A14: Antidotes in Depth

Pyridoxine (vitamin B₆), a water-soluble vitamin, is an antidote for overdoses of isonicotinic acid hydrazide (Isoniazid, INH), Gyromitra esculenta mushrooms, hydrazine, methylated hydrazines, and ethylene glycol. With the exception of ethylene glycol, all of these xenobiotics produce seizures by the competitive inhibition of pyridoxal-5′-phosphate (PLP). Pyridoxine overcomes this inhibition and may also enhance the less toxic pathway of ethylene glycol metabolism to form benzoic and hippuric acid, instead of oxalic acid.⁶ Hydrazine and methylated hydrazines (1,1-dimethylhydrazine, UDMH; monomethylhydrazine, MMH) are used as rocket fuels, and MMH is also found in Gyromitra esculenta mushrooms.³

Pyridoxine deficiency, which is characterized by seborrheic dermatitis, cheilosis, stomatitis, and glossitis, was first identified in 1926 but was mistakenly attributed to the absence of vitamin B₂(Chap. 47).³¹ Ten years later, the deficiency was fully characterized and correctly recognized as a deficiency of vitamin B₆.³¹ A rare genetic abnormality that produces pyridoxine-responsive seizures in newborns was described in 1954.⁵

Chemistry

The active form of pyridoxine is PLP.³¹ The alcohol pyridoxine, the aldehyde pyridoxal, and the aminomethyl pyridoxamine are all naturally occurring, related compounds that are metabolized by the body to its active form PLP.³¹ Pyridoxine was chosen by the Council on Pharmacy and Chemistry to represent vitamin B₆.³¹ Pyridoxine hydrochloride was chosen as the commercial preparation because of its stability.⁵⁵

Mechanism of Action

Pyridoxal-5′-phosphate is an important cofactor in more than 100 enzymatic reactions, including decarboxylation and transamination of amino acids, and the metabolism of tryptophan to 5-hydroxytryptamine (serotonin) and methionine to cysteine.^23,31 In animals, iatrogenic pyridoxine deficiency produces seizures, resulting from reduced brain concentrations of PLP, glutamic acid decarboxylase, and γ-aminobutyric acid (GABA).¹⁶

Isoniazid and methylated hydrazines such as MMH interfere with the normal function of pyridoxine as a coenzyme. INH produces a syndrome resembling cerebral vitamin B₆ deficiency, which results in seizures.⁴³ Specifically, INH and other hydrazides and hydrazines inhibit the enzyme pyridoxine phosphokinase that converts pyridoxine to PLP (Fig. 58–3).²³ In addition, hydrazides directly combine with PLP, causing inactivation through the production of hydrazones that are rapidly excreted by the kidney.^23,50 PLP is a coenzyme for l-glutamic acid decarboxylase, which facilitates the synthesis of GABA from l-glutamic acid. Animal studies suggest that interference with PLP limits the formation of GABA,^23,50,51 which results in increased glutamic acid, thereby reducing cerebral inhibition, which contributes to the INH and methylated hydrazine–induced seizures.^41,53 The administration of large doses of pyridoxine overcomes the deficiency.

Pharmacokinetics

Whereas pyridoxine is not protein bound, has a volume of distribution of 0.6 L/kg, and easily crosses cell membranes, PLP is nearly entirely plasma protein bound.⁵⁵ At extrahepatic sites, pyridoxine is rapidly metabolized to pyridoxal, PLP, and 4-pyridoxic acid, with only 7% excreted unchanged in the urine.⁵⁵ After intravenous (IV) infusion of 100 mg of pyridoxine, PLP concentration increases rapidly in serum and in erythrocytes.⁵⁵ PLP rises from 37 to 2183 nmol/L in serum and from undetectable to 5593 nmol/L in erythrocytes.⁵⁵ Oral pyridoxine, in doses of 600 mg, is 50% absorbed within 20 minutes of ingestion by a first-order process, with rapid achievement of peak serum concentrations of pyridoxine, PLP, and pyridoxal.⁵⁴ The concentration of PLP appears to be tightly controlled in the serum and related to alkaline phosphatase activity.^24,54 Oral doses of pyridoxine from 10 to 800 mg result in PLP concentrations of 518 to 732 nmol/L at 4 hours after ingestion.⁵⁴ Chronic alcoholic patients have lower baseline serum PLP concentrations because acetaldehyde enhances the degradation of PLP in erythrocytes through stimulation of an erythrocyte membrane-bound phosphatase that hydrolyzes phosphate containing B₆ compounds.³⁰

Animal Studies

In a canine model of INH induced toxicity, pyridoxine reduced the severity of seizures, increased the duration of seizure free periods, and prevented death from a previously determined lethal dose of INH in a dose dependent fashion.^13,14 Lower molar ratios prevented deaths, and higher molar ratios prevented both deaths and seizures.¹⁴ When used as single treatments for INH induced seizures, phenobarbital, pentobarbital, phenytoin, ethanol, and diazepam were ineffective in controlling seizures and death, but when combined with pyridoxine, each protected the animals from seizures and death.¹³ Other small animal experiments have documented the effectiveness of pyridoxine against MMH induced seizures when used without^23,34,46 and with diazepam.²⁰ Anticonvulsant efficacy is also demonstrated in feline⁴² and primate⁴⁴ models.

Rat studies with intraperitoneal UDMH also demonstrate the protective effects of pyridoxine, which prevented seizures and death in a model that produced 94% mortality and 100% seizures without pyridoxine.¹⁵ Other studies in dogs and monkeys also demonstrate the effectiveness of pyridoxine in preventing seizures and mortality, and in treating seizures.⁴ Intramuscular pyridoxine protected the monkeys from death and stopped the seizures caused by IV exposure to UDMH.

Human Data

Clinical experience with pyridoxine for INH overdose in humans demonstrates favorable results.^2,11 Rapid seizure control with no morbidity or ­mortality was achieved when the ratio in grams of pyridoxine administered to INH ingested ranged from 0.14 to 1.3, although in practice, most patients receive approximately gram-for-gram amounts. In five patients, the use of gram-for-gram amounts of pyridoxine resulted in the complete control of seizures and a resolution of the metabolic acidosis.⁴⁹ In eight patients with intentional INH overdoses, basic poison management, intensive supportive care, and a mean dose of 5 g of pyridoxine IV resulted in no fatalities.⁸ Seizures were controlled in a 22 month-old boy given 100 mg of IV pyridoxine after an estimated INH ingestion of 5 g.⁴³ Variable results are reported when lesser amounts of pyridoxine are used.³² Seizures were reported in two patients after ingestion of INH–pyridoxine combination tablets, although the actual amount of pyridoxine ingested was not noted.⁴⁵

In addition to controlling seizures, administration of pyridoxine also appears to restore consciousness. Two patients, who remained obtunded for as long as 72 hours after the apparent resolution of the seizures, were reported to awaken immediately after 3 to 10 g of IV pyridoxine was administered.¹⁰ A third patient who was lethargic awakened with IV pyridoxine. This suggests that mental status abnormalities associated with INH overdose (and possibly hydrazine overdoses) may be responsive to pyridoxine and may also require repetitive dosing.^11,49 Patients treated with large doses of pyridoxine awaken more rapidly even after experiencing sustained seizure activity or status epilepticus.

Monomethylhydrazine poisoning can be encountered in a variety of clinical situations. In the aerospace industry, where MMH is used as a rocket propellant, percutaneous or inhalational poisoning may occur. Ingestion of the false morel mushroom, Gyromitra esculenta, can also produce toxicity when its major toxic compound, gyromitrin, is metabolized to MMH (Chap. 120).^3,18

The neurologic effects of MMH poisoning are similar to those of INH toxicity and include seizures and respiratory failure.¹⁶ Severe liver damage similar to INH induced hepatotoxicity is also described.⁹ As in the case of INH induced hepatotoxicity, there is no evidence that MMH induced hepato­toxicity can be treated by administration of pyridoxine.⁹

A patient who was exposed to hydrazine became comatose 14 hours later and remained comatose for 60 hours until treated with 25 mg/kg of pyridoxine.²⁵ A man with an altered consciousness who had ingested an unknown quantity of hydrazine improved after treatment with 10 g of pyridoxine.²² This improvement occurred over 24 hours and may have been unrelated to pyridoxine therapy. A severe sensory peripheral neuropathy lasting for 6 months developed one week after the overdose and was most likely a result of the hydrazine ingestion and not the pyridoxine. Six patients exposed to an Aerozine-50 (hydrazine and UDMH) spill were effectively treated with pyridoxine after developing twitching, clonic movements, hyperactivity, or gastrointestinal symptoms.¹⁹ A patient exposed to UDMH during an explosion developed extensive burns, diverse neurologic manifestations, and electroencephalographic findings that resolved rapidly after the administration of IV pyridoxine.¹⁷

Pyridoxal-5′-phosphate is a cofactor in the conversion of glycolic acid to nonoxalate compounds (Chap. 109). Patients poisoned with ethylene glycol should receive 100 mg/d of pyridoxine IV in an attempt to shunt metabolism preferentially away from the production of oxalic acid. This approach is supported by an animal model⁶ and the study of primary hyperoxaluria,²¹ although there are no adequate studies of human ethylene glycol poisoning.³⁶

Pyridoxal-5′-phosphate is neurotoxic to animals and humans when administered chronically in supraphysiologic doses.^25,27,37 Delayed peripheral neurotoxicity occurred in patients taking daily doses of 200 mg to 6 g of pyridoxine for one month.^35,40,41 Healthy volunteers given 1 or 3 g/d developed a small and large fiber distal axonopathy, with sensory findings and quantitative sensory threshold abnormalities occurring after 1.5 months at the high dose and 4.5 months at the low dose exposure. When symptoms occurred, the pyridoxine was immediately stopped, but symptoms progressed for 2 to 3 weeks (Chap. 24).⁷

Pyridoxine may also induce a sensory neuropathy when massive doses are administered, either as a single dose or over several days.^1,26,48 Ataxia occurred in dogs receiving 1 g/kg of pyridoxine.⁴⁸ Larger doses of pyridoxine result in loss of coordination, ataxia, seizures, and death.⁴⁸ Death after pyridoxine administration was sometimes delayed for 2 to 3 days.⁴⁸

Two patients treated with 2 g/kg of IV pyridoxine (132 and 183 g, res­pectively) over 3 days developed severe and disabling sensory neuropathies.¹ One year later, both patients were unable to walk. Inadequate information is available to determine the maximal single acute nontoxic dose in humans; however, there appears to be a wide margin of safety. Doses of pyridoxine ranging from 70 to 375 mg/kg or doses equivalent to the milligram-per-kilogram historical dose of ingested INH have been administered without adverse effects.^28,49

The 0.5% chlorobutanol preservative in IV pyridoxine equates to doses of 250 to 500 mg of chlorobutanol when 5 and 10 g doses of pyridoxine are administered. Chlorobutanol is a sedative with a long elimination half-life, but doses of 600 mg were given to human volunteers without complication.^12,47 A dose of 5 g IV pyridoxine administered over 5 minutes to five healthy volunteers produced a transient minor increase in base deficit without any alteration in the level of consciousness.²⁹

Pyridoxine is Food and Drug Administration pregnancy category A. The recommended daily allowance for pyridoxine in pregnancy is 2.2 mg. There has never been a controlled trial in pregnant women of gram doses of pyridoxine, but the benefit of using pyridoxine for INH induced seizures would clearly exceed the theoretical risk to the fetus. Pyridoxine enters breast milk and is considered compatible with breastfeeding. However, concentrations of pyridoxine in breast milk after maternal gram doses of pyridoxine have not been studied.

A safe and effective pyridoxine regimen for INH overdoses in adults is 1 g of pyridoxine for each gram of INH ingested, or 70 mg/kg in a child both to a maximum of 5 g.⁴⁹ These doses are sufficient in the majority of patients, but the dose can be repeated if necessary. The best way to administer pyridoxine in a patient after an INH overdose has not been established. For a patient who is actively seizing, pyridoxine may be given by slow IV infusion at approximately 0.5 g/min until the seizures stop or the maximum dose has been reached. When the seizures stop, the remainder of the dose should be infused over 4 to 6 hours to maintain pyridoxine availability while the INH is being eliminated. The dose should be repeated if seizures persist or recur or if the patient exhibits mental status depression, which could be an indication of persistent neurotoxicity and electrical status epilepticus. If IV pyridoxine is unavailable, oral pyridoxine should be administered.^39,52

For hydrazine and methylated hydrazines (ie, MMH, UDMH) poisoning, there is no established dose.⁵³ Using the same dosage regimen as in the case of INH poisoning is theoretically reasonable and appropriate, although it has never been tested in humans.

Pyridoxine hydrochloride is available parenterally at a concentration of 100 mg/mL with a 1 mL fill in a 2 mL vial with 0.5% chlorobutanol as the preservative and 1.4 μg/mL aluminum from APP Pharmaceuticals.³⁸ Thus, a 5 g IV dose of pyridoxine requires fifty 100 mg/mL vials. This is an exception to the rule that appropriate doses of medications rarely require multiple vials and certainly not of this magnitude. This quantity also emphasizes the necessity of maintaining an adequate supply in the emergency department as well as in the pharmacy.³³ Oral pyridoxine is available in many tablet strengths from 10 to 500 mg depending on the manufacturer.

• Pyridoxine and a benzodiazepine should be used to achieve synergistic control of INH or MMH poisoning. An adequate dose of IV pyridoxine is 70 mg/kg to a maximum of 5 g and repeated once as needed.

• Five grams of IV pyridoxine requires administration of fifty 100-mg/mL vials.

• Adequate stocks should be ensured in the ED and pharmacy.

• If IV pyridoxine is unavailable, oral pyridoxine may be used.

References