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.
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
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. 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.
Isoniazid was widely used in the treatment of Mycobacterium avium complex as part of a regimen including rifampicin and ethambutol. Evidence suggests that isoniazid prevents mycolic acid synthesis in M. avium complex as in M. tuberculosis 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.
It is recommended that women with active tuberculosis who are pregnant or breastfeeding take isoniazid. Preventive therapy should be delayed until after giving birth. 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.
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.
People with liver dysfunction are at a higher risk for hepatitis caused by INH, and may need a lower dose.
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.
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. 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. 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. When it happens, isoniazid-induced liver toxicity has been shown to occur in 50% of patients within the first 2 months of therapy.
Some recommend that liver function should be monitored carefully in all people receiving it, but others recommend monitoring only in certain populations.
Headache, poor concentration, weight gain, poor memory, insomnia, and depression have all been associated with isoniazid use. All patients and healthcare workers should be aware of these serious side effects, especially if suicidal ideation or behavior are suspected.
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.
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.
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.
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.
Isoniazid may increase the amount of phenytoin in the body. The doses of phenytoin may need to be adjusted when given with isoniazid.
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.
Valproate levels may increase when taken with isoniazid. Valproate levels should be monitored and its dose adjusted if necessary.
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.
First synthesis was described in 1912. A. Kachugin invented the drug against tuberculosis under name Tubazid in 1926. Three pharmaceutical companies unsuccessfully attempted to patent the drug at the same time, the most prominent one being Roche, which launched its version, Rimifon, in 1952. With the introduction of isoniazid, a cure for tuberculosis was first considered possible.
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. 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.
^World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
^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". Lancet Infect Dis. 17 (2): 223–234. doi:10.1016/S1473-3099(16)30407-8. PMID27865891.
^Van Ingen, J; Egelund, E. F; Levin, A; Totten, S. E; Boeree, M. J; Mouton, J. W; Aarnoutse, R. E; Heifets, L. B; Peloquin, C. A; Daley, C. L (2012). "The pharmacokinetics and pharmacodynamics of pulmonary Mycobacterium avium complex disease treatment". American Journal of Respiratory and Critical Care Medicine. 186 (6): 559–65. doi:10.1164/rccm.201204-0682OC. PMID22744719.
^Murphy, R.; Swartz, R.; Watkins, P.B. (November 15, 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, R.F.; Hill, K.E.; Hunt Jr., R.W.; Martin, A.E. (July 1990). "Isoniazid potentiation of acetaminophen hepatotoxicity in the rat and 4-methylpyrazole inhibition of it". Research Communications in Chemical Pathology and Pharmacolog. 69 (1): 115–118. PMID2218067.
^ abJonville, A.P.; Gauchez, A.S.; Autret, E.; Billard, C.; Barbier, P.; Nsabiyumva, F.; Breteau, M. (1991). "Interaction between isoniazid and valproate: a case of valproate overdosage". European Journal of Clinical Pharmacology. 40 (2): 197–198. doi:10.1007/BF00280078 (inactive 31 October 2021). PMID2065702.CS1 maint: DOI inactive as of October 2021 (link)
^Bass, Jr., J.B.; Farer, L.S.; Hopewell, P.C.; O'Brien, R.; Jacobs, R.F.; Ruben, F.; Snider, Jr., D.E.; Thornton, G. (May 1994). "Treatment of tuberculosis and tuberculosis infection in adults and children. American Thoracic Society and The Centers for Disease Control and Prevention". Am J Respir Crit Care Med. 149 (5): 1359–1374. doi:10.1164/ajrccm.149.5.8173779. PMID8173779.
^Höglund, P.; Nilsson, L.G.; Paulsen, O. (February 1987). "Interaction between isoniazid and theophylline". European Journal of Respiratory Diseases. 70 (2): 110–116. PMID3817069.
^Harvey, Richard A.; Howland, Richard D.; Mycek, Mary Julia; Champe, Pamela C. (2006). Harvey, Richard A.; Champe, Pamela C. (eds.). Pharmacology. 864 (4th ed.). Lippincott Williams & Wilkins. ISBN9780781741187.
^Jones, David S. (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.
^Baizer, Manuel M.; Dub, Michael; Gister, Sidney; Steinberg, Nathan G. (1956). "Synthesis of Isoniazid from Citric Acid". Journal of the American Pharmaceutical Association (Scientific Ed.). 45 (7): 478–480. doi:10.1002/jps.3030450714. ISSN0095-9553. PMID13345683.
^"Drugs@FDA". fda.gov. United States Food and Drug Administration. Archived from the original on 14 August 2012. Retrieved 22 August 2016.
^Smith, L.L.; Foell, Theodore (1959). "Differentiation of Δ4-3-Ketosteroids and Δ1,4-3-Ketosteroids with Isonicotinic Acid Hydrazide". Analytical Chemistry. 31 (1): 102–105. doi:10.1021/ac60145a020.