Isoniazid is aprodrug that, when activated by catalase-peroxidase KatG, generates adducts and radicals that inhibits the formation of themycobacterial cell wall. Side effects in those treated with isoniazid includevitamin B6 deficiency, liver toxicity,peripheral neuropathy, and a reduction in blood cell production. Mutations in theahpC,inhA,kasA,katG, genes ofM. tuberculosis may result in isoniazid resistance.
The primary use of isoniazid is as first-line treatment for latent and active infection ofMycobacterium tuberculosis, the causative agent oftuberculosis (TB).[3] In persons with isoniazid-resistantMycobacterium tuberculosis infection, drug regimens based on isoniazid have a high rate of failure.[4]
Isoniazid can be used alone or in combination withRifampin for treatment of latent tuberculosis, or as part of a four-drug regimen..[3] The drug regimen typically requires daily or weekly oral administration for a period of three to nine months, often underDirectly Observed Therapy (DOT) supervision.[5]
Isoniazid may also be usedoff-label to treatnontuberculous mycobacterial pulmonary disease..[3] Isoniazid was widely used in the treatment ofMycobacterium avium complex as part of a regimen including rifampicin and ethambutol.[6] Evidence suggests that isoniazid prevents mycolic acid synthesis inM. avium complex as inM. tuberculosis[7] and although this is not bactericidal toM. avium complex, it greatly potentiates the effect of rifampicin.[8]
It is recommended that women with active tuberculosis who are pregnant or breastfeeding take isoniazid. Preventive therapy should be delayed until after giving birth.[9] 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 takevitamin B6 in itspyridoxine form to minimize the risk of peripheral nerve damage.[10] 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.[11]
People with liver dysfunction are at a higher risk for hepatitis caused by INH, and may need a lower dose.[9] 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.[9][12]
AfterFriedrich Raschig developeda method to synthesizehydrazine,Hans Meyer and his doctoral student at theGerman University in Prague Josef Mally researched hydrazides of pyridinecarboxylic acids. By reacting ethyl isonicotinate with hydrazine hydrate, they obtained a compound which, afterrecrystallization, possessed a melting point of 163°C.[13] Despite its publication in 1912, the compound's pharmaceutical properties were not investigated for decades.
Soon, multiple laboratories discovered anti-TB activity of isoniazid.[15][16] This led three pharmaceutical companies to unsuccessfully attempted to patent the drug at the same time,[20] the most prominent one beingRoche in January 1951,[21] which launched its version, Rimifon, in 1952.[22] Additionally, Soviet physiciansA. Kachugin [ru] 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.[23][24]
The drug was first tested atMany Farms, aNavajo community inArizona, due to the Navajo reservation's tuberculosis problem and because the population had not previously been treated withstreptomycin, the main tuberculosis treatment at the time.[25] The research was led byWalsh McDermott, an infectious disease researcher with an interest in public health, who had previously taken isoniazid to treat his own tuberculosis.[26]
Isoniazid and a related drug,iproniazid, were among the first drugs to be referred to asantidepressants.[27] Psychiatric use stopped in 1961 following reports of hepatotoxicity. Use against tuberculosis continued, as isoniazid's effectiveness against the disease outweighs its risks.[28]
Seminal studies that uncovered the mechanism of action for isoniazid were largely performed inM. smegmatis, amodel for the slow-growingM. tuberculosis.[29]: 1, 7 In 1992,Stewart Cole and colleagues discovered that isoniazid was active in resistantM. smegmatis only whenKatG, acatalase-peroxidase, was expressed;[29]: 7 [30] KatG is now understood to be critical for the metabolism of the prodrug isoniazid into its active forms..[3][29]: 7
As part of standard TB chemotherapy, isoniazid is now typically administered alongside at least three other drugs—ethambutol,pyrazinamide, andrifampin—for six to nine months.[32]: 36
Due to structural similarities, isoniazid administration can causevitamin B6 deficiency via reduced activation and increased excretion.
Up to 20% of people taking isoniazid experienceperipheral neuropathy when taking daily doses of 6 mg/kg of body weight or higher.[35] Gastrointestinal reactions include nausea and vomiting.[36]Aplastic anemia,thrombocytopenia, andagranulocytosis 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 amaculopapular rash and fever.[36]Gynecomastia may also occur.[5]
Isoniazid inhibitspyridoxine 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 causepyridoxine (vitamin B6) deficiency, leading to peripheral neuropathy and (rarely)sideroblastic anemia via insufficient P5P provided to δ-aminolevulinic acid synthase.[11] 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.[37]
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.[38] 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.[36][39] 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.[36] When it happens, isoniazid-induced liver toxicity has been shown to occur in 50% of patients within the first 2 months of therapy.[40]
Some recommend that liver function should be monitored carefully in all people receiving it,[9] but others recommend monitoring only in certain populations.[38][41][42] Headache, poor concentration, weight gain, poor memory, insomnia, and depression have all been associated with isoniazid use.[43][44] All patients and healthcare workers should be aware of these serious side effects, especially if suicidal ideation or behavior are suspected.[43][45][46]
Isoniazid decreases the metabolism ofcarbamazepine, slowing down its clearance from the body. People taking carbamazepine should have their carbamazepine levels monitored and, if necessary, have their dose adjusted accordingly.[47] Isoniazid can also increase the amount of phenytoin in the body. The doses of phenytoin may need to be adjusted when given with isoniazid.[48][49] Isoniazid may increase the plasma levels oftheophylline. There are some cases of theophylline slowing down isoniazid elimination. Both theophylline and isoniazid levels should be monitored.[50]Valproate levels may increase when taken with isoniazid. Valproate levels should be monitored and its dose adjusted if necessary.[48]
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.[51][52]
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.[53]
Isoniazid is aprodrug that inhibits the formation of themycobacterial cell wall. Isoniazid must be activated by KatG, a bacterial catalase-peroxidase enzyme inMycobacterium tuberculosis.[54] KatG catalyzes the formation of the isonicotinic acyl radical, which spontaneously couples withNADH to form the nicotinoyl-NAD adduct. This complex binds tightly to theenoyl-acyl carrier protein reductase InhA, thereby blocking the natural enoyl-AcpM substrate and the action offatty acid synthase. This process inhibits the synthesis ofmycolic acids, which are required components of themycobacterial cell wall. A range of radicals are produced by KatG activation of isoniazid, includingnitric oxide,[55] which has also been shown to be important in the action of another antimycobacterial prodrugpretomanid.[56]
Isoniazid is a mild non-selectivemonoamine oxidase inhibitor (MAO-I).[59] It inhibitsdiamine oxidase more strongly. These two actions are possible explanations for its antidepressant action[60] as well as its ability to cause mania.[28]
Isoniazid reaches therapeutic concentrations in serum,cerebrospinal fluid, and withincaseous granulomas. It is metabolized in the liver viaacetylation into acetylhydrazine. Two forms of the enzyme are responsible for acetylation, so some patients metabolize the drug more quickly than others. Hence, thehalf-life isbimodal, 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 ofrenal failure.
Isoniazid causes seizure on overdose due to a depletion of pyridoxal 5′-phosphate (P5P) preventingglutamic acid decarboxylase from makinggamma aminobutyric acid (GABA). Ordinary pyridoxine is an effective antidote of this mechanism of toxicity.[61]
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