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  1. 1. Hematinics
  2. 2. • Hematinics are the agents used a) Treatment of anemia b) Increase the number of RBC or hemoglobin content of RBC or both when there is deficiency
  3. 3. Normal erythropoiesis Pluripotent stem cell Erythroid burst forming unit Erythroid colony forming unit Within BM Erythroblast Reticulocyte Mature red cell Peripheral blood
  4. 4. Normal erythropoiesis • Erythropoietin production is impaired in conditions such as RA, cancer and Sickle cell anemia • Normally survive for 120 days
  5. 5. Normal erythropoiesis • Destroyed by reticuloendothelial system found in spleen and BM • Iron is removed from haem component of Hb and transported back into bone marrow for reuse
  6. 6. Normal erythropoiesis • Pyrole ring from globin is excreted as conjugated bilirubin by the liver and the polypeptide portion enters the body’s protein pool
  7. 7. Anemia
  8. 8. Introduction • Not a single disease • Results from a number of different pathologies • Defined as a reduction from the normal quantity of Hb in blood • WHO defines anemia as Hb levels less than 13 g/dl for males and less than 12 g/dl for females • Low Hb levels results in decreased oxygen carrying capacity of blood
  9. 9. Epidemiology • Most common condition resulting in significant morbidity and mortality • Worldwide: Over 50% of pregnant women and 40 % of infants are anemic
  10. 10. Aetiology Two different mechanisms: 1. Reduced Hb synthesis (due to lack of nutrient or bone marrow failure) Reduced proliferation of precursors or defective maturation of precursors or both
  11. 11. Aetiology • Increased Hb loss due to haemorrhage (red cell loss) or hemolysis (red cell destruction) (More than one cause can be found in a patient)
  12. 12. Classification of anemia: A) Morphological classification: 1) normocytic normochromic anemia -acute blood loss -marrow failure ( aplastic anemia) - chronic renal failure - anemia of chronic disease 2) Microcytic hypochromic anemia - iron deficiency anemia - thalessemia 3) Macrocytic Anemia : - Vitamin B-12 deficiency - folic acid deficiency
  13. 13. B) Patho-physiological classification: 1) Hemorrhagic or blood loss anemia - acute blood loss - chronic blood loss 2) Impaired RBC production a) Nutritional deficiency anemia : - iron deficiency anemia - Vitamin deficiency anemia - Protein – energy malnutrition b) Aplastic Anemia - leukemia - lymphoma - myeloproliferative diseases c) Chronic Renal Failure d) Anemia of chronic Disease 3) Hemolytic Anemia
  14. 14. Symptoms and signs of anemia Symptoms • Fatigue • Faintness • Headache • Palpitations • Angina of effort • Breathlessness Signs • Pallor • Tachycardia • Systolic flow murmur • Cardiac failure • Koilonychia • Jaundice
  15. 15. Classification of hematinics 1) Drugs used in anemias : 2) Hematopoietic growth factors a) Drugs used in iron deficiency anemia: i) iron preparations ii) copper iii) cobalt iv) pyridoxin v) riboflavin b) drugs used in megaloblastic anemias : i) Vit B-12 ii) Folic acid iii) Vitamin –C a) erythropoetin b) myeloid growth factors : - G-CSF ( filgrastim) - GM-CSF ( sargramostim) - pegfilgrastim c) megakaryocyte growth factors: - interleukin -11 (oprelvekin) - thrombopoetin
  16. 16. IRON
  17. 17. Iron Absorption , transport and strorage of iron
  18. 18. Iron distribution
  19. 19. Pharmacokinetics ABSORPTION • absorbs 5–10% of iron ingested or about 0.5–1 mg daily. • normally absorbed in the duodenum and proximal jejunum. • absorption increases in response to low iron stores or increased iron requirements. • abundant in meat. heme iron in meat hemoglobin and myoglobin can be absorbed intact without first dissociated into elemental iron . Nonheme iron in foods and iron in inorganic iron salts and complexes must be reduced to ferrous iron (Fe2+) before it can be absorbed by intestinal mucosal cells. two mechanisms: i) active transport of ferrous iron and ii) absorption of iron complexed with heme • divalent metal transporter, DMT1,. • actively transported into the blood across the basolateral membrane, probably by the transporter IREG1, also known as ferroportin1. • Excess iron can be stored in the mucosal cell as ferritin, a watersoluble complex consisting of a core of ferric hydroxide covered by a shell of a specialized storage protein called apoferritin.
  20. 20. TRANSPORT • transported in the plasma bound to transferrin, a -globulin that specifically binds two molecules of ferrous iron The transferrin-iron complex enters maturing erythroid cells by a specific receptor mechanism. Transferrin receptors internalize the transferrin-iron complex through the process of receptor-mediated endocytosis. • Increased erythropoiesis is associated with an increase in the number of transferrin receptors on developing erythroid cells. Iron store depletion and iron deficiency anemia are associated with an increased concentration of serum transferrin. STORAGE • primarily as ferritin, in macrophages in the liver, spleen, and bone, and in parenchymal liver cells. Apoferritin synthesis is regulated by the levels of free iron. • Ferritin is detectable in serum. Since the ferritin 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. ELIMINATION • Small amounts are lost in the feces by exfoliation of intestinal mucosal cells, and trace amounts are excreted in bile, urine, and sweat.
  21. 21. Indications of oral iron therapy Prophylactic use : 1) pregnancy- from 4th month to lactation. 2) Menstruation 3) Infancy and childhood 4) Premature babies and babies weaned late 5) Professional blood donors Therapeutic use : 1) Iron deficiency anemia 2) Iron deficiency anemia due to: - menorrhagia - peptic ulcer - piles - hook worm infestation 3) Malabsorption syndrome 4) Anemia of pregnancy 5) Treatment of severe pernicious anemia
  22. 22. Adverse effects of oral iron therapy 1) Gastrointestinal upset - nausea - heart burn - upper abdominal discomfort - constipation or diarrhoea - abdominal cramps 2) Hemochromatosis 3) Obscure the diagnosis of git bleeding due to balckening of stools ( melena )
  23. 23. Parenteral iron preparations: • Iron dextran is a stable complex of ferric hydroxide and low-molecular-weight dextran containing 50 mg of elemental iron per milliliter of solution. It can be given by deep intramuscular injection or by intravenous infusion, although the intravenous route is used most commonly – headache, light-headedness, fever, arthralgias, nausea and vomiting, back pain, flushing, urticaria, bronchospasm, and, rarely, anaphylaxis and death. – hypersensitivity reaction to the dextran component. Hypersensitivity reactions may be delayed for 48–72 hours after administration. – Anaphylactic reactions • Iron-sucrose complex and iron sodium gluconate complex only by the intravenous route.
  24. 24. Indications of parenteral iron therapy • unable to tolerate ( GIT upset) • unable to absorb oral iron ( malabsorption syndrome, ulcerative colitis , achlorhydria, surgical resection of gut) • patients unreliable in taking drug( extreme old age and mentally ill patients ) • patients with extensive chronic blood loss who cannot be maintained with oral iron alone. • Immediate iron therapy need :premature birth, pregnancy , infancy • Blood loss from hemorrhoids , worm infection
  25. 25. • Total iron requirement (mg) = 4.4* body weight (kg)* Hb deficit ( g/dL) Adverse effects of parenteral iron • Local discomfort • Discoloration of skin • Headache ,fever , arthralgia • Anaphylactic reaction • Respiratory distress • Circulatory collapse • Severe chest pain • Hemolysis • tachycardia • Bronchospasm Contraindications : • History of asthma • Acute phase of kidney disease • History of allergy
  26. 26. Acute iron poisoning Fatal dose : 2-10 grams ( 10 tablets for children) Clinical course of acute iron poisoning : 1) First phase: 0.5-1 hrs after ingestion • • • • Abdominal pain , nausea , vomiting , diarrhoea , with black or bloody stool ( children) Constipation with black stool ( adults ) Drowsiness , cardiovascular collapse Coma 2) Second phase :8-16 hrs after ingestion • Period of improvement or pass onto third phase 3) Third phase : 24 hrs after ingestion • Cardiovascular collapse • Convulsion, coma • Liver damage 4) Fourth phase : 1-2 months after ingestion • Recovery with pyloric stenosis due to scarring
  27. 27. Treatment 1) Prevent further absorption: • induce vomiting or gastric lavage by 1% NaHCO3 • give egg yolk or milk orally • Desferroxamine (5-10g in 100 ml saline ) 2) Specific antidote : • Desferroxamine : 1-2 g i/v or i/m 3) Supportive measures : • maintenance of fluid , electrolytes and acid base balance • Diazepam or phenobarbitone i/v • Cardiopulmonary support
  28. 28. Chronic iron poisoning – Excess iron deposited in heart , liver , pancreas and other organs leading to organ failure and death. Results from: – Excessive parenteral therapy – Repeated blood transfusion to treat hemolytic anemia – Inherited disorder • Hemosiderosis – Excess accumulation of hemosiderin in liver • Hemochromatosis : – Inherited disorder , excessive iron absorption – Brown pigmentation of skin – Pancreatic damage leading to diabetes – Cirrhosis of liver with ascites – Hepatic coma – Gonadal atrophy Treatment: 1) Intermittent phlebotomy (Removal of one unit of blood per week ) 2) Iron chelation therapy – desferoxamine, deferasirox (oral) 3) High intake of tea
  29. 29. Desferroxamine • Isolated from Streptomyces pilosus • Has high affinity for ferric iron. Competes with iron of ferritin and hemosiderin . • Iron+desferroxamine = ferrioxamine( nonabsorbable) and is excreted in bile and faeces • Oral absorption poor , so given parenterally. • Therapeutically used in acute iron poisoning and diagnosis and treatment of chronic iron poisoning. • 100 mg chelates 8.5 mg of iron • Adverse effects: – – – – – – – – – – – – Hypotension Pruritus Wheals Rash Anaphylaxis Dysuria Abdominal discomfort Fever Leg cramps Tachycardia Neurotoxicity Visual and auditory changes
  30. 30. Folic acid • Structure 3 building blocks a) pteridine group b) para – amino benzoic acid ( PABA) c) glutamic acid • Not present in nature but parent compound of folates
  31. 31. • Sources : yeast , liver , green vegetables Fruits , nuts and cereals Daily requirements : Adult: 50 mcg / day Pregnant women : 100-200 mcg / day Lactating women : 100-200 mcg / day
  32. 32. Pharmacokinetics : • • • • Route : oral , parenteral Absorption: from proximal jejunum Distribution: widely distributed Folates are excreted in the urine and stool and are also destroyed by catabolism • folic acid deficiency and megaloblastic anemia can develop within 1–6 months after the intake of folic acid stops • Dietary folates 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")
  33. 33. Pharmacodynamics • Functions : Tetrahydrofolate cofactors participate in one-carbon transfer reactions 1) DNA synthesis : cofactors for the synthesis of purines and pyrimidines 2) Synthesis of thymidylic acid : enzyme thymidylate synthase catalyzes the transfer of the one-carbon unit of N5,N10methylenetetrahydrofolate to deoxyuridine monophosphate (dUMP) to form dTMP
  34. 34. Causes of folate deficiency A) Nutritional ( major causes) 1) poor intake due to • old age • Starvation • Anorexia • • • 2) gastrointestinal disease Partial gastrectomy Coeliac disease Crohn’s disease B) Poor Utilisation: 1) Physiological • pregnancy • starvation • prematurity 2) Pathological • hemolytic disease with excess RBC formation • malignant disease with increased cell turnover • inflammatory disease
  35. 35. C) Malabsorption syndrome D) Antifolate drugs : – anticonvulsants ( phenytoin , primidone ) – methotrexate – Pyrimethamine – Trimethoprim – Sulfonamides
  36. 36. Effects of folate deficiency • Megaloblastic anemia • Neural tube defect ( spina bifida ) in the foetus High-risk patients: • pregnant women • patients with alcohol dependence, • hemolytic anemia • liver disease • certain skin diseases • patients on renal dialysis
  37. 37. Indications of folic acid 1) Treat magaloblastic anemia due to folate deficiency 2) Pregnant women 3) Premature infants 4) Patients with hemolytic anemia 5) Liver disease 6) Chronic skin disease 7) Renal dialysis 8) With anti convulsant drugs
  38. 38. • Folinic acid (leucovorin calcium, citrovorum factor) is the 5-formyl derivative of tetrahydrofolic acid used in methotrexate therapy • Folic acid in large amounts may counteract the antiepileptic effect of phenobarbital, phenytoin, and primidone, and increase the frequency of seizures in susceptible children
  39. 39. Preparations and doses of folic acid : Liquid oral preparations and injectables in combination form Given im Dose Therapeutic : 2-5 mg / day Prophylactic : 0.5 mg / day
  40. 40. Vit B12 • consists of a porphyrin-like ring with a central cobalt atom attached to a nucleotide. • Deoxyadenosylcobalamin and methylcobalamin are the active forms • The chief dietary source of vitamin B12 is microbially derived vitamin B12 in meat (especially liver), eggs, and dairy products • extrinsic factor
  41. 41. Pharmacokinetics • stored, primarily in the liver, with an average adult having a total vitamin B12 storage pool of 3000–5000 mcg • normal daily requirements of vitamin B12 are only about 2 mcg • is absorbed only after it complexes with intrinsic factor, a glycoprotein secreted by the parietal cells of the gastric mucosa • the intrinsic factor-vitamin B12 complex is subsequently absorbed in the distal ileum by a highly specific receptor-mediated transport system. • Nutritional deficiency is rare but may be seen in strict vegetarians after many years without meat, eggs, or dairy products. • vitamin B12 is transported to the various cells of the body bound to a plasma glycoprotein, transcobalamin II • Stored in liver • Excreted through urine
  42. 42. Pharmacodynamics 1) transfer of a methyl group from N5methyltetrahydrofolate to homocysteine, forming methionine • conversion of the major dietary and storage folate, N5-methyltetrahydrofolate, to tetrahydrofolate necessary for transfer of onecarbon groups. 2) isomerization of methylmalonyl-CoA to succinylCoA by the enzyme methylmalonyl-CoA mutase
  43. 43. Indications of Vit B12 a) b) c) Megaloblastic anemia Neurologic syndrome associated with cobalamin deficiency Pernicious anemia • Vitamin B12 for parenteral injection is available as cyanocobalamin or hydroxocobalamin Administered im Initial therapy should consist of 100–1000 mcg of vitamin B12 Maintenance therapy consists of 100–1000 mcg intramuscularly once a month for life neurologic abnormalities are present, maintenance therapy injections should be given every 1–2 weeks for 6 months before switching to monthly injections oral doses of 1000 mcg of vitamin B12 daily are usually sufficient to treat patients with pernicious anemia • • • • •
  44. 44. Erythropoetin • most important regulator of the proliferation of committed progenitors (CFU-E) and their immediate progeny • cytokine receptors that use protein phosphorylation and transcription factor activation to regulate cellular function • induces release of reticulocytes from the bone marrow • Hypoxia-inducible factor (HIF-1)--a sensor in the kidney detects changes in oxygen delivery to modulate the erythropoietin secretion
  45. 45. • Recombinant human erythropoietin (epoetin alfa), produced using engineered Chinese hamster ovary cells • supplied in single-use vials of from 2000 to 40,000 units/ml for intravenous or subcutaneous administration, three times a week • epoetin alfa is cleared from plasma with a half-life of 4 to 8 hours. • erythropoiesis-stimulating protein or darbapoetin alfa • Epoetin alfa is effective in the treatment of anemias associated with surgery, AIDS, cancer chemotherapy, prematurity, and certain chronic inflammatory conditions • rapid increase in hematocrit and hemoglobin and include hypertension and thrombotic complications • absolute or functional iron deficiency may develop • Serious thromboembolic events have been reported, including migratory thrombophlebitis, microvascular thrombosis, pulmonary embolism, and thrombosis of the retinal artery