Vitamins: clinical aspects of vitamins, and effects of free radicals, synthesis of vitamins: vit-c, nicotinamide, and mechanism of action of vitamins.

1. Md. Imran Nur Manik
Lecturer
Department of Pharmacy
Northern University Bangladesh
Natural products and
secondary metabolites

2. Syllabus for Vitamins: clinical aspects of vitamins, and effects of free radicals,
synthesis of vitamins: vit-c, nicotinamide, and mechanism of action of vitamins.
Definition:
Vitamins are organic chemical compounds/substances which cannot be
synthesized (in sufficient quantities) in the body but are essential for normal
metabolic functions/reactions.
Vitamins do not furnish energy and they aren’t used as building units for cellular
structures. Lack of specific vitamins leads to distinctive deficiency states such as
Beriberi, Rickets, and Scurvy etc.
Classification:
It is convenient for a number of purposes to classify the vitamins as-
1. Fat soluble and
2. Water soluble.

3. Classification:
Based on the nature of solubility vitamins were classified into two groups.
vitamins
Fat soluble water soluble
Vitamin A Non B-complex vitamin B-complex
Vitamin D Vitamin C Energy releasing Hematopoitic
Vitamin E Thiamin B1 Folic acid
Vitamin K Riboflavin B2 Cyanocobalamin
Niacin B3 (vitaminB12)
Pantothenic acid B5
Pyridoxine B6
Biotin B7

4. Read only
[L. vita, life, amine] An accessory but vital nutrient that serves as a
coenzyme or cofactor in an essential metabolic process. Small quantities of
the substance assist biological reactions such as oxidation and reduction,
or the synthesis of nucleic acids, hemoglobin, clotting factors, or collagen.
Vitamin deficiencies produce well-recognized syndromes (e.g., scurvy
[vitamin C deficiency], or beriberi [thiamine deficiency]).
Unlike proteins, carbohydrates, fats, and organic salts, vitamins are not
energy sources or components of body structures. Instead, they are agents
that hasten or facilitate biochemical processes involving these other organic
molecules.

5. Fat soluble vitamins:
The vitamins which are soluble in fat solvents (dietary and body fat) but relatively
insoluble in water, their absorption from the intestinal tract is associated with that of
lipids and are stored in the body in same fashion as fat are known as fat soluble
vitamins. Fat soluble vitamins are vitamin A, D, E & K.
It can be noted that fat soluble vitamins might be toxic in large doses and are stored in
the body for a long period. Their deficiency state may be caused by conditions that
impair fat absorption.
Water soluble vitamins:
These vitamins are soluble in water but generally not soluble in lipid (however some
are slightly soluble in certain organic solvents) and therefore easily eliminated from the
body.
The water soluble vitamins are vitamin B complex (including vitamin H also known as
vitamin B7) and vitamin C. Our discussion will be confined within the
water-soluble vitamins.
It should be noted that since water-soluble vitamins are easily excreted, they have
greater chance of being deficit than being overabundant.

6. Introduction:
Vitamin C or Ascorbic acid (toxic to viruses, bacteria and some malignant tumor cells) is a
naturally occurring vitamin which prevents scurvy and has antioxidant properties. It is a
water soluble vitamin.
Deficiency symptoms:
Scurvy: It consists of the degeneration of collagen and intracellular ground substances
resulting in disturbances of bone growth, hemorrhage of the gums and other part of the
body, loosening of the teeth, capillary fragility with consequent cutaneous hemorrhages
and other abnormalities.
Uses:
1. Prevention and treatment of scurvy
2. Facilitation of healing and recovery from extensive burns and severe trauma
3. Treatment of some types of anemia (associated with scurvy)
4. Maintenance of an acidic urine

7. Symptoms of Scurvy
• There are many symptoms of Scurvy
• Swelling and bleeding of the gums (G
ingival Hemorrhage)
• Often sick
• Easily bruised and bleeding
• Poor wound healing
• Pain and swelling of the joints
• Hair and tooth loss
• Small bleeding around the hair follicl
es (Corkscrew Hair)
• Small bleeding under nails (Periungua
l Hemorrhage)
• Fatigue
• Dry, pale skin

8. Synthesis
The synthesis of vitamin C is done from D-glucose. It is a semi-synthesis.
In this process D-glucose is hydrogenated to D-sorbitol which by oxidation
with Acetobactor suboxydans (fermentation) yields L-sorbose. When
L-sorbose is treated with acetone in presence of conc. H2SO4 and the
catalyst (used in dehydrogenation) diacetone sorbose is formed.
When it is oxidized with KMnO4 in strong alkaline medium diacetone
sorburonic acid is formed which upon heating with conc. HCl gives 2-keto-
L-gulonic acid. This when treated with a solution of aqueous HCl in ethanol-
chloroform solvent leads to ascorbic acid.
Dosage:
Prophylactic dose → 45-60 mg/per day via oral or IM routes, during
pregnancy and lactation an additional 20-40 mg is required.
Therapeutic dose:
– Treatment of scurvy → 100 mg three times daily for several weeks
– For severe burns → 200-500 mg daily

10. Mechanism of Action
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.
Vitamin C also acts:
• as an antioxidant (reacting directly with aqueous free radicals), which is
important in the protection of cellular function; and
• to enhance the intestinal absorption of nonhaem iron.

11. Collagen structure

12. B-complex group of vitamins comprise a large number of
water soluble vitamins which are nutritional essentials for
all forms of life, from the lowest form of yeast and bacteria
to the highest form, the man.
Apart from being important nutritionally, they form
essential co enzymes to certain important intracellular
enzyme systems. There are about individual components,
most of them are synthesized by the microbial flora.

13. Components of vitamin B complex are:-
1.Thiamine – Vit B1
2.Riboflavin – Vit B2
3. Niacin – Vit B3
4.Pantothenic acid – Vit B5
5.Pyridoxine – Vit B6
6.Biotin – Vit B7
7.Folic acid group
8.Cyanocobalamin – Vit B12

14. Introduction:
Vitamin B1 known as thiamine is a water-soluble vitamin that occurs
in moderate to rich quantity in dried yeast, nuts, rice, egg yolks, brans and
some other vegetable. It is biotransformed inside the body and function as
co-enzyme in several metabolic processes.
Deficiency symptoms:
Beriberi. It is manifested in mainly two forms-
Dry beriberi → main symptom is polyneuropathy (affect the nervous system)
Acute wet beriberi → Affect the CVS. Predominant symptoms are edema
and serous effusions

15. Deficiency Manifestations of Thiamine
• B. Wet beriberi:. cardiac beriberi
• Edema of legs
• face, trunk and se
rous cavities
• Palpitation, breath
lessness distende
d neck veins
• Death occurs due
to heart failure.

16. Deficiency Manifestations of Thiamine
• Dry Beriberi (peripheral neuritis ): Walking becomes difficult.
Peripheral neuritis with sensory disturbance leads to complete
paralysis

17. Synthesis:
Thiamine is rather synthesized than being isolated/extracted
from the food sources. It is synthesized by the direct
condensation of 2-methyl-4amino-5-chloromethylpyrimidine
hydrochloride and 4-methyl-5-(β-hydroxymethyl) thiazole.
Uses:
1. In thiamine deficiency situations e.g. beriberi, neuritis
associated with pregnancy and neuritis of pellagra
2. Chronic alcoholism
3. Wernicke’s encephalopathy
Dosage:
5-10 mg three times daily via oral, IM or IV route.

18. Biochemical functions:
Thiamine functions as a coenzyme in the oxidative
decarboxylation of alpha-ketoacids (involved in energy
production) and in the transketolase reaction of the
pentose phosphate pathway (involved in carbohydrate
metabolism).
The enzyme thiamine pyrophosphate or co-carboxylase is
intimately connected with the energy releasing reactions
in the carbohydrate metabolism.
TPP also plays an important role in the transmission of
nerve impulse. This is because TPP is required for
acetylcholine synthesis and the ion translocation of
neural tissue.

19. Functions of B1:
1. Enzyme cofactor: (Thiamine pyrophosphate TPP or TDP)
A. Decarboxylation reactions
a) Pyruvate dehydrogenase
b) α-ketoglutarate dehydrogenase
c) α-keto acid dehydrogenase – branched chain amino
acid metabolim.
B. Transketolation reactions
Transketolase – Pentose Phosphate pathway

20. A. Decarboxylation reactions
a) Pyruvate dehydrogenase complexes to TPP: It catalyzes
the breakdown of pyruvate, to acetyl CoA, and carbon dioxide

21. A. Decarboxylation reactions
b) Alpha ketoglutarate dehydrogenase: Requires TPP in the
decarboxylation of alpha ketoglutarate to succinyl CoA and
CO2

22. A. Decarboxylation reactions
c) α-keto acid dehydrogenase – branched chain amino acid
metabolim.

23. B. Transketolation reactions
Transketolase: The second group of enzymes that use TPP as
co-enzyme are the transketolases, in the Pentose phosphate
pathway( PPP ) of glucose

24. Introduction:
Riboflavin, also known as vitamin B2 is a water-soluble vitamin
occurring widely in animal and plant foodstuff. It is converted into FAD
(flavin adenosine dinucleotide) and necessary for metabolic processes.
Deficiency symptoms:
Well defined deficiency syndrome consists of
-Cheilosis,
-glossitis,
-Seborrheic follicular keratosis of nose and forehead,burning feet etc.
-Loss of hair (alopecia).
-Lesions of the skin, eyes, lips, mouth and genitalia.

25. • Cheilosis
• Glossitis
• Seborrheic
follicular
keratosis of
nose and
forehead

26. Riboflavin deficiency:

27. Synthesis:
Reaction between 4, 5-dimethyl-N-(1’-ribityl) aniline tetraacetate and
4-nitro-phenyldiazonium chloride yields an azoderivative which upon
reaction with barbituric acid yield riboflavin.
Uses:
• In well-defined vitamin B2 deficiency syndrome
• It may also help in deficiency syndromes of other vitamin-B-complex.
• Usually after the age of 40-45 vitamin deficiency becomes more
pronounced. For example deficiency of vitamin B-complex will lead to
lesions of the mouth (and other types of wounds of the mouth). Then
vitamin B administration becomes necessary. Usually riboflavin is given
with other B-complex vitamins as multivitamin preparations.
Dose:
5-25 mg daily via oral route preferably in a preparation containing other
B-complex vitamins.

28. Riboflavin functions as a component of two flavin coenzymes –
flavin mononucleotide (FMN) and flavin adenine dinucleotide
(FAD). Riboflavin through its coenzymes Flavin
mononucleotide (FMN) and Flavin adenine dinucleotide (FAD)
takes part in a variety of cellular oxidation-reduction
reactions and in energy production.
Examples include the oxidation of glucose, certain amino acids
and fatty acids; reactions with several intermediaries of the
Krebs cycle; conversion of pyridoxine to its active coenzyme;
and conversion of tryptophan to niacin.
Riboflavin has a role as an antioxidant. It may be involved in
maintaining the integrity of erythrocytes.

29. Read only: Co-enzyme forms
FMN – Flavin Mono Nucleotide FAD – Flavin Adenine Dinucletide
• Riboflavin FMN FADFlavokinase FAD synthase

30. Functions of B2:
• Integral component of electron transport chain ATP
Synthesis ----NADFMNCoQ
• Component of several enzymes in the metabolic
pathway
• TCA cycle  succinate dehydrogenase
• Fatty Acid Oxidation  acyl CoA dehydrogenase
• Amino acid oxidation As a part of alpha ketoglutarate
• Isocitrate dehydrogenase complex ( dihydrolipoate dehydrogenase)

31. FMN-dependent Enzymes
• During the amino acid oxidation, FMN is reduced. It is
reoxidized by molecular oxygen to produce hydrogen
peroxide

32. FAD-dependent enzymes
• Conversion of Succinate to fumarate by succinate
dehydrogenase in TCA requires FAD .

33. FAD-dependent enzymes
• Conversion of Pyruvate to acetyl CoA requires
FAD,NAD as part of the Pyruvate dehydrogenase.

34. NAD is also required in the conversion of Alpha
ketoglutarate to succinyl CoA (In association with a-
Ketoglutarate dehydrogenase ) in TCA cycle

35. Tryptophan can be converted to Niacin:
Tryptophan 3-OH-kynurenine
3-OH-anthranallic acid
Niacin
FAD
B6

36. NIACIN

37. Introduction:
Niacin (nicotinic acid) and niacinamide (nicotinamide) are known as
vitamin B3.
But niacin show hypocholesterolemic properties not shown by
niacinamide and excessive dosage of niacin causes flushing.
Both of these are water soluble vitamins.
Deficiency syndrome:
The well defined deficiency syndrome is pellagra (which is
associated with skin lesions, diarrhoea and other symptoms).
It is characterized by 3D(Forgetfulness, insomnia, irritability, and ner
vousness) or 4D symptoms (Diarrhoea, Dermatitis,
Dementia and Death).

38. Synthesis:
Esterification of nicotinic acid affords ethyl nicotinate.
Amidation of that with ammonia in ethanol results in
niacinamide (nicotinamide).
Use:
• Prevention and treatment of pellagra.
Dosage:
For pellagra initially 300-500 mg daily in divided doses
preferably in oral route. For maintenance multivitamin
preparation is used. In the intravenous route 25-100 mg.

39. Physiological role and actions
• Nicotinic acid is readily converted to its amide which is
acomponent of the coenzyme Nicotinamideadenine-
dinucleotide (NAD) and its phosphate (NADP) involved in
oxidation-reduction reactions.
• These pyridine nucleotides act as hydrogen acceptors in the
electron transport chain in tissue respiration, glycolysis and
fat synthesis. Flavoproteins regenerate them by oxidizing
NADH and NADPH.
• Nicotinic acid (but not nicotinamide) in large doses is a
vasodilator, particularly of cutaneous vessels. It also lowers
plasma lipids

41. Niacin: B3
• Exists in two forms
• Nicotinic acid (Niacin)
• Nicotinamide (Niacinamide)
• Two coenzyme forms of niacin
• NAD+
• NADP+

42. Functions:
• Coenzymes are active participants in oxidation-reduction
reactions – Dehydrogenases
• Function in at least 200 reaction in cellular metabolic
pathways
• NAD+
• Participates in catabolic reactions
• Electron and hydrogen ion acceptor
• NADP+
• Anabolic reactions
• Important in biochemical pathway for fatty-acid synthesis, steroid
and bile acid synthesis.

43. NAD+ dependent enzymes
• Lactate dehydrogenase (lactate → pyruvate)

44. NADPH utilizing reactions
HMG CoA reductase (HMG CoA → mevalonate) in Fatty acid
metabolism

45. General References
 KD Tripathi MD: Essentials of Medical Pharmacology, 7th Edition,
Chapter 67: Vitamins, Jaypee Brothers Medical Publishers (P) Ltd, India (2013)
pp 909-918
 Dietary Supplements, 3rd Edition (Pamela Mason) Pharmaceutical Press,
UK, 2007.
 Handbook of vitamins, 4th Edition, (Janos Zempleni, Robert B. Rucker,
Donald B. McCormick, John W. Suttie) CRC Press,U.S.A. 2007.
• Laurence KM, James N, Miller MH, et al. Doubleblind randomised controlled
trial of folate treatment before conception to prevent recurrence of neural tube
defects. BMJ 1981; 282: 1509–1511.
• National Health Service. National Library for Health.
http://www.clinicalanswers.nhs.uk/index. cfm?question=248 (Page last
accessed on October 31, 2006).