Download Phar 722 Pharmacy Practice III

Phar 722
Pharmacy Practice III
VitaminsVitamin D Family
Spring 2006
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.)
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.)
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)
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.
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-dehydrocholesterol.
• 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.
Ergocalciferol (D2) Formation
UV
HO
Ergosterol
CH2
HO
Ergocalciferol (Vitamin D2)
Cholecalciferol (D3) Formation
D
C
B
A
H
CH3
Several Steps
HO
HO
H3C
3
H
7-Dehydrocholesterol
CH3
HO
Lanosterol
(Skin)
3
Lumisterol
UV
UV
OH
3
A
heat
C
D
UV
CH3
Previtamin D3
CH3
CH2
HO
3
Tachysterol
HO
3
Cholecalciferol (Vitamin D3)
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 7dehydrocholesterol 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.
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.
Vitamin D Metabolism
• Once formed or administered by supplement the vitamin
is hydroxylated first in the liver (25hydroxycholecalciferol), transported to the kidney where
it is hydroxylated a second time forming the active 1,25dihydroxycholecalciferol.
• 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.
OH
OH
CH2
HO
OH
(Kidney
CYP 450)
OH
OH
(Kidney)
CH2
HO
1,25(OH)2D3
(Calcitriol)
CH2
HO
24,25(OH)2D3
25(OH)D3
(Calcifediol)
(Intestine)
(Liver)
CYP 450)
(Liver & kidney)
CO2H
Variety of hydroxylated
and carboxylic acid products
CH2
CH2
HO
OH
Calcitroic Acid
HO
D3
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.
Vitamin D Deficiency-2
• There have been some recommendations that postmenopausal 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.
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 doesn’t 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 AfricanAmerican children who are breast-fed and are not given a
vitamin D supplement.
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 1,25dihydroxycholecalciferol (Rocaltriol®,
calcitriol).
• Because calcitriol is a vitamin D3 metabolite, it
is not on the Medicare Part D formulary.
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.
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.
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.
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, Crohn’s 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 women’s 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.
Maligancies and Autoimmune Diseases-2
Prostate 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 downregulates 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.
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.
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.
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.
Vitamin D DRIs-1
• AI (1 μg = 40 IU)
–
–
–
–
–
–
–
–
–
–
–
–
Infants* (0 - 12 months)
Children (1 - 8 years)
Boys (9 - 18 years)
Girls (9 - 18 years)
Men (19 - 50 years)
Women (19 - 50 years)
Men (51 - 70 years)
Women (51 - 70 years)
Men (70+ years)
Women (70+ years)
Pregnancy
Lactation
5 μg (200 IU)/day
5 μg (200 IU)/day
5 μg (200 IU)/day
5 μg (200 IU)/day
5 μg (200 IU)/day
5 μg (200 IU)/day
10 μg (400 IU)/day
10 μg (400 IU)/day
15 μg (600 IU)/day
15 μg (600 IU)/day
5 μg (200 IU)/day
5 μg (200 IU)/day
• *Maternal milk is a poor source of vitamin D.
Vitamin D DRIs-2
• UL
–
–
–
–
–
Infants
Children (1 - 18 years)
Adults (over 19 years)
Pregnancy
Lactation
25 μg (1,000 IU)/day
50 μg (2,000 IU)/day
50 μg (2,000 IU)/day
50 μg (2,000 IU)/day
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.
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.
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.
Vitamin D Analogs-1
•
Indicated for hypocalcemias, hypoparathyroidism, vitamin D resistant
rickets. Their use depends on the cause.
CH3
CH2
HO
HO
OH
3
Dihydrotachysterol
1(OH)D3
(Alfacalcidol)
OH
OH
CH2
HO
OH
1,25(OH)2D3
(Calcitriol)
CH2
HO
25(OH)D3
(Calcifediol)
Vitamin D Analogs-2
• Calcipotriene (Dovenx™)
HO
– 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
H3C
H3C
H
CH
hypercalcemia.
HC
CH2
HO
OH
H
C
CH
C
H
H
CH2
CH
C
H2
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.
CH3
CH3
25
H3 C
18 CH
3
CH3
18
H
H
25
H3C
CH3
CH3
H
CH2
HO
3
1
H
19
OH
Doxercalciferol (HectoralTM)
1,3-dihydroxy-ergocalciferol
OH
H
CH3
19
HO
3
1
OH
Paricalcitol (ZemplarTM)
19-nor-1,3,25-trihydroxy-ergocalciferol
CH3