Hematinic II

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Hematinic 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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