Vitamin D, E & KVitamin D, E & K

Fat soluble vitaminsFat soluble vitamins

Vitamin D

Vitamin Vitamin DD The term “Vitamin D” refers to a family of The term “Vitamin D” refers to a family of

related compounds biosynthesized from related compounds biosynthesized from cholesterol cholesterol and and ergosterolergosterol..

Vit. D3 (cholecalciferol) Vit. D3 (cholecalciferol) is synthesized from is synthesized from 7-dehydrocholesterol7-dehydrocholesterol in sun-exposed skin in sun-exposed skin and found naturally in animal products and found naturally in animal products such as such as eggs, fish eggs, fish andand liver liver..

Vit. D2 (ergocalciferol) Vit. D2 (ergocalciferol) is another form of is another form of vit. D synthesized by certain vit. D synthesized by certain fungifungi and is and is used in many supplements.used in many supplements.

(Cholecalciferol)

VITAMIN D3

)Ergocalciferol (

VITAMIN D2

Synthesized in the body Found in plant life

Naturally derived supplement

Synthetically derived supplement

Significantly increases vitamin D levels in the body

Moderately increases vitamin D levels in the body

Recommended by experts for optimal bone and immune support

Alternative form appropriate for vegetarians

However, However, vit. D3 vit. D3 is the preferred form is the preferred form for humans for humans as its bioavailability is as its bioavailability is twicetwice that of that of vit. D2. vit. D2.

After absorption from foods or production in After absorption from foods or production in the the skin, vitamin D is stored as skin, vitamin D is stored as 25-25- hydroxy-vit. hydroxy-vit. D3 D3 in the liverin the liver. When . When needed needed by the body, it is then by the body, it is then activated to activated to 1,25-1,25- dihydroxy vit. D3 dihydroxy vit. D3 in the kidney. in the kidney.

NB: NB: A healthy liver and kidneys are essential A healthy liver and kidneys are essential for for optimum vit. D status.optimum vit. D status.

Biosynthesis and Activation of Vit. D3

Stored in Liver

Daily Requirment = 10 μg vit. D (400 IU vit. D).

1.1. Calcium metabolism (main function):Calcium metabolism (main function):

Vit. D regulates CaVit. D regulates Ca+2+2 levels in the blood and levels in the blood and tissues. A fall in blood Catissues. A fall in blood Ca+2+2 stimulate stimulate active active vit. D production vit. D production stimulate stimulate CaCa+2+2 absorption absorption from food + from food + increase increase release of release of Ca++ from bones + Ca++ from bones + decrease decrease renal excretion renal excretion of Caof Ca+2+2..

FUNCTIONS OF VITAMIN D

2. Essential for normal bone growth during 2. Essential for normal bone growth during childhood childhood and for maintaining bone and for maintaining bone density density and strength during adulthood (as and strength during adulthood (as it increases it increases CaCa+2+2 absorption from foods absorption from foods + + increases Caincreases Ca+2+2 deposition into the deposition into the skeleton).skeleton).

3. Integrated function with parathyroid hormone3. Integrated function with parathyroid hormone in stabilization of Cain stabilization of Ca+2+2 level in blood. level in blood.

4. Regulation of cell growth and development 4. Regulation of cell growth and development (particularly WBCs and epithelial cells).(particularly WBCs and epithelial cells).

1. Older people (> 50 years) due to: 1. Older people (> 50 years) due to: The decrease of ability of skinThe decrease of ability of skin to to convert 7-dehydrocholesterol to convert 7-dehydrocholesterol to pre-vit. D3.pre-vit. D3.

2. Newborn infants2. Newborn infants: : who are absolutely breastfed require who are absolutely breastfed require vit. D supplements because vit. D supplements because

mother mother milk does not contain milk does not contain significant levels of Vit. D. significant levels of Vit. D.

3.Women after labor:3.Women after labor: the serum the serum concentration of vit. D and Caconcentration of vit. D and Ca+2+2 falls falls rapidly. rapidly.

PEOPLE AT GREATER RISK OF DEVELOPING VITAMIN D DEFICIENCY

5. Dark-skinned individuals 5. Dark-skinned individuals may require may require extra extra vit. D because vit. D because melanin acts melanin acts like like

a a sun-blocksun-block, prolonging the time , prolonging the time required to generate vit. D.required to generate vit. D.6. Obese people 6. Obese people have lower levels of the have lower levels of the

circulating form of vitamin D, probably circulating form of vitamin D, probably because it is deposited in body fat because it is deposited in body fat

masses masses less bioavailable less bioavailable vit. vit. DD..7. Patients with chronic liver disease 7. Patients with chronic liver disease or or

malabsorption or parathyroidectomy.malabsorption or parathyroidectomy.8.8. Vit. D is found only in animal Vit. D is found only in animal foods. foods.

strict vegetarian people strict vegetarian people sharply sharply increase the risk of deficiency if sunlight increase the risk of deficiency if sunlight exposure is inadequate.exposure is inadequate.

Decreased intake or malabsorption.

Reduced sun exposure.

Increased hepatic catabolism (e.g. due to metabolizing induction drug)

Decreased endogenous synthesis (via 25-hydroxylation in the liver and subsequent 1-hydroxylation in the kidney).

CAUSES OF VIT. D DEFICIENCY

Vit. D deficiency causes several bone diseases:Vit. D deficiency causes several bone diseases:

Rickets:Rickets: a childhood disease characterized a childhood disease characterized by failure of growth and deformity of long by failure of growth and deformity of long

bones.bones.

Osteoporosis:Osteoporosis: a condition characterized a condition characterized by by fragile bones due to decreased bone fragile bones due to decreased bone density. density.

fragile bone easily fractured. fragile bone easily fractured.

Osteomalacia:Osteomalacia: (adult version of Rickets) is a (adult version of Rickets) is a case of softening of bones due to defective case of softening of bones due to defective

bone bone mineralization and characterized by mineralization and characterized by proximal proximal weakness and bone fragility.weakness and bone fragility.

DISEASES CAUSED BY VIT. D DEFICIENCY

Rickets

Osteoporosis Osteomalacia

GENERAL USES OF VIT. DGENERAL USES OF VIT. D

1- Prophylaxis and treatment of osteoporosis1- Prophylaxis and treatment of osteoporosis as as a result of calcium depletion. Treatment a result of calcium depletion. Treatment

require taking both calcium and vitamin D. require taking both calcium and vitamin D.

2- Trteatment of Osteomalacia and rickets.2- Trteatment of Osteomalacia and rickets.

3- Vitamin D also has a role in cancer prevention 3- Vitamin D also has a role in cancer prevention (colon cancer, breast and prostate cancer). (colon cancer, breast and prostate cancer). The action of Tamoxifen (Chemotherapeutic The action of Tamoxifen (Chemotherapeutic agent) appears to be improved with small agent) appears to be improved with small

added doses of vitamin D.added doses of vitamin D.

4- Treatment of hearing loss 4- Treatment of hearing loss resulted from vitamin resulted from vitamin D deficiency that affect the function of small D deficiency that affect the function of small bones in the ear responsible sound bones in the ear responsible sound

transmition.transmition.

6- In combination with phosphate to treat some metabolic diseases as Fanconi syndrome and familial hypophosphatemia.

Fanconi syndrome: is a disorder in which the proximal tubular function of the kidney is impaired, resulting in decreased re- absorption of electrolytes and nutrients back into the bloodstream (compounds involved include glucose, amino acids, uric acid, phosphate and bicarbonate).

INTERACTIONS WITH VIT. D

1. The absorption of vitamin D is improved by calcium, choline, fats, phosphorus, vitamins A and C.

2. Drugs as Rifampin, H2 blockers, barbiturates, heparin, cholestyramine, carbamazepine, phenytoin, fosphenytoin, and phenobarbital reduce serum levels of vitamin D and increase its metabolism.

3. Overuse of mineral oil and stimulant laxatives may deplete vitamin D.

4. Osteoporosis and hypocalcaemia can result from prolonged use of corticosteroids. It is necessary to take of calcium and vit. D together with corticosteroid drugs.

DOSAGE FORMS

Fat Soluble VitaminsFat Soluble Vitamins

VITAMINVITAMIN EE

Vit. E is a general term used for a group of compounds (α, β, , and δ-tocopherols) having a chromanol ring and phytyl side chain.

Chromanol Group Phytyl side chain

Position of Methyl groups on aromatic ring

Tocopherol structure

5,7,8 α-tocopherol

5,8 β-tocopherol

7,8 γ-tocopherol

8 δ-tocopherol

12

345

7

8

RRR

d-α -tocopherol Equivalent(TE) = 1 mg = 1.5 IURecommended daily amount= 30 IU = 20 mgLarger doses are allowed (safe)

Vitamin E

The most abundant and active form of Vit. E is α- tocopherol (α-RRR-tocopherol).

The relative activities of tocopherols vary considerably and thus Vit. E activity should referred to α-tocopherol.

For example, soybean oil has a higher total tocopherol content than sunflower oil. Most of Vit. E in soya oil is δ-tocopherol while in sunflower oil most of the Vit. E is α-tocopherol, which gives the sunflower oil a greater level of Vit. E activity.

Vit. E form Relative Biological Activity

α-tocopherol 100%

β-tocopherol 50%

-tocopherol 10-30%

δ-tocopherol 1%

Sources of Vitamin ESources of Vitamin E Natural sources of vitamin E (Natural sources of vitamin E (d-RRR-αd-RRR-α-tocopherol)-tocopherol)

Vegetable oils from seedsVegetable oils from seeds(Sunflower, Cottonseed)(Sunflower, Cottonseed)

Lettuce.Lettuce.Nuts.Nuts.Unprocessed grainsUnprocessed grains..

Synthetic sources Synthetic sources racemic-tocopherols. racemic-tocopherols.Pharmacokinetics of Vit. EPharmacokinetics of Vit. E

Gastrointestinal absorption of all forms of Vit. E is Gastrointestinal absorption of all forms of Vit. E is equivalent. equivalent.

Subsequent biological steps are sharply in Subsequent biological steps are sharply in favour of the favour of the RRRRRR form. form. Cellular liver transfer protein that maintains Cellular liver transfer protein that maintains plasma level is specific for the plasma level is specific for the RRRRRR form of α- form of α-tocopherol. tocopherol.

Functions of Vitamin EFunctions of Vitamin E1.1. Antioxidant action:Antioxidant action: Tocopherols (Vit. E) interrupt free radical chain Tocopherols (Vit. E) interrupt free radical chain

reactions by capturing free radicals (free radical reactions by capturing free radicals (free radical scavanger); this imparts to them their antioxidant scavanger); this imparts to them their antioxidant properties.properties.

Therefore, Vit. E protects the cells, with other nutrient Therefore, Vit. E protects the cells, with other nutrient (e.g. Vit. C and Selenium) against the harmful free (e.g. Vit. C and Selenium) against the harmful free radicals formed during metabolism of fatty acids.radicals formed during metabolism of fatty acids.

The free hydroxyl group on the aromatic ring is The free hydroxyl group on the aromatic ring is responsible for the antioxidant properties.responsible for the antioxidant properties. The The hydrogen from this group is easily donated to the free hydrogen from this group is easily donated to the free radical, resulting in a relatively stable free radical form radical, resulting in a relatively stable free radical form of the vitamin.of the vitamin.

2. Antithrombotic action:

Vit. E slows down the action of thrombin (a blood clotting protein) and reduces platelet aggregation by inhibiting thromboxanes. Although Vit. E is a natural “blood thinner” it does not increase risk of bleeding in healthy people.

1.1. Cardiovascular disease:Cardiovascular disease: (e.g. angina pectoris and (e.g. angina pectoris and venous thrombosis): It venous thrombosis): It inhibitsinhibits oxidation of oxidation of cholesterol in LDL and VLDL particles cholesterol in LDL and VLDL particles decreasedecrease the risk of coronary heart diseasethe risk of coronary heart disease..

2. 2. Anemia:Anemia: It functions as an antioxidant, enhancing It functions as an antioxidant, enhancing

function and durability of RBCs and stabilizes their function and durability of RBCs and stabilizes their membranes membranes decreasedecrease syndromes of hemolytic and syndromes of hemolytic and sickle-cell anemiasickle-cell anemia..3. 3. Immunity:Immunity:

It It enhancesenhances resistance to viral and bacterial resistance to viral and bacterial infections and infections and increases increases antibody production by antibody production by WBCs and WBCs and increasesincreases phagocytosis. phagocytosis.

Uses of Vitamin E as prophylaxis and TherapyUses of Vitamin E as prophylaxis and Therapy

4. Alzheimer’s disease (AD) and memory loss:

It can decrease progression of AD and help maintain memory function through decreasing oxidative damage to neurons.

5. Eye Diseases: It inhibits oxidative damage to the lens inhibits developing of cataract. It also decrease incidence of macular degeneration.

6. Rheumatic disorders and pains: It acts as free radical scavenger and so as anti-inflammatory and analgesic. It can decrease joint inflammation and stiffness in osteoarthritis and rheumatoid arthritis.

7. 7. Protection and treatment of cancer: Protection and treatment of cancer:

Higher intakes of vitamin E Higher intakes of vitamin E decreasedecrease risk of risk of cancer of the cancer of the skin, breast, lung, esophagus, and skin, breast, lung, esophagus, and stomachstomach. It can also . It can also increaseincrease efficacy of the radiation efficacy of the radiation treatment and protects healthy cells against damage treatment and protects healthy cells against damage during radiotherapy.during radiotherapy.

8. 8. Skin CareSkin Care: : It is applied topically to abrasions, wounds, or It is applied topically to abrasions, wounds, or burns burns reducereduce scar formation and contraction, and scar formation and contraction, and improve healing.improve healing.

9. 9. HepatoprotectiveHepatoprotective

10. 10. Disorders of premature infants:Disorders of premature infants:

It It decreasesdecreases the risk of hemolytic anemia and the risk of hemolytic anemia and bronchopulmonary dysplasia (characterized bronchopulmonary dysplasia (characterized by inflammation and scarring in the lungs).by inflammation and scarring in the lungs).

Toxicity and side effectsToxicity and side effects

Vit. E is well-toleratedVit. E is well-tolerated, and side effects are , and side effects are rare even at higher doses (up to 2000 mg/day). rare even at higher doses (up to 2000 mg/day). However, in some individuals who are Vit. K However, in some individuals who are Vit. K deficient, Vit. E may increase the risk for deficient, Vit. E may increase the risk for hemorrhage or bleeding.hemorrhage or bleeding.

People taking anticoagulant drugs should People taking anticoagulant drugs should also be cautious with high doses.also be cautious with high doses.

People with diabetes should be cautious People with diabetes should be cautious when starting high doses of Vit. E because it when starting high doses of Vit. E because it may enhance the action of insulin, but rarely.may enhance the action of insulin, but rarely.

People at greater risk of developing Vit. E deficiencyPeople at greater risk of developing Vit. E deficiency

Many peopleMany people do not obtain adequate dietary Vit. do not obtain adequate dietary Vit. E E when depends more on processed food when depends more on processed food (e.g. (e.g. refined flour and white rice lose nearly all of refined flour and white rice lose nearly all of original vitamin present in whole grain).original vitamin present in whole grain).

People who consume much of polyunsaturated People who consume much of polyunsaturated fatty acids fatty acids (PUFAs) as in USA and Europe need (PUFAs) as in USA and Europe need more Vit. E to protect PUFAs in their tissues from more Vit. E to protect PUFAs in their tissues from oxidation particularly if dietary intake of Vit. E is oxidation particularly if dietary intake of Vit. E is marginal.marginal.

Newborn and premature infants Newborn and premature infants are at high risk are at high risk for deficiency due to their poor ability to absorb Vit. for deficiency due to their poor ability to absorb Vit. E and very limited tissue reserves of Vit. E.E and very limited tissue reserves of Vit. E.

Drug and Herbal Interactions with Vit. EDrug and Herbal Interactions with Vit. E

It can alter the efficacy of It can alter the efficacy of anticoagulantanticoagulant..

It increases It increases bleeding time bleeding time in patient taking herbal in patient taking herbal preparations as preparations as Feverfew or Feverfew or Gingko bilobaGingko biloba..

Inorganic Inorganic iron supplements iron supplements destroy Vit. E, so destroy Vit. E, so individuals taking iron should space out their doses individuals taking iron should space out their doses (e.g., iron in the morning and Vit. E in the evening).(e.g., iron in the morning and Vit. E in the evening).

Large doses of Large doses of Vit. A Vit. A can decrease can decrease the the absorption absorption of Vit. E.of Vit. E.

Alcohol and mineral oil Alcohol and mineral oil can reduce Vit. E can reduce Vit. E absorption, and thus should be avoided in Vit. E absorption, and thus should be avoided in Vit. E deficient individuals.deficient individuals.

VITAMIN K

A group of compounds derived from A group of compounds derived from 2-methyl-1,4-2-methyl-1,4-naphthoquinonenaphthoquinone that act as antihemorrhagic factor in that act as antihemorrhagic factor in birds and mammals. There are 3 forms of vitamin K:birds and mammals. There are 3 forms of vitamin K:

a)a) Vit. Vit. K1 (Phylloquinone) found K1 (Phylloquinone) found in plant in plant foods.foods.

b)b) Vit. K2 (Menaquinone)Vit. K2 (Menaquinone) from animal and from animal and bacterial sources.bacterial sources.

c)c) Synthetic Vitamin Synthetic Vitamin K3 (MenadioneK3 (Menadione).).

VITAMINVITAMIN KK

Vit. KVit. K11 ( (Phylloquinone)Phylloquinone) Vit. KVit. K2 2 ((MenaquinoneMenaquinone))

Commercial infant Commercial infant formula contain 50- 125 formula contain 50- 125 μμg/dayg/day

Vit. KVit. K3 3 ((Menadione)Menadione)

Recommended Recommended Daily amount Daily amount

New born: 500- 1000 μg onceNew born: 500- 1000 μg once1- 6 Months: 5 mg/day1- 6 Months: 5 mg/day6- 12 Months: 15 mg/day6- 12 Months: 15 mg/dayAdult: 80 mg/Kg (body weight) / dayAdult: 80 mg/Kg (body weight) / day

2-methyl-1,4-2-methyl-1,4-naphthoquinonenaphthoquinone

Sources of Vitamin K

Foods rich in Vitamin K: Spinach, Green cabbage, Turnip, Parsley, lettuce, beef liver, green tea (in decreasing order), etc.

Spinach Green cabbage Turnip

Parsley Beef liver Green tea

Structure Activity RelationshipStructure Activity Relationship

1.1. Activity is maximum when:Activity is maximum when:

Ring A and Ring B are aromatic.Ring A and Ring B are aromatic. Ring A is not substituted.Ring A is not substituted. Methyl group at C-2.Methyl group at C-2. Unsaturation of phytyl side chain Unsaturation of phytyl side chain at C-3.at C-3.

2.2. Activity is decreased when:Activity is decreased when:

Alkyl group larger than Methyl at C-2.Alkyl group larger than Methyl at C-2. Hydroxyl group at C-3.Hydroxyl group at C-3. Hydroxylation or saturation or cis-configuration Hydroxylation or saturation or cis-configuration of the phytyl side chain at C-3.of the phytyl side chain at C-3.

Activity not affected:Activity not affected:if positions 1 and 4 are substituted if positions 1 and 4 are substituted with OH, O-Ac, with OH, O-Ac, NHNH22, ,

OCHOCH33, OC, OC22HH55, C=O, C=O

AA BB

11

33

22

44

Metabolism of Vit. KMetabolism of Vit. K

1.1. 70% of Vit. K3 (menadione) excreted in urine in 24 h 70% of Vit. K3 (menadione) excreted in urine in 24 h in the form of sulphate, phosphate and glucuronic in the form of sulphate, phosphate and glucuronic acid conjugate.acid conjugate.

2.2. Small % excreted in faces as glucuronic acid Small % excreted in faces as glucuronic acid conjugate.conjugate.

3.3. Vit K2 and K3 undergo slower metabolism to Vit K2 and K3 undergo slower metabolism to shorten the side chain to 5- 7 carbons carboxylate.shorten the side chain to 5- 7 carbons carboxylate.

Symptoms of Vit. K deficiencySymptoms of Vit. K deficiency1.1. Uncontrolled internal bleeding.Uncontrolled internal bleeding.2.2. Cartilage calcification and malformation of Cartilage calcification and malformation of

developing bone.developing bone.3.3. Deposition of insoluble calcium salts in the arterial Deposition of insoluble calcium salts in the arterial

vessel walls.vessel walls.

The basic factors needed to prevent vitamin K The basic factors needed to prevent vitamin K deficiency:deficiency:

a)a) Normal diet containing the Vit. K.Normal diet containing the Vit. K.b)b) Presence of bile in the intestine.Presence of bile in the intestine.c)c) Normal intestinal uptake or absorption.Normal intestinal uptake or absorption.d)d) Normal liver i.e. no interference with Vit. K Normal liver i.e. no interference with Vit. K

metabolism or use of Vit. K antagonists metabolism or use of Vit. K antagonists therapeutically or accidently.therapeutically or accidently.

e)e) Heavy alcohol consumptionHeavy alcohol consumption impairs the impairs the liver’s ability to produce vitamin K-liver’s ability to produce vitamin K-dependent coagulation factors and impair dependent coagulation factors and impair recycling of vitamin K.recycling of vitamin K.

Newborn infants Newborn infants exclusively breastfed are exclusively breastfed are susceptible to abnormal bleeding due to Vit. K susceptible to abnormal bleeding due to Vit. K deficiency. deficiency.

Breast milk contains very little Vit. K and the Breast milk contains very little Vit. K and the immature liver of the newborn immature liver of the newborn does not synthesize the does not synthesize the Vit. K-dependent clotting factors efficientlyVit. K-dependent clotting factors efficiently. .

Also, because the newborn’s colon is sterile for the Also, because the newborn’s colon is sterile for the first few days after birth, first few days after birth, no bacterial synthesis of Vit. K no bacterial synthesis of Vit. K occurs in the colon. occurs in the colon.

To reduce the risk of Vit. K deficiency, most babies To reduce the risk of Vit. K deficiency, most babies receive intramuscular vitamin K at birth.receive intramuscular vitamin K at birth.

People at greater risk of developing Vit. K deficiencyPeople at greater risk of developing Vit. K deficiency

Symptoms of Vit. K ToxicitySymptoms of Vit. K Toxicity Vitamins K1 and K2 are non-toxic in large doses.Vitamins K1 and K2 are non-toxic in large doses. Vitamin K3 (the synthetic one) is toxic in doses Vitamin K3 (the synthetic one) is toxic in doses three three time more than the usual dose.time more than the usual dose.

Toxicity manifestations:Toxicity manifestations:Hyperbilirubinemia.Hyperbilirubinemia.Severe Jaundice.Severe Jaundice.Anemia.Anemia.

Drug Interaction with Vitamin KDrug Interaction with Vitamin K

1.1. Antibiotics:Antibiotics: Prevent absorption and kill normal Prevent absorption and kill normal bacterial flora.bacterial flora.

2.2. AnticonvulsantsAnticonvulsants e.g. Phenytoin : Affect Vit K e.g. Phenytoin : Affect Vit K metabolism. metabolism.

Functions of Vitamin K

Vit. K is involved as a cofactor in the carboxylation of certain glutamate residues of proteins to form - carboxyglutamate residues (Gla-residues). Gla-residues are usually involved in binding calcium and are essential for the following biological activities:

1. Blood coagulation Several proteins promote coagulation (prothrombin, VII, IX, X) while others slow it down (proteins C and S). Thus, activity of vitamin K balances the two opposing sides of coagulation system in blood.

2. Bone metabolism• Bone Gla-protein (Osteocalcin): Regulate

incorporation of calcium Phosphate into bones.• Matrix GLA protein (MGP): Clearance of extracellular

Calcium to protect against soft tissue calcification.

3. Bile acid sequestrants (Cholestyramine) and Aspirin: Affect absorption.

4. Weight Loss Products (Chitosan, Orlistat, and olestra): Affect absorption as they prevent absorption of fats.

5. Mineral oil laxatives: Affect absorption.

6. X-rays and Radiation: Deplete vitamin K levels and raise vitamin K requirements.

THANX