VITAMINS

 Vitamins are nonenergy yielding organic compounds, essential for

normal human metabolism, that must be supplied in small
quantities in the diet.
 This definition excludes the inorganic essential trace minerals and
essential amino acids and fatty acids which are required in much
larger quantities.
 The importance of vitamins as drugs is primarily in the prevention
and treatment of deficiency diseases.
 Some vitamins do have other empirical uses in pharmacological
doses.
 Vitamin deficiencies occur due to inadequate intake,
malabsorption, increased tissue needs, increased excretion, certain
genetic abnormalities and drug-vitamin interactions.

 Vitamins, as a class, are over-promoted, over-prescribed and over-

used.
VITAMINS ARE TRADITIONALLY DIVIDED INTO TWO GROUPS:

 Fat-soluble (A, D, E, K): These (except vit K) are stored in the body
for prolonged periods and are liable to cause cumulative toxicity
after regular ingestion of large amounts. Some interact with
specific cellular receptors analogous to hormones.

 Water-soluble (B complex, C): These are meagerly stored: excess is

excreted with little chance of toxicity. They act as cofactors for
specific enzymes of intermediary metabolism.
FAT-SOLUBLE VITAMINS
 VITAMIN A
 Vitamin A occurs in nature in several forms.

 Retinol (Vit. A1) is an unsaturated alcohol containing an ‘ionone’

ring. Marine fish (cod, shark, halibut) liver oils are rich sources.
Appreciable amounts are present in egg yolk, milk and butter.

 Dehydroretinol (Vit A2) is present in fresh water fishes.

 Carotenoids are pigments found in green plants (carrot, turnip,
spinach), β Carotene (provitamin) is the most important carotenoid
and is a precursor of vitA.
 Physiological role and actions
 Visual cycle

 Epithelial tissue

 Reproduction

 Immunity
 Deficiency symptoms
 Since vitamin A is stored in liver, deficiency symptoms appear only after
long-term deprivation, but vit A deficiency is quite prevalent, especially
among infants and children in developing countries.
 Manifestations are:
 Xerosis (dryness) of eye (xerophthalmia), ‘Bitot’s spots’, keratomalacia
(softening of cornea), corneal opacities, night blindness (nyctalopia)
progressing to total blindness.
 Dry and rough skin with papules (phrynoderma), hyperkeratinization,
atrophy of sweat glands.
 Keratinization of bronchopulmonary epithelium, increased susceptibility to
infection.
 Unhealthy gastrointestinal mucosa, diarrhea.
 Increased tendency to urinary stone formation due to shedding of ureteric
epithelial lining which acts as a nidus.
 Sterility due to faulty spermatogenesis, abortions, foetal malformations.
 Growth retardation, impairment of special senses.
Therapeutic uses
 1. Prophylaxis of vit A deficiency during infancy, pregnancy, lactation,
hepatobiliary diseases, steatorrhoea: 3000–5000 IU/day.

 2. Treatment of established vit A deficiency: 50,000–100,000 IU i.m or

orally for 1–3 days followed by intermittent supplemental doses.

 3. Skin diseases like acne, psoriasis, ichthyosis.

 Retinoic acid and 2nd or 3rd generation retinoids are used.

Interaction
 Long-term oral neomycin induces steatorrhoea and interferes with vit
A absorption
SYSTEMIC RETINOIDS
 Tretinoin and isotretinoin (1. generation)
 Etretinate, Acitretin, Motretinid (2. generation – aromatics)

 Bexarotene (3. generation – aratinoids)

Retinoids exert their effects by activating retinoic acid receptors

(RARs) and retinoid X receptors (RXRs)

TOPICAL RETINOIDS
 Tretionin, isotretinoin, alitretinoin, adapalene, tazarotene,
bexarotene
INDICATIONS
 Tretinoin: Acne (topical), photo-aging, AML promyelocytit (M2)
type
 Adapalene: less irritant

 Tazarotene: Acne, psoriais, photo-aging

 Alitretinoin: cutaneous lesions in patients with AIDS-related

Kaposi’s sarcoma
 Isotretinoin: oral treatment of severe recalcitrant nodular acne,
hyperkeratotic skin disorders
 Etretinat (prodrug)

 Acitretin: is effective in the treatment of psoriasis

 Bexarotene: cutaneous T-cell lymphoma

HYPERVITAMINOSIS A
 Regular ingestion of gross excess of retinol (100,000 IU daily for
months) has produced toxicity— nausea, vomiting, itching,
erythema, dermatitis, exfoliation, hair loss, bone and joint pains,
loss of appetite, irritability, bleeding, increased intracranial
tension and chronic liver disease.

 Excess retinol is also teratogenic in animals and man.

 Daily intake should not exceed 20,000 IU.

 Excess intake of carotenoids does not produce hypervitaminosis A,

because conversion to retinol has a ceiling.
RETINOIC ACID (VIT A ACID)
 Retinoic acid has vit A activity in epithelial tissues and promotes
growth, but is inactive in eye and reproductive organs.
 13-cis retinoic acid (Isotretinoin) is given orally for acne.

 Unlike retinol, it is not stored but rapidly metabolized and excreted

in bile and urine.
 The cellular retinoic acid binding protein (CRABP) is different from
CRBP, is present in skin and other tissues but not in retina

 Retinol and retinoic acid act through nuclear retinoid receptors

which function in a manner analogous to the steroid receptors.
 VITAMIN D

 is the collective name given to antirachitic substances synthesized in the body

and found in foods activated by UV radiation.

 D3 : cholecalciferol — synthesized in the skin under the influence of UV rays.

 D2 : ergocalciferol—present in irradiated food— yeasts, fungi, bread, milk.

 D1 : mixture of antirachitic substances found in food—only of historic interest.

 In human vit D2 and D3 are equally active and calcitriol (active form of D3) is
more important physiologically
ACTİONS

 1. Calcitriol enhances absorption of calcium and phosphate from

intestine.
 2. Calcitriol enhances resorption of calcium and phosphate from
bone by promoting recruitment and differentiation of osteoclast
precursors in the bone remodeling units
 3. Calcitriol enhances tubular reabsorption of calcium and
phosphate in the kidney.
 4. Other actions of calcitriol (on immunological cells, lymphokine
production, proliferation and differentiation of epidermal and
certain malignant cells, neuronal and skeletal muscle function
have also been demonstrated.)
 Hypervitaminosis D
 It may occur due to chronic ingestion of large doses (~50,000
IU/day) or due to increased sensitivity of tissues to vit D.
Manifestations are due to elevated plasma calcium and its ectopic
deposition. These are: hypercalcaemia, weakness, fatigue,
vomiting, diarrhoea, sluggishness, polyuria, albuminuria, ectopic
Ca2+ deposition (in soft tissues, blood vessels, parenchymal
organs), renal stones or nephrocalcinosis, hypertension, growth
retardation in children. Even coma has been reported.
Use
 1. Prophylaxis (400 IU/day) and treatment (3000–4000 IU/day) of
nutritional vit D deficiency
 2. Metabolic rickets (rachitis) (Vit D resistant rickets, Vit D
dependent rickets, Renal rickets)
 3. Senile or postmenopausal osteoporosis

 4. Hypoparathyroidism

 5. Fanconi syndrome

 6. Psoriasis (locally)
 Cholestyramine and chronic use of liquid paraffine can reduce vit
D absorption.
 Phenytoin and phenobarbitone reduce the responsiveness of target
tissues to calcitriol
VITAMIN E
 A number of tocopherols, of which α tocopherol is the most
abundant and potent, have vit E activity.
 The d-isomer is more potent than l-isomer.

 Wheat germ oil is the richest source, others are cereals, nuts,
spinach and egg yolk.
 The daily requirement of vit. E is estimated at 10 mg. It is
increased by high intake of polyunsaturated fats.
 Physiological role and actions
 Vit E acts as antioxidant, protecting unsaturated lipids in cell
membranes, coenzyme Q, etc. from free radical oxidation damage and
curbing generation of toxic peroxidation products.
 Feeding animals with polyunsaturated fats increases vit E
requirement, while antioxidants like cystein, methionine, selenium,
chromenols prevent some vit E deficiency symptoms in animals.
 Deficiency symptoms
 Experimental vit E deficiency in animals produces recurrent
abortion, degenerative changes in spinal cord, skeletal muscles and
heart, and haemolytic anaemia.
 No clear-cut vit E deficiency syndrome has been described in
humans, but vit E deficiency has been implicated in certain
neuromuscular diseases in children, neurological defects in
hepatobiliary disease and some cases of haemolytic anaemia.
 Therapeutic uses
 1. Primary vit E deficiency does not occur clinically. Supplemental
doses (10–30 mg/ day) may be given to patients at risk.
 2. G-6-PD deficiency—prolonged treatment with 100 mg/day increases
survival time of erythrocytes.
 3. Acanthocytosis—100 mg /week i.m: normalizes oxidative fragility of
erythrocytes.
 4. The risk of retrolental fibroplasia in premature infants exposed to
high oxygen concentrations can be reduced by 100 mg/kg/day oral
vitamin E.
 5. Alongwith vit A to enhance its absorption and storage, and in
hypervitaminosis A to reduce its toxicity.
 6. Large doses (400–600 mg/day) have been reported to afford
symptomatic improvement in intermittent claudication, fibrocystic
breast disease and nocturnal muscle cramps.
 Toxicity
 Even large doses of vit E for long periods have not produced any
significant toxicity, but creatinuria and impaired wound healing have
been reported; abdominal cramps, loose motions and lethargy have
been described as side effects of vit. E.

 Vit E can interfere with iron therapy.

VITAMIN K

 It is a fat-soluble dietary principle required for the synthesis of

clotting factors.
 Dietary sources are—green leafy vegetables, such as cabbage,
spinach; and liver, cheese, etc.
 Action

 Vit K acts as a cofactor at a late stage in the synthesis by liver of

coagulation proteins— prothrombin, factors VII, IX and X.
 The vit K dependent change (γ carboxylation of glutamate residues
of these zymogen proteins) confers on them the capacity to bind
Ca2+ and to get bound to phospholipid surfaces—properties
essential for participation in the coagulation cascade.
 Use
 The only use of vit K is in prophylaxis and treatment of bleeding due to
deficiency of clotting factors.
 Dietary deficiency, Prolonged antimicrobial therapy, Obstructive
jaundice (icterus) or malabsorption syndromes, Liver disease (cirrhosis,
viral hepatitis), Overdose of oral anticoagulants, Prolonged high dose
salicylate therapy can cause deficiency of clotting factors.
 Adverse effects

 Severe anaphylactoid reactions can occur on i.v. injection of emulsified

formulation; this route should not be used.
 Menadione (water-soluble derivative) can cause haemolysis in a dose-
dependent manner.
WATER-SOLUBLE VITAMINS
 THE VITAMIN B COMPLEX GROUP
 Thiamine (Aneurine, vit B1)

 It is present in the outer layers of cereals (rice polishing), pulses,

nuts, green vegetables, yeasts, egg and meat.
 Limited amounts are stored in tissues.

 After conversion in the body to Thiamine pyrophosphate, it acts as

a coenzyme in carbohydrate metabolism.
 It also appears to play some role in neuromuscular transmission.

 Pyrithiamine and oxythiamine are synthetic thiamine antagonists.

Tea also contains a thiamine antagonist.
 Deficiency symptoms
 The syndrome of thiamine deficiency beriberi is seen in dry and wet forms:
 Dry beriberi: Neurological symptoms are prominent
 Wet beriberi: Cardiovascular system is primarily affected.

 Therapeutic uses
 1. Prophylactically (2–10 mg daily) in infants, pregnant women, chronic
diarrhoeas, patients on parenteral alimentation.
 2. Beriberi
 3. Acute alcoholic intoxication
 4. In neurological and cardiovascular disorders, hyperemesis gravidarum,
chronic anorexia and obstinate constipation—thiamine

 Thiamine is nontoxic. Sensitivity reactions sometimes occur on parenteral

injection.
 Riboflavin (vit B2)
 A yellow flavone compound found in milk, egg, liver, green leafy
vegetables, grains.
 Flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN)
are coenzymes for flavoproteins involved in many oxidation-reduction
reactions. Thiamine and riboflavin are devoid of pharmacological
actions.
 Riboflavin deficiency generally occurs in association with other
deficiencies.

 To prevent and treat ariboflavinosis (2–20 mg/day oral or parenteral),

generally along with other B complex members.
 Niacin (vit B3)
 Niacin refers to Nicotinic acid as well as Nicotinamide —pyridine
compounds, initially termed pellagra preventing factor.
 Sources are liver, fish, meat, cereal husk, nuts and pulses.
 Nicotinic acid is readily converted to its amide which is a component of
the coenzyme Nicotinamide-adenine-dinucleotide (NAD) and its
phosphate (NADP) involved in oxidation-reduction reactions.

 Niacin deficiency produces ‘Pellagra’, cardinal manifestations of which

are: dermatitis, diarrhoea, dementia.
 Anaemia and hypoproteinaemia are common in pellagra. Chronic
alcoholics are particularly at risk of developing pellagra, because in
addition to dietary deficiency, niacin absorption is impaired in them.
Other B vitamin deficiencies are often associated.
 Therapeutic uses
 1. Prophylactically (20–50 mg/day oral) in people at risk of developing
pellagra.
 2. Treatment of pellagra

 3. Hartnup’s disease: in which tryptophan transport is impaired, and

in carcinoid tumours which use up tryptophan for manufacturing 5-
HT, need niacin supplementation.
 4. Nicotinic acid (not nicotinamide) has been used in peripheral
vascular disease and as hypolipidaemic.

 Nicotinic acid, in pharmacological doses, has many side effects and

toxicities. Nicotinamide is innocuous.
 Pyridoxine (vit B6)
 Pyridoxine, Pyriodoxal and Pyridoxamine are related naturally
occurring pyridine compounds that have vit B6 activity.
 Dietary sources are—liver, meat, egg, soybean, vegetables and whole
grain.
 Pyridoxine and pyridoxamine are converted to pyridoxal phosphate
(the coenzyme form).
 Pyridoxal dependent enzymes include transaminases and
decarboxylases involved in synthesis of nonessential amino acids,
tryptophan and sulfur containing amino acid metabolism, formation of
5-HT, dopamine, histamine, GABA and aminolevulinic acid (first step
in the synthesis of haeme). High protein diet increases pyridoxine
requirement.
 Drug interactions
 1.Isoniazid reacts with pyridoxal to form a hydrazone, and thus
inhibits generation of pyridoxal phosphate.
 2. Hydralazine, cycloserine and penicillamine also interfere with
pyridoxine utilization and action.
 3. Oral contraceptives reduce pyridoxal phosphate levels in some
women.
 4. Pyridoxine

 5. 4-deoxypyridoxine is a vit B6 antagonist.

 Deficiency of vit B6 usually occurs in association with that of other B
vitamins.
 Therapeutic uses
 1. Prophylactically (2–5 mg daily) in alcoholics, infants and patients
with deficiency of other B vitamins.
 2. To prevent and treat (10–50 mg/day) isoniazid, hydralazine and
cycloserine induced neurological disturbances. Acute isoniazid
poisoning has been successfully treated with massive doses (in grams)
of pyridoxine.
 3. To treat mental symptoms in women on oral contraceptives.
 4. Pyridoxine responsive anaemia (due to defective haeme synthesis)
and homocystinuria are rare genetic disorders that are benefited by
large doses of pyridoxine (50–200 mg/day).
 5. Convulsions in infants and children.
 Pantothenic acid (vitB5)
 Pantothenic acid is an organic acid, widely distributed in food
sources, especially liver, mutton, egg yolk and vegetables.
 It is a component of coenzyme-A which functions in carbohydrate,
fat, steroid and porphyrin metabolism by catalysing acetate
transfer reactions.
 Clinical deficiency of pantothenic acid is not known.
 Biotin (vitB7)
 Biotin is a sulfur containing organic acid found in egg yolk, liver, nuts
and many other articles of food.
 Some of the biotin synthesized by intestinal bacteria is also absorbed.

 Avidin, a heat labile protein in egg white, binds and prevents the
absorption of biotin. Some other biotin antagonists are also known.
 Biotin is a coenzyme for several carboxylases involved in carbohydrate
and fat metabolism. Deficiency symptoms include seborrheic
dermatitis, alopecia, anorexia, glossitis and muscular pain.
 Except for unusual instances and rare genetic abnormalities of biotin
dependent enzymes, there are no clearly defined therapeutic uses of
biotin.
VITAMIN-B12

 Cyanocobalamin and hydroxocobalamin are complex cobalt

containing compounds present in the diet and referred to as vit
B12.
 Liver, kidney, sea fish, egg yolk, meat, cheese are the main vit B12
containing constituents of diet. The only vegetable source is
legumes (pulses) which get it from microorganisms harboured in
their root nodules.
 Metabolic functions
 Vit B12 is intricately linked with folate metabolism in many ways;
megaloblastic anaemia occurring due to deficiency of either is
indistinguishable.
 In addition, vit B12 has some independent metabolic functions as
well. The active coenzyme forms of B12 generated in the body are
deoxyadenosyl-cobalamin (DAB12) and methyl-cobalamin (methyl
B12).
 Vit B12 is essential for cell growth and multiplication.
 Utilization of vit B12
 Vit B12 is present in food as protein conjugates and is released by
cooking or by proteolysis in stomach facilitated by gastric acid.
Intrinsic factor (a glycoprotein) secreted by stomach forms a
complex with B12—attaches to specific receptors present on
intestinal mucosal cells and is absorbed by active carrier mediated
transport. This mechanism is essential for absorption of vit B12
ingested in physiological amounts.
 Vit B12 deficiency occurs due to:
 Addisonian pernicious anaemia, gastric mucosal damage,
malabsorption, consumption of vit B12 by abnormal flora in
intestine, nutritional deficiency, increased demand.

 Manifestations of deficiency are:

 Megaloblastic anaemia, Glossitis, neurological symptoms
 Because of higher protein binding and better retention in blood,
hydroxocobalamin is preferred for parenteral administration to
treat vit B12 deficiency.
 Uses

 1. Treatment of vit B12 deficiency

 2. Prophylaxis

 3. Mega doses of vit B12 have been used in neuropathies,

psychiatric disorders, cutaneous sarcoid and as a general tonic to
allay fatigue, improve growth
 VITAMIN C (ASCORBIC ACID)
 Citrus fruits (lemons, oranges) and black currants are the richest
sources; others are tomato, potato, green chillies, cabbage and other
vegetables.
 Human milk is richer in vit C (25–50 mg/L) than cow’s milk.
 Vit C plays a role in many oxidative and other metabolic reactions, e.g.
hydroxylation of proline and lysine residues of protocollagen—essential
for formation and stabilization of collagen triple helix; hydroxylation of
carnitine, conversion of folic acid to folinic acid, biosynthesis of adrenal
steroids, catecholamines, oxytocin and vasopressin and metabolism of
cyclic nucleotides and prostaglandins.
 It directly stimulates collagen synthesis and is very important for
maintenance of intercellular connective tissue. A number of ill-defined
actions have been ascribed to ascorbic acid in mega doses, but none is
proven.
 Deficiency symptoms
 Severe vit C deficiency Scurvy, once prevalent among sailors is now
seen only in malnourished infants, children, elderly, alcoholics and
drug addicts. Symptoms stem primarily from connective tissue
defect:
 increased capillary fragility—swollen and bleeding gums, petechial
and subperiosteal haemorrhages, deformed teeth, brittle bones,
impaired wound healing, anaemia and growth retardation.
 Therapeutic uses
 1. Prevention of ascorbic acid deficiency in individuals at risk and in infants: 50–
100 mg/ day. Vit C or orange juice can be routinely included in infant diet.
 2. Treatment of scurvy—0.5–1.5 g/day.
 3. Postoperatively (500 mg daily): though vit C does not enhance normal healing,
suboptimal healing can be guarded against. It has also been found to accelerate
healing of bedsores and chronic leg ulcers. Requirement of ascorbic acid is
increased in postinjury periods.
 4. Anaemia: Ascorbic acid enhances iron absorption and is frequently combined
with ferrous salts (maintains them in reduced state). Anaemia of scurvy is
corrected by ascorbic acid, but it has no adjuvant value in other anaemias.
 5. To acidify urine (1 g TDS–QID) in urinary tract infections.
 6. Large doses (2–6 g/day) of ascorbic acid have been tried for a variety of
purposes (common cold to cancer) with inconsistent results. No definite beneficial
effect has been noted in asthma, cataract, cancer, atherosclerosis, psychological
symptoms, infertility, etc. However, severity of common cold symptoms may be
somewhat reduced, but not the duration of illness or its incidence. Improved
working capacity at submaximal workloads has been found in athletes but
endurance is not increased.
 Ascorbic acid is well tolerated in usual doses.
 Mega doses given for long periods can cause ‘rebound scurvy’ on
stop-page—probably due to enhancement of its own metabolism or
tissue acclimatization.
 The risk of urinary oxalate stones may be increased.

 High doses may also be cytotoxic when added to iron preparations.