Isoniazid

Isoniazid, also known as isonicotinic acid hydrazide (INH), is an antibiotic used for the treatment of tuberculosis.<ref name=AHFS2016>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> For active tuberculosis, it is often used together with rifampicin, pyrazinamide, and either streptomycin or ethambutol.<ref name=WHO2008>Template:Cite book</ref> For latent tuberculosis, it is often used alone.<ref name=AHFS2016/> It may also be used for atypical types of mycobacteria, such as M. avium, M. kansasii, and M. xenopi.<ref name=AHFS2016/> It is usually taken by mouth, but may be used by injection into muscle.<ref name=AHFS2016/>

History

After F. Raschig developed a method to synthesize hydrazine, Hans Meyer and his doctoral student at the German University in Prague Josef Mally studied hydrazides of pyridinecarboxylic acids. By reacting ethyl isonicotinate with hydrazine hydrate they obtained a compound which, after a recrystallization, had a melting point of 163°C.<ref>Template:Cite journal</ref> Despite their results published in 1912, its pharmaceutical properties weren't 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>{{#if:2676178 |[{{#ifeq:|uspto|http://patft.uspto.gov/netacgi/nph-Parser?patentnumber=%7Chttps://patents.google.com/patent/US}}{{#iferror:{{#expr:2676178 }}|2676178}} U.S. patent {{#ifeq:Template:Replace|Template:Digits|Template:Replace|2676178}}] |{{US patent|123456|link text}}}}</ref> Soon, multiple laboratories discovered anti-TB activity of isoniazid.<ref name="Chakraborty_2015" /><ref name="McDermott_1969" />

It's believed that Soviet physicians Template:Ill and Bella Keyfman also discovered this activity in 1949 but neither published their findings in a peer-reviewed article nor applied for an inventor's certificate.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>Template:Cite news</ref>

Three pharmaceutical companies 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>{{#if:2685580 |[{{#ifeq:|uspto|http://patft.uspto.gov/netacgi/nph-Parser?patentnumber=%7Chttps://patents.google.com/patent/US}}{{#iferror:{{#expr:2685580 }}|2685580}} U.S. patent {{#ifeq:Template:Replace|Template:Digits|Template:Replace|2685580}}] |{{US patent|123456|link text}}}}</ref> which launched its version, Rimifon, in 1952.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</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>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>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=mania>Template:Cite journal</ref>

It is on the World Health Organization's List of Essential Medicines.<ref name="WHO21st">Template:Cite book</ref> The World Health Organization classifies isoniazid as critically important for human medicine.<ref>Template:Cite book</ref> Isoniazid is available as a generic medication.<ref name=AHFS2016/>

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.<ref>Template:Cite journal</ref>

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

• People with HIV infection and a PPD (purified protein derivative) 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<ref name="Isoniazid_2023" /><ref>Template:Cite journal</ref>

Isoniazid can be used alone or in combination with Rifampin for treatment of latent tuberculosis, or as part of a four-drug regimen for treatment of active tuberculosis.<ref name="Lewis_2013">Template:Cite book</ref> 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" />

Non-tuberculous mycobacteria

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>Template:Cite journal</ref> 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.<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="Isoniazid label">{{#invoke:citation/CS1|citation |CitationClass=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>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="Isoniazid label"/>

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="Isoniazid label"/><ref>Template:Cite journal</ref>

Side effects

Up to 20% of people taking isoniazid experience peripheral neuropathy when taking daily doses of 6 mg/kg of body weight or higher.<ref>Template:Cite book</ref> Gastrointestinal reactions include nausea and vomiting.<ref name="Isoniazid_2023">{{#invoke:citation/CS1|citation |CitationClass=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.<ref name="Isoniazid_2023"/> Hypersensitivity reactions are also common and can present with a maculopapular rash and fever.<ref name="Isoniazid_2023" /> Gynecomastia may occur.<ref name="Lewis_2013" />

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-ltbi>{{#invoke:citation/CS1|citation |CitationClass=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_2023" /><ref>Template:Cite book</ref> Symptoms suggestive of liver toxicity include nausea, vomiting, abdominal pain, dark urine, right upper quadrant pain, and loss of appetite.<ref name="Isoniazid_2023" /> Black and Hispanic women are at higher risk for isoniazid-induced hepatotoxicity.<ref name="Isoniazid_2023" /> When it happens, isoniazid-induced liver toxicity has been shown to occur in 50% of patients within the first 2 months of therapy.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Some recommend that liver function should be monitored carefully in all people receiving it,<ref name="Isoniazid label"/> but others recommend monitoring only in certain populations.<ref name=cdc-ltbi/><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>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" /><ref>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">Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

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 δ-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.<ref name="Steichen_2006" />

Isoniazid was found to significantly elevate the in vivo concentration of GABA and homocarnosine in a single subject via magnetic resonance spectroscopy.<ref>Template:Cite journal</ref>

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.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

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.<ref>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>Template:Cite journal</ref>

Isoniazid may increase the amount of phenytoin in the body. The doses of phenytoin may need to be adjusted when given with isoniazid.<ref name=Jonville>Template:Cite journal</ref><ref>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>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"/>

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>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>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>Template:Cite journal</ref> It inhibits the cytochrome P450 system and hence acts as a source of free radicals.<ref>Template:Cite book</ref>

Isoniazid is a mild non-selective monoamine oxidase inhibitor (MAO-I).<ref name=maoi>Template:Cite journal</ref> It inhibits diamine oxidase more strongly. These two actions are possible explanations for its antidepressant action<ref name="isbn1-86036-010-6">Template:Cite book</ref> as well as its ability to cause mania.<ref name=mania/>

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.Template:Cn

Preparation

Isoniazid is an isonicotinic acid derivative. It is manufactured using 4-cyanopyridine and hydrazine hydrate.<ref name=William>Template:Cite book</ref> In another method, isoniazid was claimed to have been made from citric acid starting material.<ref name="BaizerDub1956">Template:Cite journal</ref>

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

Brand names

Hydra, Hyzyd, Isovit, Laniazid, Nydrazid, Rimifon, and Stanozide.<ref>{{#invoke:citation/CS1|citation |CitationClass=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>Template:Cite journal</ref> The test works by forming a hydrazone which can be detected by its bathochromic shift.Template:Cn

Dogs

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

Further reading

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External links

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