Basics
Description
- Complexes with and inactivates pyridoxal-5 phosphate, the active form of pyridoxine (vitamin B6)
- Inhibits pyridoxine phosphokinase, hindering the conversion of pyridoxine to its active form
- Yields a net decrease in ³-aminobutyric acid (GABA) production:
- Depressed GABA causes cerebral excitability and seizures
- Inhibits lactate dehydrogenase, decreasing the conversion of lactate to pyruvate:
- Contributes to the profound anion gap metabolic acidosis
- Chronic toxicity:
- Interferes with synthesis of nicotinic acid (niacin)
- May cause syndrome indistinguishable from pellagra after months of therapy (niacin deficiency)
- Some actions similar to the monoamine oxidase inhibitors:
- Reports of a tyramine-like reaction to isoniazid (INH)
- Rare cases of mania, diaphoresis, depression, obsessive " compulsive disorder, and psychosis
- Pharmacokinetics:
- Rapidly absorbed, peak levels within 1 " 2 hr
- Volume of distribution is 0.6 L/kg and protein binding is low (10%)
- Renally excreted within 24 hr after acetylation in the liver
- Half-life is <1 hr in fast acetylators and 2 " 4 hr in slow-acetylating individuals
Etiology
- High-risk groups include:
- Immigrants
- Homeless
- HIV infected
- Alcoholics
- Lower socioeconomic status populations
- Slow acetylators (60% of African Americans and Whites compared to 20% of Asians) are more prone to chronic effects/toxicity
- LD50 estimated at 80 " 150 mg/kg
- Ingestions <1.5 g lead to mild toxicity, and those of 10 g or more often result in fatality
Diagnosis
Signs and Symptoms
- Acute toxicity:
- Neurologic:
- Altered mental status
- Seizures refractory to standard therapy
- Agitation
- Coma
- Dizziness
- Ataxia
- Hyper-reflexia
- Slurred speech
- Hallucinations
- Psychosis
- GI:
- Renal:
- Cardiovascular:
- Hypotension
- Tachycardia
- Shock
- Cyanosis
- Metabolic:
- Profound anion gap metabolic acidosis (elevated lactate)
- Hyperthermia
- Chronic toxicity:
- Neurologic:
- Peripheral neuropathy
- Optic neuritis, optic atrophy
- Psychosis
- Insomnia
- Vertigo
- Pellagra
- GI hepatitis:
- Liver failure, hepatitis
- Nausea, vomiting, constipation
- Anorexia
Essential Workup
Without specific history of ingestion, initiate general workup for:
- Altered mental status
- Seizures
- Metabolic acidosis
Diagnosis Tests & Interpretation
Lab
- Arterial blood gas:
- Profound metabolic acidosis
- Electrolytes, BUN/creatinine, glucose:
- Elevated anion gap acidosis
- Hyperglycemia
- CBC:
- Acute toxicity:
- Chronic toxicity:
- Agranulocytosis
- Eosinophilia
- Hemolysis
- Anemia
Imaging
- CXR:
- Evidence of tuberculosis increases suspicion for ingestion/toxicity.
- Evaluate for aspiration pneumonia.
- CT/lumbar puncture if indicated and questionable history
Differential Diagnosis
- Toxins:
- Tricyclic antidepressants
- Salicylates (aspirin)
- Theophylline
- Methanol/ethylene glycol
- Lithium
- Carbon monoxide
- Cocaine/cyanide
- Agents that cause metabolic acidosis
- CNS:
- Cerebrovascular accident
- Intracranial hemorrhage/mass/trauma/abscess
- Hypoglycemia
- Uremia
- Thyrotoxicosis
Treatment
Pre-Hospital
Collect prescription bottles/medications for identification in the ED
Initial Stabilization/Therapy
- ABCs:
- Supplemental oxygen
- Intubate if necessary for airway protection
- Secure IV access
- Cardiac monitor
- 0.9% NS access
- Naloxone, thiamine, D50W (Accu-Chek) if altered mental status
Ed Treatment/Procedures
- Vitamin B6 (pyridoxine):
- Specific antidotal treatment for INH toxicity
- Goal: 1 g of pyridoxine for each gram of INH ingested (1 g q2 " 3min)
- 5 g for unknown amount ingested
- May repeat in 20 min for refractory seizures or persistent coma
- If insufficient quantity of pyridoxine available, contact other hospital pharmacies and the regional poison control center to obtain more
- If no parenteral pyridoxine available, crush tablets and give as a slurry via NG tube
- Seizure control:
- Pyridoxine restores deficiency in GABA
- Benzodiazepines are synergistic with pyridoxine
- Phenytoin has no role
- Gastric decontamination after stabilization:
- Consider gastric lavage only in life-threatening ingestions presenting within 1 hr with a protected airway (being aware of potential seizure activity and obtundation)
- Activated charcoal (AC) dosed at 10:1 ratio (AC:drug)
- Hemodialysis:
- Persistent symptoms despite adequate therapy
- Renal insufficiency in symptomatic patients
- Sodium bicarbonate:
- Acidosis usually resolves spontaneously after elimination of seizures
Medication
- Dextrose: D50W 1 amp (50 mL or 25 g) (peds: D25W 2 " 4 mL/kg) IV
- Diazepam (benzodiazepine): 5 " 10 mg (peds: 0.2 " 0.5 mg/kg) IV
- Lorazepam (benzodiazepine): 2 " 6 mg (peds: 0.03 " 0.05 mg/kg) IV
- Naloxone (Narcan): 2 mg (peds: 0.1 mg/kg) IV/IM initial dose
- Pyridoxine (vitamin B6): 1 g IV for each gram of INH ingested (see above)
- Thiamine (vitamin B1): 100 mg (peds: 50 mg) IV/IM
Follow-Up
Disposition
Admission Criteria
- ICU admission for refractory seizures, severe acidosis, coma, altered mental status
- Uncontrolled nausea/vomiting, unclear history of ingestion, or suicidal
- Consult regional poison center:
Discharge Criteria
- Symptoms are usually observed within 45 min of an acute overdose but may be delayed for ≥2 hr
- Discharge if asymptomatic after 6 hr
Followup Recommendations
Psychiatric referral for intentional overdoses or suicidal patients
Pearls and Pitfalls
- Inadequate appreciation and management of INH poisoning:
- Refractory seizures to standard treatments is a fundamental clue to INH poisoning
- Severe acidemia with elevated lactate in altered patients with seizures
- Never paralyze a seizing patient without the use of continuous EEG monitoring
- Goal of pyridoxine therapy is gram for gram of INH
- If pyridoxine adequately treats seizures, may give more if patient remains comatose
Additional Reading
- Minns AB, Ghafouri N, Clark RF. Isoniazid-induced status epilepticus in a pediatric patient after inadequate pyridoxine therapy. Pediatr Emerg Care. 2010;26:380 " 381.
- Osterhoudt KC, Henretig FM. A 16-year-old with recalcitrant seizures. Pediatr Emerg Care. 2012;28:304 " 306.
- Tajender V, Saluja J. INH inducted status epilepticus: Response to pyridoxine. Indian J Chest Dis Allied Sci. 2006;48:205 " 206.
See Also (Topic, Algorithm, Electronic Media Element)
Seizures
Codes
ICD9
961.8 Poisoning by other antimycobacterial drugs
ICD10
- T37.1X1A Poisoning by antimycobac drugs, accidental, init
- T37.1X4A Poisoning by antimycobacterial drugs, undetermined, init
SNOMED
- 67933004 Poisoning by isoniazid (disorder)
- 291679008 Accidental isoniazid poisoning (disorder)
- 291681005 Isoniazid poisoning of undetermined intent (disorder)