Pyridoxine

Why this drug is interesting

Isoniazid overdose produces a triad that is almost diagnostic: refractory seizures, profound metabolic acidosis, and coma. The seizures do not respond well to benzodiazepines or to conventional anticonvulsants, because the problem is not excess excitation but a failure to make the brain's principal inhibitory neurotransmitter.

Pyridoxine corrects that failure directly, and does so within minutes. It is one of the few antidotes on this site with a visible, immediate and near-complete effect.

Pharmacology

Mechanism

Pyridoxine is phosphorylated to pyridoxal 5′-phosphate (PLP), the cofactor for a large family of enzymes including glutamate decarboxylase, which converts glutamate to GABA.

Isoniazid interferes with this at two points. It inhibits pyridoxine phosphokinase, reducing PLP formation; and isoniazid metabolites combine with pyridoxal to form hydrazones that are excreted, depleting the pool. The consequence is loss of GABA synthesis with glutamate accumulating unopposed — seizures that are, in effect, an acute inhibitory-neurotransmitter deficiency.

The lactic acidosis

Isoniazid overdose produces a severe anion gap metabolic acidosis that is partly seizure-related lactate and partly a direct effect on NAD-dependent lactate metabolism. It typically corrects rapidly once seizures stop — so an acidosis that is not improving after the seizures have been controlled should prompt a search for another cause.

Dosing as an antidote

Isoniazid overdose — the gram-for-gram rule

The dose of pyridoxine is equivalent to the amount of isoniazid ingested, given intravenously — that is, gram for gram.²³ It is one of very few doses in emergency medicine expressed against the poison rather than against the patient.

• Known ingestion — give pyridoxine gram-for-gram of ingested isoniazid.
• Unknown ingestion in an adult — an empirical 5 g is the figure conventionally used, repeated if seizures continue.
• Unknown ingestion in a child — 70 mg/kg, commonly capped at 5 g.
• Give intravenously, and give it during the seizure — this is a treatment, not a prophylaxis.

Alongside it: benzodiazepines (midazolam) for their synergistic effect, airway control, and correction of the acidosis where severe (see sodium bicarbonate).

How much isoniazid is toxic

Toxicity can occur after acute ingestion of as little as 1.5 g in an adult; doses above 30 mg/kg often produce seizures; and 80–150 mg/kg or more can be rapidly fatal. Onset is typically 30 minutes to 2 hours after ingestion.³

The other indications

Hydrazine and derivatives

Same mechanism — rocket fuel, some industrial exposures, and the hydrazine-related isoniazid metabolites themselves

Gyromitra mushrooms

False morel poisoning; gyromitrin is metabolised to monomethylhydrazine, producing the identical PLP-depletion seizure syndrome

Ethylene glycol

Adjunctive, with thiamine — the traditional rationale is diverting glyoxylate towards glycine rather than oxalate. Weak evidence, low harm; see fomepizole

Isoniazid neuritis (licensed)

50 mg three times daily orally for treatment; the 50 mg tablet presentation is stated as unsuitable for prophylaxis¹

Safety

Chronic high-dose neuropathy

Acute administration

Large intravenous doses are generally well tolerated acutely. Sedation and, at very high doses, transient neurological effects have been described. The practical constraints in an emergency are more often the volume and the number of vials than any pharmacological limit.

Interactions

Levodopa

Pyridoxine "may reduce the effect of levodopa … unless a dopa decarboxylase inhibitor is also given".¹ Modern combination preparations (co-careldopa, co-beneldopa) contain such an inhibitor, so this is largely historical — but it is in the label

Isoniazid and penicillamine

Both increase pyridoxine requirements¹

Oral contraceptives

Listed as altering pyridoxine metabolism or bioavailability¹

Contraindications

Hypersensitivity to any ingredient.¹ In pregnancy, data on exposed pregnancies indicate no adverse effects at therapeutic doses; caution is advised.¹ Pyridoxine is, separately, a component of licensed antiemetic therapy in pregnancy (with doxylamine).

Practical use in the ED

1. Think of it in the right patient. Seizures that will not stop, plus a severe metabolic acidosis, plus tuberculosis treatment in the household — the patient does not have to be the one prescribed the isoniazid.
2. Ask what was taken and how much. The dose of the antidote is the dose of the poison; this is the rare case where an exact tablet count changes the prescription.
3. Find the pyridoxine early. Ring pharmacy while the patient is being resuscitated. There is no licensed IV product, so it will not be in the standard antidote box in every hospital.
4. Give a benzodiazepine anyway. It is synergistic and it is available now.
5. Give pyridoxine gram-for-gram, or 5 g empirically in an adult, intravenously.
6. Correct the acidosis and manage the airway. Expect the acidosis to improve rapidly once seizures stop; if it does not, question the diagnosis.
7. Call NPIS on 0344 892 0111. Both the drug and the route are unlicensed for this indication.

Critical appraisal

Pyridoxine's evidence base is entirely case reports, case series and mechanism. There is no controlled trial and there will not be one — isoniazid overdose is uncommon, and withholding the antidote from a fitting patient is not a study anyone would run. The 1995 Intensive Care Medicine review states the position that has held for thirty years: pyridoxine "is the only effective antidote".²

The gram-for-gram rule itself is convention rather than pharmacokinetic derivation. It is stated in the literature as "a dose equivalent to the amount of INH ingested"² and "gram-per-gram amounts of the isoniazid ingested"³, and the empirical 5 g for an unknown ingestion is a pragmatic ceiling rather than a validated figure. It is nonetheless a good rule, because the harm from a single large dose is negligible and the harm from under-dosing is continued status epilepticus.

The larger observation is structural. A cheap, effective, mechanism-obvious antidote with no licensed intravenous product in the UK is the same pattern seen on the pralidoxime, desferrioxamine and activated charcoal pages: the commercial and regulatory system is poorly aligned with rare-but-critical antidotes, and UK practice runs on TOXBASE and on regional stockholding rather than on labels.

References

1. 1
   Pyridoxine 50 mg Tablets — Summary of Product Characteristics. electronic Medicines Compendium, product 1208. Sections 4.1–4.8. Source of the licensed indications (isoniazid-induced peripheral neuritis, sideroblastic anaemia, deficiency states), the 50 mg three times daily dose, the levodopa and penicillamine interactions and the chronic high-dose peripheral neuritis warning. An emc search on 31 Aug 2026 found no licensed intravenous pyridoxine product in the UK — only oral tablets and multivitamin preparations including Pabrinex (product 1427).
2. 2
   Alvarez FG, Guntupalli KK. Isoniazid overdose: four case reports and review of the literature. Intensive Care Medicine 1995;21:641–644. PubMed 8522667. "Pyridoxine, in a dose equivalent to the amount of INH ingested, is the only effective antidote."
3. 3
   Romero JA, Kuczler FJ. Isoniazid overdose: recognition and management. American Family Physician 1998;57:749–752. PubMed 9490997. Source of the toxic-dose thresholds (1.5 g, >30 mg/kg, 80–150 mg/kg), the 30 minute to 2 hour onset, and the gram-per-gram dosing statement.
4. 4
   Hoegberg LCG, Gosselin S, Buckley NA, Wood DM, et al. Recommendations from the Clinical Toxicology Recommendations Collaborative on the administration of activated charcoal in acute oral overdose. Clinical Toxicology 2026;64(6):419–475. PubMed 41906697. Table 4: isoniazid single-dose threshold 40 mg/kg, GRADE D; strong recommendation against multiple-dose charcoal. Full text read 4 Sep 2026.
5. 5
   National Poisons Information Service. TOXBASE · NPIS 0344 892 0111. Required: pyridoxine in isoniazid overdose is off-label use of an unlicensed intravenous preparation in the UK.