Phar 722 Pharmacy Practice III

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Phar 722Pharmacy Practice III

• Vitamins-
• Vitamin A Family
• Spring 2006

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Vitamin A Study Guide

• The applicable study guide items in the Vitamin
  Introduction.
• History
• Structures of the vitamins 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

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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.

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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.

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Vitamin A Chemistry-2

• Carotenes
• These are the yellow/orange pigments which can be
  considered as provitamins A.
• There are three main pigments with ß-carotene
  considered the standard because each mole
  contains two equivalents of vitamin A.
• The carotenes are oxidatively cleaved in the
  intestinal mucosa cell.

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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.

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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.

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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.

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Vitamin A Deficiency-2Retinoic Acid - Cell
differentiation

• The retinoic acid receptors that belong to the
  nuclear receptor family and are classified as
• RARa,ß,? (ligand trans-retinoic acid)
• RXRa,ß,? (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.

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Vitamin A Deficiency-3Retinoic 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.

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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.

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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.

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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.

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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
  all-trans-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 1,800,000-17,500,00
  0 IU (540 - 5,250 mg).
• The symptoms for acute hypervitaminosis A include
  headache, vertigo, diarrhea, nausea, and
  vomiting. Recovery requires about 2-4 weeks.

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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.

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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.

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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 ß-carotene and
  are indicated for the photosensitivity seen in
  erythropoietic porphyria.
• Patients who drink large amounts of carrot juice
  sometimes show signs of hypercarotenosis.
• ß-Carotene was included in several vitamin
  products and was promoted for its antioxidant
  properties.
• Most studies on the use of EXCESSIVE ß-carotene
  show it to be ineffective and may be detrimental.

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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.

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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

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DRIs (1 µg 0.001 mg)

• AI (infants 1 - 12 months) 400 - 500 µg/day
• EAR
• Children (1 - 8 years) 210 - 275 µg/day
• Boys (9 - 18 years) 445 - 630 µg/day
• Girls (9 - 18 years) 420 - 485 µg/day
• Men (19 - 70 years) 625 µg/day
• Women (19 - 70) 500 µg/day
• Lactating 880 - 900 µg/day
• RDA
• Men 900 µg/day
• Women 700 µg/day
• Pregnant 770 µg/day
• Lactating 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.

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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
  ß-carotene).

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Retinoid and Retinoid-like Drugs Indicated for
Acne-1
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.
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Retinoid and Retinoid-like Drugs Indicated for
Acne-2
Oral Mechanism poorly understood. It can
produce severe birth defects in the
fetus of pregnant women taking the drug.
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Retinoid and Retinoid-like Drugs Indicated for
Acne-3
Topical Binds to the retinoic acid nuclear
receptor that modulates cell
differentiation, keratinization and inflammatory
responses.
Topical Binds to the retinoic acid nuclear
receptor that modulates cell differentiation,
keratinization and inflammatory responses.
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Retinoid and Retinoid-like Drugs Indicated for
Acne and Psoriasis
See next slide for warnings!
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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.

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Retinoids Used in the Treatment of Psoriasis
See next slide for information and warnings.
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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

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Retinoids Used in the Treatment of Malignancies
Topical This retinoid binds RXR nuclear
receptor families.
It is used in the treatment of Kaposis sarcoma,
a malignant tumor usually involving the skin and
commonly encountered in HIV-positive 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.
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Retinoids Used in the Treatment of Malignancies
This rexinoid binds to the RXR, RAR and VDR
nuclear receptor families. Indication
Refractory cutaneous T cell lymphoma. Oral with
warnings regarding teratogenesis.
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Retinoid Drugs in Trial
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.