Transcript Phar 722 Pharmacy Practice III

Phar 722
Pharmacy Practice III
VitaminsNiacin
and
Niacinamide
Spring 2005
Niacin Study Guide
• The applicable study guide items in the Vitamin
Introduction
• History
• Synonyms
• The structural relationships of Niacin and
Niacinamide and the advantages or disadvantages of
each
• Structures and conversion to the cofactor forms
• Function of the cofactor including the specific type
of reactions
• Deficiency syndrome
• Commercial forms of the vitamins
Current and Old Nomenclature
• Niacin (formerly Nicotinic Acid)
• Niacinamide (formerly Nicotinamide)
History-1
• Pellagra has been a serious nutritional disorder in
the United States, mostly in the southeast.
– Two thousand deaths from pellagra were reported in 1941.
– This is ironic because nicotinic acid, later known as niacin,
was first reported in 1867.
• Individuals at risk for pellagra consume a diet in
which zein from corn is the main source of protein.
– Zein is a poor source of both tryptophan and niacin.
– Further, what niacin is present is so tightly bound that is
has poor bioavailability.
– Nevertheless, the very low income Mexican subsisting on a
corn meal diet, treats the corn meal with lime, Ca(OH)2
which frees enough of the niacin that pellagra does not
develop.
CH2
CH
O
CO2-
O
C
NH3+
CH2
CH
CO2-
C
CH2
NH3+
Tryptophan-2,3dioxygenase
N
H
Tryptophan
N
H
Formylkynurenine
CO2-
NH3+
Kynurenine
formamidase
CHO
CH
NH3+
Kynurenine
Kynurenine
hydroxylase
(FAD dependent)
O
+
NH
Quinollinic acid
CO2-
CO2-
CO2-
CO2-
nonenzymatic
C
CH2
CH
NH3+
CHO
-
O2C
NH3+
Amino-carboxymuconic
semialdehyde
3-Hydroxyanthranilic
acid oxidase
NH3+
OH
3-Hydroxyanthranilic Acid
Kynureninase
NH3+
OH
3-Hydroxykynurenine
NAD
Tradition: 60 mg tryptophan is required to form 1 mg niacin.
This has been questioned in tryptophan feeding experiments in humans.
CO2-
History-2
•
1867
– Nicotinic acid was first reported during the structural elucidation of the
alkaloid nicotine. At that time there was no indication that this product was
a vitamin.
•
1914
– Niacin was first isolated by Funk, but he did not realize that it was a vitamin
because it would not cure beriberi.
•
1915
– Niacin's ability to cure pellagra was first demonstrated.
•
1916
– Finally concluded that pellagra was of dietary origin
•
1922
– The role of dietary tryptophan (precursor to niacin) was first demonstrated.
•
1945
– The precursor role of tryptophan was reported.
History-3
• Pellagra may be prevented completely
by a suitable diet without intervention
of any other factor, hygienic or sanitary.
There is no sound evidence that the
disease is controllable in any other
way.
– J. Am. Med. Assoc. 66, 471 (1916)
History-4
• Scientists of the National Institute of Health are seeking to
ascertain the crops having the highest pellagra-preventive values
that may be grown most easily by farmers in the areas in which
pellagra is prevalent. The nutrition specialists of the United States
Public Health Service, working at the Institute, hope that their
studies will result in a practical solution of the problem of
preventing pellagra, a nutritional disease, which has become
widespread in parts of the area. In conjunction with its study of
the nutritive value of crops the Institute is attempting to
concentrate--and if possible to isolate--the pellagra-preventive
vitamin. The Institute, or Hygienic Laboratory, as it was then
know, discovered the cause of pellagra. This discovery is
probably one of the most significant steps forward in public health
during the past decade. The late Dr. Joseph Goldberger of the
Public Health Service found that pellagra was caused by lack of a
certain nutritive substance in the diet. This finding threw a new
light on pellagra and has made possible the beneficial work now
being done by the Public Health Service in attempting to eradicate
the disease.
– Scientific American, November 1931; reprinted in 245, Nov. 1981.
Chemistry
• Both the acid and amide forms are
considered equally active.
•
• Niacinamide usually is the preferred form
because niacin can cause a flushing
syndrome in many individuals.
• Note: Only niacin, and NOT niacinamide, is
effective in treating hypercholesterolemia.
O
O
C
C
OH
NH2
N
N
Niacin
(Nicotinic Acid)
1 gm/ml
Niacinamide
(Nicotinamide)
1 gm/60m
NH2
O
C
N
N
NH2
O
N
N
O
CH2
O
P
O
P
O
CH2
N+
O
O-
HO
O
OH
O-
HO
Nicotinamide Adenine Dinucleotide (NAD)
OH
Niacin & Niacinamide Uptake and
Metabolism
• Little information has been reported
regarding the intestinal transport of
either form of the vitamin.
• Conversion to the NAD/NADP cofactor
forms presumably occurs in each cell
using these cofactors. Presumably this
would be nearly every cell in the body.
Tryptophan
O
O
C
C
O_
NH2
O
O
Nicotinic Acid (Niacin)
O-
PRPP
-
NH+
NH+
NH+
C
Nicotinate
PRPP
transferase
C
PPi
O
Quinollinic acid
PRPP
Nicotinamide
PRPP
transferase
PPi
Quinolinate
PRPP
transferase
PRPP
Nicotinamide (Niacinamide)
O
PPi + CO2
O
O-
NH2
O
O
N+
-O
P
O
N+
-O
O
H
O-
P
H
O
O
O-
H
H
OH
H
OH
OH
H
OH
Nicotinate
mononucleotide
2 ATP + Gln + H2O
H
H
Nicotinamide
mononucleotide
1. NAD+ pyrophosphorylase
ATP
NAD+
pyrophosphorylase
2. NAD+ synthetase
ADP + PPi + Glu
PPi
NH2
O
N
N
NH2
N
N
O
O
H
H2C
H
H
O
P
O-
O
N+
O
P
O
O
H
O-
H
OR
CH2
H
H
OH
H
OH
OH
Nicotinamide adenine dinucleotide (NAD ); R = H; (NADP ) R = PO3=
+
+
Biochemical Functions-1
• Niacinamide as NAD or NADP is a cofactor in over
200 biochemical reactions.
– In general, those oxidation reactions that result in ATP
production use NAD. It is found in oxidation-reductions of
carbon-oxygen bonds.
– NADP is required for biosynthetic reactions and is required
for oxidation-reduction of both carbon-carbon and carbonoxygen bonds.
NAD+
R1
H
C
O
R2
R1
C
H
NAD+
I or II alcohol
NADH + H+
NADH + H+
O
R2
Aldehyde or ketone
• NAD also appears to participate in cell signaling.
Biochemical Functions-2
• NAD also appears to participate in cell signaling.
Niacin & Niacinamide Deficiency-2
• A deficiency of this vitamin can cause one of the most
serious deficiency syndrome seen in humans, pellagra.
Pellagra has been characterized by the 4Ds:
–
–
–
–
dermatitis
diarrhea
dementia
death
• It is difficult to diagnose unless the physician has reason
to suspect a vitamin deficiency.
– The dermatitis is characterized by sensitivity to heat. Areas
protected by clothing will appear normal, while exposed
skin will have severe scabbing.
– Areas like the elbow be markedly affected.
– Niacin/niacinamide supplements will reverse most
symptoms (obviously not the latter stages that will result in
death).
Niacin & Niacinamide Deficiency-3
• It is easy to see why a lack of this
vitamin can be so serious.
• There is hardly a metabolic
scheme/route that doesn't require
NAD/NADP for successful completion.
– NAD is required for oxidative
phosphorylation and the Krebs cycle.
– It is essential for aerobic and anaerobic
glycolysis.
– The oxidative route in the pentose
phosphate pathway or β-oxidation of fatty
acids cannot function without the vitamin.
Hypervitaminosis Niacin
•
Niacin is considered quite safe. It is given in pharmacological doses
for hyperlipidemia in doses of 2 - 9 grams/day. Some report doses
approaching 18 grams/day.
•
Its use in Raynaud's Syndrome is based on niacin's vasodilation
effects that cause the flushing and sensation that the patient's hair is
standing on end.
•
Niacinamide is very safe, but it is not given in high doses because:
– It is ineffective for the treatment of hyperlipidemia.
– It does not cause vasodilation.
•
The UL for niacin (both niacin and niacinamide) is based on the
flushing syndrome, potential problems with glucose tolerance and
possible liver toxicities.
•
There are liver toxicities and possible insulin tolerance reported for
ingestion of 2 – 3 gram quantities of niacinamide.
Dosage Forms
• Overall, this is an easy vitamin to
formulate. It is obtained from synthetic
sources.
• Solubility
– Niacin:
– Niacinamide:
1 gm/60 ml
1 gm/1 ml
DRIs-1
• Most DRIs are expressed as niacin
equivalents (NE).
– 1 mg niacin equals 1 niacin equivalent
– 60 mg tryptophan currently is considered
equivalent to 1 niacin equivalent
• This may not be valid.
DRIs-2
• AI
– Infants (0 - 5 months)
niacin
– Infants (6 - 11 months)
2 mg/day of preformed
4 mg NE/day
• EAR
–
–
–
–
–
–
–
Children (1 - 13 years)
Boys (14 - 18 years)
Girls (14 - 18 years)
Men (19 - 70+ years)
Women (19 - 70+ years)
Pregnancy
Lactation
5 - 9 mg NE/day
12 mg NE/day
11 mg NE/day
12 mg NE/day
11 mg NE/day
14 mg NE/day
13 mg NE/day
DRIs-3
• RDA
–
–
–
–
–
–
–
Children (1 - 13 years) 6 - 12 mg NE/day
Girls (14 - 19 years)
13 mg NE/day
Boys (14 - 19 years)
16 mg NE/day
Men (19 - 70+ years)
16 mg NE/day
Women (19 - 70+ years) 14 mg NE/day
Pregnancy
18 mg NE/day
Lactation
17 mg NE/day
• UL (Niacin is defined as both niacin and niacinamide.)
–
–
–
–
–
–
Infants Source should only be formula and food.
Children (1 – 13)
10 – 20 mg niacin/day
Adolescents (14 - 18)
30 mg niacin/day
Adults (19+)
35 mg niacin/day
Pregnancy (14 – older)
30 - 35 mg niacin/day
Lactation (14 – older)
30 - 35 mg niacin/day
Food Sources
•
•
•
•
•
•
•
Liver
Kidney
Lean meat
Wheat germ
Yeast
Soybean
Peanuts