Hematinic agent ii

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  • Vitamin B 12 is a complex cobalamin compound consists of a porphyrin-like ring with a central cobalt atom attached to a nucleotide
  • Various organic groups may be covalently bound to the cobalt atom, forming different cobalamins. Deoxyadenosylcobalamin and methylcobalamin are the active forms of the vitamin in humans. Cyanocobalamin and hydroxocobalamin (both available for therapeutic use) and other cobalamins found in food sources are converted to the above active forms. Hydroxocobalamin is bound to plasma protein to a greater extent than is cyanocobalamin, with the result that there is less free to be excreted in the urine after an injection and rather lower doses at longer intervals are adequate. Thus hydroxocobalamin is preferred to cyanocobalamin, though the latter can give satisfactory results as the doses administered are much greater than are required physiologically. Cyanocobalamin remains available.
  • All cobalamins, dietary and therapeutic, must be converted to methylcobalamin (methyl-B 12 ) or 5'- deoxyadenosylcobalamin (ado-B 12 ) for activity in the body. The average daily diet in Western Europe contains 5-25 μg of vitamin B 12 and the daily requirement is 2-3 μg. The ultimate source of vitamin B 12 is from microbial synthesis; the vitamin is not synthesized by animals or plants. The chief dietary source of vitamin B 12 is microbially derived vitamin B 12 in meat (especially liver), eggs, and dairy products. Vitamin B 12 is sometimes called extrinsic factor to differentiate it from intrinsic factor, a protein normally secreted by the stomach that is required for gastrointestinal uptake of dietary vitamin B 12 . Cobalamin is produced in nature only by cobalamin-producing microorganisms, and herbivores obtain their supply from plants contaminated with bacteria and faeces. Carnivores obtain their supply by ingesting the muscular and parenchymal tissues of these animals. Animal protein is the major dietary source of cobalamin in man. Although bacteria in the human colon synthesise cobalamin, it is formed too distally for absorption by the ileal transport system. Rabbits in the wild would suffer from B12 deficiency if they did not eat their own faeces. In the presence of intrinsic factor about 70% of ingested cobalamin is absorbed, in its absence < 2% is absorbed. Some cyanocobalamin may be absorbed by passive diffusion, i.e. independently of intrinsic factor, though less reliably and only with large doses.
  • The conversion of methyl-FH 4 to FH 4 The role of vitamin B 12 in folate coenzyme synthesis is illustrated in Figure 21.4 . It is through these mechanisms that the metabolic activities of vitamin B 12 and folic acid are linked and implicated in the synthesis of DNA. It is also through this pathway that folate/vitamin B 12 treatment can lower plasma homocysteine concentration . Since increased homocysteine concentrations may have undesirable vascular effects ( Ch. 18 ), this has potential therapeutic implications . ▾The reaction involves conversion of both methyl-FH 4 to FH 4 and homocysteine to methionine . The enzyme that accomplishes this is homocysteine-methionine methyltransferase; the reaction requires vitamin B 12 as cofactor and methyl-FH 4 as methyl donor . Methyl-FH 4 donates the methyl group to B 12 , the cofactor. The methyl group is then transferred to homocysteine to form methionine ( Fig. 21.4 ). This vitamin-B 12 -dependent reaction generates active FH 4 from inactive methyl-FH 4 and converts homocysteine to methionine . Vitamin B 12 deficiency thus traps folate in the inactive methyl-FH 4 form, thereby depleting the folate polyglutamate coenzymes needed for DNA synthesis (see above). Vitamin B 12 -dependent methionine synthesis also affects the synthesis of folate polyglutamate coenzymes by an additional mechanism. The preferred substrate for polyglutamate synthesis is formyl-FH 4 , and the conversion of FH 4 to formyl-FH 4 requires a formate donor such as methionine In one, methylcobalamin serves as an intermediate in the transfer of a methyl group from N5- methyltetrahydrofolate to methionine (Figure 33–1 A; Figure 33–2, reaction 1). In the absence of vitamin B12, conversion of the major dietary and storage folate, N5-methyltetrahydrofolate, to tetrahydrofolate, the precursor of folate cofactors, cannot occur. As a result, a deficiency of folate cofactors necessary for several biochemical reactions involving the transfer of one-carbon groups develops. In particular, the depletion of tetrahydrofolate prevents synthesis of adequate supplies of the deoxythymidylate (dTMP) and purines required for DNA synthesis in rapidly dividing cells as shown in Figure 33–3, reaction 2. The accumulation of folate as N5-methyltetrahydrofolate and the associated depletion of tetrahydrofolate cofactors in vitamin B12 deficiency have been referred to as the "methylfolate trap." This is the biochemical step whereby vitamin B12 and folic acid metabolism are linked and explains why the megaloblastic anemia of vitamin B12 deficiency can be partially corrected by ingestion of relatively large amounts of folic acid. Folic acid can be reduced to dihydrofolate by the enzyme dihydrofolate reductase (Figure 33–2, reaction 3) and thus serve as a source of the tetrahydrofolate required for synthesis of the purines and dTMP that are needed for DNA synthesis
  • Isomerisation of methylmalonyl-CoA to succinyl-CoA This isomerisation reaction is part of a route by which propionate is converted to succinate. Through this pathway, cholesterol, odd-chain fatty acids, some amino acids and thymine can be used for gluconeogenesis or for energy production via the tricarboxylic acid cycle. Ado-B 12 is an essential cofactor, so methylmalonyl-CoA accumulates in vitamin B 12 deficiency. This distorts fatty acid synthesis in neural tissue and may be the basis of neuropathy in vitamin B 12 deficiency. The other enzymatic reaction that requires vitamin B12 is isomerization of methylmalonyl-CoA to succinyl-CoA by the enzyme methylmalonyl-CoA mutase (Figure 33–1 B). In vitamin B12 deficiency, this conversion cannot take place, and the substrate, methylmalonyl-CoA, accumulates. In the past, it was thought that abnormal accumulation of methylmalonyl-CoA causes the neurologic manifestations of vitamin B12 deficiency. However, newer evidence instead implicates the disruption of the methionine synthesis pathway as the cause of neurologic problems. Whatever the biochemical explanation for neurologic damage, the important point is that administration of folic acid in the setting of vitamin B12 deficiency will not prevent neurologic manifestations even though it will largely correct the anemia caused by the vitamin B12 deficiency.
  • Vitamin B12 in physiologic amounts is absorbed only after it complexes with intrinsic factor, a glycoprotein secreted by the parietal cells of the gastric mucosa. Intrinsic factor combines with the vitamin B12 that is liberated from dietary sources in the stomach and duodenum, and the intrinsic factor-vitamin B12 complex is subsequently absorbed in the distal ileum by a highly specific receptor-mediated transport system. Vitamin B12 deficiency in humans most often results from malabsorption of vitamin B12, due either to lack of intrinsic factor or to loss or malfunction of the specific absorptive mechanism in the distal ileum. Nutritional deficiency is rare but may be seen in strict vegetarians after many years without meat, eggs, or dairy products. Once absorbed, vitamin B12 is transported to the various cells of the body bound to a plasma glycoprotein, transcobalamin II. Excess vitamin B12 is transported to the liver for storage. Significant amounts of vitamin B12 are excreted in the urine only when very large amounts are given parenterally, overcoming the binding capacities of the transcobalamins (50–100 g).
  • The daily requirement of cobalamin is about 3.0 micrograms. The average diet in the USA contains 5–30 mcg of vitamin B 12 daily, 1–5 mcg of which is usually absorbed. Absorption takes place mainly in the terminal ileum, and it is carried in plasma bound to proteins called transcobalamins (TCs). . 90% of recently absorbed or administered cobalamin is carried on transcobalamin II an important transport protein which is rapidly cleared from the circulation (t1/2 6-9 minutes). Hereditary deficiency of transcobalamin II causes severe cobalamin deficiency. 80% of all circulating cobalamin is bound to transcobalamin I (t1/2 9-12 days) which is possibly a plasma storage form (hereditary deficiency of which is of no consequence). Cobalamin in its reduced formcob(I)alamin functions as a coenzyme for methionine synthase in a reaction that generates tetrahydrofolate,and is critical for DNA and RNA synthessis. Cobalamin is not significantly metabolised and passes into the bile (there is enterohepatic circulation which can be interrupted by intestinal diseaseand hastens the onset of clinical deficiency), and is excreted via the kidney. Only trace amounts of vitamin B 12 are normally lost in urine and stool Body stores amount to about 3- 5 mg (mainly in the liver) and are sufficient for 2-4 years if absorption ceases. This store is so large compared with the daily requirement that if vitamin B 12 absorption is stopped suddenly-as after a total gastrectomy-it takes 2-4 years for evidence of deficiency to become manifest. it would take about 5 years for all of the stored vitamin B 12 to be exhausted and for megaloblastic anemia to develop if B 12 absorption were stopped. Vitamin B 12 in physiologic amounts is absorbed only after it complexes with intrinsic factor , a glycoprotein secreted by the parietal cells of the gastric mucosa. Intrinsic factor combines with the vitamin B 12 that is liberated from dietary sources in the stomach and duodenum, and the intrinsic factor-vitamin B 12 complex is subsequently absorbed in the distal ileum by a highly selective receptor-mediated transport system. Vitamin B 12 deficiency in humans most often results from malabsorption of vitamin B 12 due either to lack of intrinsic factor or to loss or malfunction of the specific absorptive mechanism in the distal ileum. Nutritional deficiency is rare but may be seen in strict vegetarians after many years without meat, eggs, or dairy products.
  • Absorption and distribution of vitamin B12 Def vit B12 can result from congenital or acquired defect in any of one of the following: Inadequate dietary supply Inadequate secretion of intrinsic factor (classic pernicious anemia) Illeal disease Congenital absence of transcobalamin II (TcII) Rapid depletion of hepatic stores by interference with reabsorption of vitamin B12 excreted in bile The utility of measurement of the conc B12 in plasma to estimate supply available to tissue can be compromised by liver disease and (6) the appearance of abnormal amount of transcobalamin I and III (TcI and III) in plasma. Finally, the formation of methylcobalamin requires (7) normal transport into cells and adequate suply of folic acid as CH3H4PteGlu1 In the presence of gastric acid and pancreatic proteases, dietary vitamin B12 is released from food and bound to gastric intrinsic factor. When the vitamin B12–intrinsic factor complex reaches the ileum, it interacts with a receptor on the mucosal cell surface and is actively transported into circulation. Adequate intrinsic factor, bile, and sodium bicarbonate (to provide a suitable pH) all are required for ileal transport of vitamin B12. Vitamin B12 deficiency in adults rarely results from a deficient diet per se; rather, it usually reflects a defect in one or another aspect of this sequence of absorption (Figure 53–8). Achlorhydria and decreased secretion of intrinsic factor by parietal cells secondary to gastric atrophy or gastric surgery is a common cause of vitamin B12 deficiency in adults. Antibodies to parietal cells or intrinsic factor complex also can play a prominent role. A number of intestinal diseases can interfere with absorption, including pancreatic disorders (loss of pancreatic protease secretion), bacterial overgrowth, intestinal parasites, sprue, and localized damage to ileal mucosal cells by disease or as a result of surgery. Once absorbed, vitamin B12 binds to transcobalamin II, a plasma b-globulin, for transport to tissues. Two other transcobalamins (I and III) also are present in plasma; their concentrations are related to the rate of turnover of granulocytes. They may represent intracellular storage proteins that are released with cell death. Vitamin B12 bound to transcobalamin II is rapidly cleared from plasma and preferentially distributed to hepatic parenchymal cells, which comprise a storage depot for other tissues. In normal adults, as much as 90% of the body’s stores of vitamin B12, from 1 to 10 mg, is in the liver. Vitamin B12 is stored as the active coenzyme with a turnover rate of 0.5–8 mg/day, depending on the size of the body stores. The recommended daily intake of the vitamin in adults is 2.4 mg. Approximately 3 mg of cobalamins is secreted into bile each day, 50–60% of which is not destined for reabsorption. This enterohepatic cycle is important because interference with reabsorption by intestinal disease can progressively deplete hepatic stores of the vitamin. This process may help explain why patients can develop vitamin B12 deficiency within 3–4 years of major gastric surgery, even though a daily requirement of 1–2 mg would not be expected to deplete hepatic stores of more than 2–3 mg during this time
  • Pernicious (Addisonian) anaemia. The atrophic gastric mucosa is unable to produce intrinsic factor (and acid) due to an autoimmune reaction to gastric parietal cells and intrinsic factor itself, there is failure to absorb vitamin B12 in the terminal ileum so that deficiency results. Despite its name (given when no treatment was known and it was believed to be a neoplastic disorder due to the appearance of the megaloblastic bone marrow), the prognosis of a patient with uncomplicated pernicious anaemia, properly treated with hydroxocobalamin, is little different from that of the rest of the population. The neurological complications, particuarly spasticity, develop only after prolonged severe deficiency but may be permanent; they are rarely seen today. Total removal of the stomach or atrophy of the mucous membrane in a postgastrectomy remnant may, after several years, lead to a similar anaemia Malabsorption syndromes. In stagnant loop syndrome (bacterial overgrowth which competes for the available cobalamin and can be remedied by a broad-spectrum antimicrobial), ileal resection, Crohn's disease and chronic tropical sprue affecting the terminal ileum, vitamin B12 deficiency is common although megaloblastic anaemia occurs only relatively late. The fish tape worm Diphyllobothrum latum which can infest humans who eat raw or partially cooked freshwater fish roe can grow up to 10 meters in the gut and competes for ingested cobalamin Tobacco amblyopia has been attributed to cyanide intoxication from strong tobacco which interferes with the coenzyme function of vitamin B12; hydroxocobalamin (not cyanocobalamin) may be given. Cyanocobalamin is indicated in the treatment of vitamin B12 deficiency caused by Inadequate utilization of vitamin B12; dietary deficiency of vitamin B12 occurring in strict vegetarians, malabsorption syndrome of various causes (e.g., pernicious anemia, GI pathology, fish tapeworm infestation, malignancy of pancreas or bowel, gluten enteropathy, small bowel bacterial overgrowth, gastrectomy, accompanying folic acid deficiency); Supplementation because of increased requirements (e.g., associated with pregnancy, thyrotoxicosis, hemolytic anemia, hemorrhage, malignancy, hepatic and renal disease); vitamin B12 absorption test (e.g., Schilling test
  • vitamin B 12 deficiency also causes important disorders of nerves, which are not corrected (or may even be made worse) by treatment with folic acid . Deficiency of either vitamin causes megaloblastic haemopoiesis in which there is disordered erythroblast differentiation and defective erythropoiesis in the bone marrow. Large abnormal erythrocyte precursors appear in the marrow, each with a high RNA:DNA ratio as a result of decreased DNA synthesis. The circulating erythrocytes ('macrocytes') are large fragile cells, often distorted in shape. Mild leucopenia and thrombocytopenia usually accompany the anaemia, and the nuclei of polymorphonuclear leucocytes are abnormal (hypersegmented). Neurological disorders caused by deficiency of B 12 include peripheral neuropathy and dementia , as well as subacute combined * degeneration of the spinal cord. Vitamin B 12 deficiency, however, is usually caused by decreased absorption, caused either by a lack of intrinsic factor (see below) or conditions that interfere with its absorption in the terminal ileum, for example resection of diseased ileum in patients with Crohn's disease (a chronic inflammatory bowel disease that can affect this part of the gut). Intrinsic factor is a glycoprotein secreted by the stomach and is essential for vitamin B 12 absorption. It is lacking in patients with pernicious anaemia and in individuals who have had total gastrectomies. In pernicious anaemia there is atrophic gastritis caused by autoimmune injury of the stomach, and antibodies to gastric parietal cells are often present in the plasma of such patients. megaloblastic anemia. The typical clinical findings in megaloblastic anemia are macrocytic anemia (MCV usually > 120 fL), often with associated mild or moderate leukopenia or thrombocytopenia (or both), and a characteristic hypercellular bone marrow with megaloblastic maturation of erythroid and other precursor cells. Vitamin B12 deficiency also causes a neurologic syndrome that usually begins with paresthesias and weakness in peripheral nerves and progresses to spasticity, ataxia, and other central nervous system dysfunctions. A characteristic pathologic feature of the neurologic syndrome is degeneration of myelin sheaths followed by disruption of axons in the dorsal and lateral horns of the spinal cord and in peripheral nerves. Correction of vitamin B12 deficiency arrests the progression of neurologic disease, but it may not fully reverse neurologic symptoms that have been present for several months. Although most patients with neurologic abnormalities caused by vitamin B12 deficiency have full-blown megaloblastic anemias when first seen, occasional patients have few if any hematologic abnormalities The most common causes of vitamin B12 deficiency are pernicious anemia, partial or total gastrectomy, and diseases that affect the distal ileum, such as malabsorption syndromes, inflammatory bowel disease, or small bowel resection.
  • The serum concentration of vitamin B12 is low (normal 170-925 nanogram/1). In severe deficiency there is pancytopenia, the blood film shows anisopoikilocytosis with oval macrocytes and hypersegmented neutrophils; the marrow is megaloblastic. In many patients with pernicious anaemia antibodies to intrinsic factor can be identified in the serum. Absorption of radioactive vitamin B12 (Schilling test) helps to distinguish between gastric and intestinal causes. First: the patient is given a small dose of radioactive vitamin B12 orally, with a simultaneous large dose of nonradioactive vitamin B12 intramuscularly. The large injected dose saturates binding sites so that any of the oral radioactive dose that is absorbed cannot bind and will be eliminated in the urine where it can easily be measured (normally > 10% of the administered dose appears in urine collected for 24 h, if renal function is normal). In pernicious anaemia and in malabsorption, gut absorption and therefore subsequent appearance of radioactivity in the plasma (measured 8-12 h later) and urine are negligible. Second: the test is repeated with intrinsic factor added to the oral dose. The radioactive vitamin B12 is now absorbed in pernicious anaemia (but not in intestinal malabsorption) and is detected in plasma and urine. Both stages of the test are needed to maximise reliability of diagnosis of pernicious anaemia.
  • Pernicious anemia results from defective secretion of intrinsic factor by the gastric mucosal cells. Patients with pernicious anemia have gastric atrophy and fail to secrete intrinsic factor (as well as hydrochloric acid). The Schilling test shows diminished absorption of radioactively labeled vitamin B12, which is corrected when hog intrinsic factor is administered with radioactive B12, since the vitamin can then be normally absorbed. Vitamin B12 deficiency also occurs when the region of the distal ileum that absorbs the vitamin B12-intrinsic factor complex is damaged, as when the ileum is involved with inflammatory bowel disease, or when the ileum is surgically resected. In these situations, radioactively labeled vitamin B12 is not absorbed in the Schilling test, even when intrinsic factor is added. Other rare causes of vitamin B12 deficiency include bacterial overgrowth of the small bowel, chronic pancreatitis, and thyroid disease. Rare cases of vitamin B12 deficiency in children have been found to be secondary to congenital deficiency of intrinsic factor and congenital selective vitamin B12 malabsorption due to defects of the receptor sites in the distal ileum.
  • Inconclusively diagnosed anaemia is an important contraindication. Therapy of pernicious anaemia must be both adequate and lifelong, so that accuratediagnosis is essential. Even a single dose of vitamin B12 interferes with the haematological picture for weeks (megaloblastic haematopoiesis reverts to normal within 12 hours), although the Schilling test remains diagnostic.
  • Hydroxocobalamin is bound to plasma protein to a greater extent than is cyanocobalamin, with the result that there is less free to be excreted in the urine after an injection and rather lower doses at longer intervals are adequate. Thus hydroxocobalamin is preferred to cyanocobalamin, though the latter can give satisfactory results as the doses administered are much greater than are required physiologically. Cyanocobalamin remains available. The initial dose in cobalamin deficiency anaemias, including uncomplicated pernicious anaemia, is hydroxocobalamin 1 mg i.m. every 2-3 days for 5 doses to induce remission and to replenish stores. Maintenance may be 1 mg every 3 months; higher doses will not find binding sites and will be eliminated in the urine. Higher doses are justified during renal or peritoneal dialysis where hydroxycobalamin clearance is increased, and resultan raised plasma methylmalonic acid and homocysteine represent an independent risk factor for vascular events in these patients (see later). Routine low dose supplements of hydroxycobalamin, folate and pyridoxine fail to control hyperhomocysteinaemia in 75% of dialysis patients but supraphysiological doses are effective: hydroxycobalamin 1 mg/d, folic acid 15 mg/d and pyridoxine 100 mg/d. After initiation of therapy, patients feel better in 2 days, reticulocytes peak at 5-7 days and the haemoglobin, red cell count and haematocrit rise by the end of the first week. These indices normalise within 2 months irrespective of the starting level. Failure to respond implies a wrong or incomplete diagnosis (coexistent deficiency of another haematinic). The initial stimulation of haemoglobin synthesis often depletes the iron and folate stores and supplements of these may be needed. Hypokalaemia may occur at the height of the erythrocyte response in severe cases. It is attributed to uptake of potassium by the rapidly increasing erythron (erythrocyte mass). Oral potassium should be given prior to initiating therapy in a patient with low or borderline potassiuim levels. Once alternative or additional causes of the anaemia have been excluded, inadequate response should be treated by increased frequency of injections as well as increased amount (because of urinary loss with high plasma concentrations). The reversal of neurological damage is slow (and rarely marked) and the degree of functional recovery is inversely related to the extent and duration of symptoms. Haemoglobin estimations are necessary at least every 6 months to check adequacy of therapy and for early detection of iron deficiency anaemia due to achlorhydria (common in patients with pernicious anaemia > 60 years) or carcinoma of the stomach, which occurs in about 5% of patients with pernicious anaemia. The parenteral route is used because the vitamin is ineffective orally due to the absence of the intrinsic factor in the stomach, which is necessary for utilization of vitamin B12. After
  • When injections are refused or are impracticable (rare allergy, bleeding disorder), administration as snuff or aerosol has been effective, but these routes are less reliable. Large daily oral doses (1000 micrograms) are probably preferable; 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 and adequate serum vitamin B12 levels must be demonstrated. The choice of a preparation always depends on the cause of the deficiency. Although oral preparations may be used to supplement deficient diets, they are of limited value in the treatment of patients with deficiency of intrinsic factor or ileal disease. Even though small amounts of vitamin B12 may be absorbed by simple diffusion, the oral route of administration cannot be relied upon for effective therapy in the patient with a marked deficiency of vitamin B12 and abnormal hematopoiesis or neurological deficits. Therefore, the treatment of choice for vitamin B12–deficiency is cyanocobalamin administered by intramuscular or subcutaneous injection. following principles: 1. Vitamin B12 should be given prophylactically only when there is a reasonable probability that a deficiency exists or will exist. Dietary deficiency in the strict vegetarian, the predictable malabsorption of vitamin B12 in patients who have had a gastrectomy, and certain diseases of the small intestine constitute such indications. When GI function is normal, an oral prophylactic supplement of vitamins and minerals, including vitamin B12, may be indicated. Otherwise, the patient should receive monthly injections of cyanocobalamin. 2. The relative ease of treatment with vitamin B12 should not prevent a full investigation of the etiology of the deficiency. The initial diagnosis usually is suggested by a macrocytic anemia or an unexplained neuropsychiatric disorder. Full understanding of the etiology of vitamin B12 deficiency involves studies of dietary supply, GI absorption, and transport. 3. Therapy always should be as specific as possible. While a large number of multivitamin preparations are available, the use of “shotgun” vitamin therapy in the treatment of vitamin B12 deficiency can be dangerous. With such therapy, there is the danger that sufficient folic acid will be given to result in a hematological recovery, which can mask continued vitamin B12 deficiency and permit neurological damage to develop or progress. 4. Although a therapeutic trial with small amounts of vitamin B12 can help confirm the diagnosis, acutely ill, elderly patients may not be able to tolerate the delay in the correction of a severe anemia. Such patients require supplemental blood transfusions and immediate therapy with folic acid and vitamin B12 to guarantee rapid recovery. 5. Long-term therapy with vitamin B12 must be evaluated at intervals of 6–12 months in patients who are otherwise well. If there is an additional illness or a condition that may increase the requirement for the vitamin ( e.g., pregnancy), reassessment should be performed more frequently.
  • Adverse effects virtually do not occur, but use of vitamin B12 as a 'tonic' is an abuse of a powerful remedy for it may obscure the diagnosis of pernicious anaemia, which is a matter of great importance in a disease requiring lifelong therapy and prone to serious neurological complications. The latter danger is of particular significance 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.
  • Dihydrofolate (FH 2 ) and tetrahydrofolate (FH 4 ) act as carriers and donors of methyl groups (1-carbon transfers) in a number of important metabolic pathways. The latter is essential for DNA synthesis as cofactor in the synthesis of purines and pyrimidines. It is also necessary for reactions involved in amino acid metabolism. For activity, folate must be in the FH 4 form, in which it is maintained by dihydrofolate reductase . This enzyme reduces dietary folic acid to FH 4 and also regenerates FH 4 from FH 2 produced from FH 4 during thymidylate synthesis (see Figs 21.2 and 21.3 ). Folate antagonists act by inhibiting dihydrofolate reductase (see also Chs 45 and 50 ). Folates are especially important for the conversion of deoxyuridylate monophosphate to deoxythymidylate mono-phosphate. This is rate limiting in mammalian DNA synthesis and is catalysed by thymidylate synthetase, with folate acting as methyl donor ( Fig. 21.3 ). The clinical use of folic acid is given in the box. Tetrahydrofolate cofactors participate in one-carbon transfer reactions. As described earlier in the discussion of vitamin B12 , one of these essential reactions produces the dTMP needed for DNA synthesis. In this reaction, the enzyme thymidylate synthase catalyzes the transfer of the one-carbon unit of N 5 , N 10 -methylenetetrahydrofolate to deoxyuridine monophosphate (dUMP) to form dTMP (Figure 33–3, section 2). Unlike all the other enzymatic reactions that use folate cofactors, in this reaction the cofactor is oxidized to dihydrofolate, and for each mole of dTMP produced, 1 mole of tetrahydrofolate is consumed. In rapidly proliferating tissues, considerable amounts of tetrahydrofolate are consumed in this reaction, and continued DNA synthesis requires continued regeneration of tetrahydrofolate by reduction of dihydrofolate, catalyzed by the enzyme dihydrofolate reductase. The tetrahydrofolate thus produced can then reform the cofactor N 5 , N 10 -methylenetetrahydrofolate by the action of serine transhydroxymethylase and thus allow for the continued synthesis of dTMP. The combined catalytic activities of dTMP synthase, dihydrofolate reductase, and serine transhydroxymethylase are referred to as the dTMP synthesis cycle. Enzymes in the dTMP cycle are the targets of two anticancer drugs; methotrexate inhibits dihydrofolate reductase, and a metabolite of 5-fluorouracil inhibits thymidylate synthase (see Chapter 54). Cofactors of tetrahydrofolate participate in several other essential reactions. N 5 -Methylenetetrahydrofolate is required for the vitamin B12 -dependent reaction that generates methionine from homocysteine (Figure 33–2A; Figure 33–3, section 1). In addition, tetrahydrofolate cofactors donate one-carbon units during the de novo synthesis of essential purines. In these reactions, tetrahydrofolate is regenerated and can reenter the tetrahydrofolate cofactor pool.
  • Tetrahydrofolate cofactors participate in one-carbon transfer reactions produces the dTMP needed for DNA synthesis. the enzyme thymidylate synthase catalyzes the transfer of the one-carbon unit of N5,N10-methylenetetrahydrofolate to deoxyuridine monophosphate (dUMP) to form dTMP (Figure 33–2, reaction 2). in this reaction the cofactor is oxidized to dihydrofolate, and for each mole of dTMP produced, one mole of tetrahydrofolate is consumed. In rapidly proliferating tissues, considerable amounts of tetrahydrofolate can be consumed in this reaction, and continued DNA synthesis requires continued regeneration of tetrahydrofolate by reduction of dihydrofolate, catalyzed by theenzyme dihydrofolate reductase. The tetrahydrofolate thus produced can then reform the cofactor N5,N10-methylenetetrahydrofolate by the action of serine transhydroxy- methylase and thus allow for the continued synthesis of dTMP. The combined catalytic activities of dTMP synthase, dihydrofolate reductase, and serine transhydroxymethylase are often referred to as the dTMP synthesis cycle. Enzymes in the dTMP cycle are the targets of two anticancer drugs; methotrexate inhibits dihydrofolate reductase, and a metabolite of 5-fluorouracil inhibits thymidylate synthase For activity, folate must be in the FH 4 form, in which it is maintained by dihydrofolate reductase . This enzyme reduces dietary folic acid to FH 4 and also regenerates FH 4 from FH 2 produced from FH 4 during thymidylate synthesis (see Figs 21.2 and 21.3 ). Folate antagonists act by inhibiting dihydrofolate reductase (see also Chs 45 and 50 ). Folates are especially important for the conversion of deoxyuridylate monophosphate to deoxythymidylate mono-phosphate. This is rate limiting in mammalian DNA synthesis and is catalysed by thymidylate synthetase, with folate acting as methyl donor ( Fig. 21.3 ). The clinical use of folic acid is given in the box.
  • The average diet in the USA contains 500–700 g of folates daily, 50–200 g of which is usually absorbed, depending on metabolic requirements (pregnant women may absorb as much as 300–400 g of folic acid daily). Normally, 5–20 mg of folates are stored in the liver and other tissues. Folates are excreted in the urine and stool and are also destroyed by catabolism, so serum levels fall within a few days when intake is diminished. Since body stores of folates are relatively low and daily requirements high, folic acid deficiency and megaloblastic anemia can develop within 1–6 months after the intake of folic acid stops, depending on the patient's nutritional status and the rate of folate utilization. Unaltered folic acid is readily and completely absorbed in the proximal jejunum. Dietary folates, however, consist primarily of polyglutamate forms of N5-methyltetrahydrofolate. Before absorption, all but one of the glutamyl residues of the polyglutamates must be hydrolyzed by the enzyme -1-glutamyl transferase ("conjugase") within the brush border of the intestinal mucosa. The monoglutamate N5-methyltetrahydrofolate is subsequently transported into the bloodstream by both active and passive transport and is then widely distributed throughout the body. Inside cells, N5-methyltetrahydrofolate is converted to tetrahydrofolate by the demethylation reaction that requires vitamin B12 (Figure 33–2, reaction 1).
  • Folate deficiency commonly result from: Inadequate dietary supply Small intestinal disease In patient with uremia, alcoholism, or hepatic disease there may be defects in the concentration of folate binding proteins in plasma and the flow of Ch3.Hpteglu into bile for reabsorption and transport to tissue (folate enterohepatic cycle) Vitamin B12 deficiency will trap folate as CH3H4PteGlu, reducing availability of tetrahydrofolates Folates in food are in the form of polyglutamates. These are converted to monoglutamates before absorption and are transported in blood as such. They are converted back into polyglutamates, which are considerably more active than monoglutamates, in the tissues. Therapeutically, folic acid is given orally (or, in exceptional circumstances, parenterally) and is absorbed in the ileum. Methyl-FH 4 is the form in which folate is usually carried in blood and which enters cells. It is functionally inactive until it is demethylated in a vitamin B 12 -dependent reaction (see below). This is because unlike FH 2 , FH 4 and formyl-FH 4 , methyl-FH 4 is a poor substrate for polyglutamate formation. This has relevance for the effect of vitamin B 12 deficiency on folate metabolism, as is explained below. Folate is taken up into hepatocytes and bone marrow cells by active transport. Within the cells, folic acid is reduced and formylated before being converted to the active polyglutamate form. Folinic acid , a synthetic FH 4 , is converted much more rapidly to the polyglutamate form. The clinical use of folic acid is given in the box on p. 335 .
  • Folic acid is present in a variety of foods.
  • Ibuprofen – like Motrin Naprosyn – like Aleve Acetaminophen – like Tylenol
  • Unwanted effects do not occur even with large doses of folic acid-except possibly in the presence of vitamin B 12 deficiency, because if the vitamin deficiency is treated with folic acid , the blood picture may improve and give the appearance of cure while the neurological lesions get worse. It is, therefore, important to determine whether a megaloblastic anaemia is caused by a folate or a vitamin B 12 deficiency. This could be important in the setting of supplementation of bread with folate, which is used in the USA as a public health measure to reduce the number of neural tube defects. There is a theoretical risk of precipitating neuropathy in the small group of people with undiagnosed pernicious anaemia, by such measures.
  • Hematinic agent ii

    1. 1. Aditia Retno Fitri Department of Pharmacology Faculty of Medicine Diponegoro University Indonesia
    2. 2. <ul><li>Overview </li></ul><ul><li>Hematinic Agents </li></ul><ul><ul><li>Iron </li></ul></ul><ul><ul><li>Folic Acid and Vitamine B12 </li></ul></ul><ul><li>Haemopoetic Growth Factors </li></ul>
    3. 4. <ul><li>a porphyrin-like ring with a central cobalt ( Co ) atom attached to a nucleotide </li></ul>
    4. 5. <ul><ul><li>Cyanocobalamin </li></ul></ul><ul><ul><li>Hydrox ocobalamin </li></ul></ul>
    5. 6. <ul><li>Mostly animal products: </li></ul><ul><ul><ul><li>Meat </li></ul></ul></ul><ul><ul><ul><li>Fish </li></ul></ul></ul><ul><ul><ul><li>Eggs </li></ul></ul></ul><ul><ul><ul><li>Milk and Milk products like yogurt </li></ul></ul></ul><ul><li>fortified with Vitamin B 12 : </li></ul><ul><ul><ul><li>Breakfast Cereals </li></ul></ul></ul><ul><ul><ul><li>Bread </li></ul></ul></ul>
    6. 7. <ul><li>U ltimate source : microbial synthesis </li></ul><ul><ul><ul><li> not synthesized by animals / plants. </li></ul></ul></ul><ul><li>M ust be converted to methyl-B 12 o r ado-B 12 </li></ul><ul><li>D aily diet = 5-25 μg </li></ul><ul><li>D aily requirement = 2-3 μg. </li></ul><ul><li>= extrinsic factor </li></ul><ul><li>Role: DNA synthesis </li></ul>
    7. 8. <ul><li>C onversion of methyl-FH 4 to FH 4 </li></ul><ul><ul><li> synthesis DNA </li></ul></ul><ul><li>Iso merisation of methylmalonyl-CoA to succinyl-CoA . </li></ul>
    8. 9. <ul><li>Methyl-FH 4 donates the methyl group to B 12 , the cofactor. </li></ul><ul><li>The methyl group is then transferred to homocysteine to form methionine </li></ul><ul><li>Deficiency: “methylfolate trap” </li></ul>Synthesis of DNA
    9. 10. <ul><li>Vit B12 deficiency : acummulation of methyl malonate-CoA  basis of neuropathy in vit B12 deficiency </li></ul>
    10. 11. <ul><li>Cobalamin is a cofactor for the enzyme Methylmalonyl-CoA mutase which converts methylmalonyl-CoA to succinyl-CoA . </li></ul><ul><li>Succinyl-CoA enters the Krebs cycles and goes into nerves to make myelin . </li></ul><ul><li>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. </li></ul>
    11. 12. <ul><li>Normal B-12 absorption: </li></ul><ul><ul><li>Dietary B-12 binds to R factor in saliva and gastric juices. </li></ul></ul><ul><ul><li>In duodenum, pancreatic enzymes promote dissociation from R factor and binding to Intrinsic Factor (IF) </li></ul></ul><ul><ul><li>IF-B12 complex taken up by ileal receptor cubilin. </li></ul></ul><ul><ul><li>Released into plasma bound to transcobalamines TC I, II, or III. </li></ul></ul><ul><ul><li>Enters cells through receptor mediated endocytosis and metabolized into two coenzymes: adenosyl-Cbl and methyl-Cbl. </li></ul></ul>
    12. 13. <ul><li>Another mechanism for B 12 absorption involves diffusion and not IF : jejunum </li></ul><ul><li>In circulation, cobalamin binds to transcobalamin II; transporting the vitamin from the enterocyte to the liver and other organs </li></ul><ul><li>Biliary excretion of B 12 is much higher than excretion in urine or feces </li></ul>
    13. 15. <ul><li>I t can take up to 20 years to show symptoms of deficiency in people who have recently changed to low-B 12 diets !!! </li></ul><ul><ul><li>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. </li></ul></ul>
    14. 16. V egetarian P ernicious Anemia I leal disease I iver disease
    15. 17. <ul><li>P ernicious anaemia :deficiency IF </li></ul><ul><li>Dietary deficiency: vegetarian </li></ul><ul><li>Malabsorption syndromes (>>>) : </li></ul><ul><ul><li>stagnant loop syndrome , Crohn’s disease, Fish tape worm infestation, gastrectomy </li></ul></ul><ul><li>↑ requirements: </li></ul><ul><ul><li>pregnancy, hemolytic anemia, hepatic disease </li></ul></ul><ul><li>Vit b12 absorption test </li></ul><ul><li>Neurologic syndrome: Vit B12 deficiency </li></ul>
    16. 18. <ul><li>Caused by ↓ absorption </li></ul><ul><ul><li>↓ intrinsic factor </li></ul></ul><ul><ul><li>Interference of absorption in the terminal ileum </li></ul></ul><ul><ul><ul><li>e.g. Colon resection in Crohn's disease </li></ul></ul></ul><ul><li>Clinical form: </li></ul><ul><ul><li>Pernicious anemia </li></ul></ul><ul><ul><li>Neurological disease </li></ul></ul><ul><ul><ul><li>peripheral neuropathy , D ementia , subacute combined degeneration of the spinal cord </li></ul></ul></ul><ul><ul><li>Abnormalities of epithelial tissue , </li></ul></ul><ul><ul><ul><li>e.g. sore tongue and malabsorption </li></ul></ul></ul>
    17. 19. <ul><li>Lab: </li></ul><ul><ul><li>↓ serum vit B12 (N: 170-925 nanogram/1) </li></ul></ul><ul><li>Blood film: </li></ul><ul><ul><li>pancytopenia, anisopoikilocytosis with oval macrocytes and hypersegmented neutrophils; the marrow is megaloblastic </li></ul></ul><ul><li>Schilling test : </li></ul><ul><ul><li>distinguish between gastric and intestinal causes </li></ul></ul>
    18. 20. <ul><li>Schilling Test </li></ul><ul><ul><li>Stage I </li></ul></ul><ul><ul><ul><li>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% ) . </li></ul></ul></ul><ul><ul><li>Stage II </li></ul></ul><ul><ul><ul><li>only if Stage I is abnormal. </li></ul></ul></ul><ul><ul><ul><li>Repeat Stage I, except with the addition of added oral IF which should normalize B-12 absorption in P.A., but not intestinal malabsorption. </li></ul></ul></ul>
    19. 23. <ul><li>Contraindication </li></ul><ul><ul><li>Inconclusively diagnosed anaemia </li></ul></ul><ul><ul><li>Allergic to cobalt </li></ul></ul><ul><li>Interaction </li></ul><ul><ul><li>Alcohol, aminosalicylic acid, neomicine and colchicine may decrease the absorption of oral vit B12 </li></ul></ul>
    20. 24. <ul><li>Hydroxocobalamin is preferred to cyanocobalamin : </li></ul><ul><li>First choice : injection </li></ul><ul><li>Initial dose: </li></ul><ul><ul><li>hydroxocobalamin 1 mg i.m. every 2-3 days for 5 doses to induce remission and to replenish stores </li></ul></ul><ul><li>Maintanance dose: 1 mg/3 months </li></ul><ul><li>Response: </li></ul><ul><ul><li>Feel better : 2 days </li></ul></ul><ul><ul><li>Reticulocyte peak : 5-7 days </li></ul></ul><ul><ul><li>Hb, RBC, Ht ↑ : first week  normalize: 2 months </li></ul></ul><ul><ul><li>Watch: hypokalemia!! </li></ul></ul>
    21. 25. <ul><li>If injections are refused </li></ul><ul><ul><li>rare allergy, bleeding disorder </li></ul></ul><ul><ul><li>Alternative: snuff , aerosol , oral </li></ul></ul><ul><ul><li>Large daily oral doses (1000 micrograms) </li></ul></ul><ul><ul><ul><li>depleted stores must be replaced by parenteral cobalamin before switching to the oral preparation; </li></ul></ul></ul><ul><ul><ul><li>the patient must be compliant; </li></ul></ul></ul><ul><ul><ul><li>monitoring of the blood must be more frequent </li></ul></ul></ul><ul><ul><ul><li>adequate serum vitamin B12 levels must be demonstrated. </li></ul></ul></ul>
    22. 26. <ul><li>Synthetic vitamin B 12 </li></ul><ul><li>Cyanocobalamin, hydroxocobalamin </li></ul><ul><li>Oral cyanocobalamin : well absorbed, highly protein bound to the transcobalamins </li></ul><ul><li>Metabolize in the liver, followed by biliary and urinary excretion </li></ul><ul><li>T 1/2 is about 6 days </li></ul><ul><li>Cyanocobalamin injection containing benzyl alcohol : should not be used for neonates or immature infants </li></ul>
    23. 27. <ul><li>Reduction of absorption of B 12 from GI tract </li></ul><ul><ul><li>excessive consumption of ethanol for longer than 2 weeks </li></ul></ul><ul><ul><li>prolonged use of cholestyramine, colchicine </li></ul></ul><ul><ul><li>large doses of ascorbic acid may destroy B 12 </li></ul></ul>
    24. 28. <ul><li>Folate (Folic Acid) can mask signs of B 12 deficiency </li></ul><ul><ul><li>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. </li></ul></ul>
    25. 29. <ul><li>Usually do not occur </li></ul><ul><li>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. </li></ul>
    26. 30. <ul><li>Exposure to Nitrous Oxide can cause B 12 deficiency in cases of abuse, anesthesia usage during surgery, or occupational exposure for hospital workers. </li></ul><ul><li>NO actually inactivates B 12 , so while those affected have enough in their system, they are effectively B 12 deficient . </li></ul>
    27. 31. <ul><li>needs an 'intrinsic factor ' for absorption in terminal ileum. It is stored in the liver. </li></ul><ul><li>It is required for: </li></ul><ul><ul><li>synthesis of purines and pyrimidines (see above) </li></ul></ul><ul><ul><li>isomerisation of methylmalonyl-CoA to succinyl-CoA. </li></ul></ul><ul><li>Deficiency : pernicious anaemia , </li></ul><ul><li>Vitamin B 12 is given by injection to treat pernicious anaemia. </li></ul>
    28. 33. <ul><li>composed of a heterocycle, p-aminobenzoic acid, and glutamic acid </li></ul>
    29. 34. Folate: Pharmacodynamics
    30. 35. 5-FU methotrexate
    31. 36. <ul><li>Human requirement : </li></ul><ul><ul><li>varies from 25-35 mcg/d in infancy to up to 100 mcg/d in adults </li></ul></ul><ul><li>Total body folic acid stores : </li></ul><ul><ul><li>5-10 mg, half of which is stored in the liver as N-5-methyltetrahydrofolate </li></ul></ul><ul><li>> 2% is degraded daily </li></ul><ul><ul><li>so a continuous dietary is essential </li></ul></ul>
    32. 37. <ul><li>Active absorption : mainly in the proximal part of the small intestine </li></ul><ul><li>Conjugate in the epithelial cells converts the polyglutamates into absorbable monoglutamates </li></ul><ul><li>Pharmaceutical product : completely absorbed in the upper duodenum, even in the presence of malabsorption </li></ul><ul><li>Excret ion : entirely as metabolites by the kidney </li></ul>
    33. 39. Folate: Pharmacokinetics Inadequate dietary supply Small intestinal disease Uremia alcoholism, hepatic disease Vitamin B12 deficiency
    34. 40. <ul><li>Etiology : </li></ul><ul><ul><li>Most causes : inadequate diet, alcoholism, pregnancy, malabsorption syndrome </li></ul></ul><ul><ul><li>Other causes : increased requirement, enhanced metabolism, interference in the metabolism </li></ul></ul><ul><li>Several reasons for folate def. in alcoholics </li></ul><ul><ul><li>reduced dietary intakes, inactivation of folate conjugate, impaired enterohepatic cycling, depletion of liver folate stores </li></ul></ul>
    35. 41. <ul><li>More often malnourished than those with cobalamin deficiency </li></ul><ul><li>Gastrointestinal manifestations </li></ul><ul><ul><li>More widespread and more severe than those of pernicious anemia </li></ul></ul><ul><ul><li>Diarrhea is often present </li></ul></ul><ul><ul><li>Cheilosis </li></ul></ul><ul><ul><li>Glossitis </li></ul></ul><ul><li>Neurologic abnormalities do not occur </li></ul>
    36. 42. <ul><li>Negative folate balance (decreased serum folate) </li></ul><ul><li>Decreased RBC folate levels and hypersegmented neutrophils </li></ul><ul><li>Macroovalocytes, increased MCV, and decreased hemoglobin </li></ul>
    37. 43. <ul><li>Diagnosis : </li></ul><ul><li>Megaloblastosis </li></ul><ul><ul><li>possibly due to folic acid deficiency must be interpreted in the light of B 12 status </li></ul></ul><ul><ul><li>Peripheral blood and bone marrow biopsy look exactly like B12 deficiency </li></ul></ul><ul><li>Reduced folate tissue levels : </li></ul><ul><ul><li>erythrocyte folate concentration <140 ng/ml </li></ul></ul><ul><ul><li>more reliable of tissue stores </li></ul></ul><ul><li>Plasma folate level : <3 ng/ml—fluctuates </li></ul><ul><li>Only increased serum homocysteine levels but NOT serum methylmalonic acid levels </li></ul>
    38. 44. <ul><li>Management : </li></ul><ul><li>Folic acid should not be given until B 12 def. and pernicious anemia have been excluded </li></ul><ul><li>Oral dose: 1 mg/day </li></ul><ul><li>Absorption is normal : 50-100 mcg/d </li></ul><ul><li>Malabsorption : 250-500 mcg/d </li></ul><ul><li>To replenish depleted folate stores, a daily dose of 1-2 mg/d for 2-3 weeks </li></ul><ul><li>Duration of therapy depend on underlying causes : 3-4 months to clear folate-deficient erythrocytes from the blood </li></ul>
    39. 45. <ul><li>Prophylactic folate therapy : </li></ul><ul><ul><li>pregnancy, particularly in women with poor diets, multiple pregnancies, or thalassemia minor : 300 mcg/d in the last trimester </li></ul></ul><ul><li>Monitoring : </li></ul><ul><ul><li>Reticulocyte count : peaks 5-8 days after treatment </li></ul></ul><ul><ul><li>Increase Hct </li></ul></ul><ul><ul><li>Decrease to normal MCV </li></ul></ul>
    40. 46. <ul><li>Vitamin B 12 deficiency anemia can be temporarily corrected by folate supplementation </li></ul><ul><li>However, this does not correct the neurologic deficits </li></ul><ul><ul><li>Folate “draws” vitamin B 12 away from neurologic system for RBC production and can exacerbate combined systems degeneration </li></ul></ul>
    41. 47. <ul><li>Megaloblastic Anemia </li></ul><ul><ul><li>due to inadequate dietary intake of folic acid </li></ul></ul><ul><ul><li>due to chronic alcoholism, pregnancy, infancy, impaired utilization: uremia, cancer or hepatic disease. </li></ul></ul><ul><li>A nemia associated with dihydrofolate reductase inhibitors. </li></ul><ul><ul><li>i.e. Methotrexate (Cancer chemotherapy), Pyrimethamine (Antimalarial) </li></ul></ul><ul><ul><li>Administration of citrovorum factor (methylated folic acid) alleviates the anemia. </li></ul></ul>
    42. 48. <ul><li>Ingestion of drugs that interfere with intestinal absorption and storage of folic acid. </li></ul><ul><ul><li>Mechanism- inhibition of the conjugases that break off folic acid from its food chelators. </li></ul></ul><ul><ul><li>Ex. – phenytoin, progestin/estrogens (oral contraceptives) </li></ul></ul><ul><li>Malabsorption – Sprue, Celiac disease, partial gastrectomy. </li></ul><ul><li>Rheumatoid arthritis – increased folic acid demand or utilization. </li></ul>
    43. 49. <ul><li>Oral replacement therapy </li></ul><ul><li>Folate prophylaxis </li></ul><ul><ul><li>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) </li></ul></ul><ul><ul><li>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. </li></ul></ul><ul><ul><li>Prophylactic folate is also recommended in other states of increased demand such as long-term hemodialysis and chronic haemolytic disorders </li></ul></ul>
    44. 50. <ul><li>Dark green leafy vegetables, like spinach </li></ul><ul><li>Broccoli, asparagus, green peas and okra </li></ul><ul><li>Orange juice </li></ul><ul><li>Papaya </li></ul><ul><li>Beans, lentils and black-eyed peas </li></ul><ul><li>Soybeans and tofu </li></ul><ul><li>Peanut butter </li></ul><ul><li>Fortified foods: Cereal, rice, pasta, tortillas, grits </li></ul>Be sure to eat 5 servings of fruits & vegetables such as these every day!
    45. 52. <ul><li>Drugs implicated in causing : </li></ul><ul><li>* malabsorption ? * impaired metabolism </li></ul><ul><li>- phenytoin - methotrexate </li></ul><ul><li>- barbiturates - pyrimethamine </li></ul><ul><li>- sulfasalazine - trimethoprim </li></ul><ul><li>- cholestyramine - pentamidine </li></ul><ul><li>- oral contraceptives </li></ul>
    46. 53. <ul><li>Alcohol </li></ul><ul><li>Tobacco </li></ul><ul><li>Aspirin, ibuprofen, naprosyn and acetaminophen </li></ul><ul><li>Antacids & anti-ulcer medications </li></ul><ul><li>Some antiseizure medications </li></ul><ul><li>Some anticancer drugs </li></ul><ul><li>Some antibiotics/ antibacterials </li></ul><ul><li>Oral hypoglycemic agents </li></ul>Source: Folicacid.net .
    47. 54. <ul><li>No known level at which it is toxic , even in high amounts </li></ul><ul><li>Even if you eat fruits and vegetables containing folic acid, eat a bowl of cereal and take a multivitamin with folic acid in one day, you would not have a problem with too much folic acid </li></ul>
    48. 55. <ul><li>do not occur even with large doses of folic acid </li></ul><ul><li>except possibly in vitamin B 12 deficiency , </li></ul><ul><ul><li>the blood picture may improve and give the appearance of cure while the neurological lesions get worse. </li></ul></ul><ul><ul><li>I mportant to determine whether a megaloblastic anaemia is caused by a folate or a vitamin B 12 deficiency. </li></ul></ul>
    49. 56. Mechanism Effect Indication Pharmacokinetic
    50. 57. <ul><li>Color atlas of pharmacology </li></ul><ul><li>Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 11th ed. </li></ul><ul><li>Clinical Pharmacology, 9th Ed </li></ul><ul><li>USMLE Pharmacology Recall </li></ul><ul><li>Pharmacology for the health care profession </li></ul><ul><li>Pharmacology Rang et al 5th Edition </li></ul><ul><li>Basic and Clinical Pharmacology 11th Ed, Katzung </li></ul><ul><li>Desk reference of clinical pharmacology </li></ul>

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