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Toxicity, Isoniazid

Updated: Mar 24, 2009

Introduction

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.

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 liver 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

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

Differential Diagnoses

Metabolic Acidosis
Pediatrics, Status Epilepticus
Status Epilepticus

Workup

Laboratory Studies

No correlation exists between serum isoniazid (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

Prehospital Care

Prehospital therapy for isoniazid poisoning 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 isoniazid (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

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.

Vitamin

Vitamins are involved in synthesis of GABA within the CNS.

Pyridoxine (Nestrex)

Vitamin B-6 and DOC for managing INH-induced seizures, metabolic acidosis, and mental status changes. Advisable to know in advance the availability of high doses in an institution.
Gram-for-gram dose based on the amount of INH ingested.

Dosing

Adult

5 g IV over 3-5 min; repeat q5-20min until seizures resolve or patient regains consciousness

Pediatric

70 mg/kg IV; not to exceed 5 g

Interactions

May decrease levodopa, phenytoin, and phenobarbital serum levels

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

>200 mg/d may precipitate withdrawal effects when medication is discontinued; may cause tachypnea, orthostatic hypotension, and seizures (rare)

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.

Lorazepam (Ativan)

DOC for status epilepticus because persists in CNS longer than diazepam. Rate of injection should not exceed 2 mg/min. May be administered IM if unable to obtain vascular access.

Dosing

Adult

0.044 mg/kg (2-4 mg) IV, titrate to effect
Status epilepticus: 4 mg IV over 2-5 min; may repeat second dose in 10-15 min, if needed; not to exceed 8 mg

Pediatric

Children: 0.05 mg/kg IV (range, 0.02-0.1 mg/kg)
Adolescents: Administer as in adults
Status epilepticus:
Neonates: 0.05 mg/kg over 2-5 min; repeat in 10-15 min, if needed
Infants and children: 0.1 mg/kg over 2-5 min; repeat dose of 0.05 mg/kg IV at 10-15 min, if needed; not to exceed 4 mg
Adolescents: 0.7 mg/kg; not to exceed 4 mg, slowly over 2-5 min; repeat dose in 10-15 min, if needed

Interactions

Alcohol, phenothiazines, barbiturates, and MAOIs increase CNS toxicity

Contraindications

Documented hypersensitivity; preexisting CNS depression; hypotension; narrow-angle glaucoma

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Monitor for respiratory depression with high or repeated doses; contains benzyl alcohol, which may be toxic to infants in high doses; caution in renal or hepatic impairment, myasthenia gravis, organic brain syndrome, Parkinson disease, or patients who may have inhibition of benzodiazepine metabolism and clearance (eg, using nicotine, taking cimetidine)

Diazepam (Valium)

Depresses all levels of CNS (eg, limbic and reticular formation), possibly by increasing activity of GABA. Third-line agent for agitation or seizures because of shorter duration of anticonvulsive effects and accumulation of active metabolites that may prolong sedation.

Dosing

Adult

5-10 mg IV q10-15min until symptoms resolve; not to exceed 30 mg

Pediatric

30 days to 5 years: 0.2-0.5 mg IV, slowly q2-5min until symptoms resolve; not to exceed 5 mg
>5 years: 1 mg IV, slowly q2-5min until symptoms resolve; not to exceed 10 mg

Interactions

Increases toxicity of benzodiazepines in CNS with coadministration of phenothiazines, H1 blockers, barbiturates, alcohols, and MAOIs

Contraindications

Documented hypersensitivity; hypotension; acute narrow-angle glaucoma

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution with other CNS depressants, low albumin levels, or renal and hepatic disease (may increase toxicity); monitor for respiratory depression with high or repeated doses

Midazolam (Versed)

Used as alternative in termination of refractory status epilepticus. Because water soluble, takes approximately 3 times longer than diazepam to peak EEG effects. Thus, clinician must wait 2-3 min to fully evaluate sedative effects before initiating procedure or repeating dose. Has twice the affinity for benzodiazepine receptors than diazepam. May be administered IM if unable to obtain vascular access.

Dosing

Adult

0.01-0.05 mg/kg (usually 0.5-4 mg, up to 10 mg) IV, slowly over several min; may repeat q10-15min prn

Pediatric

<32 weeks: 0.5 mcg/kg/min IV infusion
>32 weeks: 1 mcg/kg/min IV infusion
Children: 0.05-0.2 mg/kg IV over 2-3 min, followed by 1-2 mcg/kg/min continuous infusion
Status epilepticus (refractory to standard therapy), >2 months and children: 0.15 mg/kg followed by continuous infusion of 1 mcg/kg/min, titrating dose upward q5min prn

Interactions

Sedative effects may be antagonized by theophyllines; narcotics, cimetidine, ethanol, and erythromycin may accentuate sedative effects caused by decreased clearance; reduce dose of thiopental by 15% when using together

Contraindications

Documented hypersensitivity; preexisting hypotension; narrow-angle glaucoma; sensitivity to propylene glycol (diluent)

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution in congestive heart failure, pulmonary disease, renal impairment, hepatic failure, neuromuscular disease, hypotension, and patients >60 y; monitor for respiratory depression with high or repeated doses; consider lower dosages in organic brain syndrome and patients who may have inhibition of benzodiazepine metabolism and clearance (eg, using nicotine, taking cimetidine)

Follow-up

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 isoniazid (INH) prophylaxis may detect early cases of hepatotoxicity.

Complications

Complications of isoniazid toxicity include the following:

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

Medicolegal 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

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Keywords

isoniazid toxicity, isoniazid poisoning, isoniazid exposure, treatment, symptoms, causes, isonicotinic acid hydrazide, INH, antituberculous medications, treatment of tuberculosis, prophylaxis of tuberculosis, isoniazid overdose, INH overdose, INH toxicity, INH poisoning, isoniazid ingestion, INH ingestion, tuberculosis treatment

Contributor Information and Disclosures

Author

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.

Medical Editor

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.

Pharmacy Editor

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.

Managing Editor

John G Benitez, MD, MPH, FACMT, FACPM, FAAEM, Associate Professor, Department of Medicine, Clinical Pharmacology Division, Vanderbilt University; Managing Director, Tennessee Poison Center
John G Benitez, MD, MPH, FACMT, FACPM, FAAEM is a member of the following medical societies: 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.

CME Editor

John D Halamka, MD, MS, Associate Professor of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center; Chief Information Officer, CareGroup Healthcare System and Harvard Medical School; Attending Physician, Division of Emergency Medicine, Beth Israel Deaconess Medical Center
John D Halamka, MD, MS is a member of the following medical societies: American College of Emergency Physicians, American Medical Informatics Association, Phi Beta Kappa, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Chief Editor

Asim Tarabar, MD, Assistant Professor, Department of Surgery, Section of Emergency Medicine, Yale University School of Medicine; Consulting Staff, Department of Emergency Medicine, Yale-New Haven Hospital
Disclosure: Nothing to disclose.

Further Reading