Phar 737 PathoBiopharmaceutical ChemistryScience

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Phar 737Patho-Biopharmaceutical Chemistry/Science

• Vitamins-
• Niacin
• and
• Niacinamide
• Spring 2007

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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

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Current and Old Nomenclature

• Niacin (formerly Nicotinic Acid)
• Niacinamide (formerly Nicotinamide)

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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.

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Tradition 60 mg tryptophan is required to form 1
mg niacin. This has been questioned in tryptophan
feeding experiments in humans.
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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.

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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)

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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.

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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.

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1 gm/ml
1 gm/60m
Two commercial forms
A dietary form
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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.

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Two dietary forms
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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.

• NAD also appears to participate in cell
  signaling.

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Biochemical Functions-2

• 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
• 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).

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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.
• 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 ß-oxidation of fatty acids cannot
  function without the vitamin.

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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 can cause vasodilation in high doses.
• 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.

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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

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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.

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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

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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

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Food Sources

• Liver
• Kidney
• Lean meat
• Wheat germ
• Yeast
• Soybean
• Peanuts