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Transcript
Phar 722
Pharmacy Practice III
VitaminsAscorbic Acid (C)
Spring 2006
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
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.
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.
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.
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.
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.
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
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.
Ascorbic Acid Chemistry-2
CH2OH
CH2OH
H
C
O
[O]
HO
OH O
C
O
CH2OH
O
HO
H
C
O
O
HO
[H]
pKa 4.2
HO
O
OH pKa 11.6
L-Ascorbic Acid
O
Na+
H2 O
H
C
OOH
O
HO
O
O
L-2,3-Diketogluonate
OH
Sodium L-Ascorbate
Dehydro-L-Ascorbic Acid
CH2OH
-O
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 Lgulonlactone and then oxidize it to
ascorbic acid.
• Why would humans not have this
enzyme?
Ascorbic Acid Biosynthesis
6 CO26 CH2OH
6 CO2-
O
O
1
OH
OH
Glucuronate
reductase
1
Several
OH
HO
CH
HO
CH
OH
HC
OH
Steps
OH
OH
NADPH + H+
OH
HO
NADP+
OH
D-Glucose
CH
1 CH2OH
D-Glucuronate
L-Gulonic Acid
Aldonolactonase
Humans and primates
Pentose Phosphate Pathway
H2 O
CH2OH
CH2OH
H
C
O
O
CH
HO
C
HO
L-Ascorbic Acid
Gulonolactone
oxidase
OH
O
CH
HO
C
O
H
C
[2 H]
CH
HO
CH
OH
L-Gulonolactone
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.
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 antiinflammatory properties.)
Hydroxylation of steroids in the adrenal gland
forming hydrocortisone and cortisone.
Formation of bile acids from cholesterol.
Ascorbic Acid Deficiency
• Scurvy (anti-scorbutic vitamin) and
Barlow’s 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.
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.
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
Pauling’s 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.
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)
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.
Ascorbic Acid Dosage Forms-2
The 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.
O
O
CH2OH
CH2OH
H
C
O
H
C
O
H2C
O
O
HO
HO
HO
L-Ascorbic Acid
OH
C(CH2)14CH3
H
C
O
O
HO
Na+
-O
OH
Sodium L-Ascorbate
HO
OH
L-Ascorbic Acid Palmitate
Ascorbic Acid DRIs-1
• AI
– Infants
40 - 50 mg/day
• EAR
–
–
–
–
–
–
–
Children (1 - 8 years)
Boys (9 - 18 years)
Girls (9 - 18 years)
Men (19 - 70+ years)
Women (19 - 70+)
Pregnancy
Lactation
13 - 22 mg/day
39 - 63 mg/day
39 - 56 mg/day
75 mg/day
60 mg/day
66 - 70 mg/day
96 - 100 mg/day
Ascorbic Acid DRIs-2
• RDA
– Children (1 - 8 years)
– Boys (9 - 18 years)
– Girls (9 - 18 years)
– Men (19 - 70+ years)
– Women (19 - 70+)
– Pregnancy
– Lactation
15 - 25 mg/day
45 - 75 mg/day
45 - 65 mg/day
90 mg/day
75 mg/day
80 - 85 mg/day
115 - 120 mg/day
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
Food Sources
•
•
•
•
•
Citrus fruits
Berries
Broccoli
Green cabbage
Potatoes