Isoniazid Toxicity



This article focuses on the acute and chronic isoniazid (isonicotinic acid hydrazide [INH] toxicity. Acute INH toxicity leads to central nervous system (CNS) toxicity, including seizures, whereas chronic INH toxicity results in hepatotoxicity.

Since 1952, INH has been used as a front-line antimicrobial for tuberculosis (TB).[1, 2] INH is commonly used for prophylaxis of patients with a recently converted Mantoux tuberculin skin test (TST) with purified protein derivative (PPD) or in conjunction with other medications for the treatment of active TB infection.

A typical regimen for tuberculosis includes INH, rifampin, pyrazinamide, and ethambutol or streptomycin. Treatment lasts for 6 months for active TB, assuming responsiveness to antimicrobial therapy. Although the exact mechanism of activity is unknown, INH is believed to act by interfering with the mycobacterial cell wall synthesis.

Acute toxicity

Acute INH overdose predominantly involves the brain and may cause prolonged seizures, anion gap metabolic acidosis, and coma. Note the following:

Chronic toxicity

INH hepatotoxicity is a common complication of antituberculosis therapy, ranging in severity from asymptomatic elevation of serum transaminases to hepatic failure necessitating liver transplantation. This toxicity is not caused by high plasma INH levels but appears to represent an idiosyncratic response.[3]

INH hepatotoxicity presents a difficult management problem, for several reasons, including the following:

Guidelines for the diagnosis, treatment, control, and prevention of tuberculosis, including the medications used, have been established by the American Thoracic Society (ATS), the Centers for Disease Control and Prevention (CDC), and the Infectious Diseases Society of America (IDSA).[4] Awareness of INH poisoning may prevent severe morbidity and mortality.

A list of guidelines for TB from the CDC by topic is available at The World Health Organization also has TB guidelines at and


Acute toxicity

Acute isoniazid (INH) overdose results in decreased pyridoxal-5'-phosphate levels, decreased gamma-aminobutyric acid (GABA) synthesis, increased cerebral excitability, and seizures. The presumed mechanism of INH-induced seizure involves a decrease in the availability of GABA, which is the major inhibitory neurotransmitter in the central nervous system (CNS), as well as a relative increase in the amounts of glutamate, the primary excitatory neurotransmitter. INH metabolites directly inhibit pyridoxine phosphokinase. This enzyme converts pyridoxine (vitamin B-6) to its active form, pyridoxal-5'-phosphate, a key cofactor in the production of GABA. This functional depletion of pyridoxine causes a disruption of glutamate and GABA homeostasis and leads to an excessive excitatory milieu in the brain.

Chronic toxicity

Chronic INH hepatotoxicity results in the induction of hepatocyte apoptosis, with associated disruption of mitochondrial membrane potential and DNA strand breaks.[5] The most likely biochemical mechanism is that the metabolism of INH produces reactive metabolites that bind and damage cellular macromolecules in the liver. INH is mostly acetylated via the liver and the subsequent product, acetylisoniazid, and further (1) eliminated by the kidney; (2) oxidized to hydroxylamine, a toxic metabolite; (3) hydrolyzed into hydrazine, also toxic; or (4) further hydrolyzed to another toxic compound, acetylhydrazine. Patients who are slow acetylators may be at higher risk for hepatotoxicity.[6, 7, 8, 9]

The mild elevation of transaminases seen in as many as 20% of patients who are treated during the first 2 months of therapy may reflect direct toxicity from hydrazine metabolites, which can covalently bind to cellular macromolecules, including DNA. The more severe form of hepatitis, seen in up to 1% of adults who are treated, may be a consequence of the production of more reactive species by the CYP-450 enzyme system.

Although the most common presentation of INH hepatotoxicity is hepatocellular damage, patients occasionally may present with true drug hypersensitivity characterized by skin rash, fever, and eosinophilia.


Acute central nervous system (CNS) toxicity typically occurs in isoniazid (INH) overdose, but it may also be found with therapeutic use if administered in conjunction with rifampin, ethanol, barbiturates, and other CYP-450 inducers.

A number of risk factors for the development of severe INH hepatotoxicity have been identified.

Genetic predisposition is an important factor, but no clinical test for this predisposition is currently available.[10, 11, 12] Age is an important risk factor, presumably reflecting aging-related changes in hepatic metabolism. Female sex increases both the risk of developing INH hepatitis and the risk of death once hepatitis develops. Animal studies suggest that low levels of certain antioxidants such as glutathione which are associated with poor nutrition increase the risk for hepatotoxicity. However, human studies to support these findings are lacking.

Patients taking carbamazepine, phenobarbital, or rifampin, or those who abuse alcohol while taking INH have a higher risk for hepatotoxicity.[13, 14, 15] Ethionamide and para-aminosalicylic acid may exacerbate the toxicity of INH by interfering with its acetylation. High plasma levels of INH do not increase the risk of hepatoxicity. Conversely, neither administering lower INH doses nor monitoring plasma levels during therapy helps to decrease the rate of hepatotoxicity.

In a study of genetic predisposition to hepatotoxicity induced by anti-tuberculosis (TB) drugs that investigated the association between INH hepatitis and polymorphisms in genes for 7 drug-metabolizing enzymes (CYP2C9, CYP2C19, CYP2D6, CYP2E1, NAT2, UGT1A1, and UGT1A3) in 67 patients with INH hepatitis and 159 control subjects, Kim et al identified a significant association between INH hepatitis and 2 mutations in NAT2 (-9796T>A in the promoter and R197Q) but found no association between the disorder and mutations in the other 6 genes.[16]

The rise in INH toxicity correlates with the rise in TB. During the late 1980s, the resurgence of TB in the United States caused the highest number of reported cases of INH exposures. Contributing factors include the following:


United States statistics

Acute toxicity

From 2009 to 2014, there were 1373 cases of isoniazid (INH) overdose reported by the American Association of Poison Control Centers’ National Data Collection System. Of these cases, 558 (40.6%) occurred in patients younger than 20 years, and 219 (16%) occurred in children younger than 5 years. In the past 6 years, 94 cases were reported as having a major effect, with two reported fatalities associated with INH.[17, 18, 19, 20, 21, 22]

Chronic toxicity

The frequency of INH hepatotoxicity depends on the threshold for making the diagnosis.

Approximately 10%-20% of adult patients receiving INH show elevations in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) to about 1-3 times the upper limit of normal during the first two months of therapy. These elevations typically normalize within 3-6 weeks after discontinuance of the drug. However, most patients who continue taking INH normalize the transaminase levels within several months, with no apparent adverse effects from continuing the drug.

A comprehensive study of 13,838 INH-treated patients published by the US Public Health Service (USPHS) in 1978 found that about 10% of patients with mild transaminase elevations (1-2% of all adults treated) progress to severe hepatitis and liver failure unless the drug is discontinued.[12] Death occurred in 8 patients (0.06%). When INH is given together with other drugs for active TB, the incidence of severe hepatotoxicity is greater.

Subsequent retrospective studies suggested a much lower incidence of toxicity, provided that patients were monitored according to the current guidelines. On average, hepatotoxicity occurs in 9.2 of 1000 patients taking INH for antituberculosis therapy.[23]

International statistics

Rates within different countries reflect the frequency of INH use and tend to be highest in countries that have both sufficient public health resources to treat TB and large populations of patients infected with TB. Many of these persons are coinfected with the human immunodeficiency virus (HIV). Patients who are coinfected are at a particularly high risk for hepatitis, because both antituberculosis therapy and antiviral therapy may produce hepatotoxicity.

Age-related demographics

Patients of all ages may experience either chronic or acute INH hepatotoxicity. However, susceptibility to INH-induced hepatitis and subsequent death appears to increase dramatically with advancing age.

According to the USPHS study of 13,838 INH-treated patients reported by Kopanoff et al in 1978, hepatitis was uncommon in patients younger than 20 years and occurred in 0.3% of patients aged 20-34 years, 1.2% of patients aged 35-49 years, and 2.3% of patients aged 50-64 years.[12] Although subsequent studies have reported lower rates of hepatotoxicity, age remains an important risk factor for INH hepatotoxicity.

A study of a 7-year experience with INH hepatotoxicity in a public health TB clinic reported 4.40 events per 1000 for patients aged 25-34 years, 8.54 per 1000 for patients aged 35-49 years, and 20.83 per 1000 for those aged 50 years or older.[24]

Sex-related demographics

INH hepatotoxicity may be more common in females than in males, especially the more severe forms of hepatitis leading to liver failure and death; however, not all studies have shown this finding. In a review of all possible INH-associated hepatitis fatalities from 1969 to 1989 in which the sex of the patient was identified, 111 cases (69%) occurred in females. In a study of 41 patients in New York City who were hospitalized at least overnight for INH toxicity, 27 (82%) were female.[25]

Women in the immediate postpartum period appear to be commonly affected. However, this may be because women are more likely to have their TB infection diagnosed during pregnancy, with treatment delayed until after childbirth.

Race-related demographics

Racial differences in the susceptibility to INH hepatotoxicity are relatively small, and no studies have shown any substantial race-based predilection for this condition.

The rate of acetylation of INH in the liver is race-dependent, with 60% of black patients and white patients being slow acetylators, compared with 10%-20% of Asians. Whereas slow acetylators appear to be more prone to INH-induced hepatitis and neuropathy with long-term use, it is unclear whether the rate of acetylation affects acute toxicity.

A 1975 study of more than 14,000 persons who were treated with INH found that hepatitis developed in 1.1% (55/5190) of white patients, 0.6% (36/6140) of black patients, and 0.9% (23/2608) of Asians, although follow-up was incomplete. Because fewer Asians (34%) than white (52%) or black (59%) patients dropped out of this study, the data suggest that the risk is lowest in Asians. Black females appeared to be at particularly high risk. However, a subsequent study by Yee and coworkers found a significantly elevated risk in Asians.[26]

Endemic cases of INH toxicity have been reported in persons who have emigrated from Southeast Asia because of their increased risk of TB and greater likelihood of undergoing INH therapy. Inuits and American Indians are also at an increased risk for TB and thus for INH toxicity.

In a review of possible INH-associated hepatitis fatalities identified between 1969 and 1989, a total of 38% occurred in black patients, 40% in non-Hispanic white patients, 15% in Hispanics, 4% in Native Americans, and 1% in Asians.


Acute toxicity

In adults, acute ingestion of as little as 1.5 g of isoniazid (INH) can lead to mild toxicity.[27] Acute ingestion of over 20 mg/kg can cause convulsions. Patients who ingest 80-150 mg/kg develop severe central nervous system (CNS) symptoms.[28] Ingestion of 6-10 g may be fatal, and ingestion of 15 g is usually fatal if not appropriately treated. Reported deaths from acute INH toxicity are rare.

Chronic toxicity

The overall mortality for INH toxicity has been estimated to be as high as 20%. With current methods of supportive care, which include liver transplantation, mortality may now be lower. From 1972 to 1988, an estimated 152 fatalities were caused by INH-related hepatitis. A 2006 literature review estimated that hepatotoxicity occurred in 9.2 of every 1000 patients taking INH as anti-tuberculosis (TB) therapy, with a case-fatality rate of 4.7%.[23]

Survival rates depend on the severity of the hepatitis and on how early it is detected. If drug therapy is discontinued promptly when a 5-fold or greater transaminase elevation occurs (or a 3-fold or greater elevation with symptoms), mortality should be negligible. If INH is continued after this point or after symptoms develop, mortality due to hepatic failure may exceed 50% unless liver transplantation is performed. Patients who survive usually recover completely, without residual liver damage.

When hepatic failure occurs, prognosis depends on early identification and correction of complications (eg, aspiration pneumonia, hypotension, and cardiopulmonary arrest). Advanced age, underlying seizure disorder, severe metabolic acidosis, and decreased renal function are associated with a poor prognosis. Serum eosinophilia may be associated with a favorable outcome in patients with INH-induced hepatotoxicity.

Patient Education

All patients who receive isoniazid (INH) therapy should be counseled about the risk of severe hepatitis and the harmful effects of overdose. Warn all patients started on INH that the medication should be taken only as prescribed, and urge them to immediately report any symptoms suggestive of hepatitis, including nausea, fatigue, jaundice, and abdominal distress.

Advise patients to avoid heavy use of alcohol or acetaminophen and to maintain good nutrition.

Parents of pediatric patients should be instructed not to try to make up for any missed INH doses. Patients should be instructed to place INH pill bottle out of reach of young children to avoid accidental overdose.


Acute toxicity

In an acute isoniazid (INH) overdose, patients are typically symptomatic within 30-45 minutes. However, symptoms may be delayed for up to 2 hours, when the peak serum level occurs. Potential symptoms include the following:

When INH is taken daily at approved doses, INH hepatotoxicity typically develops within the first few months of therapy, but it may also present later. Symptoms may remain mild until after potentially lethal liver damage has occurred. Thus, patients taking INH should be educated to look for signs of liver toxicity and to report them immediately if they occur.

Symptoms typically precede jaundice and liver failure by only a few days. Constitutional symptoms include fatigue, anorexia, nausea, myalgia, and arthralgia. Symptoms due to liver failure include jaundice, dark urine, light-colored stools, bleeding diathesis, pruritus, confusion, and coma. Symptoms due to hepatic inflammation include right upper quadrant tenderness and gastrointestinal (GI) distress including anorexia, nausea, and vomiting. Immediate cessation of INH and any other potentially hepatotoxic drugs is required.

Physical Examination

Acute toxicity

Ingestion of isoniazid (INH) in excess of 200 mg/kg produces a characteristic clinical triad, as follows:

Other signs of acute INH toxicity include the following:

Chronic toxicity

Jaundice, evidenced by yellowing of the skin, sclera, or mucous membranes, is present in more severe cases as a late manifestation. Right upper quadrant tenderness may be elicited. Hepatomegaly may be present, but splenomegaly and ascites usually are absent. Stigmata of chronic liver disease typically are absent unless prior liver disease exists. In advanced cases, patients may exhibit ecchymoses, bleeding from the gingiva, or have other manifestations of coagulopathy.

Various adverse effects of long-term ingestion of INH have been identified. Peripheral neuropathy and optic neuritis is uncommon in healthy individuals, but it is more common in persons with diabetes, those with alcoholism, and malnourished elderly individuals. An increased risk of hepatitis has been noted in patients who are concomitantly using carbamazepine, phenobarbital, or rifampin, as well as in those who abuse alcohol.

INH is known to cause a positive antinuclear antibody (ANA) test result in 25% of patients and to cause clinically apparent drug-induced lupus, characterized by fever, rash, arthralgias, arthritis, and constitutional symptoms, in approximately 1% of patients.

In rare cases, INH causes mania, depression, obsessive-compulsive disorder, and psychosis, probably either by acting as a monoamine oxidase inhibitor (MAOI) or by depleting pyridoxine. Rarely, an MAOI tyramine syndrome may occur after the ingestion of tyramine-containing foods (eg, red wines or cheeses).

A hypersensitivity reaction is usually absent but may be observed in 2% of patients using INH. Signs and symptoms include fever, lymphadenopathy, and skin rashes.

Other adverse effects from long-term INH use include the following:

Approach Considerations

Serum isoniazid (INH) levels are not readily available and do not help in the initial management of INH toxicity.

Laboratory studies generally are not helpful in the diagnosis of acute INH toxicity but may identify complications. Laboratory abnormalities observed with acute INH toxicity complications may include the following:

Laboratory abnormalities seen with hepatotoxicity from INH therapy includes the following:

Laboratory Studies

Serum transaminases

Levels of serum transaminases (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) should be determined. Patients with pretreatment AST levels above the upper limit of normal are predisposed to hepatotoxicity.

If transaminase values are elevated less than 3-fold in a patient who is asymptomatic, cautious continued administration of isoniazid (INH) is permissible. However, additional testing to exclude other causes of hepatitis is usually indicated. If transaminase levels are elevated more than 3-fold, discontinue INH and other hepatotoxic drugs.

Viral serologies

Hepatitis A may be excluded by a negative test result for anti-HAV (hepatitis A virus) immunoglobulin M (IgM). Hepatitis C is excluded by a negative result for anti-HCV (hepatitis C virus) antibody; however, this test occasionally may remain negative for several weeks after the onset of hepatitis C. Hepatitis B may be excluded by a negative result for either hepatitis B surface antigen (HBsAg) or antibody to hepatitis B core antigen (anti-HBc). Testing for viral DNA or RNA also may be used, but it is more expensive.


Potential hepatotoxins other than INH should be considered. In patients with a compatible history, blood acetaminophen and ethanol levels may be useful.

Prothrombin time/international normalized ratio

The international normalized ratio (INR) usually is normal in early and mild cases of INH overdose. Significant elevation of the INR that does not respond to parenteral vitamin K is a grave sign that should prompt evaluation for liver transplantation.

Serum iron

High transferrin saturations associated with high ferritin levels suggest hemochromatosis, which often presents with transaminase abnormalities. However, ferritin is an acute-phase reactant that often is elevated in other types of hepatitis. Thus, the presence of high ferritin levels does not suggest hemochromatosis unless the iron saturation also is high. Genetic testing for hemochromatosis may be useful in these patients.

Serum ceruloplasmin

In younger persons, effort must be made exclude Wilson disease, especially if any neuropsychiatric component exists.

Additional tests

Additional laboratory studies may be performed to assess for the following:

Other Studies

Electrocardiography (ECG) may be useful if seizure is precipitated by cardiac dysrhythmia. ECG may identify a multitude of cardiac abnormalities including prolonged QTc, widened QRS, prominent R in aVR, and heart block.

Electroencephalography (EEG) is not routinely available in the emergency department (ED). EEG should be part of the full neurodiagnostic workup, as it has substantial yield and ability to predict the risk of seizure recurrence.

Histologic Findings

Liver biopsy is rarely indicated for evaluation of acute hepatitis, because the histologic features typically are nonspecific. Liver histology findings closely resemble that of acute viral hepatitis and includes ballooning degeneration, sinusoidal acidophilic bodies, and focal necrosis occasionally accompanied by slight cholestasis. Necrosis is more extensive in cases that are more severe. Inflammatory infiltrates with lymphocytes and plasma cells are common, whereas eosinophilic infiltrates are rarely seen.

Imaging Studies

For patients with new-onset seizures, unexplained seizures, or status epilepticus, noncontrast computed tomography (CT) scanning of the head is the imaging procedure of choice because of its ready availability and its ability to identify potential catastrophic pathologies.

Abdominal imaging is not normally required and should only be considered in patients with symptoms suggesting biliary disease or to exclude biliary obstruction if the alkaline phosphatase level is elevated more than the transaminase levels are. Abdominal imaging may show hepatomegaly, but splenomegaly and ascites typically are absent

Approach Considerations

Medical care for isoniazid (INH) hepatotoxicity is essentially supportive. Discontinue INH and any other potentially toxic drug, and closely monitor the patient.

Hospitalize persons who are more severely affected (eg, with significant elevation of the prothrombin time [PT]) for monitoring and potential liver transplantation; early hospitalization in a suitable institution carries less risk and permits more time to evaluate the patient for transplantation. Care of such patients is identical to that for other causes of fulminant hepatitis.

Admit patients to the intensive care unit (ICU) if they are lethargic, comatose, or severely acidotic or are experiencing refractory seizures. Transfer patients after stabilization of vital signs if ICU facilities or the services of a medical toxicologist or transplantation hepatologist are warranted but unavailable.

Consider INH toxicity in patients with unexplained new onset, recurrent, or intractable seizure. If the seizures are refractory to standard anticonvulsant therapy, consider acute INH toxicity, and administer pyridoxine.

No activity restrictions are necessary unless the PT level is elevated. Activity often is limited by fatigue.

Supportive and Pharmacologic Therapy

Therapy for acute isoniazid (INH) overdose includes controlling the ABCs (airway, breathing, and circulation), providing antidotal therapy with pyridoxine, and supportive care. For patients who remain asymptomatic for 4 hours following an ingestion of less than 20 mg/kg, expectant management is generally sufficient.

If acute neurotoxicity (seizure, coma) occurs, administer pyridoxine immediately. If the amount of INH ingested in overdose is known, administer a gram-per-gram equal amount of pyridoxine (max 5 g) intravenously for the first dose. Benzodiazepines and barbiturates can be used to potentiate the anticonvulsant effect of pyridoxine or as first-line therapy if pyridoxine is not immediately available. If the amount of INH ingested is unknown, empiric dosing of pyridoxine 70 mg/kg (max 5 g) is recommended. Pyridoxine administration can be repeated if seizures persist or recur.[4, 25, 29, 30]

The cessation of seizure activity is crucial in preventing the development of a metabolic acidosis. Intravenous fluid resuscitation and ventilation management are key to treating the metabolic acidosis associated with prolonged seizures.

The most recent consensus on the stocking of antidotes in hospitals that provide emergency care recommends 8 g of pyridoxine be immediately available for emergency use and 24 g for the first 24 hours.[31] Insufficient stockpiling of pyridoxine for the management of critically-ill INH toxicity patients has been encountered in the past. For example, a survey of 130 US institutions (in which 80% responded) found that at least 33% of the responding institutions were inadequately equipped with pyridoxine to treat acute INH toxicity.[32] Establishing a network of pharmacy resources for hospitals to obtain adequate quantities rapidly should be considered. Management of a single severely intoxicated patient may require 20 g of pyridoxine. If pyridoxine solution for injection is unavailable, pyridoxine tablets can be crushed and administered via nasogastric tube (NGT). Hospitals in urban areas with a high incidence of tuberculosis (TB) should have larger stockpiles of pyridoxine.

Once the airway is secured, gastric lavage may be considered if a recent severe overdose is suspected. Administration of activated charcoal in a 10-fold dose compared to the amount of INH ingested is recommended. Empiric activated charcoal dosing is recommended if the amount of INH ingested is unknown (children aged < 1 year: 10-25 g; children aged 1 -12 years: 25-50 g; those aged >12 years: 50-100 g). Lavage and activated charcoal are more likely to be effective if administered early or within 1 hour of an acute ingestion.

Although INH is dialyzable, dialysis is unnecessary if adequate doses of anticonvulsants and pyridoxine are administered. Hemodialysis may be indicated if the patient fails to improve with standard therapy or if adequate doses of pyridoxine cannot be obtained.

Patients with clinically significant INH-associated hepatitis and progressive hepatic failure may be successfully treated with liver transplantation. INH is second only to acetaminophen among drugs resulting in hepatotoxicity severe enough to warrant liver transplantation.

Monitor all patients until the transaminase levels normalize. Patients with minor transaminase elevations who continue to take INH require frequent monitoring (as much as twice weekly). Patients who have stopped using INH because of transaminase elevations should generally avoid subsequent use of the drug.

Reintroduction of INH does not always produce hepatitis, which suggests that environmental factors (eg, other medications, illness, and malnutrition) also may be important in some patients.


The incidence of acute and chronic toxicity from isoniazid (INH) may be reduced by applying the following measures:

Animal studies suggest that certain antioxidants may reduce the risk of INH hepatitis; these include silymarin, vitamin E, N- acetylcysteine, and melatonin. Although it is not known whether these results apply to humans, correcting nutritional deficiencies before starting INH may be warranted.

Routine monitoring of ALT is not required in healthy young persons treated for latent tuberculosis (TB), provided that they are instructed to immediately report any symptoms that suggest toxicity. However, the American Thoracic Society (ATS) recommends monitoring of transaminases for patients who have a history of long-term alcohol use, who take concomitant hepatotoxic drugs, who have known liver disease, or who are or were recently pregnant.[33] Some experts also recommend monitoring for those older than 35 years.

Routine monitoring of aspartate aminotransferase (AST) levels among patients undergoing INH prophylaxis may detect early cases of hepatotoxicity.


Consider consultation with a medical toxicologist, if available, for bedside evaluation. US Poison Help Line 1-800-222-1222 (affiliated with the American Academy of Poison Control Centers) is available 24 hours, 7 days a week if a medical toxicologist is not available at your institution.

Consider a psychiatric consultation in all cases of intentional overdose before the patient is discharged from the hospital. Consider neuropsychiatric evaluation for possible dementia.

Consider consultation with a hepatologist or gastroenterologist for patients with elevated serum transaminases. For patients with coagulopathy, consider evaluation for liver transplantation.

Medication Summary

Pyridoxine is the drug of choice for isoniazid (INH)-induced seizure or coma. If pyridoxine is not available, lorazepam or phenobarbital may be administered as a temporary measure to control seizures until sufficient pyridoxine is available.

Pyridoxine (Vitamin B6)

Clinical Context:  Pyridoxine, also known as vitamin B-6, is the drug of choice for managing INH-induced seizures, metabolic acidosis, and mental status changes. It is involved in the synthesis of GABA within the CNS. INH depletes pyridoxine, thus decreasing the synthesis of GABA and increasing the potential for seizures.

For each 1 g of INH ingested, 1 g of parenteral pyridoxine should be given (max 5 g). If the quantity of INH ingested is unknown, empiric dosing of 70 mg/kg (max 5 g) is recommended.

If the parenteral form is not available, tablets can be crushed and given as a slurry; gram-for-gram replacement can also be carried out with pyridoxine tablets.

Class Summary

Vitamins are organic substances that are required by the body in small amounts for various metabolic processes, such as synthesis of gamma-aminobutyric acid (GABA) within the central nervous system (CNS). They may be synthesized in small or insufficient amounts in the body or may not be synthesized at all; supplementation thus may be required. Vitamins are used clinically for the prevention and treatment of specific vitamin deficiency states.

Lorazepam (Ativan)

Clinical Context:  Lorazepam is the drug of choice for status epilepticus. It enhances the activity of GABA centrally to control seizures. Lorazepam may be administered intramuscularly (IM) if vascular access cannot be obtained.

Diazepam (Valium, Diastat)

Clinical Context:  Diazepam acts similarly to lorazepam, as it enhances GABA activity and causes sedation. It can also be administered rectally if vascular access cannot be obtained rapidly.


Clinical Context:  Midazolam is used as an alternative in the termination of refractory status epilepticus. Because it is water-soluble, it takes approximately 3 times longer to achieve peak electroencephalographic (EEG) effects than diazepam does. Thus, clinicians must wait 2-3 minutes to evaluate sedative effects fully before initiating procedures or repeating doses. It may be administered IM if vascular access cannot be obtained.


Clinical Context:  Phenobarbital works at the CNS GABA receptors to potentiate CNS inhibition. It exhibits anticonvulsant activity in anesthetic doses independently of GABA. Phenobarbital is the best-studied barbiturate in the treatment of status epilepticus. With phenobarbital, it is important to achieve therapeutic levels as quickly as possible. The intravenous (IV) dose may require approximately 15 minutes to attain peak levels in the brain. If the drug is injected continuously until convulsions stop, brain concentrations may continue to rise and can exceed that which is required to control seizures. It is important to use the minimal amount required and to wait for the anticonvulsant effect to develop before giving a second dose.

Propofol (Diprivan)

Clinical Context:  A phenolic compound unrelated to other types of anticonvulsants, propofol has general anesthetic properties when administered IV and acts independently of GABA. Propofol is a third-line agent and should be used for refractory status epilepticus. Intubation and ventilation are often required.

Class Summary

Anticonvulsants are used to prevent seizure recurrence and terminate clinical and electrical seizure activity. Standard anticonvulsants, when used alone, may be ineffective in controlling seizures. Phenytoin should be used with caution, because INH may inhibit phenytoin metabolism.


Joseph L D'Orazio, MD, FAAEM, Director, Division of Medical Toxicology, Director, Medical Toxicology Fellowship Program, Department of Emergency Medicine, Einstein Medical Center; Consulting Staff in Medical Toxicology, Department of Pediatrics, Division of Emergency Medicine, Children's Hospital of Philadelphia

Disclosure: Nothing to disclose.


Michael A Hayoun, MD, MPhil, Resident Physician, Department of Emergency Medicine, Einstein Healthcare Network

Disclosure: Nothing to disclose.

Chief Editor

BS Anand, MD, Professor, Department of Internal Medicine, Division of Gastroenterology, Baylor College of Medicine

Disclosure: Nothing to disclose.

Additional Contributors

Richard A Weisiger, MD, PhD, Emeritus Professor, Department of Internal Medicine, University of California, San Francisco, School of Medicine

Disclosure: Nothing to disclose.


John G Benitez, MD, MPH, FACMT, FAACT, FACPM, FAAEM, Associate Professor, Department of Medicine, Medical Toxicology, Vanderbilt University Medical Center; Managing Director, Tennessee Poison Center

John G Benitez, MD, MPH, FACMT, FAACT, FACPM, FAAEM, is a member of the following medical societies: American Academy of Clinical Toxicology, American Academy of Emergency Medicine, American College of Medical Toxicology, American College of Preventive Medicine, Society for Academic Emergency Medicine, Undersea and Hyperbaric Medical Society, and Wilderness Medical Society

Disclosure: Nothing to disclose.

Timothy E Corden, MD Associate Professor of Pediatrics, Co-Director, Policy Core, Injury Research Center, Medical College of Wisconsin; Associate Director, PICU, Children's Hospital of Wisconsin

Timothy E Corden, MD is a member of the following medical societies: American Academy of Pediatrics, Phi Beta Kappa, Society of Critical Care Medicine, and Wisconsin Medical Society

Disclosure: Nothing to disclose.

Douglas M Heuman, MD, FACP, FACG, AGAF Chief of GI, Hepatology, and Nutrition at North Shore University Hospital/Long Island Jewish Medical Center; Professor, Department of Medicine, Hofstra North Shore-LIJ School of Medicine

Douglas M Heuman, MD, FACP, FACG, AGAF is a member of the following medical societies: American Association for the Study of Liver Diseases, American College of Physicians, and American Gastroenterological Association

Disclosure: Novartis Grant/research funds Other; Bayer Grant/research funds Other; Otsuka Grant/research funds None; Bristol Myers Squibb Grant/research funds Other; Scynexis None None; Salix Grant/research funds Other; MannKind Other

David C Lee, MD Research Director, Department of Emergency Medicine, Associate Professor, North Shore University Hospital and New York University Medical School

David C Lee, MD is a member of the following medical societies: American Academy of Emergency Medicine, American College of Emergency Physicians, American College of Medical Toxicology, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Terence David Lewis, MBBS, FRACP, FRCPC, FACP Program Director, Internal Medicine Residency, & Assistant Chairman, Associate Professor, Department of Internal Medicine, Division of Gastroenterology, Loma Linda University Medical Center

Terence David Lewis, MBBS, FRACP, FRCPC, FACP is a member of the following medical societies: American College of Gastroenterology, American College of Physicians, American Gastroenterological Association, American Medical Association, California Medical Association, Royal College of Physicians and Surgeons of Canada, and Sigma Xi

Disclosure: Nothing to disclose.

C Crawford Mechem, MD, MS, FACEP Associate Professor, Department of Emergency Medicine, University of Pennsylvania School of Medicine; Emergency Medical Services Medical Director, Philadelphia Fire Department

C Crawford Mechem, MD, MS, FACEP is a member of the following medical societies: American College of Emergency Physicians, National Association of EMS Physicians, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Binita R Shah, MD, FAAP Professor of Clinical Pediatrics and Emergency Medicine, SUNY Health Sciences Center at Brooklyn; Director of Pediatric Emergency Medicine, Departments of Emergency Medicine and Pediatrics, Kings County Hospital Center

Binita R Shah, MD, FAAP is a member of the following medical societies: American Academy of Pediatrics

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Asim Tarabar, MD Assistant Professor, Director, Medical Toxicology, Department of Emergency Medicine, Yale University School of Medicine; Consulting Staff, Department of Emergency Medicine, Yale-New Haven Hospital

Disclosure: Nothing to disclose.

David Tran, MD Attending Physician, Department of Emergency Medicine, North Shore-LIJ Plainview Hospital

David Tran, MD is a member of the following medical societies: American Academy of Emergency Medicine and American College of Emergency Physicians

Disclosure: Nothing to disclose.

Jeffrey R Tucker, MD Assistant Professor, Department of Pediatrics, Division of Emergency Medicine, University of Connecticut School of Medicine, Connecticut Children's Medical Center

Disclosure: Merck Salary Employment

John T VanDeVoort, PharmD Regional Director of Pharmacy, Sacred Heart & St. Joseph's Hospitals

John T VanDeVoort, PharmD is a member of the following medical societies: American Society of Health-System Pharmacists

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

William T Zempsky, MD Associate Director, Assistant Professor, Department of Pediatrics, Division of Pediatric Emergency Medicine, University of Connecticut and Connecticut Children's Medical Center

William T Zempsky, MD is a member of the following medical societies: American Academy of Pediatrics

Disclosure: Nothing to disclose.


  1. Agrawal RL, Dwivedi NC, Agrawal M, Jain S, Agrawal A. Accidental isoniazid poisoning--a report. Indian J Tuberc. 2008 Apr. 55(2):94-6. [View Abstract]
  2. Tostmann A, Boeree MJ, Peters WH, et al. Isoniazid and its toxic metabolite hydrazine induce in vitro pyrazinamide toxicity. Int J Antimicrob Agents. 2008 Jun. 31(6):577-80. [View Abstract]
  3. Roy PD, Majumder M, Roy B. Pharmacogenomics of anti-TB drugs-related hepatotoxicity. Pharmacogenomics. 2008 Mar. 9(3):311-21. [View Abstract]
  4. Taylor Z, Nolan CM, Blumberg HM. Controlling tuberculosis in the United States. Recommendations from the American Thoracic Society, CDC, and the Infectious Diseases Society of America. MMWR Recomm Rep. 2005 Nov 4. 54:1-81. [View Abstract]
  5. Schwab CE, Tuschl H. In vitro studies on the toxicity of isoniazid in different cell lines. Hum Exp Toxicol. 2003 Nov. 22(11):607-15. [View Abstract]
  6. Ben Mahmoud L, Ghozzi H, Kamoun A, et al. Polymorphism of the N-acetyltransferase 2 gene as a susceptibility risk factor for antituberculosis drug-induced hepatotoxicity in Tunisian patients with tuberculosis. Pathol Biol (Paris). 2012 Oct. 60(5):324-30. [View Abstract]
  7. Vuilleumier N, Rossier MF, Chiappe A, et al. CYP2E1 genotype and isoniazid-induced hepatotoxicity in patients treated for latent tuberculosis. Eur J Clin Pharmacol. 2006 Jun. 62(6):423-9. [View Abstract]
  8. Santos NP, Callegari-Jacques SM, Ribeiro Dos Santos AK, et al. N-acetyl transferase 2 and cytochrome P450 2E1 genes and isoniazid-induced hepatotoxicity in Brazilian patients. Int J Tuberc Lung Dis. 2013 Apr. 17(4):499-504. [View Abstract]
  9. Chamorro JG, Castagnino JP, Musella RM, et al. Sex, ethnicity, and slow acetylator profile are the major causes of hepatotoxicity induced by antituberculosis drugs. J Gastroenterol Hepatol. 2013 Feb. 28(2):323-8. [View Abstract]
  10. Yamada S, Tang M, Richardson K, et al. Genetic variations of NAT2 and CYP2E1 and isoniazid hepatotoxicity in a diverse population. Pharmacogenomics. 2009 Sep. 10(9):1433-45. [View Abstract]
  11. Yue J, Peng R. Does CYP2E1 play a major role in the aggravation of isoniazid toxicity by rifampicin in human hepatocytes?. Br J Pharmacol. 2009 Jun. 157(3):331-3. [View Abstract]
  12. Kopanoff DE, Snider DE Jr, Caras GJ. Isoniazid-related hepatitis: a U.S. Public Health Service cooperative surveillance study. Am Rev Respir Dis. 1978 Jun. 117(6):991-1001. [View Abstract]
  13. Ozick LA, Jacob L, Comer GM, et al. Hepatotoxicity from isoniazid and rifampin in inner-city AIDS patients. Am J Gastroenterol. 1995 Nov. 90(11):1978-80. [View Abstract]
  14. Attri S, Rana SV, Vaiphei K, et al. Isoniazid- and rifampicin-induced oxidative hepatic injury--protection by N-acetylcysteine. Hum Exp Toxicol. 2000 Sep. 19(9):517-22. [View Abstract]
  15. Menzies D, Long R, Trajman A, et al. Adverse events with 4 months of rifampin therapy or 9 months of isoniazid therapy for latent tuberculosis infection: a randomized trial. Ann Intern Med. 2008 Nov 18. 149(10):689-97. [View Abstract]
  16. Kim SH, Kim SH, Bahn JW, et al. Genetic polymorphisms of drug-metabolizing enzymes and anti-TB drug-induced hepatitis. Pharmacogenomics. 2009 Nov. 10(11):1767-79. [View Abstract]
  17. Bronstein AC, Spyker DA, Cantilena LR Jr, Green JL, Rumack BH, Giffin SL. 2009 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 27th Annual Report. Clin Toxicol (Phila). 2010 Dec. 48(10):979-1178. [View Abstract]
  18. Bronstein AC, Spyker DA, Cantilena LR Jr, Green JL, Rumack BH, Dart RC. 2010 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 28th Annual Report. Clin Toxicol (Phila). 2011 Dec. 49(10):910-41. [View Abstract]
  19. Bronstein AC, Spyker DA, Cantilena LR Jr, Rumack BH, Dart RC. 2011 Annual report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 29th Annual Report. Clin Toxicol (Phila). 2012 Dec. 50(10):911-1164. [View Abstract]
  20. Mowry JB, Spyker DA, Cantilena LR Jr, Bailey JE, Ford M. 2012 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 30th Annual Report. Clin Toxicol (Phila). 2013 Dec. 51(10):949-1229. [View Abstract]
  21. Mowry JB, Spyker DA, Cantilena LR Jr, McMillan N, Ford M. 2013 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 31st Annual Report. Clin Toxicol (Phila). 2014 Dec. 52(10):1032-283. [View Abstract]
  22. Mowry JB, Spyker DA, Brooks DE, McMillan N, Schauben JL. 2014 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 32nd Annual Report. Clin Toxicol (Phila). 2015 Dec. 53(10):962-1147. [View Abstract]
  23. Forget EJ, Menzies D. Adverse reactions to first-line antituberculosis drugs. Expert Opin Drug Saf. 2006 Mar. 5(2):231-49. [View Abstract]
  24. Fountain FF, Tolley E, Chrisman CR, Self TH. Isoniazid hepatotoxicity associated with treatment of latent tuberculosis infection: a 7-year evaluation from a public health tuberculosis clinic. Chest. 2005 Jul. 128(1):116-23. [View Abstract]
  25. Sullivan EA, Geoffroy P, Weisman R, Hoffman R, Frieden TR. Isoniazid poisonings in New York City. J Emerg Med. 1998 Jan-Feb. 16(1):57-9. [View Abstract]
  26. Yee D, Valiquette C, Pelletier M, Parisien I, Rocher I, Menzies D. Incidence of serious side effects from first-line antituberculosis drugs among patients treated for active tuberculosis. Am J Respir Crit Care Med. 2003 Jun 1. 167(11):1472-7. [View Abstract]
  27. Romero JA, Kuczler FJ Jr. Isoniazid overdose: recognition and management. Am Fam Physician. 1998 Feb 15. 57(4):749-52. [View Abstract]
  28. Kalaci A, Duru M, Karazincir S, Sevinc TT, Kuvandik G, Balci A. Thoracic spine compression fracture during isoniazid-induced seizures: case report. Pediatr Emerg Care. 2008 Dec. 24(12):842-4. [View Abstract]
  29. Wason S, Lacouture PG, Lovejoy FH Jr. Single high-dose pyridoxine treatment for isoniazid overdose. JAMA. 1981 Sep 4. 246(10):1102-4. [View Abstract]
  30. Howland MA. Antidotes in depth: pyridoxine. In: Hoffman RS, Howland MA, Lewin NA, Nelson LS, Goldfrank LR, eds. Goldfrank's Toxicologic Emergencies. 10th ed. New York, NY: McGraw-Hill; 2015. 797-9.
  31. Dart RC, Borron SW, Caravati EM, et al. Expert consensus guidelines for stocking of antidotes in hospitals that provide emergency care. Ann Emerg Med. 2009 Sep. 54(3):386-394.e1. [View Abstract]
  32. Santucci KA, Shah BR, Linakis JG. Acute isoniazid exposures and antidote availability. Pediatr Emerg Care. 1999 Apr. 15(2):99-101. [View Abstract]
  33. Saukkonen JJ, Cohn DL, Jasmer RM, et al, for the ATS (American Thoracic Society) Hepatotoxicity of Antituberculosis Therapy Subcommittee. An official ATS statement: hepatotoxicity of antituberculosis therapy. Am J Respir Crit Care Med. 2006 Oct 15. 174(8):935-52. [View Abstract]
  34. Raghu R, Karthikeyan S. Zidovudine and isoniazid induced liver toxicity and oxidative stress: Evaluation of mitigating properties of silibinin. Environ Toxicol Pharmacol. 2016 Sep. 46:217-26. [View Abstract]
  35. Sekaggya-Wiltshire C, von Braun A, Scherrer AU, et al. Anti-TB drug concentrations and drug-associated toxicities among TB/HIV-coinfected patients. J Antimicrob Chemother. 2017 Apr 1. 72(4):1172-7. [View Abstract]
  36. Shah I, Jadhao N, Mali N, Deshpande S, Gogtay N, Thatte U. Pharmacokinetics of isoniazid in Indian children with tuberculosis on daily treatment. Int J Tuberc Lung Dis. 2019 Jan 1. 23(1):52-7. [View Abstract]
  37. Badrinath M, John S. Isoniazid Toxicity. StatPearls [Internet]. 2018 Oct 27. [View Abstract]

Isoniazid causes a depletion of pyridoxal-5'-phosphate (the active form of pyridoxine) by inhibiting pyridoxine phosphokinase. This inhibition leads to decreased gamma-aminobutyric acid (GABA) synthesis and acute toxicity that is manifested as seizures.