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