metabolic role and therapeutic use of b complex vitamins
DESCRIPTION
metabolic role and therapeutic use of b complex vitaminsTRANSCRIPT
Vitamin Defined‘An organic substance that occurs in foods
in small amounts and is necessary for normal metabolic functioning of the body’
VITAMIN” means “vital for life”May be water soluble or fat soluble
Do not contribute directly to the structure of the body, nor do they supply energy.
They regulate metabolism by releasing energy from fats and carbohydrates
They are involved in amino acid metabolism and also assist in forming blood, bones and tissues
Essential Vitamins For Human Being
vitamins
water -soluble lipid-soluble
Vit C Vit B A,D,E,K
B1, B2, B6, B12, PP, patothenic acid , folic acid,biotin ,lipoic acid
Overview of Water Soluble Vitamins
Heterogeneous( differ chemically)Dissolve in waterReadily excreted through urineContinuous supply neededNon-toxicCooking lossesFunction as a coenzymeGenerally deficiencies due to water soluble vitamins
are multiple rather than individual with overlapping symptoms.
The water soluble vitamins form coenzymes (active form of the vitamin).
Co-enzyme
Co-enzyme
Thiamine- Vitamin B-1
• “thio”-vitamin (sulfur-containing vitamin)• Ist vitamin to be identified• Other names
– Anti neuretic– Anti Beri Beri
• Only synthesized by bacteria, fungi & plants • Animals must obtain it from their diet
• Relatively unstable-Destroyed with heat and in alkaline environment-Lost by milling flour, leaching into cooking liquids
and in thawing frozen food • Co-enzyme: helps release energy from carbohydrates
Thiamine
Sources Pork, hot dogs &
luncheon meat Cold cereals Sunflower seeds Green beans Whole/Enriched
Grains
RDA and Toxicity
• 1to 1.5 mg/day
• Requirement increases in pregnancy & lactation(2mg), old age & alcoholism.
• Daily intake depends on carbohydrate metabolism
Toxicity
• Upto 50mg/d can brought to control
• anaphylaxis
Pyrimidine
Thiazole
The Active Form
Thiamine contains an aminopyrimidine ring and a thiazole ring.
Active forms - Thiamine Pyrophosphate
Thiamine triphosphate
• The TPP reaction is catalyzed by enzyme thiamine pyrophosphate transferase.
• Activation occurs mainly in liver.
Biochemical FunctionsNeeded for the metabolism of carbohydrates, proteins and fats
Thiamine pyrophosphate (TPP) is involved with the energy releasing reactions of carbohydrate metabolism.
Glycolysis
TCA cycle
10–15 % of total energy in the form of ATP.
Oxidative Phosphorylation
85–90% of total energy in the form of ATP.G
LY
CO
LY
SIS
TCA Cycle
Oxidative Decarboxylation reactions
Pyruvate Dehydrogenase (PDH)
Ketoglutarate Dehydrogenase.
Transketolation reaction
Transketolase.in HMP shunt pentose sugar (ribose) hexose sugar (glucose) which is then used to produce energy in the form of ATP.
GL
YC
OL
YS
ISTCA Cycle
Reactions requiring TPP
The branched chain aminoacid dehydrogenase
(decarboxylase)
Leucine, isoleucine , valine to form keto acid. Pts of Maple syrup disease(defect in decarboxylation reaction) are treated with large dose of thiamine
Transmission of nerve impulse
TPP is required for acetylcholine synthesis and ion translocation of neurnal tissue. Thiamine triphosphate form is also involved.
Absorption, Transport & Metabolism
• Absorbed in the upper small intestine
– Low concentration = carrier mediated– High concentration = passive diffusion
• Transported by RBC in the blood(90% of total thiamine of blood )
• Excreted in the urine
Thiamine Deficiency
Causes: Inadequate Diet (polished rice)
Alcoholism
chronic illness(liver cirrhoses,
disease affecting absorbtion in small intestine,cancer)
Pregnancy and lactation
• Thiaminase ( in raw fish) inactivates thiamine by breaking the thiazole ring.
DeficiencyWomen with hyperemesis
gravidarum and anorexia
• Pt on parental glucose
• Pt on chronic diurectic therapy
• Maternal thiamine def in breast fed child, Infantile
• Increased Carbohydrate intake
• Increased metabolic activity due to Hyperthyroidism and fever
Thiamine DeficiencyBiochemical Changes:
Carbohydrate metabolism is impaired.acc of pyruvate in tissues
Increased pyruvate concentration and is excreted in urine.
Increased pyruvate in plasma Lactate Lactic acidosis
Inc permeability of Blood Brain Barrier. Pyruvate entry & brain directed poly neuritis
The transketolase activity in erythrocytes is decreased.
Who is at Risk For Deficiency? Poor , Alcoholics, Elderly, Diet consisting of highly processed
foods
Clinical manifestations
Deficiency leads to Beri-beri which is of three types.
Wet Beri-beri: CVS manifestations are prominent
Edema of legs, face & trunk Pleural effusion & ascites Breathlessness and palpitation. systolic murmurs Fast and bouncing pulse Weak heart muscles resulting in death due cardiac
failure.
Clinical manifestations Dry Beri-beri: CNS manifestations prominent.
Edema not commonly seen.
Neurological manifestation resulting from accumulation of pyruvate in the nerves.
polyneuritis with numbness , loss of nerve transmission resulting in 'wrist drop', 'foot drop', irritability, poor arm/leg coordination even paralysis of whole limb.
mental changes, sluggishness, poor memory, loss of appetite and constipation
Infantile Beri-beri:
Seen in infants born to mothers suffering from thiamine deficiency.
Sleeplessness, restlessness, vomiting, convulsions and finally death.
Clinical manifestations
Wernicke-Korsakoff syndrome: Seen in chronic alcoholics and is characterized by:
Loss of memory
Apathy (absence of emotions)
Nystagmus (rhythmical to-and-fro motion of the eyeballs)
Ataxia (Unstable gait)
Opthalmoplegia (paralysis of the eye muscles)
Encephalopathy: Congestion and hemorrhages in parts of the brain.
Lab diagnosisLack of nerve impulse transmissionRBC transketolase activity is dec, its
measurement is diagnostic This is the earliest indicator and reliable diagnostic test to assess thiamine deficiency
HPLC measures thiamine and its phosphorylated esters in serum or blood is measured.
Therapeutic Use
• 1 . Prophylactically (2-10 mg daily) in infants,pregnant women, chronic diarrhoeas, patients on parenteral alimentation. Glucose infusion unmasks marginal thiamine deficiency.
• 2. Beriberi-100 mg/day i.m. or i.v. till symptoms regress-then maintenance doses orally.
• 3. Acute alcoholic intoxication: thiamine 100 mg is added to each vac of glucose solution infused. Most neurological symptoms in chronic alcoholics are due to thiamine deficiency-peripheral neuritis, Wernick's encephalopathy, Korsakoff'spsychosis: give 100 mg/ day parenterally.
4. In neurological and cardiovascular disorders, hyperemesis gravidarum, chronic anorexia and obstinate constipation-thiamine has been used even without definite proof of its deficiency.symptoms improve dramatically if thiaminedeficiency has been causative.
5. Maple syrup disorder
Adverse effects Thiamine is nontoxic. Sensitivity reactions sometimes occur on parenteral injection.
Riboflavin (Vit. B2)
• The name "riboflavin" comes from “ribose” and “flavin”• Coenzymes:
– Flavin mononucleotide (FMN)– Flavin adenine dinucleotide (FAD)
• Stable to heat but sensitive to light (photosensitive). When exposed to UV rays it gets destroyed
• Oxidation-reduction reactions• Electron transport chain• Citric Acid Cycle• Drug and steroid metabolism, including detoxification
reaction (called the drug vitamin)
RiboflavinSources• Milk/products
– Yogurt, Cheese• Meat & eggs• Liver• Enriched /whole grains• Oyster• Brewer’s yeast• Tryptophan rich food
RDA– 1.1 mg/day for women– 1.3 mg/day for men
Absorption, Transport, & Metabolism
• HCL in the stomach releases riboflavin from its bound form
• Absorption– Active or facilitated transport during low to
moderate intake– Passive absorption during high intake
• Transported by a protein carrier in the blood• Excess riboflavin is excreted unchanged in the
urine
Active Coenzymes of Riboflavin
• FMN: Flavin mononucleotide:
Formed in the intestine by phosphorylation of Riboflavin in the presence of enzyme ‘Flavokinase’
FAD: Flavin adenine dinucleotide:
Formed in the liver from FMN by the transfer of an AMP from ATP .
FAD = FMN + AMP
Functions
•Growth promoting factor: –Repair & development of body tissues - healthy skin
•Act as “coenzymes” in many reactions including the oxidation-reduction reactions and electron transport chain. by serving as an acceptor of two hydrogen atoms (with electrons)
FMN FMNH2
FAD FADH2
Accepts electrons Electron Transport Chain FAD FADH2 Succinate Fumarate Citric Acid Cycle
Assist in the metabolism carbohydrates, protein and fats
Who is at Risk For Deficiency?
Rare, usually with other vit b deficiency Low milk/dairy intakeGastrointestinal disease that causes vomiting and hypermotility of the gastrointestinal tractPhototherapy (neonatal jaundice) Pregnancy & lactation Alcoholics Long term phenobarbital & Chlorpromazine use
Deficiency• Ariboflavinosis:
– Glossitis, cheilosis & angular stomatitis– Sore & raw tongue– seborrheic dermatitis– Loss of appetite– Dry scaly skin, loss of hair– anaemia and neuropathy– vascularization of cornea– Occurs within 2 months – Most often seen in association with protein energy malnutrition– Also in cases of alcoholism
• Deficiency can be seen in anorexia , malabsorbtion.• Drugs eg. Barbiturates (microsomal oxidation of
vitamin)• Symptoms of ariboflavinosis are relatively mild and
not life threatening because• 1 riboflavin are associated with protein diet.• 2.recycling of riboflavin from FMN & FAD is very
efficient.
Lab Diagnosis • Lab measurement of RBC and urinary riboflavin• Measurement of erythrocyte glutathoine reductase
activity (deficiency)as an index of riboflavin status
Therapeutic uses• To prevent and treat ariboflavinosis(2-20 mg/ day oral or parenteral), generally along with other B complex members.
Niacin (Vit. B3)
• 2 Forms– Nicotinic acid (niacin) – Nicotinamide (niacinamide)
• Coenzyme (liver)– Nicotinamide adenine dinucleotide (NAD)– Nicotinamide adenine dinucleotide phosphate (NADP)– oxidation-reduction & oxidative-phosphorylation reactions
• Heat stable
• A peculiar vitamin since it can be synthesized in body (via tryptophan) 60mg of
tryptophan is equivalent to 1 mg of niacin for the synthesis of niacin coenzyme(B6)
NiacinSources• All protein foods• Milk, eggs, meat, fish,
poultry• Whole/Enriched
grains• Nuts, Mushrooms• Can be synthesized
endogenously from Tryptophan.
• Tryptophan rich food
RDA• 15 – 20 mg/day
Absorption and Metabolism
• Absorbed in the upper part of the small intestine
• It is stored only sparingly in the kidney, heart, brain, and liver and is exreted in the urine
RDAAdult 15-20mg/d children 10-15mg/d
Niacin equivalent = 1mg niacin= 60mg tryptophan
ma ize eaters have suffered from pellagra because corn flour is poor in tryptophan and
it is believedto contain a niacin antagonist. Thus, dailyrequirement of niacin is affected by the
amount of tryptophan in diet
Therapeutic uses1. Prophylactically (20-50 mg/ day oral) in
people at risk of developing pellagra.2. Treatment of pellagra-200 to 500 mg/ day individed doses orally or parenterally. Striking
improvement occurs in 1-2 days, but skin lesionstake weeks to months. Nicotinamide is preferred,especially for injection, because it does not causeflushing and other side effects seen with nicotinic
acid.3. Hartnup's disease: in which tryptophan
transport is impaired, and in carcinoid tumourswhich use up tryptophan for manufacturing
5-HT, need niacin supplementation.4. Nicotinic acid (not nicotinamide) has been
used in peripheral vascular disease and ashypolipidaemic (Ch. 45).
Adverse effects Nicotinic acid, in pharmacologicaldoses, has many side effects and toxicities
(p. 618). Nicotinamide is innocuous.Pyridoxi
The oxidation–reduction reactions catalyzed by enzymes belonging to ‘oxido-reductases’
α- ketoglutarate Succinyl CoA
NAD+ NADH + H+
Malate Oxaloacetate
NAD+ NADH + H+
TC
A C
yc
le
NAD+
Functions• Forms the active portion of the coenzymes(40) that play an
essential role in cells.
Glucose-6P 6-phospho-gluconolactone
NADP+ NADPH + H+
Pen
tose
Ph
osp
hat
e p
ath
way
The Oxidative-Phosphorylation: NADH that is produced in TCA cycle, will undergo oxidative phosphorylation (NADH + H+ into NAD+ ) in the Electron Transport Chain to generate ATP.
Responsible for major energy production in the form of ATP.
1 NADH = 3 ATP
NADP+
Functions
Functions
NADPH is important in Reductive Anabolic Pathways (Reductive Biosynthesis) by donating reducing equivalents (NADPH + H+ into NADP+).
No energy is produced.
NADPH is also required to maintain the structure of erythrocyte membrane. (Deficiency leads to hemolytic anemia)
Function
• . Flavoproteins regenerate them by oxidizing N ADH and NADPH.
• Nicotinic acid (but not nicotinamide) in large doses is a vasodilator, particularly of cutaneous vessels.
• It also lowers plasma lipids(in large doses)
Pellagra [3 D’s]– Dermatitis
• scaly dermatitis• sun exposed surfaces of skin• starts as red pigmentation which turn to be dark later
– Dementia • Confused & disoriented
– Diarrhea • irritation/inflammation of mucous membranes
– Reduced appetite & weight.– Occurs in 50-60 days.– Prevented with an adequate protein diet
Deficiency
Deficiency
• Pellagra – characterized as the disease causing 4D’s– Dermatitis– Diarrhea– Depression– Death
Symptoms
• Weakness• Persistent fatigability • Irritability• Headache• Depression• Soreness and inflammation of the tongue
(glossitis) and mouth (stomatitis)
Laboratory assessment
• Urinary excretion of niacin metabolites
N-methyl nicotinamide 2-pyridone
Causes of Deficiency
Vitamin B6 deficiency
Isoniazid:
Hartnup Disease: Tryptophan absorption from intestine is defective.
Pregnancy and Lactation
Corn as main staple
Poor diet & alcoholics
Niacin as a Medicine
• Inhibits lipolysis in adipose tissues• 75-100 x RDA can lower LDL and TG and increase HDL• Slow/ reverse progression of atherosclerosis with diet and
exercise• Toxicity effects
– Flushing of skin– Itching – Nausea – Liver damage– Hyperuricemia (exacerbate gout)
Pantothenic Acid
• Vitamin B-5
• Its name derives from the Greek word pantothen meaning
"from everywhere“.
• Easily destroyed by food processing
• Part of coenzyme A, used in energy metabolism
• Essential for metabolism of CHO, fat & protein
Pantothenic acidSources• Widespread in foods• Meat, Liver• Milk• Mushrooms• Avacado• Peanuts• Broccoli• Whole grainsRDA• 5 mgs/day
Structure:
•Pantothenic acid contains β alanine and pantoic acid.
•The active Coenzyme A (CoA) differs according to the group added in place of H in the –SH (sulphahydryl group)
Acetate is added to form acetyl CoA. Succinate is added to form succinyl CoA.
Biochemical functions
Acetyl CoA TCA cycle Acetyl choline synthesis (neurotransmitter) Fatty acid metabolism
Succinyl CoA Heme synthesis
• Toxicity symptoms: none reported
Deficiency
• Rare• Usually in combination with other deficiencies• Signs/symptoms
Irritability, fatigue & apathy Neurological symptoms: numbness, paresthesia & muscle
cramps Hypoglycemia d/t increased sensitivity to insulin Restlessness, malaise, sleep disturbances, nausea,
vomiting & abdominal cramps. Burning foot syndrome: painful burning sensations of the
feet• Alcoholics at risk
Biotin
• Vitamin B-7 & Vitamin H
• Anti Egg White Injury Factor: Avidin, a protein found in raw
egg white, inhibits the absorption of biotin.
• Free and bound form
• Biocytin (protein bound form)
• Biotinidase (allows the body to use and to recycle biotin)
BiotinSources:
• Organ meats, fish• Egg yolks• Soybeans• Whole grains• Cheese• Peanuts• Also produced by GI
bacteria
RDA:• 30 g/day
Active form of Biotin acts as coenzyme for Carboxylation reactions (addition of carbon in the form of CO2).
Examples:
Carboxylation of Acetyl CoA ( Biosynthesis of FA) Acetyl CoA + CO2 Malonyl CoA
Carboxylation of Pyruvate (Gluconeogenesis) Pyruvate + CO2 Oxaloacetate
Metabolism of fat & amino acids (leucine)
Cell growth
Steady blood sugar level
Biochemical Functions
Signs/symptoms: Hair loss (alopecia) Depression, lethargy, hallucinations, numbness and
tingling of the extremities Dermatitis Conjunctivitis
Causes:
Raw eggs
Biotinidase deficiency
Alcoholics
Antibiotics
Deficiency
Vitamin B-6 Various forms: [pyridine derivatives]
– Pyridoxine– Pyridoxal– Pyridoxamine
Pyridoxal phosphate [PLP]– active coenzyme form
Heat and alkaline sensitive RDA:
– 1.3 mg/day for adults– 1.7 mg/day for men over 50– 1.5 mg/day for women over 50
Vitamin B6
Sources• Meat, fish, poultry, liver• Potatoes, Legumes• Banana• Spinach• Avocado• Whole grains• Soy products
Absorption, Transport & Metabolism
• Absorbed passively• Binds to albumin for transport in the blood• B-6 is stored in the liver and muscle tissue• All three forms of B-6 are phosphorylated in
the liver• Excess is excreted in urine
Functions
• Amino acid metabolismTransaminationDeaminationDecarboxylation (Histamine synthesis)Condensation (Haemoglobin synthesis)Racemization (Structural rearrangement of amino acids)
• Carbohydrate metabolismGluconeogenesis
• Lipid metabolismBiosynthesis of sphingolipids
• Neurotransmitter Synthesis• Gene expression• Conversion of tryptophan to niacin
Deficiency
Microcytic hypochromic anemia Seborrhoeic dermatitis Atrophic glossitis with ulceration Angular cheilitis Conjunctivitis Neurological symptoms
– Drowsiness, depression, confusion & neuropathyCauses
IsoniazidAlcoholicsOCPsElderly
B-6 As A Medicine
• Morning sickness in early pregnancy• PMS• Mental depression• Cut the risk of parkinson’s disease by half• Carpal tunnel syndrome
Toxicity potential• Can lead to irreversible nerve damage with doses > 2
g/day
Folic acid
• From the Latin word “folium” (which means “leaf”)• Other names
FolacinVitamin B-9, Vitamin M & Vitamin Bc
• Consists of Pteridine group Para-amino benzoic acid (PABA) and Glutamic acid
• Coenzyme form: Tetrahydorfolic acid (THFA) Dihydrofolic acid (DHFA)
• Susceptible to heat, oxidation & ultraviolet light
Folic acid
Sources• Leafy Green
Vegetables• Fortified Grains• Legumes, Seeds• Liver
RDA• 400 ug/day for
adults
Absorption, Transport & Metabolism
• Absorbed in the monoglutamate form with help of folate conjugase – Active absorption = low to moderate intake– Passive absorption = high intake
• Delivered to the liver where it is changed back to the polyglutamate form
• Mostly stored in the liver
• Excreted in urine and bile (entero-hepatic circulation)
Functions
• Synthesis, repair & methylation of DNA– Transfer of single carbon units– Synthesis of amino acids, purines & thymidine mono-phosphate
• Cell division & growth• Homocysteine metabolism• Produce healthy red blood cells & prevent anemia
Deficiency Sign/symptoms
– Anemia (megaloblastic)– Neural tube defects (in developing embryo)– Peripheral neuropathy– Glossitis with peptic and mouth ulcers– Mental confusion, depression, weakness, fatigue & irritability– Headache, diarrhea & palpitations– Cancer development
At risk– Pregnant women– Alcoholics
Megaloblastic Anemia
Toxicity
• Risk is low• Upper limit
1 mg/day – adult men & women 0.8 mg/day – women < 18 yrs of age
• Signs Epilepsy Skin & respiratory disorder
• Excess can mask vitamin B-12 deficiency
Vitamin B-12
• Also known as cobalamin• contains cobalt• Consists of a class of chemically-related compounds
(vitamers) Methyl-cobalamin Adenosyl-cobalamin Hydroxo-cobalamin Cyano-cobalamin (synthetic form)
• Basic structure: Synthesized only by bacteria, fungi and algae• Heat stable up to 100°C• Affected by strong acids/alkalis• Affected by light
Vitamin B12
Sources:• Animal products
– Meat, poultry, fish, shellfish
– Milk, cheese– Eggs
• Fortified cereals
RDA:• 3-4 ug/ day
Absorption & Metabolism
Functions
Citric acid cycle Nerve functions
Maintains myelin sheath Folic acid metabolism RBC formation & prevents megaloblastic anemia t/t of pernicious anemia
Deficiency
Megaloblastic anemia
– Delayed or failure of normal cell division due to impaired DNA synthesis
Pernicious anemia– Destruction of parietal cells– Achlorhydria & atrophic gastritis
Neuropathy– defective myelination – never degeneration– progressive peripheral weakening– Tingling/numbness in the extremities (parasthesia)
Vitamin C
• Vitamers of vitamin C– Ascorbic acid (reduced form)– Salts of ascorbic acid
• Vitamin C is purely the L-enantiomer of ascorbic acid• Synthesized by most animals (not by human)• The name is derived from ”a”- (meaning "no")
and ”scorbutus” (scurvy)
• RDA 90 mg/day for male adults 75 mg/day for female adults +35 mg/day for smokers
Vitamin C
Sources– Citrus fruits– Potatoes– Green peppers– Cauliflower– Broccoli– Strawberries– Lettuce & spinach
Functions
Reducing agent (antioxidant) Boost Immunity Iron absorption Collagen synthesis
Healthy blood vessels Promotes wound healing
Synthesis of carnitine & tyrosine Anti-histaminic
Prevents histamine release Increases the detoxification of histamine
Collagen Synthesis
Deficiency
ScurvyEarly symptoms
Malaise & lethargyAfter 1-3 months
Easy bruising & petechiae Bleeding gums & loose teeth Swollen ankle & wrists Poor wound healing Shortness of breath, fatigue & weakness Bone pain & myalgia Anemia & cessation of
growth
Toxicity
Adverse effects (doses > 2 gms/day):• Indigestion & diarrhea• Iron poisoning (in people with iron overload disorders)• Suppresses the production of progesterone from
corpus luteum• Increases insulin production• Interference with blood coagulation therapy• Kidney stones [oxalate]• Gout
Thank YouA presentation by
Akif Ahsan