Vitamin D PDF

VITAMIN D DR. AFSHAN SIDDIQ ASSOCIATE PROFESSOR DEPT. PHARMACOLOGY “INTRODUCTION” Vitamin D is a group of fat-soluble secsteroids (those steroid having one ring open among four rings in vit. D, ring B is open) that have hormone-like action. Vitamin D is a unique vitamin as it can be made in the bo...

VITAMIN D DR. AFSHAN SIDDIQ ASSOCIATE PROFESSOR DEPT. PHARMACOLOGY “INTRODUCTION” Vitamin D is a group of fat-soluble secsteroids (those steroid having one ring open among four rings in vit. D, ring B is open) that have hormone-like action. Vitamin D is a unique vitamin as it can be made in the body when the skin is exposed to the sun and hence it is also called "Sunshine vitamin". It also occurs naturally in food. It is responsible for increasing intestinal absorption of calcium, magnesium and phosphate and many other biological effects. The two major forms of vitamin D:  vitamin D2 or ergocalciferol  vitamin D3 or cholecalciferol which are collectively known as Calciferol.  “Chemistry and types Of Vitamin D”  D1-----D5  Ergosterol: Provitamin D2 found in plants.  7-dehydrocholesterol: Provitamin D3 found in the skin and animal source. Essential structural characteristics:  OH group at C3  Two conjugated double-bonds between C5-C6 and between C7-C8.  A hydrocarbon chain at C17. 1. D2(Ergocalciferol):- 2. D3(Cholecalciferol):- It is made in large quantities in  It is synthesized by plants the skin when sunlight strikes mainly by the irradiation of bare skin. It can also be ingested from Ergosterol. animal sources.  It was first isolated from a In humans or animals, seaweed type plant called cholesterol present in the malphigian layer of epidermis ergot,hence it is of converts into provitamin D3 vegetable origin (7-dehydrocholestrol) with the  It is not produced by the help of ultra violet radiation. Ergosterol and 7- human body itself. dehydrocholestrol both are preliminary forms of vitamin D. “Structures Of Vitamin D2 & D3” Occurrence:  D3 is less widespread then A. Fish liver oil , egg yolk are best sources.  Milk and livers of mammals are poor in D vit--- egg and milk contents depends on the diet of cows and hens and exposure of light.  Plant and vegetable are poor source of D vit.  Food containing Cholesterol can form cholecalciferol by UV rays Sources: Main reason of Deficiency:  Excessive Melanin in the skin , blocks UV radiation from reaching 7-DHC, thus limiting D3 production, as do clothing and sun-screen.  Poor exposure to sun light  Thick skin  William Boyd mentioned in his book that incident of D deficiency is greater in rich women than poor who get up early and work on boats. Absorption, storage and Excretion:  Bile salts needed  Absorption occurs in chylomicrons.  Stored in fat tissues  Transported in plasma after binding with D binding protein  Mainly eliminated by bile some part is deactivated in the liver by enzyme system  “Metabolism Of Vitamin D” Calcitriol is biologically active form mainly synthesized in kidney.  Formation of Calcitriol: Transported by vitamin D binding protein (DBP) (85-88%) and albumin (12-15%). Vitamin D2 and D3 bind to specific vitamin d binding proteins and is transported to liver from skin. 1. Hepatic production of 25OHD3 (calcidiol): D binds to the DBP transported to liver and undergoes hydroxylation at 25 position by the enzyme 25- hydroxylase in the endoplasmic reticulum of the mitochondria of liver cell. continuation  Coenzyme/cofactors required are:  Mg++ NADPH, and Molecular O2, cytochrome P450 reductase and a cytochrome P450  25- OH -D3 (calcidiol) is a major storage form of vitamin-D in liver and found in excellent amount in circulation. the blood level of 25 -OH- D3 exerts feedback inhibition on the enzyme 25- hydroxylase.  2. Renal production of 1,25-OH-D3 (calcitriol):  25-OH-D3 is bound to specific vitamin d binding protein and is carried to kidneys.  It undergoes hydroxylation at 1 -position by the enzyme 1 - Alpha -hydroxylase in endoplasmic reticulum of mitochondria of proximal convoluted tubules of kidney.  Factors Regulating Calcitriol: Regulation of calcitriol synthesis is done by Its own concentration—by feedback inhibition of 1 α-hydroxylase. Stimulated by Parathyroid hormone (PTH), Estrogen, prolactin, progesterone, GH Serum phosphate level. Hypocalcaemia leads to marked increase in 1 αhydroxylase activity, the effect requires PTH. calcitriol regulates its own concentration since high levels of calcitriol inhibit “1 α-hydroxylase” and stimulates the formation of 24,25-di-OH-D3 which is not potent as calcitriol and now supposed to be a storage form. Factors regulating active D3:  Calcitonin increases 1,25 dihydroxy vitD formation by producing hypocalcaemia  It is suppressed by a high intake of D and high levels of Plasma Ca+2 and Pi as well as 1,25 dihydroxy D (as negative feed back).  Bone is a connective tissue made rigid by mineral deposition. Main protein in bone fiber is Ossein (two other proteins too). Bones are continuously destroyed and renewed so these are dynamic not inert. Water = 25% Inorganic matter (Ca and Pi) = 45% Organic (Protein and mucopolysaccharides) = 30% (ossein 95% in it) End of long bone is cartilage------ degenerated and replaced by osteoblasts produce organic matter in it is termed as osteoid tissue. Also bring some seeding of inorganic ca and pi. Along with mineral deposition glycolysis and production of organic phosphate take place in osteoblast cell. These cell contains Alkaline phosphatase which split organic phosphate into inorganic Pi to be deposited in bone. This enzyme also act on pyrophosphate that demineralize bones. ALP IS A MAJOR REGULATOR OF BONE MINERALIZATION BONE PHYSIOLOGY: Bone physiology:  ALP provides inorganic phosphate from pyrophosphate and organic Phosphate for the synthesis of bone crystals (CaOH, Ca(PO4). ALP are of different types bone ALP, liver ALP and in bones it is present at outer.  Bone become dense by crystal growth and displacement of water.  Action of Calcitriol 1. It increases the formation of two Ca binding protein (Calbindins 9K and 28K) in the intestine which increases Ca absorption. 2. It increase reabsorption of Ca and Pi from renal tubules. 3. It increases mobilization of ca and pi from old bones means stimulate both bone forming and bone mobilizing osteoclast net activity is clast 4. All above result in raised plasma Ca and Pi 5. Calcitriol exert anti proliferative effect on PTH activity. On other hand PTH activity is stimulated when body has less vit D---hypocalcaemia-- hyperParathism. Main MOA of Calcitriol is to: 1. induce gene for Osteoblast forming protein. 2. Gene for Ca binding 9K and 28K 3. Gene in PTH to decrease PTH formation Functions of vitamin :  It acts on target organs like bones, kidneys, intestinal mucosa to regulate calcium and phosphate metabolisms. Intestinal absorption of calcium and phosphate:  expresses the genes for calcium binding protein as well as Ca++ ATPase in intestinal cells. This increases the Ca++ absorption  Mineralisation of bones: Mineralisation of bones is promoted by 1, 25, (OH)2D3 as well as 24, 25(OH)2D3. It is believed that the synthesis of Ca++-binding proteins like osteocalcin and alkaline phosphatase is promoted which increases calcium and phosphate ions in the bone. These ions enhance the mineral deposition in the bone.  24, 25(OH)2D3 helps the deposition of hydroxyapatite in bone. Vitamin D is also believed to promote bone resorption and calcium mobilization to raise the levels of Ca and P in blood in association with PTH DRA: Depends upon certain factors: Age, Sex, clothing, season and Exposure of sunecommendount: For Women: Age 1-70: 15 mcg / 600 IU per day. Age above 70: 20mcg / 800 IU per day. For Men: Age 1-70:. 15mcg or 600 IU per day. Age above 70: 20mcg or 800 IU per day. For breastfed babies supplementation is recommended as breast milk is a poor source of vitamin D. up to age 12 400 IU DRA:  Blood levels above 20 ng/ml or 30 ng/ml are considered as “sufficient”  Vitamin D deficient needed 5,000 IU to reach blood levels above 30 ng/ml.  postmenopausal women with vitamin D levels below 20 ng/ml found that ingesting 800–2,000 IU raised blood levels above 20 ng/ml. However, higher doses are needed to reach 30 ng/ml  “Deficiency of Vitamin D” “Hypovitaminosis D Rickets: In growing children deficiency of vit D causes Rickets. Low vit D intake results low ca and Pi which stimulate PTH and that act to restore the Plasma Ca from bone and in infant newly form osteoid tissue fail to be mineralized. So bones have less inorganic matter that decrease mineral contents of bone the first defect. So the cartilage cell at the end of long bones do not degenerate but proliferate and raised level of AlkPhosphatase. Signs & Symptoms: Some signs and symptoms of rickets may include the following: bone pain or tenderness. a large forehead or abdomen. bones that grow slowly. an unusual shape to the ribs bowed or curved legs. and breastbone. muscle weakness. wide joints in the elbows and bones that are soft and wrists. break easily. dental cavities and irregularities. Diagnosis in Rickets:  Plasma Ca level initially low but later increase due to PTH  Serum Alkaline Phosphatase is increased in rickets help in diagnosis as enzyme is removing phosphate from organic phosphates.  Defective enamel production  Poor musculature of child in pot belly.  It must be diagnosed early once bone develop it is difficult to reverse.  Rickets also seen when defective conversion of vit D.  Osteomalacia: Adult rickets usually affect women poor economically and undergone repeated cycle of pregnancy and lactation. In the process of mineralization, the inner layer, comprising of collagen, normally becomes coated with minerals that form a hard outer shell. When people have osteomalacia, the shell does not form fully, leaving the collagen soft. Signs & Symptoms: pain in the legs, upper thighs, and knees. weak, sore, and stiff muscles, and upper legs. difficulty walking.. pseudofractures of weight-bearing bones, such as the feet and pelvis. Some individuals may not have any symptoms. Other clinical aspects of Deficiency:  Heart ailments: vitamin D deficiency is indicator of future heart attack than cholesterol.  Diabetes insulin dependent Type-1 (IDDM-1) occurred commonly in areas which receive less sunlight.  Breast cancer have Vit D receptors that can be slow down cancer cells.  Peripheral artery disease (PAD): Vitamin D may protect against an arterial disease in which fatty deposits restrict blood flow to the limbs Causes of Vitamin D deficiency: Poor intake Breastfed infants, because human milk is a poor source of vitamin D. An infant should be given a supplement of 400 IU of vitamin D every day. Older adults, because their skin doesn't make vitamin D when exposed to sunlight as efficiently as when you were young, and your kidneys are less able to convert vitamin D to its active form. People with dark skin, which has less ability to produce vitamin D from the sun. People with disorders such as Crohn's disease or celiac disease who don't handle fat properly, because vitamin D needs fat to be absorbed. People who have obesity, because their body fat binds to some vitamin D and prevents it from getting into the blood. People who have had gastric bypass surgery People with osteoporosis People with chronic kidney or liver disease. People with hyperparathyroidism (too much of a hormone that controls the body's calcium level) People with sarcoidosis, tuberculosis, histoplasmosis, or other granulomatous disease (disease with granulomas, collections of cells caused by chronic inflammation) People with some lymphomas, a type of cancer. People who take medicines that affect vitamin D metabolism, such as cholestyramine (a cholesterol drug), anti-seizure drugs, glucocorticoids, antifungal drugs, and HIV/ AIDS medicines. Prevention & Treatment: The goals of treatment and prevention are the same—to reach, and maintain, an adequate level of vitamin D in the body. Taking good sources of food but no UV interaction may not help to cover deficiency of D. In that case supplementation is needed. Hypervitaminosis:  Vitamin D toxicity, is a rare but potentially serious  The main consequence of vitamin D toxicity is a buildup of calcium in your blood (hypercalcemia)  Taking 60,000 (IU) /day for several months has been shown to cause toxicity. This level is many times higher than the U.S. Recommended Dietary Allowance (RDA) for most adults of 600 IU of vitamin D /day. Hypervitaminosis  1. Immediate effects: Include anorexia, thirst, lassitude, constipation and polyuria. Followed later on by nausea, vomiting and diarrhoea.  2. Delayed effects: Persistent hypercalcaemia and hyperphosphataemia may produce:  Urinary lithiasis Metastatic calcification which may affect kidneys, bronchi, pulmonary alveoli, muscles, arteries and gastric mucosa. Renal failure may develop and can lead to death. Thank you