Phar 722 Pharmacy Practice III Vitamins- Pyridoxine (B 6 ) Spring 2006.
Phar 722 Pharmacy Practice III Vitamins- Ascorbic Acid (C) Spring 2006.
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Transcript of Phar 722 Pharmacy Practice III Vitamins- Ascorbic Acid (C) Spring 2006.
Phar 722Pharmacy Practice III
Vitamins-Ascorbic 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.
OO
OHHO
C
CH2OH
H
[O]
[H]
H2O
OHO
OO
C
CH2OH
HO-
OO
OO
C
CH2OH
OH
Na+
OO
OH-O
C
CH2OH
H
L-Ascorbic Acid Dehydro-L-Ascorbic Acid
pKa 4.2 pKa 11.6
Sodium L-Ascorbate
L-2,3-Diketogluonate
HO
HO
HO HO
Ascorbic Acid Chemistry-2
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?
Ascorbic Acid BiosynthesisCO2
-
CH
CH
HC
CH
CH2OH
HO
HO
OH
HO
CH
CH CH
OO
OHHO
C
CH2OH
H
H2O
[2 H]
O
OH
OH
CO2-
OH
OH
CH
C C
OO
OHHO
C
CH2OH
H
O
OH
OH
CH2OH
OH
OH
D-Glucose
Several
Steps
D-Glucuronate
1
66
1
L-Gulonic Acid
6
1
L-Gulonolactone
Glucuronatereductase
NADPH + H+ NADP+
Aldono-lactonase
Gulonolactoneoxidase
L-Ascorbic Acid
HOHO
Pentose Phosphate Pathway Humans and primates
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 anti-inflammatory 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-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.
OO
OHHO
C
CH2OH
H
L-Ascorbic Acid
HO
Na+
OO
OH-O
C
CH2OH
H
Sodium L-Ascorbate
HO
OO
OHHO
C
H2C
H
L-Ascorbic Acid Palmitate
HO
O C(CH2)14CH3
O
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
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
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