 times more common than in slow acetylators. 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, weight-gain, poor memory, and depression have all been associated with isoniazid use. All patients and healthcare workers should be aware of these serious adverse effects, especially if suicidal thinking or behavior are suspected.
INH is known to reduce cytochrome P450 and in theory promote the efficacy of Contraceptives. Therapy is often combined with Rifampin. Rifampin increases the P450 enzyme and can reduce the efficacy of contraceptives. Alternative means of birth control should be used when taking these medications.
As p450 is required for porphyrin synthesis its deficiency leads to poor heme formation in early RBCs leads to sideroblastic anemia
Sideroblastic anemia
Sideroblastic anemia or sideroachrestic anemia is a disease in which the bone marrow produces ringed sideroblasts rather than healthy red blood cells . It may be caused either by a genetic disorder or indirectly as part of myelodysplastic syndrome, which can evolve into hematological malignancies...
.
Synonyms and abbreviations
- Isonicotinyl hydrazine
- Isonicotinic acid hydrazide
- INH
- H (for "hydrazide", and also the WHO standard abbreviation)
External links
- Core Curriculum on Tuberculosis (2000) Division of Tuberculosis Elimination, Centers for Disease Control and Prevention
-
- 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
- See Chapter 6, Treatment of LTBI Regimens - Isoniazid::
- Isoniazid Overdose: Recognition and Management American Family Physician 1998 Feb 15