Download Phar 722 Pharmacy Practice III

Phar 722
Pharmacy Practice III
VitaminsPyridoxine (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.
COOCH2OH
HO
H3C
N
4-Pyridoxic Acid
(metabolite)
Plants
FADH2
Oxidase
Animals
FAD
CHO
CH2OH
HO
CH2OH
CH2NH3+
+ HO
NAD+ NADH + H
HO
CH2OH
CH2OH
Oxidase
Oxidase
H3C
N
H3C
Pyridoxine
(a commercial form)
Phosphatase
Pyridoxine P
Phosphatase
ATP
HO
ADP
Kinase
ATP
Pi
CH2NH3+
CHO
CH2OP
N
N
Pyridoxamine
(a commerical form)
Kinase
Phosphatase
FMN
H3C
H3C
ADP
Pi
CH2OH
HO
FMN
Pyridoxal
ADP
Kinase
ATP
Pi
FMNH2
N
HO
CH2OP
FMNH2
CH2OP
Oxidase
Oxidase
H3C
N
Pyridoxal P
(coenzyme/cofactor)
FMNH2
FMN
H3C
N
Pyridoxamine P
Biochemical Functions
• 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.
H
R
C
CO2-
NH3+
-amino acid
+
O
Deamination
H
R
H2O
C
CO2-
R
NH+
C
R
O
CO2-
-keto acid
NH+
H2O
+
H
C
HO
CH
CH2OP
NH3+
CH2
HO
CH2OP
CO2-
C
HO
CH2OP
CH2
HO
H3C
N
H3C
N
H3C
N
Aldimine
Pyridoxal P
H3C
H+
R'
C
R
H
R
H
C
H
R'
NH+
NH3+
H2O
CO2
-
O
Decarboxylation
H
CO2-
Transamination
CO2-
O
H
H 2O
R'
CH2OP
HO
O
CH2OP
H
C
HO
N
C
CO2-
CH2
Amine
HO
C
C
NH+
CH
H3C
N
Pyridoxamine P
CO2
R
CH2OP
H3C
-amino acid
CH2OP
N
H3C
NH3+
N
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.
H
N
O
O
C
H
NH2
HO
CH2OP
+
N
H3C
Isoniazid (INH)
Isonicotinic Acid Hydrazide
N
Pyridoxal P
H2O
H
H
N
O
C
N
CH2OP
HO
N
N
H3C
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 LDOPA (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)
Males (14 - 19 years)
Females (14 - 19 years)
Men (19 - 50 years)
Men (51+ years)
Women (19 - 50 years)
Women (51+ years)
Pregnancy
Lactation
0.4 - 0.8 mg/day
1.1 mg/day
1.0 mg/day
1.1 mg/day
1.4 mg/day
1.1 mg/day
1.3 mg/day
1.6 mg/day
1.7 mg/day
DRIs-2
• RDA
–
–
–
–
–
–
–
–
–
Children (1 - 13 years)
Males (14 - 19 years)
Females (14 - 19 years)
Men (19 - 50 years)
Men (51+ years)
Women (19 - 50 years)
Women (51+ years)
Pregnancy
Lactation
0.5 - 1.0 mg/day
1.3 mg/day
1.2 mg/day
1.3 mg/day
1.7 mg/day
1.3 mg/day
1.5 mg/day
1.9 mg/day
2.0 mg/day
• UL
– Children (1 - 18 years)
– Adults (19 an older)
30 - 80 mg/day
100 mg/day
Food Sources
•
•
•
•
•
Wheat germ
Milk
Legumes
Meat
Vegetables
• Dietary forms will be the various
cofactor structures.