Phar 722 Pharmacy Practice III

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Phar 722Pharmacy Practice III

• Vitamins-
• Ascorbic Acid (C)
• Spring 2006

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Ascorbic Acid (C) Study Guide

• The applicable study guide items in the Vitamin
  Introduction
• History
• Structures of both forms
• Salt formation
• Major routes of degradation and how to minimize
  them
• Metabolic functions
• Deficiency condition
• Use of ascorbic acid esters
• Commercial forms of the vitamin

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Ascorbic Acid History-1

• In this best-fed nation in the world, one-third
  to one-half of the population lacks vitamin C.
  This vital food element-essential for vigor and
  efficiency-is now available in a new
  mass-produced synthetic form. Technicians have
  developed successful manufacturing processes
  based on combining ascorbic acid and sodium in
  water-free methyl alcohol. The new vitamin C is
  precipitated as a pure, white crystalline mass.
• Scientific American, reprinted from an article
  published November 1946, November, 275 (5) 10,
  1996.

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Ascorbic Acid History-2

• 1498 - After about 10 weeks as sea, Vasco da
  Gama's crew experienced a new illness which
  caused ...their feet and hands swelling and their
  gums growing over their teeth so they could not
  eat.
• The crew recovered within a week after eating
  oranges purchased in East African ports.
• The illness reoccurred on the voyage back which,
  again, responded to fresh oranges. About half
  the crew died at sea from scurvy.
• 1530s - Jacques Cartier, who explored the St.
  Lawrence River in Canada, lost sailors to scurvy
  until the local Indians explained how the use of
  a tea made from birch bark cured the disease.
• Chemical and Engineering News, Indians in Canada
  used birch bark tea for scurvy, Chemical and
  Engineering News, February 19, 1991, p. 56.

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Ascorbic Acid History-3

• Scurvy became the worst of the occupational
  illnesses because approximately 2,000,000 million
  sailors died from the disease over the next 300
  years.
• Large numbers of African slaves also died during
  transport from Africa to the Americas.
• 1747
• Dr. James Lind, a British naval surgeon, reported
  on an experiment where he tried various
  treatments for scurvy while aboard a ship.
• These ranged from oranges and lemons, to drinking
  seawater daily, to using vinegar with each meal.
• Only the patients on oranges and lemons improved.

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Ascorbic Acid History-4

• Forty years later the British Navy finally began
  issuing 0.75 oz of lime or orange juice per day
  to the sailors. The East India Company also
  followed this procedure.
• By the 1850s, most commercial sailing vessels
  used steam.
• The result was faster trips and fresher food for
  the crew. Scurvy ceased to be a problem among
  sailors.
• Dr. Lind was a very dedicated and intelligent
  naval surgeon.
• He recommended shipboard delousing methods like
  those used today to combat typhus, suggested the
  use of hospital ships for sick sailors in
  tropical ports, and in 1761 arranged for
  shipboard production of drinking water by
  distillation.

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Ascorbic Acid History-5

• Scurvy on land - This was seen in convicts, the
  California gold miners, prisoners of war, Irish
  farmers deprived of fresh potatoes (a good source
  of vitamin C) during the potato blight, Arctic
  explorers, populations in cities under long term
  siege, etc.
• Barlow's Disease - scurvy in infants.
• It resembles adult scurvy except that infants
  don't have any teeth to lose.
• It was common in during the late-Victorian
  periods and affluent London and New York mothers
  bottle-fed their infants. The product was
  acceptable except for its lack of Vitamin C.
• Breast-fed infants generally do not get scurvy
  because the maternal milk can contain up to seven
  times the ascorbic acid concentration of maternal
  blood plasma.
• Because of this fact, scurvy was not seen in
  infants in czarist Russia even though it was
  endemic among the adult peasant population.
• Scurvy became a disease among the affluent in the
  late 19th century particularly due to the
  pasteurization of milk used in infant formula.

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Ascorbic Acid History-6

• 1907
• A paper was published by two researchers who were
  investigating beriberi reported that guinea pigs
  fed solely on grain developed scurvy.
• This was the first report of an animal model for
  this nutritional disorder.
• 1932
• Ascorbic acid was isolated

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Ascorbic Acid Chemistry

• In theory, either the reduced or oxidized form of
  the vitamin is effective.
• In practice, the oxidized vitamin C is very
  unstable with hydrolysis of the lactone ring the
  site of degradation.
• This is why vitamin C activity can decrease in a
  pitcher of orange juice over time, particularly
  at room temperature.
• The D-isomer has no vitamin activity, but it can
  be used as an antioxidant in foods.

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Ascorbic Acid Chemistry-2
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Why Is Ascorbate Essential?

• Ascorbic acid is not a vitamin in most animals.
• It is synthesized from glucose.
• Humans, other primates and guinea pigs lack the
  ability to make L-gulonlactone and then oxidize
  it to ascorbic acid.
• Why would humans not have this enzyme?

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Ascorbic Acid Biosynthesis
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Ascorbate Uptake and Metabolism

• Surprisingly, little is know about the details of
  the uptake and distribution of this vitamin.
• Little is known about its pharmacokinetics.
• Little is known about its storage.

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Biochemical Functions

• The vitamin is required for many reactions
  involving oxidations. These include
• Tyrosine metabolism (phe ? tyr)
• Formation of hydroxyproline from proline
• Formation of hydroxylysine from lysine
• Synthesis of carnitine (required for fatty acid
  transport)
• Reduction of folic acid to tetrahydrofolate
• Antioxidant in the tissues. (protect vitamin A
  reduce C-reactive protein levels indicating
  anti-inflammatory properties.)
• Hydroxylation of steroids in the adrenal gland
  forming hydrocortisone and cortisone.
• Formation of bile acids from cholesterol.

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Ascorbic Acid Deficiency

• Scurvy (anti-scorbutic vitamin) and Barlows
  Disease
• Scurvy is a degeneration of the connective
  tissues probably related to the inability to form
  the hydroxylated amino acids seen in cartilage,
  elastin and other related proteins.
• The result is the hemorrhaging, loss of teeth,
  improper bone growth, etc.

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Antioxidant Role of Vitamin C

• The DRIs are based on prevention of scurvy.
• Vitamin C also is a water-soluble antioxidant.
• Should humans take larger amounts of ascorbate to
  prevent or reduce the severity of
• Common cold?
• Malignancies?
• Diabetes mellitus
• Cardiovascular disease.
• The results are mixed.
• The vitamin, along with lipid-soluble vitamin E,
  appears to be beneficial in smokers.
• Vitamins C and E do not reduce the risk of
  preeclampsia hypertension and proteinuria during
  pregnancy, the risk of intrauterine growth
  restrictions or the risk of death or other
  serious outcomes in their infants.

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Hypervitaminosis C-1

• This appears to be a very safe vitamin as
  evidenced by individuals take megadoses for a
  variety of anecdotal reasons.
• When vitamin C became popular after Linus
  Paulings book advocating megadosing of the
  vitamin, early manufacturing was sloppy producing
  products high in sodium.
• This led to the FDA requiring manufacturers to
  list the sodium content on the label.
• This led the manufacturers to clean up their
  product.

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Hypervitaminosis C-2

• There have been some problems seen when people
  suddenly reduce their intake from the megadoses
  to the levels of its RDA.
• The patient's metabolism is geared up to
  eliminating the large amounts of excess vitamin.
  Sudden cessation of vitamin intake might cause a
  transient deficiency. (Anecdotal)
• This may be most serious in infants. Babies born
  from mothers who have been taking large doses of
  Vitamin C can show clinical signs of scurvy
  because they are capable of metabolizing the
  large doses that crossed the placental barrier.
• These children may have to be withdrawn from the
  vitamin over a period of time. (Anecdotal)

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Ascorbic Acid Dosage Forms-1

• Most of the vitamin is made synthetically from
  glucose to maintain stereochemistry.
• Does that mean that synthetic ascorbic acid is
  natural?
• There is a big market for the vitamin.
• Takeda U.S.A. has a 90 million Vitamin C plant
  in Wilmington, NC which has the capacity to
  produce 11 million lb per year.
• A plant formerly owned by Roche can produce 30
  million lb per year.

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Ascorbic Acid Dosage Forms-2The sodium salt is
usually used for the parenteral dosage forms.The
palmitic acid ester is found in oral dosage forms
and oil-based dosage forms.
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Ascorbic Acid DRIs-1

• AI
• Infants 40 - 50 mg/day
• EAR
• Children (1 - 8 years) 13 - 22 mg/day
• Boys (9 - 18 years) 39 - 63 mg/day
• Girls (9 - 18 years) 39 - 56 mg/day
• Men (19 - 70 years) 75 mg/day
• Women (19 - 70) 60 mg/day
• Pregnancy 66 - 70 mg/day
• Lactation 96 - 100 mg/day

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Ascorbic Acid DRIs-2

• RDA
• Children (1 - 8 years) 15 - 25 mg/day
• Boys (9 - 18 years) 45 - 75 mg/day
• Girls (9 - 18 years) 45 - 65 mg/day
• Men (19 - 70 years) 90 mg/day
• Women (19 - 70) 75 mg/day
• Pregnancy 80 - 85 mg/day
• Lactation 115 - 120 mg/day

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Ascorbic Acid DRIs-3

• UL
• Infants Not established
• use formula and food only
• Children (1 - 8 years) 400 - 650 mg/day
• Boys Girls (9 - 13 years) 1,200 mg/day
• Adolescents (14 - 18 years) 1,800 mg/day
• Pregnancy 1,800 - 2,000 mg/day
• Lactation 1,800 - 2,000 mg/day
• Adults (19 years) 2,000 mg

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Food Sources

• Citrus fruits
• Berries
• Broccoli
• Green cabbage
• Potatoes