Isoniazid

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

Isoniazid is a prodrug that, when activated by catalase-peroxidase KatG, generates adducts and radicals that inhibits the formation of the mycobacterial cell wall. Side effects in those treated with isoniazid include vitamin B6 deficiency, liver toxicity, peripheral neuropathy, and a reduction in blood cell production. Mutations in the ahpC, inhA, kasA, katG, genes of M. tuberculosis may result in isoniazid resistance.

Although first synthesized in 1912, the anti-tuberculosis activity of isoniazid was not discovered until the 1940s. It is on the World Health Organization's List of Essential Medicines and is available as a generic medication.

Medical uses

Tuberculosis

The primary use of isoniazid is as first-line treatment for latent and active infection of Mycobacterium tuberculosis, the causative agent of tuberculosis (TB).<ref name = "O'Connor_2024">Template:Cite book</ref> In persons with isoniazid-resistant Mycobacterium tuberculosis infection, drug regimens based on isoniazid have a high rate of failure.<ref name="Gegia_2017">Template:Cite journal</ref>

In the United States, the indications for isoniazid use approved by the U.S. Food and Drug Administration (FDA) include:.<ref name = "O'Connor_2024" />

• Both active and latent TB
• Intravenous drug users with Mantoux test above 10 mm
• HIV-positive people with Mantoux test above 5 mm
• Those who had close contact with TB patient and have Mantoux test above 5 mm
• As a preventative measure for those with pulmonary silicosis or fibrotic pulmonary lesions from recovered TB

Isoniazid can be used alone or in combination with Rifampin for treatment of latent tuberculosis, or as part of a four-drug regimen..<ref name = "O'Connor_2024" /> The drug regimen typically requires daily or weekly oral administration for a period of three to nine months, often under Directly Observed Therapy (DOT) supervision.<ref name="Lewis_2013">Template:Cite book</ref>

Non-tuberculous mycobacteria

Isoniazid may also be used off-label to treat nontuberculous mycobacterial pulmonary disease..<ref name = "O'Connor_2024" /> Isoniazid was widely used in the treatment of Mycobacterium avium complex as part of a regimen including rifampicin and ethambutol.<ref>*Template:Cite journal</ref> Evidence suggests that isoniazid prevents mycolic acid synthesis in M. avium complex as in M. tuberculosis<ref name="Mdluli_1998">Template:Cite journal</ref> and although this is not bactericidal to M. avium complex, it greatly potentiates the effect of rifampicin.<ref>Template:Cite journal </ref>

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.<ref name="DailyMed_2018">Template:Cite web</ref> 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.<ref name="Bothamley_2001">Template:Cite journal</ref> 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.<ref name="Steichen_2006">Template:Cite journal</ref>

People with liver dysfunction are at a higher risk for hepatitis caused by INH, and may need a lower dose.<ref name="DailyMed_2018" /> 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.<ref name="DailyMed_2018" /><ref name="Saukkonen_2006">Template:Cite journal</ref>

History

Synthesis

File:Friedrich Raschig 1897.jpg

Friedrich Raschig's (right) development of the Olin Raschig process enabled the synthesis of isoniazid in 1912.

After Friedrich Raschig developed a method to synthesize hydrazine, Hans Meyer and his doctoral student at the German University in Prague Josef Mally researched hydrazides of pyridinecarboxylic acids. By reacting ethyl isonicotinate with hydrazine hydrate, they obtained a compound which, after recrystallization, possessed a melting point of 163°C.<ref name="Meyer_1912">Template:Cite journal</ref> Despite its publication in 1912, the compound's pharmaceutical properties were not investigated for decades.

In the 1940s, French physicians discovered that nicotinamide had some activity against tubercle bacilli in vitro and in infected guinea pigs.<ref>Template:Cite news</ref><ref name="Chakraborty_2015">Template:Cite journal</ref> At the same time, German chemists led by G. Domagk investigating sulfo drugs at Bayer developed thioacetazone.<ref name="McDermott_1969">Template:Cite journal</ref><ref name="Chakraborty_2015" /><ref>Template:Cite book</ref> After their findings were made public, in 1950 Template:Ill modified it to the less toxic thiosemicarbazone of nicotinaldehyde<ref>Template:Cite patent</ref> while H. H. Fox developed similar isonicotinaldehyde thiosemicarbazone.<ref>Template:Cite patent</ref>

Discovery of anti-TB activity

Soon, multiple laboratories discovered anti-TB activity of isoniazid.<ref name="Chakraborty_2015" /><ref name="McDermott_1969" /> This led three pharmaceutical companies to unsuccessfully attempted to patent the drug at the same time,<ref>Template:Cite journal</ref> the most prominent one being Roche in January 1951,<ref>Template:Cite patent</ref> which launched its version, Rimifon, in 1952.<ref name="Roche">Template:Cite web</ref> Additionally, Soviet physicians Template:Ill and Bella Keyfman independently discovered this activity in 1949, but neither published their findings in a peer-reviewed article nor applied for an inventor's certificate.<ref name="Genkina_2003">Template:Cite web</ref><ref>Template:Cite news</ref>

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.<ref name="Jones_2002">Template:Cite journal</ref> The research was led by Walsh McDermott, an infectious disease researcher with an interest in public health, who had previously taken isoniazid to treat his own tuberculosis.<ref name="Beeson_1990">Template:Cite book</ref>

Isoniazid and a related drug, iproniazid, were among the first drugs to be referred to as antidepressants.<ref>Template:Cite journal</ref> Psychiatric use stopped in 1961 following reports of hepatotoxicity. Use against tuberculosis continued, as isoniazid's effectiveness against the disease outweighs its risks.<ref name="Samouco_2023">Template:Cite journal</ref>

Elucidation of mechanism of action

Seminal studies that uncovered the mechanism of action for isoniazid were largely performed in M. smegmatis, a model for the slow-growing M. tuberculosis.<ref name="Sparks_2023">Template:Cite journal</ref>Template:Rp In 1992, Stewart Cole and colleagues discovered that isoniazid was active in resistant M. smegmatis only when KatG, a catalase-peroxidase, was expressed;<ref name="Sparks_2023" />Template:Rp<ref name="Zhang_1992">Template:Cite journal</ref> KatG is now understood to be critical for the metabolism of the prodrug isoniazid into its active forms..<ref name = "O'Connor_2024" /><ref name="Sparks_2023" />Template:Rp

At the Albert Einstein College of Medicine, William R. Jacobs Jr. and coworkers discovered that inhA—which they also found to encode an NADH-specific enoyl-acyl carrier protein reductase—as isoniazid's primary target<ref name="Banerjee_1994">Template:Cite journal</ref><ref name="Sparks_2023" />Template:Rp The isoniazid-NAD adduct was also shown to bind and inhibit InhA, the protein product of inhA.<ref name="Vilcheze_2007">Template:Cite journal</ref>Template:Rp

Modern usage

As part of standard TB chemotherapy, isoniazid is now typically administered alongside at least three other drugs—ethambutol, pyrazinamide, and rifampin—for six to nine months.<ref name="Vilcheze_2007" />Template:Rp

Isoniazid is also included on the World Health Organization's List of Essential Medicines.<ref>Template:Cite book</ref> The World Health Organization classifies isoniazid as critically important for human medicine.<ref name="WHO_2019">Template:Cite book</ref>

Adverse effects

Side effects

Template:Multiple image Up to 20% of people taking isoniazid experience peripheral neuropathy when taking daily doses of 6 mg/kg of body weight or higher.<ref name="Alldredge_2013">Template:Cite book</ref> Gastrointestinal reactions include nausea and vomiting.<ref name="Isoniazid_insert">Template:Cite web</ref> 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 common and can present with a maculopapular rash and fever.<ref name="Isoniazid_insert" /> Gynecomastia may also occur.<ref name="Lewis_2013"/>

Isoniazid inhibits pyridoxine phosphokinase, which is responsible for maintaining the active form of vitamin B6, pyridoxal 5′-phosphate (P5P). Isoniazid is also associated with increased excretion of pyridoxine. Altogether, this means that isoniazid can cause pyridoxine (vitamin B6) deficiency, leading to peripheral neuropathy and (rarely) sideroblastic anemia via insufficient P5P provided to δ-aminolevulinic acid synthase.<ref name="Steichen_2006" /> It is recommended that isoniazid be taken with pyridoxine in persons at risk of peripheral neuropathy as well as those who have already developed peripheral neuropathy.<ref>Template:Cite web</ref>

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.<ref name="CDC_2016">Template:Cite web</ref> 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.<ref name="Isoniazid_insert" /><ref name="Trevor_2013">Template:Cite book</ref> 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.<ref name="Isoniazid_insert" /> When it happens, isoniazid-induced liver toxicity has been shown to occur in 50% of patients within the first 2 months of therapy.<ref name="Drew_2015">Template:Cite web</ref>

Some recommend that liver function should be monitored carefully in all people receiving it,<ref name="DailyMed_2018" /> but others recommend monitoring only in certain populations.<ref name="CDC_2016" /><ref>Template:Cite book</ref><ref name="Ormerod_1998">Template:Cite journal</ref> Headache, poor concentration, weight gain, poor memory, insomnia, and depression have all been associated with isoniazid use.<ref name="Alao_1998">Template:Cite journal</ref><ref name="Mukherjee_2023">Template:Cite journal</ref> All patients and healthcare workers should be aware of these serious side effects, especially if suicidal ideation or behavior are suspected.<ref name="Alao_1998" /><ref name="Iannaccone_2002">Template:Cite journal</ref><ref name="Pallone_1993">Template:Cite journal</ref>

Drug interactions

Isoniazid decreases the metabolism of carbamazepine, slowing down its clearance from the body. People taking carbamazepine should have their carbamazepine levels monitored and, if necessary, have their dose adjusted accordingly.<ref name="Fleenor_1991">Template:Cite journal</ref> Isoniazid can also increase the amount of phenytoin in the body. The doses of phenytoin may need to be adjusted when given with isoniazid.<ref name="Jonville_1991">Template:Cite journal</ref><ref name="Bass_1994">Template:Cite journal</ref> 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.<ref name="Hoglund_1987">Template:Cite journal</ref> Valproate levels may increase when taken with isoniazid. Valproate levels should be monitored and its dose adjusted if necessary.<ref name="Jonville_1991" />

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.<ref name="Murphy_1990">Template:Cite journal</ref><ref name="Burk_1990">Template:Cite journal</ref>

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.<ref name="Baciewicz_1993">Template:Cite journal</ref>

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.<ref name="Suarez_2009">Template:Cite journal</ref> 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,<ref name="Timmins_2004">Template:Cite journal</ref> which has also been shown to be important in the action of another antimycobacterial prodrug pretomanid.<ref>Template:Cite journal</ref>

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

Isoniazid is bactericidal to rapidly dividing mycobacteria, but is bacteriostatic if the mycobacteria are slow-growing.<ref name="Ahmad_2009">Template:Cite journal</ref> It inhibits the cytochrome P450 system and hence acts as a source of free radicals.<ref name="Harvey_2006">Template:Cite book</ref>

Isoniazid is a mild non-selective monoamine oxidase inhibitor (MAO-I).<ref name="Judd_1994">Template:Cite journal</ref> It inhibits diamine oxidase more strongly. These two actions are possible explanations for its antidepressant action<ref name="Healy_1998">Template:Cite book</ref> as well as its ability to cause mania.<ref name="Samouco_2023" />

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.

Overdose

Isoniazid causes seizure on overdose due to a depletion of pyridoxal 5′-phosphate (P5P) preventing glutamic acid decarboxylase from making gamma aminobutyric acid (GABA). Ordinary pyridoxine is an effective antidote of this mechanism of toxicity.<ref>Template:Cite journal</ref>

Preparation

Isoniazid is an isonicotinic acid derivative. It is manufactured using 4-cyanopyridine and hydrazine hydrate.<ref name="William_Andrew_Publishing_2008">Template:Cite book</ref> In another method, isoniazid was claimed to have been made from citric acid starting material.<ref name="Baizer_1956">Template:Cite journal</ref>

It can in theory be made from methyl isonicotinate, which is labelled a semiochemical.

Brand names

Brand names for isoniazid include Hydra, Hyzyd, Isovit, Laniazid, Nydrazid, Rimifon, and Stanozide.<ref name="FDA_2012">Template:Cite web</ref>

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.<ref name="Saygin_1959">Template:Cite journal</ref>

Dogs

Isoniazid may be used for dogs, but there have been concerns it can cause seizures.<ref name="Sykes_2013">Template:Cite book</ref>