First synthesis was described in 1912.[6] A. Kachugin invented the drug against tuberculosis under name Tubazid in 1949. Three pharmaceutical companies unsuccessfully attempted to patent the drug at the same time,[7] the most prominent one being Roche, which launched its version, Rimifon, in 1952.[8]
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.[9] 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.[10]
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.[14]
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[15][16]
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.[17] 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.[17]
Isoniazid was widely used in the treatment of Mycobacterium avium complex as part of a regimen including rifampicin and ethambutol.[18] Evidence suggests that isoniazid prevents mycolic acid synthesis in M. avium complex as in M. tuberculosis[19] 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.[20]
It is recommended that women with active tuberculosis who are pregnant or breastfeeding take isoniazid. Preventive therapy should be delayed until after giving birth.[21] 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.[22]
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.[23]
People with liver dysfunction are at a higher risk for hepatitis caused by INH, and may need a lower dose.[21]
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.[21][24]
Up to 20% of people taking isoniazid experience peripheral neuropathy when taking daily doses of 6 mg/kg of body weight or higher.[25] Gastrointestinal reactions include nausea and vomiting.[15]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.[15] Hypersensitivity reactions are also common and can present with a maculopapular rash and fever.[15]Gynecomastia may occur.[17]
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.[26] 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.[15][27] Symptoms suggestive of liver toxicity include nausea, vomiting, abdominal pain, dark urine, right upper quadrant pain, and loss of appetite.[15] Black and Hispanic women are at higher risk for isoniazid-induced hepatotoxicity.[15] When it happens, isoniazid-induced liver toxicity has been shown to occur in 50% of patients within the first 2 months of therapy.[28]
Some recommend that liver function should be monitored carefully in all people receiving it,[21] but others recommend monitoring only in certain populations.[26][29][30]
Headache, poor concentration, weight gain, poor memory, insomnia, and depression have all been associated with isoniazid use.[31] All patients and healthcare workers should be aware of these serious side effects, especially if suicidal ideation or behavior are suspected.[31][32][33]
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.[23]
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.[35][36]
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.[37]
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.[38]
Isoniazid may increase the amount of phenytoin in the body. The doses of phenytoin may need to be adjusted when given with isoniazid.[39][40]
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.[41]
Valproate levels may increase when taken with isoniazid. Valproate levels should be monitored and its dose adjusted if necessary.[39]
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.[42] 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,[43] which has also been shown to be important in the action of another antimycobacterial prodrug pretomanid.[44]
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-lifeisbimodal, 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.[citation needed]
^Jones DS (2002). "The health care experiments at Many Farms: the Navajo, tuberculosis, and the limits of modern medicine, 1952-1962". Bulletin of the History of Medicine. 76 (4): 749–790. doi:10.1353/bhm.2002.0186. PMID12446978. S2CID30166423.
^Moncrieff J (June 2008). "The creation of the concept of an antidepressant: an historical analysis". Social Science & Medicine. 66 (11): 2346–2355. doi:10.1016/j.socscimed.2008.01.047. PMID18321627.
^Gegia M, Winters N, Benedetti A, van Soolingen D, Menzies D (February 2017). "Treatment of isoniazid-resistant tuberculosis with first-line drugs: a systematic review and meta-analysis". The Lancet. Infectious Diseases. 17 (2): 223–234. doi:10.1016/S1473-3099(16)30407-8. PMID27865891.
^van Ingen J, Egelund EF, Levin A, Totten SE, Boeree MJ, Mouton JW, et al. (September 2012). "The pharmacokinetics and pharmacodynamics of pulmonary Mycobacterium avium complex disease treatment". American Journal of Respiratory and Critical Care Medicine. 186 (6): 559–565. doi:10.1164/rccm.201204-0682OC. PMID22744719.
^ abcd"Isoniazid tablet". DailyMed. 18 October 2018. Archived from the original on 13 March 2019. Retrieved 24 January 2020.
^ abSteichen O, Martinez-Almoyna L, De Broucker T (April 2006). "[Isoniazid induced neuropathy: consider prevention]". Revue des Maladies Respiratoires. 23 (2 Pt 1): 157–160. doi:10.1016/S0761-8425(06)71480-2. PMID16788441.
^Saukkonen JJ, Cohn DL, Jasmer RM, Schenker S, Jereb JA, Nolan CM, et al. (October 2006). "An official ATS statement: hepatotoxicity of antituberculosis therapy". American Journal of Respiratory and Critical Care Medicine. 174 (8): 935–952. doi:10.1164/rccm.200510-1666ST. PMID17021358. S2CID36384722.
^Alldredge B (February 12, 2013). Applied Therapeutics. Lippincott Williams & Wilkins. ISBN9781609137137.
^Pallone KA, Goldman MP, Fuller MA (February 1993). "Isoniazid-associated psychosis: case report and review of the literature". The Annals of Pharmacotherapy. 27 (2): 167–170. doi:10.1177/106002809302700205. PMID8439690. S2CID28637999.
^Landheer K, Prinsen H, Petroff OA, Rothman DL, Juchem C (June 2020). "Elevated homocarnosine and GABA in subject on isoniazid as assessed through 1H MRS at 7T". Analytical Biochemistry. 599: 113738. doi:10.1016/j.ab.2020.113738. PMID32302606. S2CID215809029.
^Murphy R, Swartz R, Watkins PB (November 1990). "Severe acetaminophen toxicity in a patient receiving isoniazid". Annals of Internal Medicine. 113 (10): 799–800. doi:10.7326/0003-4819-113-10-799. PMID2240884.
^Burk RF, Hill KE, Hunt RW, Martin AE (July 1990). "Isoniazid potentiation of acetaminophen hepatotoxicity in the rat and 4-methylpyrazole inhibition of it". Research Communications in Chemical Pathology and Pharmacology. 69 (1): 115–118. PMID2218067.
^Baciewicz AM, Baciewicz FA (September 1993). "Ketoconazole and fluconazole drug interactions". Archives of Internal Medicine. 153 (17): 1970–1976. doi:10.1001/archinte.153.17.1970. PMID8357281.
^ abJonville AP, Gauchez AS, Autret E, Billard C, Barbier P, Nsabiyumva F, et al. (1991). "Interaction between isoniazid and valproate: a case of valproate overdosage". European Journal of Clinical Pharmacology. 40 (2): 197–198. doi:10.1007/BF00280078. PMID2065702. S2CID22218366.
^Bass JB, Farer LS, Hopewell PC, O'Brien R, Jacobs RF, Ruben F, et al. (May 1994). "Treatment of tuberculosis and tuberculosis infection in adults and children. American Thoracic Society and The Centers for Disease Control and Prevention". American Journal of Respiratory and Critical Care Medicine. 149 (5): 1359–1374. doi:10.1164/ajrccm.149.5.8173779. PMID8173779.
^Höglund P, Nilsson LG, Paulsen O (February 1987). "Interaction between isoniazid and theophylline". European Journal of Respiratory Diseases. 70 (2): 110–116. PMID3817069.
^Harvey RA, Howland RD, Mycek MJ, Champe PC (2006). Harvey RA, Champe PC (eds.). Pharmacology. Vol. 864 (4th ed.). Lippincott Williams & Wilkins. ISBN9780781741187.
^Judd FK, Mijch AM, Cockram A, Norman TR (1994). "Isoniazid and antidepressants: is there cause for concern?". International Clinical Psychopharmacology. 9 (2): 123–125. doi:10.1097/00004850-199400920-00009. PMID8056994.
^Baizer MM, Dub M, Gister S, Steinberg NG (July 1956). "Synthesis of isoniazid from citric acid". Journal of the American Pharmaceutical Association. 45 (7): 478–480. doi:10.1002/jps.3030450714. PMID13345683.
^"Drugs@FDA". fda.gov. United States Food and Drug Administration. Archived from the original on 14 August 2012. Retrieved 22 August 2016.
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