Phar 722 Pharmacy Practice III

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Phar 722Pharmacy Practice III

• Vitamins-
• Vitamin D Family
• Spring 2006

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Vitamin D Study Guide

• The applicable study guide items in the Vitamin
  Introduction
• History
• General structures and nomenclature of the
  commercial forms and the active forms
• Controls used by the skin to regulate Vitamin D3
  conversions
• Main steps in the conversion of the vitamin to
  the active form and the organs where this occurs
• Postulated biochemical mechanism of action
• Causes for deficiencies
• Effects of and reasons for symptoms associated
  with a deficiency
• Symptoms and occurrences of hypervitaminosis D
• Vitamin-drug interactions
• Approaches to formulation
• Non-vitamin drug uses (It is not necessary to
  know drug names.)

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Vitamin D History-1

• 1650 - rickets first reported
• 1910-1961 (United States)
• a minimum of 13,807 deaths attributed to rickets,
  of which 8,387 occurred in infants less than 12
  months old.
• From 1910 to 1933 there was an average of 400 to
  500 deaths per year from rickets. The death rate
  began to fall off dramatically beginning in 1934.
  By 1939 there were 143 deaths in 1945 93
  deaths in 1951 42 deaths and in 1961 4 deaths.
• 17th and 18th centuries
• Rickets was very prevalent in the New England
  colonies just as it had been in the home
  countries of the colonists.
• It correlated with the industrial revolution and
  its working inside rather than outside in the
  fields.
• The treatment for rickets included snail liquor,
  roots, grasses, molasses, dipping in cold water,
  drawing blood, good diet, laxatives.
• Mid 19 century
• There were the beginnings of the realization that
  rickets was not seen in countries with abundant
  sunlight.
• There was some use of cod liver oil.
• In 1870 it was found that 25 of all Philadelphia
  children were rachitic (notice the different
  spelling for the adjective.)

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Vitamin D History-1

• 1913
• importance of sunlight for bone mineralization
  was confirmed.
• Increasingly, rickets was concentrated in the
  poor who lived in the tenements with inadequate
  exposure to sunlight. Diet began to be examined
  even more closely.
• 1914
• Federal Childrens Bureau omitted cod liver oil
  from the list of suggested foods, but did suggest
  sunshine.
• There was a bad lot of cod liver oil that lacked
  adequate vitamin D.
• 1917
• Hess prescribed cod liver oils and recommended
  dispensing it at clinics at cost.
• This was rejected by the official medical
  establishment who claimed that cod liver oil was
  effective only because of its fat content.
• Milk with its mineral content was the preferred
  treatment.
• Hess correctly replied that milk was not
  antirachitic.
• NOTE Spellings Rickets (noun) and Rachitic
  (adjective)

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Vitamin D History-2

• 1924
• Hess and Steenbock (U. of Wis) independently
  irradiated foods including milk and produced food
  which were antirachitic. Steenbock obtained a
  patent for his discover.
• The Wisconsin Alumni Research Foundation (WARF)
  was organized in 1925 to administer this patent
  and any others that might be forthcoming. This
  may be the first example of a university
  receiving significant income from a patent. It
  gave the University of Wisconsin a head start at
  being able to provide its faculty significant
  start up funding for their research. The
  University of Wisconsin has received royalties
  for all of the milk containing irradiated
  ergosterol.
• 1929
• The Federal Childrens Bureau put cod liver oil on
  the recommended list of foods.
• 1934
• AMA approved vitamin D milk produced in
  Tennessee, Oregon, Utah, Michigan, Illinois,
  Connecticut, and North Carolina.
• 1990s to the present
• The daily requirements for vitamin D is being
  re-evaluated because its role is much broader
  than regulating calcium transport.

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Calciferol Chemistry

• There are two forms of vitamin D. They are
  considered biologically equivalent.
• Ergocalciferol (Vitamin D2)
• Produced by UV irradiation of the plant sterol
  ergosterol.
• Cholecalciferol (Vitamin D3)
• Produced by irradiation of the animal sterol
  7-dehydro-cholesterol.
• NOTE Once the B ring of the two steroids has
  been cleaved, the products should no longer be
  referred to as steroids. It is INCORRECT to call
  these compounds steroidal vitamins.

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Ergocalciferol (D2) Formation
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Cholecalciferol (D3) Formation
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Vitamin D Uptake-1

• Cholecalciferol (D3) produced in the skin.
• This is very complicated and is dependent upon
  the source.
• Essentially, cholecalciferol should not be
  considered a vitamin.
• It is a hormone because in the presence of
  adequate sunlight, enough of the vitamin is
  produced from the 7-dehydrocholesterol in the
  skin.
• There is no evidence of calciferol overdose
  caused by extensive exposure to the sun.
• In this context vitamin D could be considered
  replacement therapy.
• One of the definitions of a vitamin is that it be
  a normal constituent of the diet. Vitamin D
  definitely is not a normal constituent of most
  diets except for those populations living along
  oceans or large bodies of water that produce
  adequate amounts of fish.
• Vitamin D is in our milk because it was added.

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Vitamin D Uptake-2

• Oral Vitamin D
• Ergocalciferol (D2) has to be oral.
• Cholecalciferol (D3) in milk and vitamin capsules
  has to be oral.
• Being lipid soluble, oral Vitamin D will follow
  other lipids into the intestinal mucosa, added to
  chylomicrons, dumped into the lymphatic system,
  enter the portal vein via the thoracic duct and
  into the liver for 25-hydroxylation.

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Vitamin D Metabolism

• Once formed or administered by supplement the
  vitamin is hydroxylated first in the liver
  (25-hydroxycholecalciferol), transported to the
  kidney where it is hydroxylated a second time
  forming the active 1,25-dihydroxycholecalciferol.
  
• The latter is then transported to the intestinal
  tract where, through the vitamin D receptor (VDR)
  it signals the mucosa cell to synthesize a
  calcium transport protein.
• The final product can be considered a kidney
  hormone that regulates calcium intake. (See
  discussion of the VDR below.)
• It is excreted as a variety of hydroxylated and
  sulfated products.

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Vitamin D Deficiency-1

• Rickets in infants and children and osteomalacia
  in adults is the deficiency syndrome seen with
  the vitamin D family.
• Normal growth requires that the osteoblasts lay
  the hydroxyapatite down onto a cartilage matrix.
  
• A deficiency of vitamin D means that there is no
  mixed calcium salt available to the osteoblast
  cells.
• But the cartilage continues to grow.
• Cartilage, being soft, cannot support the child's
  weight leading to the typical bowlegs seen in a
  rachitic child.
• An adult also will have bone deformations due a
  softening.

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Vitamin D Deficiency-2

• There have been some recommendations that
  post-menopausal women should consume 400 500 IU
  daily of vitamin D. (AI 400 IU/10 µg) 1 µg
  40 IU
• Post-menopausal women are at increased risk from
  osteoporosis because they no longer are producing
  estrogen.
• It has been assumed that women were obtaining
  enough vitamin D, either from diet or sunlight.
• One study has shown that most women in the
  northern United States (above the 42nd parallel)
  and other northern countries do not have enough
  vitamin D in their tissues during the winter when
  there is less sunlight.
• Further, home-bound elderly are not getting
  adequate exposure to sunlight.
• Depending on the person's serum lipid levels,
  drinking a quart of milk may not be advisable.
• It is possible that vitamin D supplements plus
  calcium tablets may be advisable.

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Vitamin D Deficiency-3

• Rickets is still seen in the United States which
  is evidence that infants and children are not
  receiving enough vitamin D. There could be at
  least two reasons for this
• Inadequate intake of vitamin D fortified milk
• This can be caused by poverty, milk allergies
  either in the parent who doesnt stock milk or in
  the infant. Breast milk contains little vitamin
  D leading to the recommendation that these
  infants received 200 IU of vitamin D per day.
• Most soy milks are fortified.
• Inadequate exposure to sunlight.
• Besides geographical location, increasing use of
  sun screens with SPF of 8 or higher on infants
  and children will block the wavelength of
  sunlight that causes the photochemical reaction
  leading to vitamin D.
• In the United States, the vast majority of
  rickets are in African-American children who are
  breast-fed and are not given a vitamin D
  supplement.

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Vitamin D Deficiency-4

• Vitamin D Resistant Rickets
• This is seen in kidney failure because these
  patients cannot carry out the final hydroxylation
  step. They must take 1,25-dihydroxycholecalcifero
  l (Rocaltriol, calcitriol).
• Because calcitriol is a vitamin D3 metabolite, it
  is not on the Medicare Part D formulary.

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Calciferol-Drug Interactions

• Phenobarbital and possibly other anticonvulsants
  used in epilepsy induce liver hydroxylation
  leading to subsequent formation of the inactive
  end products.
• As long as the epileptic child receives a normal
  amount of fortified milk, there is no problem
  with this interaction.

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Vitamin D Receptor (VDR)-1

• Like vitamin A and its receptors, vitamin D has a
  receptor (VDR) that is part of the same super
  family of nuclear receptors.
• VDR are found on nearly all cells. The function
  is poorly understood, but its seems to be
  involved with
• regulation of cell division,
• apoptosis,
• differentiation and angiogenesis,
• calcium transport.
• How this correlates with calcium transport beyond
  the intestinal mucosa is poorly understood.

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Vitamin D Receptor (VDR)-2

• The Vitamin D receptor (VDR) for this drug
  belongs to the steroid receptor family that
  includes receptors for estrogen, glucocorticoids,
  thyroid hormones, and retinoic acid.
• Available evidence suggests that a single Vitamin
  D receptor is common to all cells and tissues.
• When the ligand binds to this receptor, there is
  inhibition of cell proliferation.
• To date, hundreds of deltanoids have been
  synthesized and tested for the prevention and
  treatment of malignancies.
• In terms of the selective toxicity model, the
  goal is to separate the calcium transport
  property of these compounds from their ability to
  regulate cell proliferation, apooptosis,
  differentiation and angiogenesis.
• So far, there has been little success.

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Maligancies and Autoimmune Diseases-1

• Beginning about 2002, there have been reports
  relating exposure to sunlight and incidence of
  prostate cancer and autoimmune diseases (multiple
  sclerosis, Crohns Disease, lupus).
• These results are based on incidence of a disease
  and geographical location (more cases of multiple
  sclerosis in the northern latitudes) and higher
  incidence in people of color (higher incidence of
  prostate cancer in African-American males).
• Data mining of the womens health initiative
  databases showed that women who took vitamin D
  had a lower incidence multiple sclerosis.
• The first conclusion would be that vitamin D has
  a protective effect.
• Remember that the VDR is found on nearly all
  cells.
• Other hypotheses point to the role of calcium in
  regulating cell chemistry.

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Maligancies and Autoimmune Diseases-2Prostate
Cancer

• Some epidemiological studies associate increased
  intake of prostate cancer with increased intake
  of calcium and/or dairy products.
• A possible mechanism is that high calcium intake
  down-regulates 1,25-dihydroxy vitamin D3 leading
  to increased cell proliferation in the prostate.
  
• In other words, increased calcium intake reduces
  the need to produce the active form of the
  vitamin.
• This model could explain the higher incidence of
  prostate cancer in the African-American male.
  Because of increased skin pigmentation, this
  population would not produce the required amount
  of vitamin D to overcome the down regulation of
  this vitamin.

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Hypervitaminosis D-1

• Think of a vitamin D overdose in the same way as
  an oversupply of a hormone. The role of the
  hormone is exaggerated or magnified.
• Hypervitaminosis D causes increased absorption of
  calcium and phosphorous (P follows Ca) leading to
  calcification of the tissues, vomiting, kidney
  damage, etc. It can be the most serious of the
  hypervitaminoses.
• Reported toxic doses range from
• 250 - 500 µg/day (10,000 20,000 IU),
• 625 - 1,250 µg/day (25,000 50,000 IU),
• 2,500 µg/day (100,000).
• For comparison purposes, the adult AI is 5 - 10
  µg (200 - 400 IU) which is the amount found in a
  quart of milk. In today's regulatory climate, it
  is difficult to find high potency vitamin D
  supplements.

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Hypervitaminosis D-2

• There have been some reports in the news media
  that the U.S. population may be receiving too
  much cholecalciferol because of its addition to
  milk. Standards call for 80 to 120 of the
  labeled amount.
• Some surveys have indicated that diary processors
  have been lax in monitoring cholecalciferol
  addition to milk.
• Hypervitaminosis D was reported in Boston when a
  dairy allowed 580 of the labeled amount to be
  added to the milk.

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Hypervitaminosis D-3

• NOTE
• There is debate that the traditional concern
  regarding overdosing of calciferol might be
  overstated.
• Some researchers are recommending daily adult
  doses of 25 µg (1,000 IU)
• Current Adult AI 5 15 µg (200 600 IU)
• Calciferol is replacing vitamins E and C as a
  vitamin that reduces the risk of breast cancer,
  prostate cancer, lupus, multiple sclerosis,
  rheumatoid arthritis and other autoimmune
  diseases.
• A meta analysis concluded that 17-20 µg (680
  800 IU) reduces the risk of falls in the elderly.

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Vitamin D DRIs-1

• AI (1 µg 40 IU)
• Infants (0 - 12 months) 5 µg (200 IU)/day
• Children (1 - 8 years) 5 µg (200 IU)/day
• Boys (9 - 18 years) 5 µg (200 IU)/day
• Girls (9 - 18 years) 5 µg (200 IU)/day
• Men (19 - 50 years) 5 µg (200 IU)/day
• Women (19 - 50 years) 5 µg (200 IU)/day
• Men (51 - 70 years) 10 µg (400 IU)/day
• Women (51 - 70 years) 10 µg (400 IU)/day
• Men (70 years) 15 µg (600 IU)/day
• Women (70 years) 15 µg (600 IU)/day
• Pregnancy 5 µg (200 IU)/day
• Lactation 5 µg (200 IU)/day
• Maternal milk is a poor source of vitamin D.

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Vitamin D DRIs-2

• UL
• Infants 25 µg (1,000 IU)/day
• Children (1 - 18 years) 50 µg (2,000 IU)/day
• Adults (over 19 years) 50 µg (2,000 IU)/day
• Pregnancy 50 µg (2,000 IU)/day
• Lactation 50 µg (2,000 IU)/day
• NOTE There are reports now appearing that
  adults who do not go outdoors may need as much as
  3000 to 5000 IU per day. However, the number of
  people in these studies were small and some
  conclusions are based on retrospective studies.

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Vitamin D Dosage Forms

• Commercial Forms
• Cholecalciferol
• Ergocalciferol
• The commercial products are produced by
  irradiation under controlled conditions. The
  final yield is about 50. This is why until
  quite recently, vitamin D potency was determined
  by a rat bone growth test rather than the usual
  instrumental analysis.
• Stability
• Although more stable than vitamin A, it is
  sensitive to oxygen. It does tend to isomerize
  into inactive isomers in the presence of trace
  metals which can cause problems in formulating a
  combnatin vitamin mineral supplement. It is
  stabilized with antioxidants and protective
  coatings. It is common to make a free flowing
  powder using the gelatin matrix method.

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Vitamin D Food Sources

• Pickled herring
• Catfish (steamed or poached)
• Cod liver oil
• Eastern oysters (steamed)
• Lard (pork fat)
• Mackerel (canned/drained)
• Skinless sardines (water packed)
• Smoked chinook salmon
• Sturgeon roe
• Fortified milk
• There have been reports that children of strict
  vegetarians (no food from any animal source) show
  rachitic lesions.

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Vitamin D Analogs-1

• Indicated for hypocalcemias, hypoparathyroidism,
  vitamin D resistant rickets. Their use depends
  on the cause.

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Vitamin D Analogs-2

• Calcipotriene (Dovenx)
• Calcipotriene is indicated for the treatment of
  psoriasis. When the ligand binds to this
  receptor, there is inhibition of cell
  proliferation. The reason that this drug is
  administered topically is because systemic
  administration would lead to hypercalcemia.

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Vitamin D Analogues-3 Used in Chronic Renal
Failure

• Indication
• Both of these ergocalciferol-related compounds
  are used to treat secondary hyperparathyroidism
  associated with chronic renal failure.
• Mechanism of Action
• The trihydroxy active forms of Vitamin D inhibit
  both the synthesis and release of parathyroid
  hormone (PTH).
• In chronic renal therapy, the final hydroxylation
  step at position 1 cannot occur. The net result
  is increased PTH production. This, in turn,
  increases calcium release from the bone leading
  to hypercalcemia and, eventually, osteomalacia
  (Vitamin D resistent rickets) and osteoporosis.
  Calcification of the tissues can also occur.
• Claims of Superiority
• The two ergocalciferol products are claimed to
  better regulate parathyroid hormone production
  with less complications from hypercalcemia due to
  calcium in the diet.
• In other words, there appears to be less
  transport of calcium from the intestine with
  these two products. The mechanism of this
  supposed superiority is not understood.

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