Phar 722 Pharmacy Practice III

Vitamins Niacin and Niacinamide

Spring 2005

Niacin Study Guide

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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

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Niacin (formerly Nicotinic Acid)

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Niacinamide (formerly Nicotinamide)

History-1

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Pellagra has been a serious nutritional disorder in the United States, mostly in the southeast.

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Two thousand deaths from pellagra were reported in 1941. This is ironic because nicotinic acid, later known as niacin, was first reported in 1867.

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Individuals at risk for pellagra consume a diet in which zein from corn is the main source of protein.

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Zein is a poor source of both tryptophan and niacin. Further, what niacin is present is so tightly bound that is has poor bioavailability.

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Nevertheless, the very low income Mexican subsisting on a corn meal diet, treats the corn meal with lime, Ca(OH) develop.

2 which frees enough of the niacin that pellagra does not

Tryptophan N H CH 2 CH CO 2 NH 3 + Tryptophan-2,3 dioxygenase O C CH 2 CH CO 2 NH 3 + N H Formylkynurenine CHO Kynurenine formamidase O C CH 2 CH CO 2 NH 3 + Kynurenine NH 3 + Kynurenine hydroxylase (FAD dependent) CO 2 CO 2 CO 2 NH + Quinollinic acid CO 2 non enzymatic CHO O 2 C NH 3 + Amino-carboxymuconic semialdehyde 3-Hydroxyanthranilic acid oxidase OH NH 3 + 3-Hydroxyanthranilic Acid Kynureninase O C NH 3 + OH 3-Hydroxykynurenine CH 2 CH CO 2 NH 3 + NAD

Tradition: 60 mg tryptophan is required to form 1 mg niacin

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This has been questioned in tryptophan feeding experiments in humans.

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History-2

1867

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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.

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1914

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Niacin was first isolated by Funk, but he did not realize that it was a vitamin because it would not cure beriberi.

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1915

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Niacin's ability to cure pellagra was first demonstrated.

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1916

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Finally concluded that pellagra was of dietary origin

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1922

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The role of dietary tryptophan (precursor to niacin) was first demonstrated.

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1945

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The precursor role of tryptophan was reported.

History-3

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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.

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J. Am. Med. Assoc. 66, 471 (1916)

History-4

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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.

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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 disease.

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 Scientific American, November 1931; reprinted in 245, Nov. 1981

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Chemistry

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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.

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Note: Only niacin , and NOT niacinamide, is effective in treating hypercholesterolemia.

O C OH N Niacin (Nicotinic Acid)

1 gm/60m

O C NH 2 N Niacinamide (Nicotinamide)

1 gm/ml

N NH 2 N N N O CH 2 O O P O O O P O O CH 2 O N + O C NH 2 HO OH HO Nicotinamide Adenine Dinucleotide (NAD) OH

Niacin & Niacinamide Uptake and Metabolism

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Little information has been reported regarding the intestinal transport of either form of the vitamin.

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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 C O _ O C O Nicotinic Acid (Niacin) O PRPP NH + C Quinollinic acid O PRPP Quinolinate PRPP transferase PPi PPi + CO 2 NH + Nicotinate PRPP transferase O O O -O P O O N + O H H H OH OH H Nicotinate mononucleotide O C NH 2 NH + Nicotinamide (Niacinamide) PRPP Nicotinamide PRPP transferase PPi -O O P O O N + O H H OH H OH H Nicotinamide mononucleotide O NH 2 2 ATP + Gln + H 2 O ADP + PPi + Glu 1. NAD 2. NAD + + pyrophosphorylase synthetase PPi ATP NAD + pyrophosphorylase N NH 2 N N N O O N + O H 2 C O P O P O CH 2 O H H O O H H H OR OH H Nicotinamide adenine dinucleotide (NAD + ); R = H; H OH OH H (NADP + ) R = PO 3 = O NH 2

Biochemical Functions-1

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Niacinamide as NAD or NADP is a cofactor in over 200 biochemical reactions.

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In general, those oxidation reactions that result in ATP production use NAD. It is found in oxidation-reductions of carbon-oxygen bonds.

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NADP is required for biosynthetic reactions and is required for oxidation-reduction of both carbon-carbon and carbon oxygen bonds.

R 1 NAD + NADH + H + R 1 C O H C O H R 2 I or II alcohol NAD + NADH + H + R 2 Aldehyde or ketone •

NAD also appears to participate in cell signaling.

Biochemical Functions-2

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NAD also appears to participate in cell signaling.

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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:

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dermatitis

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diarrhea dementia death

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It is difficult to diagnose unless the physician has reason to suspect a vitamin deficiency.

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The dermatitis is characterized by sensitivity to heat. Areas protected by clothing will appear normal, while exposed skin will have severe scabbing.

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Areas like the elbow be markedly affected.

Niacin/niacinamide supplements will reverse most symptoms (obviously not the latter stages that will result in death).

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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.

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NAD is required for oxidative phosphorylation and the Krebs cycle.

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It is essential for aerobic and anaerobic glycolysis.

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The oxidative route in the pentose phosphate pathway or β-oxidation of fatty acids cannot function without the vitamin.

Hypervitaminosis Niacin

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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.

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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.

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Niacinamide is very safe, but it is not given in high doses because:

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It is ineffective for the treatment of hyperlipidemia.

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It does not cause vasodilation

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The UL for niacin (both niacin and niacinamide) is based on the flushing syndrome, potential problems with glucose tolerance and possible liver toxicities.

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There are liver toxicities and possible insulin tolerance reported for ingestion of 2 – 3 gram quantities of niacinamide.

Dosage Forms

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Overall, this is an easy vitamin to formulate. It is obtained from synthetic sources.

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Solubility

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Niacin:

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Niacinamide: 1 gm/60 ml 1 gm/1 ml

DRIs-1

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Most DRIs are expressed as niacin equivalents (NE).

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1 mg niacin equals 1 niacin equivalent

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60 mg tryptophan currently is considered equivalent to 1 niacin equivalent

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This may not be valid.

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DRIs-2

AI

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Infants (0 - 5 months) niacin

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Infants (6 - 11 months) 2 mg/day of preformed 4 mg NE/day

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EAR

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Children (1 - 13 years)

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Boys (14 - 18 years) Girls (14 - 18 years)

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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

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RDA

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Children (1 - 13 years)

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Girls (14 - 19 years) Boys (14 - 19 years) Men (19 - 70+ years) 6 - 12 mg NE/day 13 mg NE/day 16 mg NE/day 16 mg NE/day Women (19 - 70+ years) 14 mg NE/day Pregnancy Lactation 18 mg NE/day 17 mg NE/day

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UL (Niacin is defined as both niacin and niacinamide.)

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Infants Source should only be formula and food.

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Children (1 – 13) Adolescents (14 - 18) Adults (19+) Pregnancy (14 – older) Lactation (14 – older) 10 – 20 mg niacin/day 30 mg niacin/day 35 mg niacin/day 30 - 35 mg niacin/day 30 - 35 mg niacin/day

Food Sources

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Liver Kidney Lean meat Wheat germ Yeast Soybean Peanuts