AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Isoniazid (isonicotinic acid hydrazide [INH]) is an antimicrobial that has been used as a first-line agent for prophylaxis and treatment of tuberculosis since 1952. Patients with a recently positive purified protein derivative (PPD) skin test and normal chest radiograph findings routinely are given a 6- to 9-month course of INH. Patients with active disease are put on a regimen of INH combined with other antituberculous medications. Because of errors in dosage or intentional overdose, life-threatening toxicity may result.

For CME activities, see CME - ICAAC 2007: Coinfections and Comorbidities in HIV -- Viral and Bacterial Infections, Malignancy, and Tuberculosis and CME - Pulmonary Tuberculosis With TB Meningitis.

Pathophysiology

Isoniazid binds to pyridoxal-5-phosphate, the active form of pyridoxine (vitamin B-6), to form INH-pyridoxal hydrazones. Pyridoxal-5-phosphate is a cofactor for glutamic acid decarboxylase and GABA transaminase in the GABA synthetic pathway. INH overdose results in decreased pyridoxal-5-phosphate, decreased GABA synthesis, increased cerebral excitability, and seizures. Co-ingestion of ethanol potentiates toxicity by enhancing degradation of phosphorylated pyridoxine.

Toxic effects of INH also result from inhibition of lactate dehydrogenase, an enzyme that converts lactate to pyruvate, and from inhibition of cytochrome P450. Pharmacogenetic studies suggest that patients with certain cytochrome P450 genotypes may be more predisposed to hepatotoxicity during INH therapy for latent tuberculosis.¹

INH undergoes N-acetylation in the liver to a variety of products that include acetylhydrazine, a potent hepatotoxin. These metabolites are excreted in the urine. With long-term administration at therapeutic doses, INH can cause clinically significant and even fatal hepatic injury in 1% of patients and elevated liver enzyme levels in 10-20% of patients.

In vitro studies of a variety of animal cell lines demonstrated that INH toxicity results from the induction of apoptosis with associated disruption of mitochondrial membrane potential and DNA strand breaks.²

Frequency

United States

A surveillance of cases of INH poisoning by the American Association of Poison Control Centers from 1985-1993 revealed a low number of 138 cases in 1985, with no fatalities, and a high number of 2656 cases in 1991, with 6 fatalities. A more recent 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.³ 

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 discontinuation of therapy.⁴

Hepatotoxicity occurs on average in 9.2 of 1000 patients taking INH for antituberculosis therapy.⁵

Mortality/Morbidity

Acute ingestion by adults with as little as 1.5 g of INH can lead to mild toxicity.⁶ Ingestion of 6-10 g may be fatal, while ingestion of 15 g is usually fatal if not appropriately treated.

• The overall mortality rate for acute INH toxicity has been estimated to be 19%. With current methods of supportive care, however, this figure may be high.
• From 1972-1988, an estimated 152 fatalities were caused by INH-related hepatitis. A more recent literature review estimates hepatotoxicity to occur in 9.2 of 1000 patients taking INH for antituberculosis therapy, with a case-fatality rate of 4.7%.⁵

Race

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.

• While slow acetylators appear more prone to INH-induced hepatitis and neuropathy with long-term use, whether the rate of acetylation affects acute toxicity is unclear.
• Because of the influx of immigrants from Southeast Asia over the past 2 decades, mini-epidemics of acute INH toxicity have been reported in this population because many of them undergo INH therapy.
• In a review of possible INH-associated hepatitis fatalities identified from 1969-1989, a total of 38% occurred in African Americans, 40% in non-Hispanic whites, 15% in Hispanics, 1% in Asians, and 4% in Native Americans.

Sex

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. Postpartum women may be at increased risk.

In a study of 41 patients in New York City who were hospitalized at least overnight for INH toxicity, 27 (82%) were female.⁷

Age

Patients of all ages may experience either chronic or acute INH toxicity. Susceptibility to INH-induced hepatitis and subsequent death appears to increase with advancing age. For example, a report of a 7-year experience with INH hepatotoxicity in a public health tuberculosis clinic revealed 4.40 events per 1000 for patients aged 25-34 years, 8.54 for patients aged 35-49 years, and 20.83 for those 50 years old or older.⁸

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

Symptoms are usually observed within 45 minutes of acute overdose but may be delayed up to 2 hours, when peak absorption occurs.

• Nausea
• Vomiting
• Dizziness
• Light sensitivity

Physical

• Seizures
• • Seizures may be observed after ingestion of less than 40 mg/kg and are typical following doses of 80-150 mg/kg.
  • Seizures may occur abruptly and are often generalized and tonic-clonic, but focal seizures have been described.
  • The clinical triad of acute neurotoxicity consists of seizures (refractory to standard anticonvulsants), metabolic acidosis, and coma; it is usually observed in ingestions of more than 200 mg/kg.
• Hyperpyrexia
• Hypotension
• Tachycardia
• Urinary retention
• Hemorrhage (in the setting of disseminated intravascular coagulation [DIC])
• Ataxia
• Slurred speech
• Stupor
• Hyperreflexia
• Areflexia
• Cyanosis
• Adverse effects from long-term ingestion include the following:
• • Peripheral neuritis - Uncommon in healthy individuals but more common in persons with diabetes, those with alcoholism, and malnourished elderly individuals
  • Hepatitis - Increased risk with concomitant use of carbamazepine, phenobarbital, rifampin, and alcohol abuse
• INH is known to cause a positive antinuclear antibody (ANA) in 25% of patients and clinically apparent drug-induced lupus, characterized by fever, rash, arthralgias, arthritis, and constitutional symptoms, in approximately 1% of patients.
• In rare cases, isoniazid causes mania, depression, obsessive-compulsive disorder, and psychosis, believed to result from its ability to act as a monoamine oxidase inhibitor (MAOI) or through depletion of pyridoxine. Rarely, an MAOI tyramine syndrome may occur following the ingestion of tyramine-containing foods (eg, red wines, cheese).
• A hypersensitivity reaction is 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:
• • Fever, gastrointestinal upset, oliguria, arthralgias, malaise
  • Ataxia
  • Optic neuritis
  • Paresthesias
  • Encephalopathy

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• No correlation exists between serum INH levels and severity of acute intoxication. Laboratory studies generally are not helpful in diagnosis of acute INH toxicity but may identify complications.
• • Elevated anion gap metabolic acidosis (caused by lactic acid)
  • Hypokalemia
  • Hyperglycemia
  • Ketonemia
  • Transient elevation of liver enzyme levels
  • Leukocytosis
  • Positive DIC panel
  • Glycosuria
  • Ketonuria
  • Cerebrospinal fluid (CSF) pleocytosis
• Laboratory abnormalities observed with INH therapy include the following:
• • Elevated liver enzyme levels - Patients with pretreatment aspartate aminotransferase (AST) levels above the upper limit of normal are predisposed to developing hepatotoxicity.
  • Granulocytopenia or agranulocytosis
  • Eosinophilia
  • Thrombocytopenia
  • Anemia

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Prehospital Care

Prehospital therapy is limited to supportive care and management of complications.

Emergency Department Care

• 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.
• Consider gastric lavage once the airway is secured; then administer activated charcoal at a dose 10 times that of the amount of ingested INH or 50 g if the ingested dose 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.
• While 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 hepatoxicity severe enough to warrant liver transplantation.

Consultations

• Discuss the patient's treatment with a regional poison control center or consult with a medical toxicologist.
• Obtain a psychiatric consultation in all cases of intentional overdose before discharge from hospital.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical management of isoniazid poisoning is directed at seizure control with pyridoxine. Benzodiazepine administration is a temporizing measure until large doses of pyridoxine are available.

Drug Category: Vitamin

Vitamins are involved in synthesis of GABA within the CNS.

Drug Category: Anticonvulsants

Standard anticonvulsants, when used alone, may be ineffective in controlling seizures. However, consider as first-line agents while pyridoxine is being prepared. Caution in using phenytoin because INH decreases metabolism of phenytoin, placing patients, especially slow-acetylators, at risk of phenytoin toxicity.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Admit patients with refractory seizures or severe acidosis to an intensive care unit.

Transfer

• Transfer patients after stabilization of vital signs if ICU facilities or a medical toxicologist is warranted but unavailable.

Deterrence/Prevention

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

Complications

• Aspiration
• Pneumonia
• Hypotension
• Cardiorespiratory arrest

Prognosis

• The prognosis is largely dependent on early identification and correction of complications.
• 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

• For excellent patient education resources, visit eMedicine's Bacterial and Viral Infections Center. Also, see eMedicine's patient education article Tuberculosis.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to consider isoniazid toxicity in both adult and pediatric patients presenting with new-onset, recurrent, or refractory seizures
• Inadequate supply of pyridoxine on-hand. Management of a single severely intoxicated patient may require 20 g of pyridoxine. Therefore, this amount should be readily available if tuberculosis is common among the patient population. Because pyridoxine has few other emergent indications, individual hospitals may have insufficient quantities to manage critically intoxicated patients. Therefore, establishment of a network of resources from which hospitals can obtain adequate quantities rapidly should be considered.
• Failure to treat seizures with traditional medications, including benzodiazepines and barbiturates, in addition to pyridoxine

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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2. 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. [Medline].
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Article Last Updated: Apr 7, 2008