Phar 722 Pharmacy Practice III

1. Phar 722Pharmacy Practice III Vitamins- Vitamin D Family Spring 2006

2. 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.)

3. 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.)

4. 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)

5. 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.

6. 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.

7. Ergocalciferol (D2) Formation

8. Cholecalciferol (D3) Formation

9. 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.

10. 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.

11. 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.

13. 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.

18. 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.

19. 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 African-American children who are breast-fed and are not given a vitamin D supplement.

20. 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-dihydroxycholecalciferol (Rocaltriol®, calcitriol). • Because calcitriol is a vitamin D3 metabolite, it is not on the Medicare Part D formulary.

21. 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.

22. 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.

23. 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.

24. 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.

25. 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.

26. 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.

27. 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.

28. 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.

29. 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 • Lactation5 μg (200 IU)/day • *Maternal milk is a poor source of vitamin D.

30. 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.

31. 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.

32. 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.

33. Vitamin D Analogs-1 • Indicated for hypocalcemias, hypoparathyroidism, vitamin D resistant rickets. Their use depends on the cause.

34. 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.

35. 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.