phar 722 pharmacy practice iii vitamins- pyridoxine (b 6 ) spring 2006
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Phar 722Pharmacy Practice III
Vitamins-
Pyridoxine (B6)
Spring 2006
Pyridoxine Study Guide• The applicable study guide items in the
Vitamin Introduction• History• Nomenclature• Structures of the vitamins and conversion to
the cofactor forms• Functions of the cofactor forms including the
specific types of reactions• Deficiency conditions• Drug-vitamin interactions• Dietary and commercial forms of the vitamin
History
• First isolated in 1934 as a factor responsible for curing a type of rat dermatitis. – Much recent research has been conducted at
Oregon State University.• There is no historical “disease” associated
with this vitamin.• The “importance” of this vitamin was
discovered when an infant milk formulation was sold without pyridoxine. – The infants developed convulsions and there
were deaths.– Initially, there was confusion as to whether there
was a contaminant in the milk.
Chemistry• There are three forms of the vitamin.
– Pyridoxine is found in plants.• Common commercial form.
– Pyridoxal found in animals.• Never commercial.
– Pyridoxamine found in animals. • Not found in common vitamin preparations.
• The forms found in animals came from eating vegetable sources or other animals.
Pyridoxine Uptake and Metabolism
• All three forms are absorbed from the intestine and transported to the liver where they are phosphorylated.
• All three are interchangeable as their respective phosphate esters.
• Transport throughout the body seems to be on serum albumin.
• Pyridoxal phosphate is considered the cofactor form of the vitamin.
ADP
ATP
NH3C
HO
CH2NH3+
CH2OH
NH3C
HO
CH2NH3+
CH2OP
FMNFMNH2
FMNFMNH2
FADH2
ADP
ATP
FAD
NH3C
HO
CHO
CH2OH
NH3C
HO
COO-
CH2OH
NH3C
HO
CHO
CH2OPFMNH2
NAD+
FMN
ADP
ATP
NH3C
HO
CH2OH
CH2OH
NH3C
HO
CH2OH
CH2OP
4-Pyridoxic Acid(metabolite)
Pyridoxal
Pyridoxal P(coenzyme/cofactor)
Pyridoxamine P
Pyridoxamine(a commerical form)
Pyridoxine(a commercial form)
Pyridoxine P
NADH + H+
Oxidase
Oxidase
Oxidase
Oxidase
Pi
Phosphatase
Pi
Phosphatase
Pi
PhosphataseKinase Kinase Kinase
OxidasePlants Animals
• Transamination: – Nearly every amino acid requires pyridoxal phosphate (PLP)
for its metabolism.
• Decarboxylation of amino acids: – DOPA to dopamine; – Histidine to histamine; – 5-OH-Tryptophan to serotonin
• Production of glucose-1-P from glycogen.
• Conversion of homocysteine to cysteine and glycogenic end products.
• Other reactions where an amine moiety is part of the reaction scheme.
Biochemical Functions
R C CO2-
H
NH3+
N
CH2OP
H3C
HO
C
O H
H2O
N
CH2OP
H3C
HO
CH
NH+
CR CO2-
H
N
CH2OP
H3C
HO
CH2
NH+
CR CO2-
H2O
CO2
N
CH2OP
H3C
HO
CH
NH+
CR
H
H
H+
H2O
R H
NH3+
H
O
CR CO2-
N
CH2OP
H3C
HO
CH2
NH3+
+
Aldimine
Amine
Pyridoxal P
-amino acid -keto acid
+
Pyridoxamine P
N
CH2OP
H3C
HO
CH2
NH+
CR' CO2-
R' C CO2-
O
R C CO2-
O
H2O
R' C CO2-
H
NH3+
-amino acid
Deamination
TransaminationDecarboxylation
N
CH2OP
H3C
HO
C
O H
Pyridoxal P
Pyridoxine deficiency-1• Deficiencies are seen with this vitamin.
– In infants there is a characteristic type of convulsions which is reversible when pyridoxine supplements are given.
– Deficient infants also show a characteristic electrical encephalogram. (This was "discovered" when infants were fed an infant formula lacking pyridoxine.)
• Pyridoxine has shown no beneficial results for adults with convulsive disorders.
• The neuropathies seen in pyridoxine deficiencies probably relate to its requirement for the biosynthesis of three neurotransmitters – serotonin from tryptophan and norepinephrine and epinephrine from L-DOPA (Dihdroxyphenylalanine). L-DOPA is formed from tyrosine by DOPA decarboxylase, a pyridoxal P containing enzyme.
Pyridoxine deficiency-2• Considering the central role that this vitamin plays in amino acid
metabolism, it is a wonder that there aren't more visible signs of this deficiency.
• A change in the glucose tolerance curve has been reported in pyridoxine deficient subjects.
• Elevated homocysteine may indicate a pyridoxine deficiency, but it also can indicate problems with folic acid and cobalamin status.
• There have been reports that pyridoxine supplements might be beneficial for neuropathies, particularly those that are drug-induced, and carpal tunnel syndrome.
• Proof of its role in treating depression and carpal tunnel syndrome is equivocal.
• Because it is required in the conversion of tryptophan to niacin, pyridoxine may have a niacin-sparing effect.
Drug – Vitamin Interactions-1• Isoniazid (INH)
– The widely used antitubercular drug isoniazid, INH, can induce a pyridoxine deficiency.
• A peripheral neuritis develops. • This interaction has no relationship to INH's antitubercular
activity. – Therefore, pyridoxine supplements do not require altering INH
dosing schedules.
• Penicillamine– This drug is a copper chelator used in Wilson’s Disease
(copper storage disease) and has two amine groups.
• There may have been an interaction of some type with the earlier high dosage oral contraceptives.– This was based on a tryptophan load test.
N
C
OHN
NH2
N
CH2OPHO
H3C
O H
N
C
OHN
N
Isoniazid (INH)Isonicotinic Acid Hydrazide
+
Pyridoxal P
H
N
CH2OP
HO
H3C
H2O
Isoniazid Pyridoxal Adduct
Drug – Vitamin Interactions-2
• L-DOPA– Parkinsonian patients taking L-DOPA must
restrict their use of pyridoxine containing vitamin supplements to formulations containing only the adult RDA.
– Excessive amounts of pyridoxine will cause peripheral decarboxylation of L-DOPA (from DOPA decarboxylase in the mucosa) producing dopamine.
• This reduces the amount of L-DOPA that will cross the blood brain barrier.
Hypervitaminosis Pyridoxine• A certain mystique has built up around this vitamin
resulting in individuals overdosing themselves. • Most of this “mystique” focuses on the role of
pyridoxal P in the conversion of glycogen to glucose-1-P. – Example: Marathon runners take pyridoxine for the final “boost” to finish the race.
• Serious neurological problems have been seen in doses of 1 - 6 gm/day for 2 - 40 months.
• Megadosing below 2 gm/day seem safe, but all of this information is based mostly on anecdotal reports.
• There is an UL for this vitamin, considerably below the 2 gm/day.
Dosage Forms
• Commercial Form:– Synthetic pyridoxine
DRIs-1• AI
– Infants (0 - 12 months) 0.1 - 0.3 mg/day (≈0.014 mg/kg to ≈0.033 mg/kg)
• EAR– Children (1 - 13 years) 0.4 - 0.8 mg/day– Males (14 - 19 years) 1.1 mg/day– Females (14 - 19 years) 1.0 mg/day– Men (19 - 50 years) 1.1 mg/day– Men (51+ years) 1.4 mg/day– Women (19 - 50 years) 1.1 mg/day– Women (51+ years) 1.3 mg/day– Pregnancy 1.6 mg/day– Lactation 1.7 mg/day
DRIs-2• RDA
– Children (1 - 13 years) 0.5 - 1.0 mg/day– Males (14 - 19 years) 1.3 mg/day– Females (14 - 19 years) 1.2 mg/day– Men (19 - 50 years) 1.3 mg/day– Men (51+ years) 1.7 mg/day– Women (19 - 50 years) 1.3 mg/day– Women (51+ years) 1.5 mg/day– Pregnancy 1.9 mg/day– Lactation 2.0 mg/day
• UL– Children (1 - 18 years) 30 - 80 mg/day– Adults (19 an older) 100 mg/day
Food Sources• Wheat germ
• Milk
• Legumes
• Meat
• Vegetables
• Dietary forms will be the various cofactor structures.
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