A14: Antidotes in Depth

INTRODUCTION

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

HISTORY

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

PHARMACOLOGY

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 ...