Vitamin D & its Analogues made easy for Dialysis students

Vitamin D

1. Vitamin D & its Analogues Dr. R.Rao Prethendhira Singh Dept of Pharmacology SRDCH

2. The first scientific description of rickets - Dr. Daniel Whistler ( 1645 ) and Professor Francis Glisson ( 1650 ). 1820’s - city children more likely to have rickets than rural children 1890’s - search for specific foods that could prevent rickets 1913 - Dr. Elmer McCollum discovered a substance in COD LIVER OIL later called as “Vitamin A” British doctor Edward Mellanby noticed dogs that were fed cod liver oil DID NOT DEVELOP RICKETS and concluded Vitamin A, or a closely associated factor, could prevent the disease 1921 - Dr. McCollum tested modified cod liver oil in which Vitamin A had been destroyed. Modified oil still cured the sick dogs so he concluded this factor distinct from Vitamin A and called it Vitamin D 1920’s - exposure to sunlight was also completely effective in curing and preventing rickets

3. Types of Vitamin D Fat-soluble vitamin There are several forms of Vitamin D Secosteroids Maintanence of plasma calcium and phosphate level , thermostabile

4. Types of Vitamin D Vitamin D 1 Ergocalciferol with lumisterol Vitamin D 2 calciferol derived from ergosterol Vitamin D 3 Cholecalciferol derived from 7- dehydrocholesterol in the skin Vitamin D 4 22- dihydroergocalciferol Vitamin D 5 Sitocalciferol derived from 7-dehydrositosterol

5. Sources of Vitamin D The body synthesizes Vitamin D when exposed to sunlight UVB Rays 15- 20 min two/three times a week from 10am-2pm Cheese Egg Yolk Milk Curd Fatty Fish Fortified Foods

6. Activation of Vitamin D ERGOSTEROL 7- DEHYDROXYCHOLESTEROL CHOLECALCIFEROL ( Vit D 3 ) CALCIFEDIOL (25-OH-D 3 ) CALCITRIOL (1,25 (OH) 2 D 3 ) CALCIFEROL ( Vit D 2 ) 25-OH-D 2 1,25 (OH) 2 D 2 UV LIGHT LIVER KIDNEY PROVITAMINS ACTIVE FORMS

7. Pharmacokinetic Profile A- Well absorbed from the intestines in the presence of bile salts D 3 absorbed better than D 2 D- Bound to a specific α globulin and stored mostly in adipose tissue for months M- Hydroxylated in the liver and kidney into active metabolites E- Excreted mainly through bile * t½ varies with different forms from 1-18 days * D 3 has a longer half life of 12-30 days

8. Daily Requirements AGE RDA/Day 0-12 MONTHS 400 IU (10mcg) 1-13 YEARS 600 IU (15mcg) 14-18 YEARS 600 IU (15mcg) 19-50 YEARS 600 IU (15mcg) 51-70 YEARS 600 IU (15mcg) >71 YEARS 800 IU (20mcg) Special Cases RDA/Day PREGNANCY 600 IU (15mcg) LACTATION 600 IU (15mcg) MENOPAUSE 600 IU (15mcg) ( Upto 1000 IU) FRACTURE HEALING 400 IU (10mcg) OBESITY/OVERWEIGHT ASSOC. W/ HYPOTHYROIDISM 800 IU (20mcg) ( Upto 1000 IU) According to the National Institute of Health Daily requirement varies upon exposure to sunlight

9. Vitamin D Serum Values Normal Level > 30 ng/mL Insufficiency 21-29 ng/mL Deficiency < 20ng/mL Severe Deficiency < 10ng/mL Exact cut-off values are still controversial for insufficiency and deficiency Researchers conclude that having low levels of Vitamin D (<17.8 ng/mL) was independently associated with an increase in morbidity in the general population 25 (OH) D is what is measured

10. Biochemical/Physiological Actions Absorption of Calcium & Phosphate in the intestine Resorption of Calcium & Phosphate from bone Tubular reabsorption of Calcium and Phosphate in the kidney Vitamin D tells cells when to DIVIDE , STOP DIVIDING or DIE (APOPTOSIS) Aids with immunity  VDR on T cells  TRANSFORMS INTO KILLER CELLS  MULTIPLY Reduces inflammation Improves insulin sensitivity Lowers blood pressure

11. A Hormone Vitamin D is technically not a vitamin IT IS A HORMONE Synthesized in the body May not be required by diet Transported in the blood, activated and then acts on specific receptors in target tissues Feedback mechanism based on plasma Ca 2+ levels and the active form of vitamin D

12. Why are more people deficient? Nearly 1 million people worldwide are Vitamin D deficient or insufficient Countrywide studies show a high prevalence in India > 70% of healthy individuals Increased use of sunscreen Increased indoor sedentary lifestyle Liver or Kidney Disease Cystic Fibrosis Crohn’s Disease Celiac Disease Gastric Bypass Surgery Obesity Age Mobility Skin Color Exclusive Breast-feeding

13. Vitamin D Preparations Formulations Tablets Capsules Granules (Sachets) Syrups Soft gel capsules Solution in oil

14. Vitamin D Analogues CALCITRIOL Expensive preparation Rapid onset of action Short half life of 6 hours Does not require hydroxylation Used in liver and chronic kidney diseases Dose: 0.25- 1 μ g orally/day/alternate day 1 μ g in 1mL aqueous IV on alternate days Watch for HYPERCALCEMIA ALFACALCIDOL (25 dihydroxy cholecalciferol) Prodrug Rapid onset of action Half life of 2-3 weeks Rapidly hydroxylated in the liver Does not require renal hydroxylation Effective in renal bone disease, severe liver disease, vitamin D dependent and resistant rickets, hypoparathyroidism, and osteoporosis Dose: 1-2 μ g orally/day Watch for HYPERCALCEMIA

15. DIHYDROTACHYSTEROL Synthetic Analogue of Vitamin D 2 Undergoes hydroxylation in liver Does not require PTH dependent activation in kidney Useful in hypoparathyroidism and renal bone disease Directly mobilizes calcium from bone Dose: 0.25- 0.5mg/day CALCIPOTRIOL Derivative of Calcitriol 0.005% ointment for local application in Psoriasis Also used successfully to treat alopecia areata PARICALCITOL Analog of active form of Vitamin D 2 Used in secondary hyperparathyroidism associated with chronic kidney disease 22-OXACALCITRIOL Analogue of Calcitriol Low affinity for Vitamin D binding protein Shorter half life Potent suppressor of PTH genes

16. Vitamin D Regimen To replenish Vitamin D levels in those who are insufficient or deficient: - Oral Ergocalciferol (D 2 ) 50,000 IU once a week X 8 weeks OR - Oral Cholecalciferol (D 3 ) 60,000 IU once a week X 8 weeks - Recheck Vitamin D serum levels GOAL  TO ACHIEVE A MINIMUM LEVEL OF 30 ng/mL - Once Vitamin D levels are replenished, maintenance dose to be continued - Oral Cholecalciferol 800- 1000 IU/day

17. Severe Deficiency States Rickets in children Osteomalcia in adults Lack of available CALCIUM and PHOSPHATE needed for bone mineralization

18. Rickets Rx: Combination of Vitamin D 3 and Calcium Vitamin D 3 300,000-600,000 IU IM/Orally X 1 day divided into 4-6 doses OR 5,000-10,000 IU daily X 2-3 months + Calcium 1000mg/day + Expose to sunlight for 30 min between 10am-2pm *SIGNS OF HEALING: ↑ in serum phosphorus levels Visible radiographic healing

19. Osteomalacia Signs & Symptoms Diffuse bone & joint pain Muscle weakness Waddling gait Compressed vertebrae Weak soft bones Rx: Goal is to remineralize bone! Vitamin D 3 50,000-100,000 IU/day orally X 1-2 weeks + Calcium 1000- 1500mg/day + Expose to sunlight for 30 min between 10am-2pm * Monitor serum and urine calcium

20. Miscellaneous Uses Osteoporosis Elderly males Postmenopausal females 800 – 1000 IU/ day + Calcium Hypoparathyroidism Dihydrotachysterol or Calcitriol/ Alfacalcido Conventional preparations of Vit . D 3 in high doses Fanconi Syndrome Vit . D given to increase serum phosphate levels Psoriasis Calcipotriol

21. Hypervitaminosis D Rx Immediately withdraw the vitamin Low calcium diet Administration of glucocorticoids Vigorous fluid support *Forced saline diuresis with loop diuretics can be useful Occurs when taking too much Vitamin D > 150 ng/mL Hypercalcemia  overcalcification of bones, soft tissues, heart and kidneys Hypertension Dehydration Vomiting Decreased appetite Muscle weakness