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

Toxicity, Isoniazid

Author: David Tran, MD, Attending Physician, Department of Emergency Medicine, North Shore-LIJ Plainview Hospital
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
Contributor Information and Disclosures

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.

Isoniazid metabolism.

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Isoniazid metabolism.

Isoniazid metabolism.


Pyridoxal-5-phosphate is required for the synthesis of GABA, which is the major inhibitory neurotransmitter in the central nervous system (see Media file 2).

Gamma-aminobutyric acid (GABA) synthesis.

Gamma-aminobutyric acid (GABA) synthesis.

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Gamma-aminobutyric acid (GABA) synthesis.

Gamma-aminobutyric acid (GABA) synthesis.


In patients with acute isoniazid overdose, the levels of pyridoxal-5-phosphate and GABA are decreased, CNS excitability increases, and seizure results.

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

More on Toxicity, Isoniazid

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Multimedia: Toxicity, Isoniazid
References
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References

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Further Reading

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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

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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.

 
 
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