Continuing Education Activity

Pyridoxine is a vitamin and a medication used in the treatment of vitamin B6 deficiency, as well as the management of nausea and vomiting of pregnancy. It is also used in vitamin B6 dependency syndromes, and controversially used in some other disorders. This activity will highlight the indications, mechanism of action, administration routes, adverse effects, monitoring, and contraindications related to the use of pyridoxine on patients with vitamin B6 deficiency and other diseases.

Objectives:

• Identify the mechanism of action and administration of vitamin B6.
• Describe the adverse effects and contraindications of vitamin B6.
• Review the importance of vitamin B6 in the management of several diseases.
• Outline the importance of improving care coordination amongst the interprofessional team to enhance the delivery of care for patients receiving pyridoxine.

Indications

Vitamin B6 (Pyridoxine) is a water-soluble substance that is converted inside the body into essential coenzymes for more than 100 enzymes in the human body.

Vitamin B6 has three natural forms: pyridoxine (PN), pyridoxal (PL), and pyridoxamine (PM), all of which transform into its active forms in the body, which is the coenzyme pyridoxal 5-phosphate (PLP or P5P).[1][2]

PLP, the functioning structure in the body, mainly serves as a coenzyme in amino acid, protein, carbohydrate, and lipid metabolism, in addition to neurotransmitter synthesis.[1] It is also involved in glycogenolysis and gluconeogenesis.[3][4]

There are only two FDA-approved drugs containing pyridoxine or its analogs; the first is a combination of several vitamins including B6 indicated for the prevention of vitamin deficiency in pediatric and adult patients receiving parenteral nutrition, and the second is a combination of doxylamine succinate and pyridoxine hydrochloride (a vitamin B6 analog) in oral tablet form for treatment of nausea and vomiting of pregnancy that does not respond to conservative management.[5][6]

Vitamin B6 is indicated in cases of its deficiency, which may be due to poor renal function, autoimmune diseases, increased alcohol intake, or isoniazid, cycloserine, valproic acid, phenytoin, carbamazepine, primidone, hydralazine, and theophylline therapy.[7][8][9][10][11][12][13] Inadequate vitamin B6 intake is a rare cause of its deficiency.

Vitamin B6 deficiency can be observed clinically as seborrheic dermatitis, microcytic anemia, dental decay, glossitis, epileptiform convulsions, peripheral neuropathy, electroencephalographic abnormalities, depression, confusion, and weakened immune function.[7][14][15][16][17]

Some rare inborn errors of metabolism result from defects in the coenzyme binding sites of the responsible enzymes where PLP is attached, and administering very high doses of vitamin B6 is crucial for the functioning of these enzymes. These disorders are called vitamin B6 dependency syndromes. Examples of these syndromes are: convulsions of the newborn, xanthurenic aciduria, cystathioninuria, primary hyperoxaluria, homocystinuria, sideroblastic anemia and gyrate atrophy with ornithinuria.[18]

Furthermore, some toxicological uses of pyridoxine include isoniazid overdose, false morel (gyromitra) mushroom poisoning, hydrazine exposure, ethylene glycol toxicity, and crimidin toxicity.[13]

There is some proof of Vitamin B6 being effective in suppression of lactation as well as in relieving side effects of oral contraceptives such as depression and nausea.[19]

Research has found conflicting results regarding the use of vitamin B6 supplements in treating gestational diabetes, premenstrual syndrome, carpal tunnel syndrome, morning sickness, and in treating and preventing essential hypertension.[19]

Even though scant evidence regarding pyridoxine’s efficacy exists regarding these uses, it has been used empirically in the treatment of some conditions including atopic dermatitis, dental caries, acute alcohol intoxication, autism, diabetic complications, Down syndrome, schizophrenia, Huntington chorea, and steroid-dependent asthma.[14][16][7][20][7][16][14][19].

Research shows a decreased risk of colorectal cancer with increased B6 intake in humans.[21] Some research has shown high B6 levels to inhibit in-vitro hepatic tumor cell multiplication in rats.[22]

Mechanism of Action

PLP catalyzes different reactions such as transamination, decarboxylation, racemization, and elimination, in either enzyme-bound or free form. These reactions are significantly facilitated and accelerated in the presence of PLP due to the electron-withdrawing nature of the molecule, which unstabilizes the bonds around the alpha-carbon atom through the system formed with amino acids.[23]

Metabolism of Vitamin B6

Pyridoxine, pyridoxamine, and pyridoxal are rapidly absorbed from food and oral drugs by mucosal cells of the small intestine, while their phosphorylated analogs first undergo dephosphorylation and are then absorbed.[24]

Vitamin B6 analogs are absorbed in the intestine by passive diffusion, which means that a very large amount of the compound is readily absorbable without cell saturation.[25][26]

After their uptake, PM and PN are acted on by PL kinase to form PMP and PNP respectively; then, these compounds are converted by pyridoxine (pyridoxamine) phosphate (PNP) oxidase enzyme into the coenzyme PLP. This process only occurs in hepatocytes, and to a lesser extent, in mucosal cells of the small intestine, due to a lack of PNP oxidase in most tissues. Due to cell membranes being impermeable to PLP, it is either dephosphorylated by phosphohydrolase enzyme so that PL can be released into the bloodstream, or is directly attached to albumin and liberated by the hepatocytes into the circulation as PLP-albumin complex.[25][27] PLP is also uptaken by erythrocytes and carried by hemoglobin to other tissues.[28]

Finally, protein-bound PLP is dephosphorylated, and the end-product PL in combination with the free PL in plasma is then transformed inside target tissues by the effect of pyridoxal kinase enzyme into the coenzyme PLP which is the active form of vitamin B6. PLP is bound to various proteins inside tissues to protect it from phosphatase enzymes.[29]

Administration

The administration of vitamin B6 can be both via oral and intravenous routes. Oral vitamin B6 is the most prevalent form available, while the intravenous form is useful in some special cases, such as malabsorption syndromes, anorexia, and in patients on parenteral nutrition. It is also present in intramuscular and subcutaneous forms.

Adverse Effects

The most known adverse effect of vitamin B6 supplementation is sensory neuropathy, but this pathology rarely occurs below toxic doses–which is 1 gm/day or more for adults–and there is no evidence of its occurrence in doses lower than 100 mg/day for less than 30 weeks in adults.[20] It is worth noting that the average dietary requirement of vitamin B6 for adults is 1.75 mg/day.[18]

There are no reported adverse effects caused by dietary concentrations nor by regular supplemental doses of vitamin B6, while higher doses below levels of toxicity may cause indigestion, nausea, breast tenderness, photosensitivity, and vesicular dermatoses.[20]

Contraindications

The only two contraindications for vitamin B6 are hypervitaminosis B6; as toxic levels may cause sensory neuropathy, and hypersensitivity to pyridoxine.

Monitoring

The therapeutic index of B6 is variable between individuals as individual susceptibility to toxic adverse effects is noted, but some studies state a cutoff value of 100 grams over 20 months, below which toxicity-related neuropathy does not occur.[30][20]

Vitamin B6 is highly absorbable from food and drugs, and high concentrations can be rapidly reached, however, the human body excretes the excess in urine as 4-pyridoxic acid, and it is also excreted unchanged when taking very high doses.[31] Monitoring of the amount of vitamin B6 in the body is for three reasons; to confirm depletion or toxicity and in research studies concerned with vitamin B6.

Vitamin B6 monitoring divides into direct and functional methods. The direct methods are through measuring the concentration of the vitamin in plasma, blood cells, or urine. Plasma PLP concentration is the best monitoring method as it reflects B6 stores in the entire body.[32]

The functional methods, such as tryptophan load test, plasma homocysteine levels, and blood transaminase activity, are also used in detecting B6 deficiency. Erythrocyte aspartate aminotransferase and alanine aminotransferase stimulation tests can evaluate long term vitamin B6 status, and their values increase with B6 depletion.[32]

Toxicity

Vitamin B6 can be toxic if its concentration in the body is too high, causing sensory neuropathy, whose mechanism is unknown. The degeneration of sensory fibers of peripheral nerves and its myelin and also the dorsal columns of the spinal cord cause bilateral loss of peripheral sensation or hyperaesthesia, accompanied by limb pain, ataxia, and loss of balance. The condition regresses gradually after cessation of taking the supplement till regaining normal activity.[13] Higher doses can cause testicular atrophy and reduced sperm motility.[33]

Research on the subject found that the duration of administration of the vitamin is directly proportional to the risk of clinically-evident toxicity with respect to the total dose given.[20]

Enhancing Healthcare Team Outcomes

Adequate nutrition is essential for any vitamin prevention. Healthcare professionals should advise consuming vitamin B6-rich foods such as chickpea, liver, poultry, and fortified ready-to-eat cereals. B6 deficiency is generally rare due to dietary inadequacy.

Gynecologists, obstetricians, neurologists, hematologists, and dermatologists often need to diagnose, treat, and collaborate about patients with Vitamin B6 deficiency or excess. The clinical picture accompanying vitamin B6 deficiency is not characteristic to it, so thorough analysis and good observation skills are needed to identify the problem. Susceptible populations, such as patients with chronic diseases and poor quality diet, should be identified and managed accordingly.

Clinical use of vitamin B6 in some diseases is controversial, as no definite evidence is available for its use in those conditions. But because of the relative safety of high doses of water-soluble vitamins, no strict monitoring of the patients is needed. Some conditions require much higher doses than normally necessary, such as dependency syndromes, and observation for adverse effects is necessary.