ToxCard: Pyridoxine Uses in Clinical Toxicology
Authors: Dominic Nicacio, MD (EM Resident Physician, Carolinas Medical Center, Charlotte, NC); Ann-Jeannette Geib, MD (EM Attending Physician, Medical Toxicologist, Carolinas Medical Center, Charlotte, NC) // Reviewed by: James Dazhe Cao, MD (@JamesCaoMD, Associate Professor of EM, Medical Toxicology, UT Southwestern Medical Center, Dallas, TX); Alex Koyfman, MD (@EMHighAK); Brit Long, MD (@long_brit)
A 3-year-old male presents to the pediatric emergency department (ED) via EMS, actively seizing. Blood glucose is 87, and vitals are stable. Physical exam shows equal and reactive pupils bilaterally, no gaze deviation, dry skin, no rashes, and no palpable abdominal masses. Two rounds of IV lorazepam at 1.5 mg do not stop the seizures. The patient becomes hypoxic and end-tidal CO2 begins to fall. He is subsequently intubated and started on propofol but continues to have subtle seizure activity. The patient’s mother arrives and tells you that she thinks her child got into her purse which contains some of her daily medications. She cannot remember all the names of them but tells you she’s being treated for latent tuberculosis. She hands over a nearly empty bottle of isoniazid (INH), filled two days ago.
- What is the treatment for INH toxicity?
Mechanism of Action:
- In the liver, pyridoxine is converted to pyridoxal-5-phosphate (PLP). PLP is a cofactor for glutamic acid decarboxylase (GAD) that converts glutamic acid to γ-aminobutyric acid (GABA), which is the major inhibitory neurotransmitter in the central nervous system (CNS)
- PLP complexes with INH to form isonicotinic hydrazide that is excreted in the urine.
- INH metabolism leads to formation of hydrazones that inhibit pyridoxine phosphokinase which converts pyridoxine to active form PLP
- Depletion of pyridoxine and inhibition of pyridoxine phosphokinase cause a reduction in GABA concentrations in synapses, resulting in CNS excitability and ultimately seizures1
- A gram-equivalent dose of pyridoxine has been associated with cessation of seizures and improvement in coma scores and pH in INH- poisoned patients2
- Known INH dose: 1 g IV per gram of INH ingested
- Unknown INH dose: 70 mg/kg IV in children or 5 g IV adults
- Repeat dosing: Can repeat above dosing one time if seizures continue to be refractory
- Infusion rate: 0.5 g/min until seizures stop
- If your ED has insufficient pyridoxine vials, you can give the remaining dose as oral formulation via nasogastric tube3
- If a patient presents within 2 hours of ingestion of a potentially toxic dose, some textbooks recommend prophylactic pyridoxine at the same dosing1
You are working in a community ED during a warm June summer day when a 37-year-old female with unknown past medical history comes in via EMS after seizing at home; blood glucose 94 mg/dL en route. EMS states she was found seizing on the floor beside the kitchen table, with a hot bowl of mushroom soup on the table. The mushrooms looked wrinkled and “brain shaped.” The daughter reports her mother attended a mushroom gathering community event earlier today and was collecting morels.
- What toxicity should you be concerned about, and what is the treatment?
- Gyromitrin toxicity from Gyromitra mushroom of the false morel family; treatment is pyridoxine
- Gyromitrin is metabolized to hydrazines that inhibit the enzyme converting pyridoxine to PLP, ultimately resulting in decreased GABA synthesis4,5
- Same as in INH toxicity, 5 g IV over 10 minutes, or 70 mg/kg in children
Four industrial workers arrive to your ED following a blast incident at an aerospace engineering facility. There was a blast and exposure to fumes. Two patients have minor burn injuries. They are all deemed stable after decontamination and initial ED assessment. During their stay three of the workers had seizures that responded poorly to benzodiazepines. You ascertain that they were working with rocket fuels just prior to the blast.
- What toxicity is likely implicated, and what is the treatment?
- Likely hydrazine-containing jet fuels, which is treated with pyridoxine when it causes seizures and altered mental status
- Hydrazines are also found in esculenta mushrooms4
Mechanism of Action:
- Hydrazines inhibit pyridoxine phosphokinase, the enzyme that converts pyridoxine to PLP, which results in decreased GABA synthesis6
- There are limited data regarding optimal dosing, but pyridoxine is likely safe in doses used for INH and Gyromitra toxicity7
Other Occasional Uses of Pyridoxine:
Indications and dosing are based on extremely limited clinical data8
Ethylene Glycol Toxicity:
- Decreases oxalic acid production responsible for renal tubular necrosis & hypocalcemia by shunting metabolism of organic acid metabolites down a less toxic pathway7
- Pyridoxine treatment dose is 100 mg IV daily7
- Pyridoxine is used in pregnancy with doses of up to 25 mg PO TID for nausea and vomiting
- Pyridoxine is FDA category A for use in pregnancy9
- Pyridoxine is often added to medication regimens in patients with Wilson’s disease as penicillamine induced neurological deterioration is thought to be related to pyridoxine deficiency10,11
Theophylline Toxicity-associated Seizures:
- Limited evidence shows that theophylline decreases PLP levels, theoretically decreasing GABA synthesis, causing seizures
- There is mixed evidence in animal models showing some efficacy in decreasing seizures and death, in groups receiving pyridoxine12
- Hernon C, and Lai JT. “Antituberculous Medications” in Nelson LS et al, eds. Goldfrank’s Toxicologic Emergencies, 11 ed. McGraw-Hill Education, 2019.
- Wason S, Lacouture PG, Lovejoy FH Jr. Single high-dose pyridoxine treatment for isoniazid overdose. JAMA. 1981 Sep 4;246(10):1102-4. PMID: 7265398.
- Dilrukshi MDSA, Ratnayake CAP, Gnanathasan CA. Oral pyridoxine can substitute for intravenous pyridoxine in managing patients with severe poisoning with isoniazid and rifampicin fixed dose combination tablets: a case report. BMC Res Notes. 2017 Aug 8;10(1):370. doi: 10.1186/s13104-017-2678-6. PMID: 28789699; PMCID: PMC5549285.
- Goldfrank LR. Mushrooms. In: Nelson LS, Howland M, Lewin NA, Smith SW, Goldfrank LR, Hoffman RS. eds. Goldfrank’s Toxicologic Emergencies, 11e. McGraw Hill; 2019. Accessed January 18, 2022.
- White J, Weinstein SA, De Haro L, Bédry R, Schaper A, Rumack BH, Zilker T. Mushroom poisoning: A proposed new clinical classification. Toxicon. 2019 Jan;157:53-65. doi: 10.1016/j.toxicon.2018.11.007. Epub 2018 Nov 12. PMID: 30439442.
- Dhennin C, Vesin L, Feauveaux J. Burns and the toxic effects of a derivative of hydrazine. Burns Incl Therm Inj. 1988 Apr;14(2):130-4. doi: 10.1016/0305-4179(88)90218-5.
- Howland M (2019). Pyridoxine. Nelson L.S., & Howland M, & Lewin N.A., & Smith S.W., & Goldfrank L.R., & Hoffman R.S.(Eds.), Goldfrank’s Toxicologic Emergencies, 11e. McGraw Hill.
- Lheureux P, Penaloza A, Gris M. Pyridoxine in clinical toxicology: a review. Eur J Emerg Med. 2005 Apr;12(2):78-85. doi: 10.1097/00063110-200504000-00007. PMID: 15756083.
- Nuangchamnong N, Niebyl J. Doxylamine succinate-pyridoxine hydrochloride (Diclegis) for the management of nausea and vomiting in pregnancy: an overview. Int J Womens Health. 2014 Apr 12;6:401-9. doi: 10.2147/IJWH.S46653. PMID: 24748822; PMCID: PMC3990370.
- Roberts, E.A. and Schilsky, M.L. (2008), Diagnosis and treatment of Wilson disease: An update. Hepatology, 47: 2089-2111. https://doi.org/10.1002/hep.22261
- Dong QY, Wu ZY. Advance in the pathogenesis and treatment of Wilson disease. Transl Neurodegener. 2012 Nov 27;1(1):23. doi: 10.1186/2047-9158-1-23. PMID: 23210912; PMCID: PMC3526418.
- Glenn GM, Krober MS, Kelly P, McCarty J, Weir M. Pyridoxine as therapy in theophylline-induced seizures. Vet Hum Toxicol. 1995 Aug;37(4):342-5. PMID: 8540225.