Download 722_Wk03_VitaminA

Phar 722
Pharmacy Practice III
VitaminsVitamin A Family
Spring 2006
Vitamin A Study Guide
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The applicable study guide items in the Vitamin Introduction.
History
Structures of the vitamin’s active forms
Structures of the vitamin and its commercial forms
Transport of the vitamin
The advantage of Vitamin A esters in dosage forms
The effects of structural changes on the activity of the vitamin
A group including retinoid and retinoid-like drugs used to treat
acne and psoriasis
Role in the visual process
Role in cell differentiation
Symptoms and occurrences of hypervitaminosis A and
hypercarotenosis
Approaches to formulation
Non-vitamin drug uses (It is not necessary to know drug
names.)
Dietary forms of the vitamin
Vitamin A History
•
1913
– McCollum, Davis, Osborne, and Mendel noted growth failure in rats fed
purified rations with lard or olive oil as the source of lipid.
• Growth resumed when butterfat, cod liver oil, or egg yolk was substituted for the
lard or olive oil.
• The active ingredient was called Fat Soluble A to differentiate it from Water
Soluble B.
• The growth factor was shown to be absent from cereal grains but present in
alfalfa and cabbage beans and in ether extracts of spinach leaf and clover.
•
1919
– Steenbock at the University of Wisconsin pointed that the vitamin A
potency of certain plant sources seemed to run parallel with the amount of
yellow, fat-soluble pigments present in them.
• He suggested that the vitamin A activity might be associated with the carotenoid
pigments.
• Since cod liver oil concentrates are colorless, but very potent in vitamin A
activity, Steenbock postulated (correctly) that the vitamin A of animals might be a
colorless form of carotene.
•
1930
– It was shown that ingested carotene is converted to vitamin A in the rat.
This established the relationship to the active yellow carotene of plants
and the nearly colorless highly active vitamin concentrates from fish liver
oils.
Vitamin A Chemistry-1
• Retinol
– The all trans retinol is colorless and is
obtained from animal sources, but animals
cannot biosynthesize it.
– In general, animals, including humans,
make the vitamin by cleavage of the plant
pigments known as the carotenes.
• All animals have to obtain their vitamin A by
eating other animals or from the consumption
of plants.
– Most vitamin A, whether in food or vitamin
supplements, is found in the ester form.
• See discussion on dosage forms.
CH3
H3C
CH3
CH3
11
CH2OH
13
9
CH3
Retinol (inactive commercial form esterified)
[O]
CH3
H3C
CH3
CH3
O
11
CH
13
9
CH3
Retinal (vision)
[O]
CH3
H3C
CH3
CH3
O
11
COH
13
9
CH3
trans-Retinoic Acid (cell differentiation)
isomerization
CH3
H 3C
CH3
9
11
CH3
13
H 3C
9-cis-Retinoic Acid (cell differentiation)
COH
O
Vitamin A Chemistry-2
• Carotenes
– These are the yellow/orange pigments
which can be considered as provitamins A.
– There are three main pigments with βcarotene considered the standard because
each mole contains two equivalents of
vitamin A.
– The carotenes are oxidatively cleaved in
the intestinal mucosa cell.
d
H3 C
CH3
H3 C
e
c
CH3
CH3
f
b
a
H3 C
CH3
CH3
CH3
CH3
-Carotene
d
H3 C
e
c
f
b
R
H3C
a
CH3
-Carotene
d
H3 C
e
b
CH3
c
a
CH3
f
R
-Carotene
Vitamin A Uptake and Metabolism
• Vitamin A esters are hydrolyzed in the intestine, and
the vitamin absorbed with other lipid material.
• Reesterification takes place in the mucosal cell and
the final product transported on the chylomicrons to
the liver where it is stored. Subsequent distribution
from the liver occurs as retinal bound to a special
retinal binding protein (RBP).
• Carotenes are absorbed in the mixed micelles into
the mucosal cells where they are cleaved to the
aldehyde, reduced to the alcohol and esterified.
• At this point, the new vitamin A esters follow the
same distribution scheme outlined for vitamin A,
itself.
• The absorption of the carotenes is poor relative to
vitamin A. There is a positive correlation between
the fat content of the diet and carotene absorption.
oxidation
carotene
retinal
mucosa cell
mucosa cell
reductase
retinol
reesterify
retinol palmitate
mucosa cell
Retinol esters
(food or vitamin supplements)
intestinal
esterases
TGs
retinal & retinoic acid
transported on Retinal
Binding Protein (RBP)
(1) esterase
(2) oxidation
liver
storage
chylomicron
remnent
chylomicron
Relationship between Protein
Malnutrition and Vitamin A Status
• Patients with kwashiorkor and other protein
malnutrition states have very low serum vitamin A
levels.
– This is because there is a deficiency of the amino acids
necessary to produce the retinal binding protein.
– Administration of protein supplements will increase serum
vitamin A levels PROVIDED there is sufficient amounts of
the vitamin in the patient's liver.
– There are reports of precipitating a vitamin A deficiency in
protein malnourished patients who are given protein
supplements. Today, it is common to use vitamin A fortified
powdered milks to insure that there will be adequate levels
of the vitamin in the patient's diet.
– Today, our milk is fortified with both vitamins A and D.
Vitamin A Deficiency-1
• Keep in mind that it is difficult to study
the effects of vitamin A deficiencies in
otherwise healthy humans because
there is enough of the vitamin stored in
the liver to last 6 - 9 months.
Vitamin A Deficiency-2
Retinoic Acid - Cell differentiation
The retinoic acid receptors that belong to the nuclear receptor family and
are classified as
– RARα,β,γ (ligand: trans-retinoic acid)
– RXRα,β,γ (ligand: 9-cis-retinoic acid)
•
Retinoic acids are required for cell differentiation in the developing
embryo.
– A preliminary report (mice) indicates that retinoic acid appears to control
the timing and perhaps the choice of germ cells to begin changing into
eggs or sperm.
•
Retinoic acid now is considered a hormone that plays a pivotal role in
cell differentiation in embryos. Improperly used, it is teratogenic.
– One metabolic defect in utilizing retinoic acid apparently leads to acute
promyelocytic leukemia. This is a rare leukemia with about 1,000 new
patients in the United States each year.
– Administration of the all-trans retinoic acid causes remissions in well over
half of the patients.
– One hypothesis is that the retinoic acid causes the immature leukemic cell
to mature, at least to the level it stops dividing.
Vitamin A Deficiency-3
Retinoic Acid - Cell differentiation
• Deficiencies affect cells of the skin, cornea, lungs and digestive
tract.
– The vitamin, as retinoic acid, is required for the development of
goblet or mucous secreting cells.
– An absence of the vitamin leads to keratinization of this tissue.
– There is some evidence that the vitamin affects certain aminoacyl
tRNA synthetase enzymes needed for the glycoproteins found in
mucous. Specific mucous glycoproteins are missing in vitamin A
deficient individual.
– For adults, this is the most serious form of the deficiency because
the mucous layer forms one of the physical barriers to microbial
infection. A vitamin A deficient individual can die from infection.
• Bear in mind that this same individual probably is deficient in several
nutrients and may have a compromised immune system.
• The patient's skin can have a goose bump or acne like
appearance.
– This has led to the suggestion that vitamin A may be effective in
the treatment of acne. With the exception of the specific local
activity of the retinoic acids, there is no evidence that acne is
related to vitamin A status in the patient.
Vitamin A and Vision
• Vitamin A is required for vision.
– It is part of the visual pigments found in the rods.
• The visual pigment in the rods is known as rhodopsin. The
rods are required for night vision.
– In bright light, such as you are using while reading this outline, the
cones are functioning.
– Try this exercise.
• Go from a brightly lit room into a closet. You probably will experience
what appear to be flashes of light. Then you will notice light coming in
from around the cracks in the closet door. The time it takes for you to
perceive light from around the cracks in the door is known as the
accommodation time.
• The rhodopsin has formed in the rods from opsin and 11-cis
retinal and then cleaves back to opsin and all-trans retinal as
light reaches the rods. These changes are transmitted to the
brain by the optic nerve.
– Notice that you cannot perceive color in very dim light.
– Now step back into the lighted room. It may seem painful and you
will try to shield your eyes.
• There has been a rapid, massive conversion of rhodopsin back to
opsin and the all-trans retinal. The rhodopsin will not form again until
subdued light return.
Rhodopsin
(visual pigment)
(Light)
Changes in the conformation
of the Rhodopsin complex and
hydrolysis of the enamine.
(Dark)
11-cis-Retinal + Opsin
Nerve impulse
Sight
to the brain
trans-Retinal + Opsin
11-cis-Retinol
trans-Retinol
(transported to the eye
from the liver on a retinol
binding protein)
Liver stores of
retinol esters
H3C
CH3
CH3
11
12
CH3
CH3
O
H
11-cis-Retinal
Opsin
CH3
CH3
H3C
11
12
CH3
CH3
N
H2C
H2C
H2C
HC
C
O
NH
Rhodopsin
Lys
H
Vitamin A Deficiency and Vision
• Night blindness results from delayed
accommodation time. A deficiency of
vitamin A means that there will be a lack of
retinal to combine with the opsin.
• Xerophthalmia is the most tragic aspect of
vitamin A deficiency. This is the result of the
vitamin deficiency in children. There is
irreversible deterioration of the developing
eye which causes blindness. There are 3 - 10
million children with this condition. Within
this group 250,000 - 500,000 still go blind
annually go blind because of a vitamin
deficiency that could be prevented by just a
few cents a year.
Hypervitaminosis A – Acute-1
• This is rare and is somewhat dependent on
the dosage form. The rate of absorption is:
– Greatest for aqueous preparations
• Vitamin A, being oil soluble, must be dispersed by
Tweens to produce an aqueous preparation. Since it
already is emulsified, it will be rapidly and efficiently
absorbed into the intestinal mucosa.
– Intermediate for standard emulsions
– Slowest for oil solutions including IM injections.
• Therefore, a toxic dose for an aqueous
preparation may be a safe dose for an oil
solution.
Hypervitaminosis A – Acute-2
Examples
– A child swallowing 50 ml of fish oil concentrate containing
3,000,000 IU (900,000 μg or 900 mg) of vitamin A experienced
nausea and vomiting. (1 IU of vitamin A activity equals 0.3 μg of alltrans-retinol)
– 300,000 IU (90 mg) would probably cause acute hypervitaminosis A
in infants
– An IM injection of 1,000,000 IU of water miscible vitamin A might
show a transient hypervitaminosis A depending on the child's age
and nutritional state.
– Polar bear liver
• 18,000-35,000 IU/gm
• A diet by a lost arctic explorer would consist of 100-500 gm of liver
containing 1,800,000-17,500,000 IU (540 - 5,250 mg).
• The symptoms for acute hypervitaminosis A include headache,
vertigo, diarrhea, nausea, and vomiting. Recovery requires
about 2-4 weeks.
Hypervitaminosis A – Chronic-1
• This is the more common form of hypervitaminosis A and can
be the result of a parent administering too much of the vitamin
to a child or teenagers with acne taking very large doses of the
vitamin.
• Examples
– 23 month male receiving 250,000 IU/day (75 mg/day) for 20 months
– 14 month male receiving 125,000 IU/day (37.5 mg/day) for 13
months
– 9 month female receiving 220,000 IU/day (66 mg/day) for 8 months
• Most of these infants received fish liver oil concentrates that
contained both vitamins A and D.
• Adults receiving 100,000 - 600,000 IU/day (30 - 180 mg) for
months and years.
– Symptoms will not appear until the binding capacity of the liver is
exhausted.
Hypervitaminosis A – Chronic-2
•
Symptoms
– fatigue, malaise, lethargy, abdominal discomfort, bone/joint pain, severe
and throbbing headache, insomnia, restlessness, dry and scaly skin, loss
of body hair, brittle nails, constipation, irregular menses.
– This is a nondescript group of symptoms that could cause the patient to
increase the dose even further.
• A characteristic of patients with any hypervitaminosis is to not disclose to the
physician that they are taking large amounts of a vitamin(s).
•
There are reports that cirrhosis of the liver can develop if the intake of
excessive vitamin A is not reduced to normal levels.
•
Nontraumatic Hip Fracture
– The Nurses’ Health Study has reported that women with the highest intake
of vitamin A (as retinol) had the higher rates of nontraumatic hip fracture.1
There is evidence that long-term intake of retinol stimulates bone
resorption and inhibits bone formation, therefore, contributing to
osteoporosis and hip fractures.
•
Teratogenesis in pregnancies
– There are warnings about taking high doses of vitamin A during pregnancy.
Hypercarotenosis
• This occurs from massive doses of carotene which
exceed the capacity of the mucosa cells to cleave
the molecule to retinal derivatives.
– The excess carotene becomes deposited in the body
tissues.
– Except for the yellow skin, there seem to be no other
symptoms. The skin coloration will slowly disappear when
carotene intake stops.
• Solatene™ capsules contain 30 mg β-carotene and
are indicated for the photosensitivity seen in
erythropoietic porphyria.
• Patients who drink large amounts of carrot juice
sometimes show signs of hypercarotenosis.
• β-Carotene was included in several vitamin products
and was promoted for its antioxidant properties.
– Most studies on the use of EXCESSIVE β-carotene show it
to be ineffective and may be detrimental.
Dosage Formulations-1
• Commercial forms
– Retinol
– Retinol Acetate
– Retinol Palmitate
• Stability
– Vitamin A is one of the more unstable vitamins. It
is sensitive to
• acid - rapidly dehydrates
• oxygen - due to the high degree of unsaturation
• UV light - due to the high degree of unsaturation
– Therefore, the vitamin must be protected from
light by protective coatings, from oxygen with
antioxidants, and acid dehydration by
esterification.
CH3
H3C
CH3
CH3
CH3
H2O
H+
H3C
CH2+
CH2OH


CH3
CH3
H3C
CH3
CH3
O
O
C
CH3
CH3
Vitamin A Acetate; Retinol Acetate
CH3
H3C
CH3
CH3
O
O
CH3
Vitamin A Palmitate; Retinol Palmitate
C
C15H31
CH3
CH3
CH3

+

Dosage Formulations-2
• Oral dosage forms
– Sealed gelatin capsules
– Oil solutions
– Water dispersible (Tweens) liquids sometimes
knows as clear emulsions.
– Granulations used in variety of dry dosage forms.
• The vitamin is dissolved in a volatile solvent and
sprayed onto a gelatin-sugar matrix. After the solvent is
removed, the coated gelatin material is powdered. The
result is a free flowing powder of an oily vitamin.
• Intramuscular
– Sterile aqueous dispersion of a vitamin A ester
– Oil solutions
DRIs (1 μg = 0.001 mg)
•
AI (infants 1 - 12 months)
•
EAR
–
–
–
–
–
–
•
210 - 275 μg/day
445 - 630 μg/day
420 - 485 μg/day
625 μg/day
500 μg/day
880 - 900 μg/day
RDA
–
–
–
–
•
Children (1 - 8 years)
Boys (9 - 18 years)
Girls (9 - 18 years)
Men (19 - 70+ years)
Women (19 - 70+)
Lactating
400 - 500 μg/day
Men
Women
Pregnant
Lactating
900 μg/day
700 μg/day
770 μg/day
1,200 - 1,300 μg/day
UL
–
3,000 μg/day for all adults including pregnant women. There is some concern of
teratogenic effects based on the experience of the retinoids used in therapy. There
are warnings for women who plan on becoming pregnant or who are pregnant to not
exceed the RDA for pregnancy.
–
Long-term intake of a diet high in retinol may promote the development of
osteoporotic hip fractures.
•
JAMA, 287(10, 47-54, January 2, 2002
Food Sources
•
•
•
•
Fish and animal liver
Carotene containing vegetables
Fortified milk
Genetically modified rice (developed
but not yet used; It is yellow because of
the presence of β-carotene).
Retinoid and Retinoid-like Drugs
Indicated for Acne-1
CH3
H3C
CH3
O
CH3
C
13
CH3
OH
Tretinoin (Retin-A)
Retinoic Acid
Topical: Produces a complex response related to increasing the turnover
of follicular epithelial cells and decreasing the cohesiveness of
follicular epithelial cells.
Topical treatment does not affect plasma concentrations of retinol, retinyl esters or
retinoic acids in female subjects of child-bearing age.
Toxicology Letters, 163, 65-76, 2006.
Retinoid and Retinoid-like Drugs
Indicated for Acne-2
CH3
H3C
CH3
CH3
13
C
CH3
Oral:
Isotretinoin (Accutane
13-cis-Retinoic Acid
TM
O
)
OH
Mechanism poorly understood. It can produce severe birth
defects in the fetus of pregnant women taking the drug.
Retinoid and Retinoid-like Drugs
Indicated for Acne-3
O
C
OH
H3CO
H2 C
C
CH2
Adapalene (Differin GelTM)
H2 C
Topical: Binds to the retinoic acid nuclear receptor that modulates
cell differentiation, keratinization and inflammatory
responses.
T
o
Retinoid and Retinoid-like Drugs
Indicated for Acne and Psoriasis
O
C
H3C
C
CH3
C
Tazarotene Gel (TazoracTM)
S
See next slide for warnings!
OCH2CH3
Tazarotene Gel-Warnings
• Topical: Indicated for both acne and psoriasis. It is a prodrug
converted to the active form by hydrolysis of the ester.
– Possible Mechanism: It binds to all three RAR receptors and also
inhibits epidermal ornithine decarboxylase. The latter is required
for cell proliferation.
• Risk:
– While it is used topically and there appears to be minimal
absorption if used over limited skin area, there is some absorption
with retention by the body for up to three months. It can cause
fetal damage and cannot be used by pregnant women or women
who may become pregnant.
– It increases the skin's sensitivity to sun, and a sunscreen of at
least SPF 15 should be used if the patient will be outside in direct
sunlight.
• New Indication:
– Tazarotene, marketed as Avage™, has been approved to treat
wrinkles and photodamaged skin.
Retinoids Used in the Treatment
of Psoriasis
CH3
CH3
H3C
CH3
O
C
OR
H3CO
CH3
Etretinate (TegisonTM); R = CH2CH3
Acitretin (SoriateneTM); R = H
See next slide for information and warnings.
Etretinate and Acitretin
•
Both drugs are orally administered and require that female patient
have:
– received oral and written warnings taking these drugs during pregnancy;
– received oral and written warnings about risk of contraception failure;
– been advised of the need to use two reliable forms of contraception
simultaneously both during therapy and for at least three years following
discontinuation of therapy.
•
The exceptions are for women who have had a hysterectomy or
practices abstinence. The woman must acknowledge her
understanding in writing.
•
Etretinate: This is a prodrug that is metabolized to acitretin.
– "Terminal" half-life after six months of therapy: 120 days
– There are boxed warnings regarding women who are pregnant or may
become pregnant. Pregnancy tests are required before administration.
•
•
Acitretin: Because of its shorter half-life, it is recommended for
women of child-bearing age.
– "Terminal" half-life: 33 – 96 hours
Retinoids Used in the Treatment
of Malignancies
CH3
H3 C
CH3
Topical: This retinoid binds RXR
nuclear receptor families.
9
CH3
Alitretinoin (PanretinTM)
9-cis-Retinoic Acid
H3C
C
O
OH
It is used in the treatment of Kaposi’s sarcoma, a malignant tumor
usually involving the skin and commonly encountered in HIVpositive patients. An oral dosage form is under evaluation for
psoriasis and a variety of cancers. The trade name, Panretin, refers
to its ability to bind to all six known intracellular retinoid/retinoic acid
subtypes.
Retinoids Used in the Treatment
of Malignancies
CH2
H3C
CH3
C
OH
CH3
H3C
C
CH3
O
Bexarotene (TargretinTM)
This “rexinoid” binds to the RXR, RAR and VDR nuclear receptor
families.
Indication: Refractory cutaneous T cell lymphoma.
Oral with warnings regarding teratogenesis.
“Retinoid” Drugs in Trial
OH
CH3
H3C
CH3
H
C
CH3
H
C
C
C
H
CH3
HN
C
C
H
C
C
H
O
Fenretinide; Retinamide
This retinoid is in trials for recurring breast cancer, neuroblastoma, ovarian
cancer and other malignancies. Like the other retinoid-based drugs, it
combines with the RXR and RAR families and, presumably other nuclear
receptors. It would cause developing cells to mature rather than revert to
“immature” or “juvenile-like” malignant cells.