Aditia Retno Fitri Department of Pharmacology Faculty of Medicine Diponegoro University Indonesia
Folic Acid and Vitamine B12
Haemopoetic Growth Factors
a porphyrin-like ring with a central cobalt ( Co ) atom attached to a nucleotide
Mostly animal products:
Milk and Milk products like yogurt
fortified with Vitamin B 12 :
U ltimate source : microbial synthesis
not synthesized by animals / plants.
M ust be converted to methyl-B 12 o r ado-B 12
D aily diet = 5-25 μg
D aily requirement = 2-3 μg.
= extrinsic factor
Role: DNA synthesis
C onversion of methyl-FH 4 to FH 4
Iso merisation of methylmalonyl-CoA to succinyl-CoA .
Methyl-FH 4 donates the methyl group to B 12 , the cofactor.
The methyl group is then transferred to homocysteine to form methionine
Deficiency: “methylfolate trap”
Synthesis of DNA
Vit B12 deficiency : acummulation of methyl malonate-CoA basis of neuropathy in vit B12 deficiency
Cobalamin is a cofactor for the enzyme Methylmalonyl-CoA mutase which converts methylmalonyl-CoA to succinyl-CoA .
Succinyl-CoA enters the Krebs cycles and goes into nerves to make myelin .
If no Vitamin B 12 , methylmalonyl-CoA goes on to form abnormal fatty acids and causes subacute degeneration of the nerves. Only B 12 can correct this problem.
Normal B-12 absorption:
Dietary B-12 binds to R factor in saliva and gastric juices.
In duodenum, pancreatic enzymes promote dissociation from R factor and binding to Intrinsic Factor (IF)
IF-B12 complex taken up by ileal receptor cubilin.
Released into plasma bound to transcobalamines TC I, II, or III.
Enters cells through receptor mediated endocytosis and metabolized into two coenzymes: adenosyl-Cbl and methyl-Cbl.
Another mechanism for B 12 absorption involves diffusion and not IF : jejunum
In circulation, cobalamin binds to transcobalamin II; transporting the vitamin from the enterocyte to the liver and other organs
Biliary excretion of B 12 is much higher than excretion in urine or feces
I t can take up to 20 years to show symptoms of deficiency in people who have recently changed to low-B 12 diets !!!
Vitamin B 12 is excreted in bile, but the body is able to reabsorb a large percentage. People who consume diets very low in B 12 may actually be reabsorbing more than they absorb from diet. This is why I t can take up to 20 years to show symptoms of deficiency in people who have recently changed to low-B 12 diets. If there is a complete absorption failure, however, deficiency symptoms can occur in 3 years.
V egetarian P ernicious Anemia I leal disease I iver disease
peripheral neuropathy , D ementia , subacute combined degeneration of the spinal cord
Abnormalities of epithelial tissue ,
e.g. sore tongue and malabsorption
↓ serum vit B12 (N: 170-925 nanogram/1)
pancytopenia, anisopoikilocytosis with oval macrocytes and hypersegmented neutrophils; the marrow is megaloblastic
Schilling test :
distinguish between gastric and intestinal causes
Give 1mcg of radiolabeled B-12 orally 1000 mcg of B-12 IM one hour later A 24-hr urine c ollect ion count radiolabeled B-12 excret ion ( N : 8-35% ) .
only if Stage I is abnormal.
Repeat Stage I, except with the addition of added oral IF which should normalize B-12 absorption in P.A., but not intestinal malabsorption.
Inconclusively diagnosed anaemia
Allergic to cobalt
Alcohol, aminosalicylic acid, neomicine and colchicine may decrease the absorption of oral vit B12
Hydroxocobalamin is preferred to cyanocobalamin :
First choice : injection
hydroxocobalamin 1 mg i.m. every 2-3 days for 5 doses to induce remission and to replenish stores
Maintanance dose: 1 mg/3 months
Feel better : 2 days
Reticulocyte peak : 5-7 days
Hb, RBC, Ht ↑ : first week normalize: 2 months
If injections are refused
rare allergy, bleeding disorder
Alternative: snuff , aerosol , oral
Large daily oral doses (1000 micrograms)
depleted stores must be replaced by parenteral cobalamin before switching to the oral preparation;
the patient must be compliant;
monitoring of the blood must be more frequent
adequate serum vitamin B12 levels must be demonstrated.
Synthetic vitamin B 12
Oral cyanocobalamin : well absorbed, highly protein bound to the transcobalamins
Metabolize in the liver, followed by biliary and urinary excretion
T 1/2 is about 6 days
Cyanocobalamin injection containing benzyl alcohol : should not be used for neonates or immature infants
Reduction of absorption of B 12 from GI tract
excessive consumption of ethanol for longer than 2 weeks
prolonged use of cholestyramine, colchicine
large doses of ascorbic acid may destroy B 12
Folate (Folic Acid) can mask signs of B 12 deficiency
because it can correct macrocytic anemia , which is often the first symptom experienced in B 12 deficiency. The folate won’t correct the deficiency, however, and because it goes undetected severe nerve damage can occur.
Usually do not occur
when a megaloblastic anaemia due to pernicious anaemia is incorrectly diagnosed as due to folate deficiency; here folic acid, if used alone (see below) may accelerate progressionof subacute combined degeneration of the nervous system.
Exposure to Nitrous Oxide can cause B 12 deficiency in cases of abuse, anesthesia usage during surgery, or occupational exposure for hospital workers.
NO actually inactivates B 12 , so while those affected have enough in their system, they are effectively B 12 deficient .
needs an 'intrinsic factor ' for absorption in terminal ileum. It is stored in the liver.
It is required for:
synthesis of purines and pyrimidines (see above)
isomerisation of methylmalonyl-CoA to succinyl-CoA.
Deficiency : pernicious anaemia ,
Vitamin B 12 is given by injection to treat pernicious anaemia.
composed of a heterocycle, p-aminobenzoic acid, and glutamic acid
Human requirement :
varies from 25-35 mcg/d in infancy to up to 100 mcg/d in adults
Total body folic acid stores :
5-10 mg, half of which is stored in the liver as N-5-methyltetrahydrofolate
> 2% is degraded daily
so a continuous dietary is essential
Active absorption : mainly in the proximal part of the small intestine
Conjugate in the epithelial cells converts the polyglutamates into absorbable monoglutamates
Pharmaceutical product : completely absorbed in the upper duodenum, even in the presence of malabsorption
Excret ion : entirely as metabolites by the kidney
Rheumatoid arthritis – increased folic acid demand or utilization.
Oral replacement therapy
Women planning pregnancy are advised to take 400 g folic acid daily before conception and until 12 weeks of pregnancy to prevent neural-tube defects (5 mg/day for women with a previous affected pregnancy)
Folate fortification of cereal grains at 1·4 mg/kg has been made mandatory in the USA as an additional method of improving the folate status of the population.
Prophylactic folate is also recommended in other states of increased demand such as long-term hemodialysis and chronic haemolytic disorders