eMedicine Specialties > Pediatrics: Cardiac Disease and Critical Care Medicine > Toxicology

Toxicity, Isoniazid

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

Updated: Apr 15, 2009

Introduction

Background

Isonicotinic acid hydrazide, commonly known as isoniazid (INH), is an antimicrobial agent that has been used to treat tuberculosis (TB).¹ Isoniazid interferes with mycobacterial cell wall synthesis, although its exact mechanism of action is unknown. Poisoning, whether intentional or unintentional, is common because the drug is widely used in the treatment and prophylaxis of tuberculosis.² Guidelines for the diagnosis, treatment, control, and prevention of tuberculosis, including the medications used, have been established by the American Thoracic Society, the Centers for Disease Control and Prevention (CDC), and the Infectious Diseases Society of America.³  Awareness of isoniazid poisoning may prevent severe morbidity and mortality. This article focuses on acute isoniazid toxicity.

Pathophysiology

The presumed etiology of isoniazid-induced seizure involves a decrease in the availability of gamma-aminobutyric acid (GABA). Isoniazid metabolites, such as isoniazid hydrazones, inhibit pyridoxine phosphokinase. This enzyme converts pyridoxine (vitamin B-6) to its active form, pyridoxal-5-phosphate. Other hydrazine or hydrazide metabolites either inactivate pyridoxal-5-phosphate or complex with pyridoxine (see Media file 1).

Isoniazid metabolism.

Gamma-aminobutyric acid (GABA) synthesis.

Frequency

United States

The American Association of Poison Control Centers' National Data Collection System compiles an annual report of human poison exposure cases. From 1989-1992, a total of 4405 cases of isoniazid overdose were reported, with 7 deaths.^4,5,6,7 Of the total reported cases, 1992 were in patients aged 17 years or younger, with 1 death. From 1993-1997, a total of 2419 cases and 8 deaths were reported.^8,9,10,11,12 Of the total reported cases, 1320 were in patients aged 19 years or younger, with 2 deaths. All pediatric mortality resulted from suicidal ingestion.

Mortality/Morbidity

Acute ingestion of 40 mg/kg or less of isoniazid 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.¹³ Death has been reported in patients who ingested 10-15 g of isoniazid and were inappropriately treated.

Race

No studies have shown any predilection in isoniazid toxicity based on race. Endemic cases of isoniazid toxicity have been reported in persons who have emigrated from Southeast Asia because of their increased risk of tuberculosis. Inuits and American Indians are at an increased risk of tuberculosis and, subsequently, isoniazid toxicity.

Sex

No sex predilection has been reported in patients with isoniazid toxicity.

Age

Acute toxicity can occur in all age groups.

Clinical

History

• In acute isoniazid (INH) toxicity, patients are usually symptomatic within 30-45 minutes. Symptoms may be delayed up to 2 hours when peak serum level occurs.
• Potential symptoms include the following:
  • Nausea
  • Vomiting
  • Diarrhea
  • Irritability
  • Lethargy
  • Vague abdominal pain
  • Confusion
  • Dizziness

Physical

• Patients usually present with generalized tonic-clonic seizures; focal seizures have been reported.
• Ingestion of isoniazid in excess of 200 mg/kg produces a characteristic clinical triad, as follows:
  • Refractory seizures that are unresponsive to standard anticonvulsants
  • Increased anion gap metabolic acidosis
  • Coma
• Other signs of isoniazid toxicity include the following:
  • Hypotension
  • Tachycardia
  • Hyperpyrexia
  • Stupor
  • Tremor
  • Choking spells
  • Slurred speech
  • Mydriasis
  • Urinary retention
  • Ataxia
  • Hyperreflexia
  • Areflexia
  • Nystagmus

Causes

• The rise in isoniazid 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 isoniazid exposures.
• Contributing factors include the following:
  • HIV/AIDS epidemic
  • Emergence of multidrug–resistant tuberculosis
  • Emigration from Southeast Asia
  • Inuit descent
  • American Indian descent
  • Alcoholism
  • Homelessness
  • Overcrowded conditions

Differential Diagnoses

Acidosis, Metabolic
Status Epilepticus
Toxicity, Acetaminophen

Other Problems to Be Considered

Seizure

Workup

Laboratory Studies

• Serum isoniazid (INH) level does not correlate with the degree of acute intoxication. Serum level is not readily available in most hospitals and does not help in the initial management of isoniazid toxicity.
• Additional laboratory studies may be performed to assess for the following:
  • Aspirin and acetaminophen levels in patients with intentional exposure
  • Urine toxicological screen, if suicide is suspected
  • Pregnancy, if indicated
  • CBC count for leukocytosis
  • Lactic acidosis secondary to seizure
  • Hyperglycemia
  • Ketonuria
  • Glycosuria
  • Ketonemia
  • Hypokalemia
  • Transient elevation of liver enzymes
  • Myoglobinuria
  • Cerebrospinal fluid (CSF) pleocytosis

Imaging Studies

• CT scans of the head, with and without intravenous contrast, are recommended in patients with questionable etiology of seizure.

Other Tests

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

Treatment

Medical Care

• Therapy is mostly supportive in isoniazid (INH) toxicity and includes airway, breathing, and circulation. Provide oxygen and continuous cardiac and pulse oximetry monitoring. Obtain intravenous access. If the patient is asymptomatic after 4 hours with ingestion of less than 20 mg/kg, supportive treatment is sufficient.
• If acute neurotoxicity (seizure, coma) occurs, administer pyridoxine immediately. Benzodiazepines and barbiturates can be used to potentiate the anticonvulsant effect of pyridoxine. Use phenytoin with caution because isoniazid inhibits the metabolism of phenytoin.
• Ipecac syrup is contraindicated in patients with acute isoniazid neurotoxicity because it may increase the risk of aspiration secondary to seizure.
• Perform gastric lavage and administer activated charcoal as soon as possible, preferably within 2 hours of acute ingestion.

Consultations

• Contact regional poison control centers for assistance, if necessary.
• Consult a psychiatrist for all suicidal cases.

Medication

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 temporary measures to control seizure while awaiting pyridoxine administration.

Vitamins

Vitamins are organic substances required by the body in small amounts for various metabolic processes. Vitamins may be synthesized in small or insufficient amounts in the body or not synthesized at all, thus requiring supplementation. They are used clinically for the prevention and treatment of specific vitamin deficiency states.

Pyridoxine (Nestrex)

Also known as vitamin B6. Involved in synthesis of GABA within the CNS. INH depletes pyridoxine, thus decreasing synthesis of GABA and increasing potential for seizures. For each gram of INH ingested, 1 g of parenteral pyridoxine should be given. If parenteral form is not available, tabs can be crushed and given as a slurry. A gram-for-gram replacement can also be used with pyridoxine tablets.

Dosing

Adult

Known amount of INH ingested: 1 g pyridoxine for 1 g of INH IV/PO, initial dose not to exceed 5 g/30 min IV
Administer remaining dose in increments of 1 g/30 min until total dosage completed
Unknown amount of INH ingested: 70 mg/kg IV, not to exceed 5 g/30 min; once seizures are controlled, administer remaining dose over 4-6 h
May repeat initial IV dose q5-20 min until seizures are controlled

Pediatric

Administer as in adults

Interactions

Pyridoxine 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

Extremely high doses may cause irreversible sensory loss

Anticonvulsants

These agents are used to prevent seizure recurrence and terminate clinical and electrical seizure activity.

Lorazepam (Ativan)

By increasing the action of GABA, which is a major inhibitory neurotransmitter in the brain, may depress all levels of CNS, including limbic and reticular formation.

Dosing

Adult

4 mg/dose IV slowly over 2-5 min and repeat in 10-15 min prn; not to exceed 8 mg/12 h

Pediatric

0.05-0.1 mg/kg IV infused at rate of 2 mg/min; not to exceed 4 mg/dose; may repeat once with 0.05 mg/kg IV in 10-15 min

Interactions

Toxicity of benzodiazepines in CNS increases when used concurrently with alcohol, phenothiazines, barbiturates, and MAOIs

Contraindications

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

Precautions

Pregnancy

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

Precautions

Caution in renal or hepatic impairment, myasthenia gravis, organic brain syndrome, or Parkinson disease

Diazepam (Valium)

Depresses all levels of CNS (eg, limbic and reticular formation), possibly by increasing activity of GABA

Dosing

Adult

5-15 mg IV q5min, repeat prn; not to exceed 30 mg in 8 h

Pediatric

0.2-0.3 mg/kg IV infused at rate of 1 mg/min; may repeat prn q15-30min, cumulative dose not to exceed 10 mg

Interactions

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

Contraindications

Documented hypersensitivity; 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 hepatic disease (may increase toxicity)

Phenobarbital (Luminal)

Achieving therapeutic levels as quickly as possible is important. The IV dose may require approximately 15 min to attain peak levels in the brain. If injected continuously until convulsions stop, brain concentrations may continue to rise and can exceed that required to control seizures. Important to use minimal amount required and to wait for anticonvulsant effect to develop before giving a second dose.

Dosing

Adult

15-20 mg/kg over 10-15 min IV in single or divided dose
Some patients may require 5 mg/kg/dose q15-30min until seizure is controlled or a total dose of 40 mg/kg is administered; rate of 30 mg/min

Pediatric

Administer as in adults

Interactions

Coadministration with alcohol may produce additive CNS effects and death; chloramphenicol and MAOIs may increase phenobarbital effects; phenobarbital may decrease chloramphenicol effects; MAOIs may enhance sedative effects of barbiturates; rifampin may decrease effects of phenobarbital; valproic acid appears to decrease barbiturate metabolism and increase toxicity; barbiturates can decrease effects of anticoagulants, and patients stabilized on anticoagulants may require dosage adjustments if barbiturates are added to or withdrawn from their regimen; phenobarbital may decrease serum carbamazepine levels
Decreased effects of contraceptives may occur because of induction of microsomal enzymes (menstrual irregularities and pregnancy may occur); barbiturates may decrease corticosteroid effects by inducing hepatic microsomal enzymes; barbiturates may increase digitoxin metabolism; phenobarbital may decrease antimicrobial effects of metronidazole; barbiturates decrease theophylline levels, possibly resulting in decreased effects; phenobarbital may decrease bioavailability of verapamil

Contraindications

Documented hypersensitivity; severe respiratory disease, marked impairment of liver function, and nephritic patients

Precautions

Pregnancy

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

Precautions

In prolonged therapy, evaluate hematopoietic, renal, hepatic, and other organ systems; exercise caution in fever, hyperthyroidism, diabetes mellitus, and severe anemia because adverse reactions can occur; exercise caution in patients with myasthenia gravis and myxedema

Follow-up

Further Inpatient Care

• Admit patients to the ICU if they are lethargic, comatose, or have refractory seizures.

Further Outpatient Care

• Consider neuropsychiatric evaluation for possible dementia.

Complications

• Aspiration pneumonia
• Hypotension
• Cardiopulmonary arrest

Prognosis

• The prognosis depends primarily on early recognition of isoniazid toxicity.

Patient Education

• Parents should instruct children not to make up for any missed doses of isoniazid.
• Medication should be taken only as prescribed.
• All patients who receive isoniazid therapy should be counseled about the harmful effects of overdose.
• For excellent patient education resources, visit eMedicine's Drug Overdose Center and Poisoning - First Aid and Emergency Center. Also, see eMedicine's patient education articles Poisoning, Drug Overdose, Activated Charcoal, and Poison Proofing Your Home.

Miscellaneous

Medicolegal Pitfalls

• Pyridoxine availability
  • A survey of 130 US institutions (in which 80% responded) found that at least 33% of the responding institutions would be ill equipped in the availability of pyridoxine to treat acute isoniazid (INH) toxicity.¹⁴
  • Hospitals in urban areas with increased incidence of tuberculosis should have at least 5 g of pyridoxine available in the emergency department. The wholesale cost for a 3-g vial of pyridoxine is approximately US $4, and it has a shelf life of 24 months.
• If seizure is refractory to standard anticonvulsant therapy, consider acute isoniazid toxicity and administer pyridoxine.
• Consider isoniazid toxicity in patients with unexplained new onset, recurrent, or intractable seizure.
• Prescribe only a one-month's supply of isoniazid at a time to prevent the availability of a large amount.

Multimedia

Media file 1: Isoniazid metabolism.

Media file 2: Gamma-aminobutyric acid (GABA) synthesis.

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Keywords

isoniazid, INH, INH toxicity, isoniazid poisoning, isonicotinic acid hydrazide, isoniazid-induced seizure, isoniazid seizure, tuberculosis, TB, overdose, seizure, tonic-clonic seizure, metabolic acidosis, treatment, diagnosis, hypotension, stupor tremor, mydriasis, urinary retention, ataxia, areflexia, nystagmus

Contributor Information and Disclosures

Author

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.

Coauthor(s)

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.

Medical Editor

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.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

Jeffrey R Tucker, MD, Assistant Professor, Department of Pediatrics, Division of Emergency Medicine, University of Connecticut and Connecticut Children's Medical Center
Jeffrey R Tucker, MD is a member of the following medical societies: American Academy of Clinical Toxicology, American Academy of Pediatrics, and Massachusetts Medical Society
Disclosure: Merck Salary Employment

CME Editor

Daniel Rauch, MD, FAAP, Director, Pediatric Hospitalist Program, Associate Professor, Department of Pediatrics, New York University School of Medicine
Daniel Rauch, MD, FAAP is a member of the following medical societies: Ambulatory Pediatric Association, American Academy of Pediatrics, and Society of Hospital Medicine
Disclosure: Baxter Honoraria Consulting

Chief Editor

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.

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author Binita R Shah, MD, FAAP, to the original writing and development of this topic.

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