Hematinic I


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Hematinic I

  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. http://www.theironfiles.co.uk/Sickle-cell/General/SCDBlood.html
  4. 5. http://www.theironfiles.co.uk/Sickle-cell/General/SCDBlood.html
  5. 6. <ul><li>4 globin + 1 haem . </li></ul><ul><li>Haem </li></ul><ul><ul><li>consists of a tetrapyrrole porphyrin ring containing ferrous (Fe 2+ ) iron. </li></ul></ul><ul><ul><li>Each haem group can carry 1 oxygen molecule </li></ul></ul><ul><ul><ul><li>bound reversibly to Fe 2+ and to a histidine residue in the globin chain  basis of oxygen transport. </li></ul></ul></ul>
  6. 7. <ul><li>Definition: ↓ [Hb] i n blood & / RBC per age, sex and geographical location. </li></ul><ul><li>Normal Hb : </li></ul><ul><ul><li>14g to 16g /dl in Male </li></ul></ul><ul><ul><li>13g to 15g /dl in Female </li></ul></ul><ul><li>Acute: fatigue  chronic : asymptomatic. </li></ul><ul><li>Classification based on indices of red cell are : </li></ul><ul><ul><li>hypochromic, microcytic anaemia </li></ul></ul><ul><ul><li>macrocytic anaemia </li></ul></ul><ul><ul><li>normochromic normocytic anaemia </li></ul></ul><ul><ul><li>mixed pictures. </li></ul></ul>
  8. 10. <ul><li><<<< INPUT: </li></ul><ul><li>Nutritional </li></ul><ul><li>deficiency </li></ul>IMBALANCE <ul><li>BROKEN MACHINE </li></ul><ul><li>- Synthesis << </li></ul><ul><li>- Chronic disease </li></ul><ul><li>>>>OUTPUT: </li></ul><ul><li>Bleeding </li></ul><ul><li>Haemolysis </li></ul>
  9. 11. <ul><li><<<< INPUT: </li></ul><ul><li>Nutritional </li></ul><ul><li>deficiency </li></ul>IMBALANCE <ul><li>BROKEN MACHINE </li></ul><ul><li>- Synthesis << </li></ul><ul><li>- Chronic disease </li></ul><ul><li>>>>OUTPUT: </li></ul><ul><li>Bleeding </li></ul><ul><li>Haemolysis </li></ul>FIX THE UNDERLYING CAUSES!!
  10. 12. <ul><li>↓↓↓↓ FORMATION </li></ul><ul><li>1.       Nutritional </li></ul><ul><ul><li>Iron Deficiency    </li></ul></ul><ul><ul><li>Folic Acid/ Vit B 12   Deficiency </li></ul></ul><ul><ul><li>Protein Deficiency </li></ul></ul><ul><li>2.       Decreased Synthesis </li></ul><ul><ul><li>Aplastic Anaemia  </li></ul></ul><ul><ul><li>Replacement of BM (e.g. Leukaemia) </li></ul></ul><ul><ul><li>Thalassaemia </li></ul></ul><ul><li>3.       Chronic Disorder </li></ul><ul><ul><li>Kidney Disease </li></ul></ul><ul><ul><li>Advanced Malignancy </li></ul></ul><ul><ul><li>Chronic Liver Disease </li></ul></ul><ul><li>↑↑ ↑↑ DESTRUCTION </li></ul><ul><li>1.       Post Haemorrhage </li></ul><ul><ul><li>Acute & chronicBlood Loss </li></ul></ul><ul><li>2.       Excessive Haemolysis </li></ul><ul><ul><li>Intracellular Defect (Defective RBC) </li></ul></ul><ul><ul><ul><li>Thalassaemia </li></ul></ul></ul><ul><ul><ul><li>Haemoglobinopathies </li></ul></ul></ul><ul><ul><ul><li>Sickle Cell Anaemia </li></ul></ul></ul><ul><ul><li>Extracellular Defect </li></ul></ul><ul><ul><ul><li>Rh Incompatibility </li></ul></ul></ul><ul><ul><ul><li>Auto Immune Haemolytic Anaemia </li></ul></ul></ul><ul><ul><ul><li>Certain Snake Venom </li></ul></ul></ul>
  11. 14. <ul><li>Hematinics are drugs used  to stimulate the  formation of red blood cells.  </li></ul><ul><li>Us ed primarily in the treatment of anemia </li></ul><ul><li>  Example: </li></ul><ul><ul><li>Iron </li></ul></ul><ul><ul><li>Folic Acid </li></ul></ul><ul><ul><li>Vitamin B12 </li></ul></ul>
  12. 16. <ul><li>Basic Pharmacology </li></ul><ul><li>Pharmacokinetic </li></ul><ul><ul><li>Absorption </li></ul></ul><ul><li>Pharmacodynamic </li></ul><ul><li>Indication </li></ul><ul><li>Drug Interaction </li></ul><ul><li>Side Effect </li></ul>
  13. 17. <ul><li>I mportant properties : </li></ul><ul><ul><li>several oxidation states </li></ul></ul><ul><ul><li>form stable coordination complexes </li></ul></ul><ul><li>F e + protoporfirin  Heme </li></ul><ul><li>Heme + globin  Hemoglobin </li></ul><ul><li>Hemoglobin binds O2 & provides O2 delivery </li></ul><ul><li>Fe deficiency  microcytic hypochromic anemia </li></ul><ul><li>Body content of iron: </li></ul><ul><ul><li>Essential: myoglobin, Hb, enzym, transferrin  not available for haemoglobin synthesis </li></ul></ul><ul><ul><li>Storage : Ferritin, hemosiderin  Hb synthesis </li></ul></ul>
  14. 20. P H A R M A C O K I N E T I C S
  15. 21. <ul><li>D aily diet : 10–15 mg  absorb ption 5–10% </li></ul><ul><li>Location : duodenum and proximal jejunum </li></ul><ul><li>H eme iron  directly absorbed </li></ul><ul><li>Nonheme iron  reduced to ferrous (Fe 2+ )  absorbed </li></ul><ul><li>Iron crosses the luminal membrane by active transport of ferrous iron and absorption of iron complexed with heme </li></ul><ul><li>DMT1  transporter </li></ul><ul><li>a bsorbed iron can be actively transported into the blood by ferroportin and oxidized to ferric iron (Fe 3+ ) </li></ul><ul><li>Excess iron can be stored in intestinal epithelial cells as ferritin </li></ul>
  16. 22. <ul><li>Iron is transported in the plasma bound to transferrin </li></ul><ul><li>T ransferrin-iron complex  receptor-mediated endocytosis  enters maturing erythroid cells </li></ul><ul><li>E ndosomes : ferric  ferrous  transported by DMT1  hemoglobin synthesis or stored as ferritin. </li></ul><ul><li>The transferrin-transferrin receptor complex is recycled to the plasma membrane, where the transferrin dissociates and returns to the plasma. </li></ul>
  17. 23. <ul><li>S torage : </li></ul><ul><ul><li>in intestinal mucosal cells : as ferritin </li></ul></ul><ul><ul><li>in macrophages in the liver, spleen, and bone, and in parenchymal liver cells . </li></ul></ul><ul><li>Apoferritin synthesis is regulated by the levels of free iron. </li></ul><ul><li>F erritin present in serum is in equilibrium with storage ferritin in reticuloendothelial tissues  the serum ferritin level can be used to estimate total body iron stores. </li></ul>
  18. 24. <ul><li>no mechanism for excretion </li></ul><ul><li>Small amounts are lost in the feces by : </li></ul><ul><ul><li>exfoliation of intestinal mucosal cells </li></ul></ul><ul><ul><li>trace amounts are excreted in bile, urine, and sweat </li></ul></ul><ul><ul><li> no more than 1 mg of iron per day. </li></ul></ul><ul><li>regulation of iron balance : absorption and storage </li></ul>
  19. 25. http://izzrawda.wordpress.com/2009/03/16/do-you-have-anemia/
  20. 26. <ul><li>The daily requirement of iron </li></ul><ul><ul><li>Male : 1mg / day </li></ul></ul><ul><ul><li>Female </li></ul></ul><ul><ul><ul><li>2mg / day </li></ul></ul></ul><ul><ul><ul><li>3mg / day (during pregnancy and lactation) </li></ul></ul></ul><ul><li>Iron de fi ciency anaemia can occur under the following four conditions: </li></ul><ul><ul><li>Less Intake of Fe, Vitamins and Protein </li></ul></ul><ul><ul><li>Diminished Absorption </li></ul></ul><ul><ul><li>Increased Loss </li></ul></ul><ul><ul><li>Excessive Demand </li></ul></ul>
  21. 28. <ul><li>Basically: Iron deficiency </li></ul><ul><li>Application: </li></ul><ul><ul><li>Iron deficiency due to dietary lack or to chronic blood loss. </li></ul></ul><ul><ul><li>Pregnancy: TM2 </li></ul></ul><ul><ul><li>GIT abnormality: malabsorption </li></ul></ul><ul><ul><li>Premature baby </li></ul></ul><ul><ul><li>Early treatment of pernicious anemia </li></ul></ul>
  22. 29. <ul><li>Oral: </li></ul><ul><ul><li>ferrous sulfate , ferrous succinate, ferrous gluconate and ferrous fumarate. </li></ul></ul><ul><ul><li>SE: GIT upset, blackened stool, teeth stain </li></ul></ul><ul><ul><li>Form: tablet, liquid, sustained-releas e </li></ul></ul><ul><li>Parenteral iron </li></ul><ul><ul><li>In dication: not able to absorb oral iron </li></ul></ul><ul><ul><li>Prep </li></ul></ul><ul><ul><ul><li>Deep IM: iron-dextran (50 mg Fe/mL) or iron-sorbitol </li></ul></ul></ul><ul><ul><ul><ul><li>precaution: local reaction, anaphylaxis </li></ul></ul></ul></ul><ul><ul><ul><li>Slow IV: iron dextran, sodium ferric gluconate complex, iron sucrose </li></ul></ul></ul><ul><ul><ul><ul><li>Precaution: risk of anaphylac sis!!! </li></ul></ul></ul></ul><ul><ul><li>Oral iron should not be given 24 h before i.m. begin and for 5 days after the last i.v. injection; </li></ul></ul>
  23. 31. <ul><li>Therapeutic dose: </li></ul><ul><ul><li>3-6 mg/Kg/day of elemental iron  Induces an ↑ Hb of 0.25-0.4 g/dl per day or 1%/day rise in hematocrit. </li></ul></ul><ul><li>Adequate response: </li></ul><ul><ul><li>↑ Hb of 2 g/dl after 3 weeks of tx </li></ul></ul><ul><li>Failure of response </li></ul><ul><ul><li>after 2 weeks of oral iron requires reevaluation for ongoing blood losses,infection,poor compliance or other causes of microcytic anaemia. </li></ul></ul><ul><li>Priority: oral preparation. </li></ul>
  24. 32. <ul><li>Iron chelates in the gut with tetracyclines, penicillamine, methyldopa, levodopa, carbidopa, ciprofloxacin, norfloxacin and ofloxacin; </li></ul><ul><li>it also forms stable complexes with thyroxine, captopril and biphosphonates. </li></ul><ul><li>Ingestion should be separated by 3 hours. </li></ul><ul><li>↑ absorption: vit C </li></ul><ul><li>↓ absorption: desferrioxamine , t ea ( tannins) , Ca, Zn, and bran </li></ul>
  25. 33. <ul><li>chronic infection </li></ul><ul><li>in haemolytic anaemias unless there is also haemoglobinuria </li></ul><ul><ul><li>increased erythropoiesis associated with chronic haemolytic states stimulates increased iron absorption and adding to the iron load may cause haemosiderosis. </li></ul></ul>
  26. 34. <ul><li>D ose related , include nausea, abdominal cramps and diarrhoea. </li></ul><ul><ul><li>overcome : ↓ dose or by taking the tablets after or with meals </li></ul></ul><ul><li>Acute iron toxicity </li></ul><ul><ul><li>I ngestion of large quantities of iron salts. </li></ul></ul><ul><ul><li>R esult : severe necrotising gastritis with vomiting, haemorrhage and diarrhoea  collapse </li></ul></ul><ul><ul><li>  T reatment : gastric lavage with NaHCO3, iron chelating agent, and treatment of causes. </li></ul></ul><ul><li>Chronic iron toxicity </li></ul><ul><ul><li>C aused by conditions other than ingestion of iron salts, </li></ul></ul><ul><ul><li>C ause pancreatic damage and leading to diabetes. </li></ul></ul>
  27. 37. <ul><li>Used for treatment of iron toxicity </li></ul><ul><ul><li>D esferrioxamine (Desferal) (t1/2 6 h) . </li></ul></ul><ul><ul><ul><li>not absorbed from the gut but is nonetheless given intragastrically following acute overdose (to bind iron in the bowel lumen and prevent its absorption) as well as IM and IV </li></ul></ul></ul><ul><ul><ul><li>In severe poisoning : slow IV  too fast: hypotension </li></ul></ul></ul><ul><ul><ul><li>forms a complex with ferric iron, excreted in the urine. </li></ul></ul></ul><ul><ul><li>D eferiprone </li></ul></ul><ul><ul><ul><li>orally absorbed </li></ul></ul></ul><ul><ul><ul><li>to treat iron overload in patients with thalassaemia major, in whom desferrioxamine is CI . </li></ul></ul></ul><ul><ul><ul><li>careful monitoring : Agranulocytosis and other blood dsyscrasias </li></ul></ul></ul>
  28. 38. <ul><li>Present as haemoglobin; myoglobin, cytochromes and other enzymes. </li></ul><ul><li>Absorption : Ferric iron (Fe 3+ )  ferrous iron (Fe 2+ ) </li></ul><ul><ul><li>active transport into mucosal cells in jejunum and upper ileum  transported into plasma and/or stored intracellularly as ferritin. </li></ul></ul><ul><ul><li>Iron loss occurs mainly by sloughing of ferritin-containing mucosal cells; iron is not excreted in the urine. </li></ul></ul><ul><li>Iron in plasma is bound to transferrin , and most is used for erythropoiesis. Some is stored as ferritin in other tissues. Iron from time-expired erythrocytes enters the plasma for re-use. </li></ul><ul><li>The main therapeutic preparation is ferrous sulfate . </li></ul><ul><li>Unwanted effects include gastrointestinal disturbances. Severe toxic effects occur if large doses are ingested; these can be countered by desferrioxamine, an iron chelator . </li></ul>
  29. 40. <ul><li>Basic and Clinical Pharmacology 11th Ed, Katzung </li></ul><ul><li>Pharmacology Rang et al 5th Edition </li></ul><ul><li>Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 11th ed. </li></ul><ul><li>Color atlas of pharmacology </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>