Phar 722 Pharmacy Practice III Vitamins- Niacin and Niacinamide Spring 2005
Jan 29, 2016
Phar 722Pharmacy Practice III
Vitamins-Niacin
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.
C
NH3+
CH2 CH CO2-
O
NH3+
C
NH3+
CH2 CH CO2-
O
NH3+
OHOH
NH3+
CO2-
C
NH
CHO
CH2 CH CO2-
O
NH3+
CHO-O2C NH3
+
CO2-
NH
CH2 CH CO2-
NH3+
NH+
CO2-
CO2-
NAD
Tryptophan
Tryptophan-2,3-dioxygenase
Formylkynurenine
Kynurenineformamidase
Kynurenine
Kynureninehydroxylase(FAD dependent)
3-Hydroxykynurenine
Kynureninase
3-Hydroxyanthranilic Acid
3-Hydroxyanthranilicacid oxidase
Amino-carboxymuconicsemialdehydeQuinollinic acid
non-enzymatic
Tradition: 60 mg tryptophan is required to form 1 mg niacin.This has been questioned in tryptophan feeding experiments in humans.
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.
N
C
OH
O
N
C
NH2
O
Niacin(Nicotinic Acid)
Niacinamide(Nicotinamide)
N+
C
NH2
O
O
OHHO
CH2OP
O
O-
OP
O
O-
OCH2O
OHHO
N
NN
N
NH2
Nicotinamide Adenine Dinucleotide (NAD)
1 gm/60m1 gm/ml
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.
NH+
C
C
Quinollinic acid
Tryptophan
NH+ NH+
C
O_
O
C
NH2
O
O-
O
O-
O
Nicotinic Acid (Niacin) Nicotinamide (Niacinamide)
PRPP
PPi
NicotinatePRPPtransferase
PRPP
PPi
NicotinamidePRPPtransferase
Nicotinatemononucleotide Nicotinamide
mononucleotide
PRPP
PPi + CO2
Quinolinate PRPP transferase
O
OHOH
HH
H
CH2
H
OPO
O-
O
N+
NH2
O
O
OHOH
HH
HH
OP-O
O-
O
N+
NH2
O
O
OHOH
HH
HH
OP-O
O-
O
N+
O-
O
N
NN
N
NH2
O
OR OH
H H
H
H2C
H
O P
O-
O
Nicotinamide adenine dinucleotide (NAD+); R = H;
ATP
PPi
NAD+
pyrophosphorylase
2 ATP + Gln + H2O
ADP + PPi + Glu
1. NAD+ pyrophosphorylase
2. NAD+ synthetase
(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 carbon-oxygen bonds.
C O
R2
R1
H C O
R2
R1
H
I or II alcohol Aldehyde or ketone
NAD+
NAD+ NADH + H+
NADH + H+
• 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: 1 gm/60 ml– Niacinamide: 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) 2 mg/day of preformed niacin
– Infants (6 - 11 months) 4 mg NE/day
• EAR– Children (1 - 13 years) 5 - 9 mg NE/day– Boys (14 - 18 years) 12 mg NE/day– Girls (14 - 18 years) 11 mg NE/day– Men (19 - 70+ years) 12 mg NE/day– Women (19 - 70+ years) 11 mg NE/day– Pregnancy 14 mg NE/day– Lactation 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