Isoniazid Toxicity

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Background

This article focuses on acute isoniazid (isonicotinic acid hydrazide [INH]) hepatotoxicity. Since 1952, this agent has been used as a front-line antimicrobial for tuberculosis (TB).[1, 2] It interferes with mycobacterial cell wall synthesis, though its exact mechanism of action is unknown. INH is commonly used alone for prophylaxis of patients who have conversion of their purified protein derivative (PPD) and normal chest x-ray films, and it also is used in combination with other medications for active disease.

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:

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.

Pathophysiology

In vitro studies of a variety of animal cell lines demonstrated that INH toxicity results in the induction of apoptosis with associated disruption of mitochondrial membrane potential and DNA strand breaks.[5]

However, the biochemical mechanism of INH hepatotoxicity has not yet been fully defined. The most widely accepted theory is that metabolism of INH produces reactive metabolites that bind to and damage cellular macromolecules in the liver. Most of the INH is acetylated and then further hydrolyzed to isonicotinic acid and acetylhydrazine (see the image below).


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Metabolism of isoniazid.

It has been suggested that persons with the rapid acetylator phenotype are more likely to display toxicity; however, most studies have failed to confirm such a correlation. In fact, some studies suggest that people who are slow acetylators are at greater risk for INH hepatotoxicity,[6] suggesting that slow metabolism results in diversion of INH metabolism to an alternative pathway (eg, one mediated by cytochrome P-450 [CYP-450]) that may produce a toxic metabolite.

This latter interpretation is supported by observations that drugs capable of inducing CYP-450 levels (including rifampin, which is often prescribed with INH) appear to increase the risk of INH toxicity. Pharmacogenetic studies suggest that patients with certain CYP-450 genotypes may be more predisposed to hepatotoxicity during INH therapy for latent tuberculosis.[7]

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 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 isoniazid hepatotoxicity is hepatocellular damage, patients occasionally may present with true drug hypersensitivity characterized by skin rash, fever, and eosinophilia.

Acute INH overdose results in decreased pyridoxal-5-phosphate levels, decreased GABA synthesis, increased cerebral excitability, and seizures. The presumed mechanism of INH-induced seizure involves a decrease in the availability of gamma-aminobutyric acid (GABA), which is the major inhibitory neurotransmitter in the central nervous system (CNS). INH metabolites, such as isoniazid hydrazones, inhibit pyridoxine phosphokinase. This enzyme converts pyridoxine (vitamin B-6) to its active form, pyridoxal-5-phosphate (see the image below).


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Isoniazid metabolism.

Pyridoxal-5-phosphate is required for the synthesis of GABA (see the image below). INH binds to pyridoxal-5-phosphate to form INH-pyridoxal hydrazones. Pyridoxal-5-phosphate is a cofactor for glutamic acid decarboxylase and GABA transaminase in the GABA synthetic pathway.


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Gamma-aminobutyric acid (GABA) synthesis.

Co-ingestion of ethanol potentiates INH toxicity by enhancing degradation of phosphorylated pyridoxine. Toxic effects of INH also result from inhibition of lactate dehydrogenase (LDH), an enzyme that converts lactate to pyruvate, and from inhibition of cytochrome P450.

Etiology

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.[8, 9, 6] Age is an important risk factor, presumably reflecting aging-related changes in hepatic metabolism. Female gender 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 (eg, glutathione), which are associated with poor nutrition, increase risk; however, human studies are lacking.

Previous or concurrent exposure to drugs that induce CYP-450 enzymes increases the risk. These drugs include the following:

Ethionamide and para-aminosalicylic acid may exacerbate the toxicity of INH by interfering with its acetylation.

Higher plasma levels of INH do not increase the risk of hepatitis. Conversely, neither administering lower INH doses nor monitoring plasma levels during therapy helps decrease the risk of toxicity.

In a study of genetic predisposition to hepatotoxicity induced by anti-TB drugs, Kim et al 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 isoniazid hepatitis and 159 control subjects.[13] They 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.

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

Epidemiology

United States statistics

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

Approximately 10-20% of adult patients receiving isoniazid show elevations in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) to about 1-3 times the upper limit of normal during the first 2 months of therapy. These elevations typically normalize within 3-6 weeks after discontinuance of the drug. However, most patients who continue on INH also have normal transaminase levels within several months, with no apparent adverse effects from continuing the drug.

A small percentage of older patients progress to more severe disease if INH is not discontinued. 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.[14] Death occurred in 8 patients (0.06%). When INH is given together with other drugs for active tuberculosis, the incidence of severe hepatotoxicity is greater.

Subsequent retrospective studies suggested a much lower incidence of toxicity, provided that patients are monitored according to current guidelines. On average, hepatotoxicity occurs in 9.2 of 1000 patients taking INH for antituberculosis therapy.[15] The reason for the apparent decline in reported cases of INH toxicity since 1978 is not known.

From 1989 to 1992, a total of 4405 cases of INH overdose and 7 deaths were reported by the American Association of Poison Control Centers’ National Data Collection System.[16, 17, 18, 19] Of the total reported cases, 1992 were in patients aged 17 years or younger, with 1 death. From 1993 to 1997, a total of 2419 cases and 8 deaths were reported.[20, 21, 22, 23, 24] Of the total reported cases, 1320 were in patients aged 19 years or younger, with 2 deaths. All pediatric mortality resulted from suicidal ingestion.

A review of all cases of drug-induced seizures reported to the California Poison Control System revealed that of 386 cases, 23 (5.9%) were due to INH.[25] In a study of 83 healthcare workers who received a 6-month course of INH, 34 (41%) developed an adverse effect. In 26 of these 34 patients, toxicity resulted in discontinuance of therapy.[26]

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 tuberculosis and large populations of patients infected with tuberculosis. Many of these persons are co-infected with the human immunodeficiency virus (HIV). Patients who are co-infected are at 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 (see the image below).[14] Although subsequent studies have reported lower rates of hepatotoxicity, age remains an important risk factor.


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Risk of developing overt hepatitis (%) versus age (y). Risks are much greater for older persons. Data are from a series of 13,838 patients on prophyla....

A study of a 7-year experience with INH hepatotoxicity in a public health tuberculosis 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.[27]

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 1969-1989 in which the sex of the patient was identified, 111 (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.[28]

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

Race-related demographics

Racial differences in 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 African Americans and whites 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 whites, 0.6% (36/6140) of blacks, and 0.9% (23/2608) of Asians, though follow-up was incomplete. Because fewer Asians (34%) than whites (52%) or blacks (59%) 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.[29]

Endemic cases of INH toxicity have been reported in persons who have emigrated from Southeast Asia because of their increased risk of tuberculosis and greater likelihood of undergoing INH therapy. Inuits and American Indians are at increased risk for tuberculosis 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 African Americans, 40% in non-Hispanic whites, 15% in Hispanics, 1% in Asians, and 4% in Native Americans.

Prognosis

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.

In adults, acute ingestion of as little as 1.5 g of INH can lead to mild toxicity.[30] Acute ingestion of 40 mg/kg or less can cause convulsion. Patients who ingest 80-150 mg/kg develop severe CNS symptoms. An 11-year-old previously healthy girl sustained a seizure-induced thoracic compression fracture due to isoniazid intoxication.[31] Ingestion of 6-10 g may be fatal, and ingestion of 15 g is usually fatal if not appropriately treated.

Overall mortality for acute INH toxicity has been estimated to be as high as 19%. 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 antituberculosis therapy, with a case-fatality rate of 4.7%.[15]

Patient Education

All patients who receive 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. Pediatric patients should be instructed by their parents not to try to make up for any INH doses they miss.

History

When taken daily at approved doses, isoniazid (isonicotinic acid hydrazide [INH]) hepatitis typically develops within the first few months of therapy, but it may present later (see the image below). Symptoms may remain mild until after potentially lethal liver damage has occurred. Thus, patients taking isoniazid should be educated to look for signs of liver toxicity and to report them immediately if they occur.


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Risk of developing overt hepatitis versus duration of therapy. Most hepatitis presents early in the course of therapy.

In acute INH overdosage, patients are usually symptomatic within 30-45 minutes. However, symptoms may be delayed up to 2 hours, when the peak serum level occurs. Potential symptoms include the following:

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. Immediate cessation of INH and any other potentially hepatotoxic drugs is required.

Physical Examination

The physical findings associated with INH hepatotoxicity resemble those characteristic of other forms of acute hepatitis.

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 bleeding from the gingiva or ecchymoses or have other manifestations of coagulopathy.

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

Other signs of INH toxicity include the following:

Various adverse effects of long-term ingestion of INH have been identified. Peripheral neuritis is uncommon in healthy individuals but 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 and 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 use include the following:

Approach Considerations

No correlation exists between serum isoniazid (isonicotinic acid hydrazide [INH]) levels and severity of acute intoxication. Serum INH levels are not readily available in most hospitals and do not help in the initial management of isoniazid toxicity.

Laboratory studies generally are not helpful in diagnosis of acute INH toxicity but may identify complications. Laboratory abnormalities observed with INH therapy include 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 INH is permissible. However, additional testing to exclude other causes of hepatitis is usually indicated. If transaminase levels are elevated more than 3-fold, it is usually necessary to discontinue INH and any other potentially 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.

Toxicology

Potential hepatotoxins other than INH must be excluded. In patients with a compatible history, blood or urine levels of other potential hepatotoxins (eg, acetaminophen and ethanol) may be useful.

Prothrombin time/international normalized ratio

The international normalized ratio (INR) usually is normal in early and mild cases. Significant elevation of the INR that does not respond to parenteral vitamin K is a grave sign that should prompt hospitalization and consultation with a transplant hepatologist.

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, efforts must be made exclude Wilson disease, especially if any neuropsychiatric components exist.

Additional tests

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

Other Studies

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. Imaging may show hepatomegaly, but splenomegaly and ascites typically are absent. Computed tomography (CT) of the head, with and without intravenous (IV) contrast, is recommended in patients with seizures of questionable etiology.

Electrocardiography (ECG) is recommended in patients with a suspected history of tricyclic antidepressant toxicity, which can reveal QRS prolongation.

Histologic Findings

Liver biopsy is rarely indicated for evaluation of acute hepatitis, because the histologic features typically are nonspecific. Liver histology closely resembles 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.

Approach Considerations

Medical care for isoniazid (isonicotinic acid hydrazide [INH]) hepatotoxicity is essentially supportive. Discontinue isoniazid 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. Prescribe only a 1-month supply of INH at a time to prevent the availability of a large amount. If seizure is refractory to standard anticonvulsant therapy, consider acute INH toxicity, and administer pyridoxine.

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

Supportive and Pharmacologic Therapy

Therapy for acute INH overdosage is mostly supportive and includes attention to the ABCs (airway, breathing, and circulation). Provide oxygen and continuous cardiac and pulse oximetry monitoring. Obtain intravenous (IV) access. If the patient shows no signs of toxicity 4 hours following an ingestion of less than 20 mg/kg, expectant management is sufficient. Treatment of patients with evidence of toxicity involves managing immediate life threats, administering pyridoxine, and supportive care.

If acute neurotoxicity (seizure, coma) occurs, administer pyridoxine immediately. Benzodiazepines and barbiturates can be used to potentiate the anticonvulsant effect of pyridoxine or as first-line therapy if pyridoxine is not yet available.[4] Use phenytoin with caution, because INH inhibits the metabolism of phenytoin. Ipecac syrup is contraindicated in patients with acute INH neurotoxicity, because it may increase the risk of aspiration secondary to seizure.

The availability of pyridoxine may be an issue. Because pyridoxine has few other emergency indications, individual hospitals may not have enough of it on hand to manage critically intoxicated patients. 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] Therefore, establishment of a network of resources from which hospitals can obtain adequate quantities rapidly should be considered.

Hospitals in urban areas with increased incidence of tuberculosis should have at least 5 g of pyridoxine available in the emergency department (ED). The wholesale cost for a 3-g vial of pyridoxine is approximately US $4, and it has a shelf life of 24 months. An argument can be made for a larger supply. Management of a single severely intoxicated patient may require 20 g of pyridoxine, which suggests that this amount should be readily available if tuberculosis is common among the patient population.

Once the airway is secured, consider gastric lavage. Next, administer activated charcoal in a dose 10 times the amount of INH ingested, or in a dose of 50 g if the amount of INH ingested is unknown. Lavage and activated charcoal may not be effective if administered more than 1-2 hours after an acute ingestion.

Control of seizures generally will correct metabolic acidosis. Administration of sodium bicarbonate may be beneficial in severe cases.

Although INH is dialyzable, dialysis is usually unnecessary if adequate doses of anticonvulsants and pyridoxine are administered. Hemodialysis may be indicated if the patient fails to improve with standard therapy.

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 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.

Prevention

The incidence of severe hepatitis and death 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, 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 recently were 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.

Consultations

Patients with serum transaminase elevations exceeding 3 times the normal level should be evaluated by a hepatologist or gastroenterologist to ensure that all possible causes of hepatitis are carefully considered. Consultation also should be obtained for those with lesser elevations that do not resolve within 2-3 months.

For patients with elevated PT, hospitalization and evaluation for possible liver transplantation are warranted.

Discuss the patient’s treatment with a regional poison control center or consult with a medical toxicologist or transplantation hepatologist as appropriate.

Obtain a psychiatric consultation in all cases of intentional overdose before discharge from hospital. Consider neuropsychiatric evaluation for possible dementia.

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 (Pyri)

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 synthesis of GABA within the CNS. INH depletes pyridoxine, thus decreasing synthesis of GABA and increasing the potential for seizures.

For each 1 g of INH ingested, 1 g of parenteral pyridoxine should be given. 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. Whenever possible, it is advisable to know in advance whether high doses are available in a given institution.

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 acts by increasing the action of GABA, which is a major inhibitory neurotransmitter in the brain. It may depress all levels of the CNS, including the limbic system and reticular formation. Lorazepam is the drug of choice for status epilepticus because persists in the CNS longer than diazepam does. The rate of injection should not exceed 2 mg/min. Lorazepam may be administered intramuscularly (IM) if vascular access cannot be obtained.

Diazepam (Valium, Diastat)

Clinical Context:  Diazepam depresses all levels of the CNS (eg, the limbic system and reticular formation), possibly by increasing GABA activity. It is a third-line agent for agitation or seizures because of its shorter duration of anticonvulsive effects and the accumulation of active metabolites that may prolong sedation.

Phenobarbital

Clinical Context:  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 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.

Midazolam

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. Midazolam has twice the affinity for benzodiazepine receptors than does diazepam. It may be administered IM if vascular access cannot be obtained.

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. However, they may be considered as first-line agents while pyridoxine is being prepared. Phenytoin should be used with caution because INH decreases phenytoin metabolism, placing patients, especially slow-acetylators, at risk for phenytoin toxicity.

Author

Richard A Weisiger, MD, PhD, Director, GI and Liver Faculty Practice, Professor, Department of Internal Medicine, University of California, San Francisco, School of Medicine

Disclosure: Nothing to disclose.

Chief Editor

Julian Katz, MD, Clinical Professor of Medicine, Drexel University College of Medicine

Disclosure: Nothing to disclose.

Additional Contributors

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.

References

  1. Agrawal RL, Dwivedi NC, Agrawal M, Jain S, Agrawal A. Accidental isoniazid poisoning--a report. Indian J Tuberc. Apr 2008;55(2):94-6. [View Abstract]
  2. Tostmann A, Boeree MJ, Peters WH, Roelofs HM, Aarnoutse RE, van der Ven AJ, et al. Isoniazid and its toxic metabolite hydrazine induce in vitro pyrazinamide toxicity. Int J Antimicrob Agents. Jun 2008;31(6):577-80. [View Abstract]
  3. Roy PD, Majumder M, Roy B. Pharmacogenomics of anti-TB drugs-related hepatotoxicity. Pharmacogenomics. Mar 2008;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. Nov 4 2005;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. Nov 2003;22(11):607-15. [View Abstract]
  6. Ben Mahmoud L, Ghozzi H, Kamoun A, Hakim A, Hachicha H, Hammami S, 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). Aug 17 2011;[View Abstract]
  7. Vuilleumier N, Rossier MF, Chiappe A, Degoumois F, Dayer P, Mermillod B, et al. CYP2E1 genotype and isoniazid-induced hepatotoxicity in patients treated for latent tuberculosis. Eur J Clin Pharmacol. Jun 2006;62(6):423-9. [View Abstract]
  8. Yamada S, Tang M, Richardson K, et al. Genetic variations of NAT2 and CYP2E1 and isoniazid hepatotoxicity in a diverse population. Pharmacogenomics. Sep 2009;10(9):1433-45. [View Abstract]
  9. Yue J, Peng R. Does CYP2E1 play a major role in the aggravation of isoniazid toxicity by rifampicin in human hepatocytes?. Br J Pharmacol. Jun 2009;157(3):331-3. [View Abstract]
  10. Ozick LA, Jacob L, Comer GM, Lee TP, Ben-Zvi J, Donelson SS, et al. Hepatotoxicity from isoniazid and rifampin in inner-city AIDS patients. Am J Gastroenterol. Nov 1995;90(11):1978-80. [View Abstract]
  11. Attri S, Rana SV, Vaiphei K, Sodhi CP, Katyal R, Goel RC, et al. Isoniazid- and rifampicin-induced oxidative hepatic injury--protection by N-acetylcysteine. Hum Exp Toxicol. Sep 2000;19(9):517-22. [View Abstract]
  12. 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. Nov 18 2008;149(10):689-97. [View Abstract]
  13. Kim SH, Kim SH, Bahn JW, et al. Genetic polymorphisms of drug-metabolizing enzymes and anti-TB drug-induced hepatitis. Pharmacogenomics. Nov 2009;10(11):1767-79. [View Abstract]
  14. Kopanoff DE, Snider DE Jr, Caras GJ. Isoniazid-related hepatitis: a U.S. Public Health Service cooperative surveillance study. Am Rev Respir Dis. Jun 1978;117(6):991-1001. [View Abstract]
  15. Forget EJ, Menzies D. Adverse reactions to first-line antituberculosis drugs. Expert Opin Drug Saf. Mar 2006;5(2):231-49. [View Abstract]
  16. Litovitz TL, Schmitz BF, Bailey KM. 1989 annual report of the American Association of Poison Control Centers National Data Collection System. Am J Emerg Med. Sep 1990;8(5):394-442. [View Abstract]
  17. Litovitz TL, Bailey KM, Schmitz BF, Holm KC, Klein-Schwartz W. 1990 annual report of the American Association of Poison Control Centers National Data Collection System. Am J Emerg Med. Sep 1991;9(5):461-509. [View Abstract]
  18. Litovitz TL, Holm KC, Bailey KM, Schmitz BF. 1991 annual report of the American Association of Poison Control Centers National Data Collection System. Am J Emerg Med. Sep 1992;10(5):452-505. [View Abstract]
  19. Litovitz TL, Holm KC, Clancy C, Schmitz BF, Clark LR, Oderda GM. 1992 annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med. Sep 1993;11(5):494-555. [View Abstract]
  20. Litovitz TL, Clark LR, Soloway RA. 1993 annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med. Sep 1994;12(5):546-84. [View Abstract]
  21. Litovitz TL, Felberg L, Soloway RA, Ford M, Geller R. 1994 annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med. Sep 1995;13(5):551-97. [View Abstract]
  22. Litovitz TL, Felberg L, White S, Klein-Schwartz W. 1995 annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med. Sep 1996;14(5):487-537. [View Abstract]
  23. Litovitz TL, Smilkstein M, Felberg L, Klein-Schwartz W, Berlin R, Morgan JL. 1996 annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med. Sep 1997;15(5):447-500. [View Abstract]
  24. Litovitz TL, Klein-Schwartz W, Dyer KS, Shannon M, Lee S, Powers M. 1997 annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med. Sep 1998;16(5):443-97. [View Abstract]
  25. Thundiyil JG, Kearney TE, Olson KR. Evolving epidemiology of drug-induced seizures reported to a Poison Control Center System. J Med Toxicol. Mar 2007;3(1):15-9. [View Abstract]
  26. Stuart RL, Wilson J, Grayson ML. Isoniazid toxicity in health care workers. Clin Infect Dis. Apr 1999;28(4):895-7. [View Abstract]
  27. 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. Jul 2005;128(1):116-23. [View Abstract]
  28. Sullivan EA, Geoffroy P, Weisman R, Hoffman R, Frieden TR. Isoniazid poisonings in New York City. J Emerg Med. Jan-Feb 1998;16(1):57-9. [View Abstract]
  29. 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. Jun 1 2003;167(11):1472-7. [View Abstract]
  30. Romero JA, Kuczler FJ Jr. Isoniazid overdose: recognition and management. Am Fam Physician. Feb 15 1998;57(4):749-52. [View Abstract]
  31. Kalaci A, Duru M, Karazincir S, Sevinç TT, Kuvandik G, Balci A. Thoracic spine compression fracture during isoniazid-induced seizures: case report. Pediatr Emerg Care. Dec 2008;24(12):842-4. [View Abstract]
  32. Santucci KA, Shah BR, Linakis JG. Acute isoniazid exposures and antidote availability. Pediatr Emerg Care. Apr 1999;15(2):99-101. [View Abstract]
  33. [Guideline] Saukkonen JJ, Cohn DL, Jasmer RM, et al. An official ATS statement: hepatotoxicity of antituberculosis therapy. Am J Respir Crit Care Med. Oct 15 2006;174(8):935-52. [View Abstract]
  34. Esfahani K, Aspler A, Menzies D, Schwartzman K. Potential cost-effectiveness of rifampin vs. isoniazid for latent tuberculosis: implications for future clinical trials. Int J Tuberc Lung Dis. Oct 2011;15(10):1340-6. [View Abstract]

Metabolism of isoniazid.

Isoniazid metabolism.

Gamma-aminobutyric acid (GABA) synthesis.

Risk of developing overt hepatitis (%) versus age (y). Risks are much greater for older persons. Data are from a series of 13,838 patients on prophylactic isoniazid therapy reported by Kopanoff and coworkers (1978).

Risk of developing overt hepatitis versus duration of therapy. Most hepatitis presents early in the course of therapy.

Metabolism of isoniazid.

Risk of developing overt hepatitis (%) versus age (y). Risks are much greater for older persons. Data are from a series of 13,838 patients on prophylactic isoniazid therapy reported by Kopanoff and coworkers (1978).

Risk of developing overt hepatitis versus duration of therapy. Most hepatitis presents early in the course of therapy.

Isoniazid metabolism.

Gamma-aminobutyric acid (GABA) synthesis.