AUTHOR AND EDITOR INFORMATION
Section 1 of 11  
Author: David Tran, MD, Department of Emergency Medicine, NSUH-LIJ at Plainview
David Tran is a member of the following medical societies: American Academy of Emergency Medicine and American College of Emergency Physicians
Coauthor(s):
Binita R Shah, MD, FAAP, Professor of Clinical Pediatrics and Emergency Medicine, SUNY Health Science Center at Brooklyn, Director of Pediatric Emergency Medicine, Depts of Emergency Medicine and Pediatrics, Kings County Hospital Center
Editors: 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; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Jeffrey R Tucker, MD, Assistant Professor, Department of Pediatrics, Division of Emergency Medicine, University of Connecticut and Connecticut Children's Medical Center; Daniel Rauch, MD, FAAP, Director, Pediatric Hospitalist Program, Associate Professor, Department of Pediatrics, New York University School of Medicine; Maureen Strafford, MD, Arnold P Gold Foundation Associate Professor, Departments of Anesthesiology and Pediatrics, Tufts University and Tufts-New England Medical Center
Author and Editor Disclosure
Synonyms and related keywords:
isoniazid, INH, INH toxicity, isoniazid poisoning, isonicotinic acid hydrazide, isoniazid-induced seizure, isoniazid seizure
Background
Isonicotinic acid hydrazide, commonly known as isoniazid (INH), is an antimicrobial agent that has been used to treat tuberculosis (TB). INH interferes with mycobacterial cell wall synthesis, although its exact mechanism of action is unknown. Poisoning, whether intentional or accidental, is not uncommon because the drug is widely used in the treatment and prophylaxis of TB. Awareness of INH poisoning may prevent severe morbidity and mortality. This article focuses on acute INH toxicity.
Pathophysiology
The presumed etiology of INH-induced seizure involves a decrease in the availability of gamma-aminobutyric acid (GABA). INH metabolites, such as INH 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 (Image 1). Pyridoxal-5-phosphate is required for the synthesis of GABA, which is the major inhibitory neurotransmitter in the central nervous system (Image 2). In patients with acute INH 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 INH overdose were reported, with 7 deaths. 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. 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 INH can cause convulsion. Patients who ingest 80-150 mg/kg develop severe CNS symptoms. Death has been reported in patients who ingested 10-15 g of INH and were inappropriately treated.
Race
- No studies have shown any predilection in INH toxicity based on race.
- Endemic cases of INH toxicity have been reported in persons who have emigrated from Southeast Asia because of their increased risk of TB.
- Inuits and American Indians are at an increased risk of TB and, subsequently, INH toxicity.
Sex
- No sex predilection has been reported in patients with INH toxicity.
Age
- Acute toxicity can occur in all age groups.
History
- In acute toxicity, patients are usually symptomatic within 30-45 minutes. Symptoms may be delayed up to 2 hours when peak serum level occurs.
- Potential symptoms
- 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 INH 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 INH toxicity include the following:
- Hypotension
- Tachycardia
- Hyperpyrexia
- Stupor
- Tremor
- Choking spells
- Slurred speech
- Mydriasis
- Urinary retention
- Ataxia
- Hyperreflexia
- Areflexia
- Nystagmus
Causes
- The rise in INH toxicity correlates with the rise in TB. During the late 1980s, the resurgence of TB in the US caused the highest number of reported cases of INH exposures.
- Contributing factors
- HIV/AIDS epidemic
- Emergence of multi-drug–resistant tuberculosis
- Emigration from Southeast Asia
- Inuit descent
- American Indian descent
- Alcoholism
- Homelessness
- Overcrowded conditions
Acidosis, Metabolic
Status Epilepticus
Toxicity, Acetaminophen
Other Problems to be Considered
Seizure
Lab Studies
- Serum 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 INH toxicity.
- Additional lab studies may be ordered 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 for leukocytosis
- Lactic acidosis secondary to seizure
- Hyperglycemia
- Ketonuria
- Glycosuria
- Ketonemia
- Hypokalemia
- Transient elevation of liver enzymes
- Myoglobinuria
- 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 show QRS prolongation.
Medical Care
- Therapy is mostly supportive, which 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 INH inhibits the metabolism of phenytoin.
- Ipecac syrup is contraindicated in patients with acute INH 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.
Pyridoxine is the drug of choice for 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.
Drug Category: 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.
| Drug Name | Pyridoxine (Nestrex) |
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| Description | 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, tablets can be crushed and given as a slurry. A gram-for-gram replacement also can be used with pyridoxine tablets. |
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| Adult Dose | 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 |
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| Pediatric Dose | Administer as in adults |
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| Contraindications | Documented hypersensitivity |
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| Interactions | Pyridoxine may decrease levodopa, phenytoin, and phenobarbital serum levels |
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| Pregnancy | C - Safety for use during pregnancy has not been established.
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| Precautions | Extremely high doses may cause irreversible sensory loss |
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Drug Category: Anticonvulsants
These agents are used to prevent seizure recurrence and terminate clinical and electrical seizure activity.
| Drug Name | Lorazepam (Ativan) |
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| Description | 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. |
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| Adult Dose | 4 mg/dose IV slowly over 2-5 min and repeat in 10-15 min prn; not to exceed 8 mg/12 h |
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| Pediatric Dose | 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 |
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| Contraindications | Documented hypersensitivity; preexisting CNS depression, hypotension, and narrow-angle glaucoma |
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| Interactions | Toxicity of benzodiazepines in CNS increases when used concurrently with alcohol, phenothiazines, barbiturates, and MAOIs |
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| Pregnancy | D - Unsafe in pregnancy
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| Precautions | Caution in renal or hepatic impairment, myasthenia gravis, organic brain syndrome, or Parkinson disease |
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| Drug Name | Diazepam (Valium) |
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| Description | Depresses all levels of CNS (eg, limbic and reticular formation), possibly by increasing activity of GABA |
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| Adult Dose | 5-15 mg IV q5min, repeat prn; not to exceed 30 mg in 8 h |
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| Pediatric Dose | 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 |
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| Contraindications | Documented hypersensitivity; narrow-angle glaucoma |
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| Interactions | Increases toxicity of benzodiazepines in CNS with coadministration of phenothiazines, barbiturates, alcohols, and MAOIs |
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| Pregnancy | D - Unsafe in pregnancy
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| Precautions | Caution with other CNS depressants, low albumin levels, or hepatic disease (may increase toxicity) |
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| Drug Name | Phenobarbital (Luminal) |
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| Description | It is important to achieve therapeutic levels as quickly as possible. 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. |
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| Adult Dose | 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 |
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| Pediatric Dose | Administer as in adults |
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| Contraindications | Documented hypersensitivity; severe respiratory disease, marked impairment of liver function, and nephritic patients |
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| 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 |
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| Pregnancy | D - Unsafe in pregnancy
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| 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 |
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Further Inpatient Care
- Admit patients to the intensive care unit (ICU) if they are lethargic, comatose, or have refractory seizures.
Complications
- Pneumonia, aspiration
- Hypotension
- Cardiopulmonary arrest
Prognosis
- The prognosis depends primarily on early recognition of INH toxicity.
Patient Education
Medical/Legal 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 INH toxicity.
- Hospitals in urban areas with increased incidence of TB should have at least 5 g of pyridoxine available in the emergency department. The wholesale cost for a 3-gram 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 INH toxicity and administer pyridoxine.
- Consider INH toxicity in patients with unexplained new onset, recurrent, or intractable seizure.
- Prescribe only a one-month's supply of INH at a time to prevent the availability of a large amount.
| Media file 2:
Isoniazid toxicity. Gamma-aminobutyric acid (GABA) synthesis. |
 |  View Full Size Image | |
Media type: Graph
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Toxicity, Isoniazid excerpt Article Last Updated: Apr 24, 2006
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