DESCRIPTION

Isoniazid (INH) is an antimicrobial used mainly in the treatment of tuberculosis.

FORMS AND USES

• INH (Laniazid, Nydrazid) is available in 50-, 150-, and 300-mg capsules and as a 50 mg/ 5 cc syrup.
• Rifamate capsules are composed of 150 mg INH with 300 mg rifampin.
• Rafater capsules are composed of 150 mg INH with 300 mg rifampin and 300 mg pyrazinamide.
• INH is used for treatment of active tuberculosis or prophylactic therapy of positive tuberculosis skin test. Adult dose is 300 mg orally per day; a typical pediatric dose is 10 mg/kg/day up to 300 mg.

TOXIC DOSE

Seizures may follow ingestion of 30 to 40 mg/kg (2-3 g in a 70-kg adult).

PATHOPHYSIOLOGY

• INH produces pyridoxine deficiency by three mechanisms:
  • Enhanced excretion of pyridoxine
  • Competitive inhibition of the enzyme that converts pyridoxine to its physiologically active form (pyridoxal 5’ phosphate)
  • Direct binding of pyridoxine to form inactive complex
• Pyridoxine depletion causes decreased levels of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). GABA deficiency can cause seizures.
• INH also promotes lactic acidosis by blocking the conversion of lactate to pyruvate.

EPIDEMIOLOGY

• Poisoning is uncommon.
• Toxic effects following exposure range from mild to severe.
• Death may occur in untreated cases.

CAUSES

• Acute INH poisoning usually results from suicidal ingestion.
• Child neglect should be considered if the patient is under 1 year of age; attempted suicide if the patient is over 6 years of age.

DRUG AND DISEASE INTERACTIONS

• Hepatotoxicity/hepatitis risk is increased by concurrent use of carbamazepine, alcohol, phenobarbital, or rifampin.
• Concurrent disulfiram use can lead to coordination difficulties, ataxia, and psychotic episodes.

PREGNANCY AND LACTATION

• US FDA Pregnancy Category C. The drug exerts animal teratogenic or embryocidal effects, but there are no controlled studies in women, or no studies are available in either animals or women.
• INH crosses the placenta and achieves fetal blood levels similar to maternal blood levels, although INH does not appear to be a teratogen.

Section Outline:

• DESCRIPTION
• FORMS AND USES
• TOXIC DOSE
• PATHOPHYSIOLOGY
• EPIDEMIOLOGY
• CAUSES
• DRUG AND DISEASE INTERACTIONS
• PREGNANCY AND LACTATION

DIFFERENTIAL DIAGNOSIS

• Other toxic agents that cause seizures and anion gap acidosis include hypoglycemic agents, sympathomimetic agents (e.g., cocaine, amphetamines), lidocaine, local anesthetics, methylxanthines, neuroleptic drugs, and tricyclic antidepressants, among others.
• Nontoxic causes of seizures and anion gap acidosis include hypoglycemia, hypoxia from any cause, alcohol withdrawal, meningitis, intracranial hemorrhage, and noncompliance with seizure medications.

SIGNS AND SYMPTOMS

• Initial effects of INH toxicity include nausea, vomiting, and progressive altered mental status.
• Sudden onset of seizures is common and often refractory to standard therapy.

Vital Signs

Hyperthermia and tachycardia are common with seizures.

HEENT

Optic neuritis and atrophy may be noted with chronic treatment.

Dermatologic

Rashes occur rarely.

Cardiovascular

• Hypotension may develop in patients with severe intoxication.
• Tachycardia is common.

Pulmonary

• Respiratory depression frequently accompanies seizure activity.
• Tachypnea and Kussmaul type respirations may be noted between seizure episodes.

Gastrointestinal

Nausea and vomiting are common prior to the onset of seizures.

Hepatic

• Mild hepatic injury has been reported with overdose.
• Asymptomatic elevation of liver enzyme test results may develop in 20% to 40% of patients taking INH in therapeutic doses.
• Hepatitis occurs in 0.3% to 1.3% of patients, and hepatic failure is a rare complication.

Fluids and Electrolytes

Severe anion gap acidosis is common if seizures develop.

Musculoskeletal

Rhabdomyolysis may develop following protracted seizures.

Neurologic

• Dizziness and slurred speech may be the earliest symptoms of INH poisoning, followed by seizures and coma.
• Chronic use of INH may produce peripheral neuropathy.

PROCEDURES AND LABORATORY TESTS

Essential Tests

No tests may be needed in asymptomatic patients.

Recommended Tests

• Serum electrolytes, calcium, magnesium, BUN, creatinine, and glucose should be obtained to assess renal injury and metabolic acidosis.
• Pulse oximetry should be performed for assessment of oxygenation.
• ECG, serum acetaminophen, aspirin, and ethanol levels should be obtained in overdose settings to detect occult ingestion.
• Urinalysis and serum creatine kinase should be obtained to evaluate for rhabdomyolysis.
• INH serum levels or urine strips may be available to confirm diagnosis but cannot be obtained in a clinically useful time frame.
• Chest radiographs, head CT, and lumbar puncture should be performed as needed to evaluate respiratory complications and assess other causes of seizures.

Section Outline:

• DIFFERENTIAL DIAGNOSIS
• SIGNS AND SYMPTOMS
  • Vital Signs
  • HEENT
  • Dermatologic
  • Cardiovascular
  • Pulmonary
  • Gastrointestinal
  • Hepatic
  • Fluids and Electrolytes
  • Musculoskeletal
  • Neurologic
• PROCEDURES AND LABORATORY TESTS
  • Essential Tests
  • Recommended Tests

• Treatment should focus on immediate airway management and treatment of seizures.
• Dose and time of exposure should be determined for all substances involved.

DIRECTING PATIENT COURSE

The health-care provider should call the poison control center when:

• Signs and symptoms are not consistent with INH toxicity.
• Coingestant, drug interaction, or underlying disease presents an unusual problem.

The patient should be referred to a health-care facility when:

• Attempted suicide or homicide is possible.
• The patient or caregiver seems unreliable.
• Any toxic effects develop acutely.
• Coingestant, drug interaction, or underlying disease presents an unusual problem.

Admission Considerations

Inpatient management is warranted for all patients who develop altered mental status, seizure, acidosis or other serious effects.

DECONTAMINATION

Out of Hospital

Emesis should not be induced; seizures may develop abruptly.

In Hospital

• Gastric lavage should be performed in pediatric (tube size 24-32 French) or adult (tube size 36-42 French) patients presenting within 1 hour of a large ingestion or if serious effects are present.
• One dose of activated charcoal (1-2 g/kg) should be administered if a substantial ingestion has occurred within the previous few hours.

ANTIDOTES

Pyridoxine

• Indications. Pyridoxine is used in conjunction with benzodiazepines for treatment of seizures induced by INH overdose and should be used empirically in patients with seizure of unknown etiology.
• Contraindications. Pyridoxine is contraindicated in patients with known pyridoxine hypersensitivity.
• Dose. If quantity of INH ingested is known, pyridoxine should be administered intravenously over 5 minutes on a gram-for-gram basis (e.g., 5 g pyridoxine for a 5-g INH ingestion).
• If quantity of INH ingested is not known, 5 g of pyridoxine should be administered intravenously over 5 minutes
  • If seizures persist, a second dose of 5 g is administered.
  • If seizures are not controlled after 10 g and the INH dose is unknown, then the diagnosis should be reconsidered.
• In pediatric patients, the initial dose of pyridoxine is reduced and should not exceed 70 mg/kg.
• Tachypnea, incoordination, ataxia, reflex abnormalities, paralysis, and convulsions may follow excessive pyridoxine administration.

ADJUNCTIVE TREATMENT

• Anion gap acidosis
  • Anion gap acidosis resulting from seizures may be refractory to sodium bicarbonate but resolves with pyridoxine therapy.
  • Acidosis should remit following termination of seizures with pyridoxine without further therapy.
• If seizures occur, a benzodiazepine familiar to the provider should be administered in addition to pyridoxine.
  • Diazepam. Adult dose is 5-10 mg initially; pediatric dose is 0.2-0.5 mg/kg.
  • Lorazepam. Adult dose is 2-4 mg intravenous push over 2-5 minutes; pediatric dose is 0.1 mg/kg intravenous push over 2-5 minutes.
  • Benzodiazepine dose may be repeated every 10 minutes, if needed.
  • The need for endotracheal intubation should be monitored frequently.
• Hemodialysis may be useful if pyridoxine and anticonvulsant therapy fail to correct metabolic acidosis.

Section Outline:

• DIRECTING PATIENT COURSE
  • Admission Considerations
• DECONTAMINATION
  • Out of Hospital
  • In Hospital
• ANTIDOTES
  • Pyridoxine
• ADJUNCTIVE TREATMENT

PATIENT MONITORING

EEG (seizure activity), vital signs, serum electrolytes, glucose, renal and hepatic function, arterial blood gases, neurologic function, and mental status should be monitored.

EXPECTED COURSE AND PROGNOSIS

• With prompt appropriate treatment, prognosis is good and recovery is expected.
• Failure to treat seizures with pyridoxine can result in prolonged hypoxia and brain injury.

DISCHARGE CRITERIA/INSTRUCTIONS

• From the emergency department. Patients may be discharged after gastrointestinal decontamination, 4 hours of observation, and psychiatric evaluation, if necessary.
• From the hospital. Patients may be discharged when liver function tests, serum electrolytes, ECG, and neurologic status are normal and metabolic acidosis is no longer present.

Section Outline:

• PATIENT MONITORING
• EXPECTED COURSE AND PROGNOSIS
• DISCHARGE CRITERIA/INSTRUCTIONS

Pyridoxine should be administered immediately when INH-induced seizures are possible.

Poisoning by other anti-infectives: other antimycobacterial drugs.

See Also: SECTION II, Seizure chapter; and SECTION III, Pyridoxine chapter.

RECOMMENDED READING

Bryson PD. Isoniazid. In: Comprehensive review in toxicology for emergency clinicians. Washington, DC: Taylor & Francis, 1996:664-667.

Wason S, Lacouture PG, Lovejoy FH. Single high-dose pyridoxine treatment for isoniazid overdose. JAMA 1981;246:1102-1104.

Author: Kevin M. Lier

Reviewer: Katherine M. Hurlbut