Antianemeic drugs

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Antianemeic drugs

• Agents to Tr anemia
• Dr Alia Alshanawani

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• Hematopoiesis production of erythrocytes,
  platelets, leukocytes from stem cells in ! Bone
  marrow.
• Require a constant supply of 3 essential
  nutrients
• - Iron
• - Vitamin B12
• - Folic acid
• hematopoietic growth factors.
• Anemia deficiency in O2-carrying erythrocytes.

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Anti-anemic drugs

• In iron deficiency other hypochromic anemia
• Iron
• Pyridoxine, Riboflavin, Copper
• In megaloblastic anemia
• Vit B12
• Folic acid
• Hematopoietic GFs
• Erythropoietin (in chronic renal failure).

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• Agents used to Tr anemia
• 1- Iron
• Iron deficiency is ! most common cause of chronic
  anemia.
• Total Body Iron
• 4 g in ! adult male
• 2.5 g in ! adult female
• Source meat green vegetables.

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• Iron forms ! nucleus of ! iron-porphyrin heme
  ring, which together with globin chains forms Hg.
• Hg reversibly binds O2 (delivery).
• Iron deficiency causes small erythrocytes with
  insufficient Hg are formed microcytic
  hypochromic anemia.
• PK
• All of ! iron used to support hematopoiesis is
  reclaimed from catalysis of ! Hg in aged /
  damaged erythrocytes.

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• Dietary requirements are small easily available
  in food.
• Iron absorption
• Actively absorbed in duodenum proximal jejunum.
• In ! ferric () form is complexed to other
  organic inorganic molecules.
• ! acids in ! stomach hydrolytic enzs in small
  intestine release ! iron from these complexes.
• It is then reduced to ! ferrous () form (more
  readily absorbed).
• Absorption is increased by glucose, amino
  acids ascorbic acid.
• decreased by phosphate bicarbonate
  bile acids, antacids tetracycline.
• Heme iron in meat Hg myoglobin can be absorbed
  intact.
• Iron in vegetables grains, tightly bound to
  organic compounds lt available for absorption.

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• Excess iron stored in mucosal cell as ferritin,
  a water-soluble complex.
• Distribution
• Iron is transported in ! plasma bound to
  transferrin, a ß globulin binds 2 molecules of
  ferrous iron. ! iron is transported to ! marrow
  for use /storage.
• ! transferrin-iron complex enters maturing
  erythroid cells by a specific R mechanism.

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• Storage
• When free iron levels are high, apoferritin is
  produced to sequester iron protect organs from
  toxic effect of excess free iron.
• Iron is stored in intestinal mucosal cells as
  ferritin, in macrophages in liver, spleen,
  bone.

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• A- Uses of iron
• Treatment of iron deficiency anemia
• Prevent anemia in increased iron requirement
• - premature infants,
• - children during rapid growth periods,
• - pregnant lactating women,
• - increased blood losses iron (heavy
  menstruation),
• - patients with chronic kidney disease
  treatment with GF erythropoietin (parenteral iron
  is preferred).
• - Malabsorption, inadequate iron absorption,
  GIT bleeding, gastrectomy severe small bowel
  disease.

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• B- Treatment
• Iron deficiency anemia is treated with po/
  parenteral iron.
• po iron if GIT is normal.
• 1- Po iron 200 400 mg for 3-6 months.
• Forms FERROUS sulfate, gluconate, fumarate or
  succinate.
• All are effective inexpensive.

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• SE
• N, epigastric discomfort, abdominal cramps,
• constipation/ diarrhea black stools.
• Treatment lower ! dose/ taking ! tablet
  immediately after/ with meal.

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• 2- Parenteral iron used in ! Following cases
• (postgasrectomy, small bowel section,
  inflammatory bowel disease, noncompliance of po,
  malabsorption syndrome, marked blood loss
  advanced chronic renal disease).
• Iron dextran stable complex of ferric hydroxide
  low molecular weight dextran (IM/ IV infusion).
• Advantage of IV eliminates local pain tissue
  staining (SE IM). allow delivery of entire
  iron dose.
• Also Iron sorbitol (IM)

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• SE headache, light-headness, fever, arthralgia,
  N, V, back pain, flushing, urticaria,
  Bronchospasm. Rare anaphylaxis death.
• Also dextran can cause hypersensitivity
  reactions.
• Alternative preparations
• Iron-sucrose complex iron Na gluconate
  complex. ONLY (IV) less hypersensitivity than
  dextran.

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• A- Acute iron tox (multiple blood transfusions
  /acute child iron poisoning)
• Signs symptoms
• Necrotizing gastroenteritis, V, abdominal pain,
  bloody diarrhea, followed by shock, lethargy,
  dyspnea. severe metabolic acidosis, coma
  death.
• Treatment
• Whole bowel irrigation/ gastric lavage 1
  NaHCO3.
• Antidote Deferoxamine (Desferroxamine), potent
  iron-chelating agent, bind absorbed iron
  promote its excretion in urine feces
  (intragastric, IM, SC, IV infusion).

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• B- Chronic iron tox
• Overload / hemochromatosis, result when excess
  iron is deposited in ! heart, liver, pancreas,
  other organs. It can lead to organ failure
  death.
• Causes
• patients with inherited hemochromatosis
  (excessive iron abs tissue damage),
• iron overload in patients who receive many RBCs
  transfusions over a long period of time as
  chronic hemolytic, microcytic anemia
  (thalassemias).

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• Treatment tox
• intermittent phlebotomy Removing one unit of
  blood every week until all excess iron is
  removed.
• Or parenteral deferoxamine (less efficient, more
  complicated, expensive, hazardous).
• Recent oral iron chelator deferasirox. Effective
  as deferoxamine at reducing liver iron conc
  more convenient.

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• 2- Cyanocobalamin Vitamin B 12 (extrinsic F)
• CoFactor for several essential biochemical
  reactions.
• Its Deficiency anemia, GI symptoms,
  neurological abnormalities.
• Chemistry
• porphyrin-like ring with a central cobalt atom
  nucleotide.
• Source Meat (liver), eggs, dairy products.
• For therapeutic use Cyanocobalamin
  hydroxycobolamin.

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• PK
• Stored mainly in liver
• Normal daily requirement 2 -3 mcg.
• For its absorption, it makes a complex with
  intrinsic Factor, a glycoprotein secreted by !
  parietal cells of ! gastric mucosa R mediated
  transport system in ! lumen.
• Must be converted to active forms b4 absorption
  Deoxy-adenosyl-cobalamin methyl-cobalamin.
• Vit B12 deficiency results from malabsorption due
  to lack/loss/ malfunction of intrinsic F.
• This intrinsic F may be absent in gastrectomy
  pernicious (megaloblastic) anemia.
• Nutritional deficiency (rare).
• Route of administration mainly parenteral,, IM
• Or po/ aerosol.
• Excretion kidney.

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• Pharmacodynamics
• essential enzymatic rxs require Vit B12
• Methylcobalamin as intermediate in ! transfer of
  methyl gp from N-methylTHF to homocysterine,
  forming methionine tetrahydrofolate (THFA).
• Required for purines DNA synthesis.
• Depletion of THFA prevent ! synthesis of DNA.
• Treatment Vit B12 folic acid.

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• Clinical pharm
• Features of Vit B12 deficiency
• Impaired DNA synthesis mainly RBCs
• Megaloblastic anemia (macrocytic anemia
  leukopenia / thrombocytopenia)
• Hematologic abnormalities
• GI symptoms
• Neurological syndrome paresthesia weakness in
  peripheral nerves, spasticity, ataxia.

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• Causes of vit B12 deficiency
• Pernicious anemia (Defective secretion of
  intrinsic F by ! gastric mucosal cells).
• Partial/ total gastrectomy
• Malabsorption syndrome, inflammatory bowel
  syndrome or small bowel resection.
• Damage of distal ileum that absorb
  vitB12-intrinsic F complex,
• Surgical resection of ! ileum.
• TR Vit B12.

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• Tr parenteral inj of vit B12. Available as
• 1-Cyanocobalamin
• 2-Hydroxycobolamin is preferred (more highly
  protein bound longer duration).
• Uses
• 1- Pernicious (Addison) anemia
• 2- Neurologic abnormalities
• 3- Gastrectomy
• 4- Cyanide poisoning Hydroxyocobalamin will bind
  circulating cellular cyanide molecules to form
  cyanocobalamin which is excreted in ! urine .

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• Initial therapy 100-1000 mcg of vit B12 IM daily
  or every other day for 1-2 wks
• Maintenance 100-1000 mcg IM once a month for
  life.
• Oral dose of 1000 mcg of vit B12 in pernicious
  anemia who refuse or cannot tolerate ! inj.
• After parenteral, ! vit can also administered as
  a spray/ gel.

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Adverse effect of Vit B12

• 1- Allergic hypersensitivity reactions
• 2- Arrhythmia secondary to hypokalemia.

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• 3- Folic acid (FA)
• Function synthesis of amino acids, purines,
  pyrimidines, DNA therefore cell division.
• Its deficiency is uncommon.
• deficiency of THFA causes anemia, congenital
  malformations in newborns occlusive vascular D.
• Chemistry
• FA is pteroglutamic acid, composed of pteridine,
  P-aminobenzoic acid glutamic acid.

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• FA can undergo reduction, catalyzed by DHFRasegtgt
  dihydroFA gtgtHFA (active form).
• Vit B12 is required for activation of FA
  (demethylation).
• PK
• Source (as polyglutamate form) yeast, liver,
  kidney, green vegetables.
• 5-20 mg of folates are stored in liver.
• Route po
• Converted to mono-glutamyl form then absorbed in
  ! proximal jejunum .
• Excreted in urine stool.

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• Preparations
• 1- Synthetic FA (tablets/ parenteral)
• 2- Folinic acid (5-formyl derivative of THFA,
  active form).

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• FA Deficiency is caused by
• Malabsorption inadequate dietary intake of
  folate.
• Alcohol dependence
• Liver Disease.
• Clinical Pharm
• Folate deficiency megaloblastic anemia.
• (1 mg po daily) reverse megaloblastic anemia,
  restore normal serum folate, replenish body
  store of folate.
• Prophylactically Pregnant women patients with
  hemolytic anemia have increase folate
  requirements may become FA-deficient, esp if
  their diets are marginal.
• Maternal FA deficiency fetal neural tube defect
  as spina bifida.

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• Patients who require renal dialysis.
• Drugs Methotrexate, trimethoprim pyrimethamine
  inhibit DHFRase deficiency of folate CoFs
  megaloblastic anemia.
• Long term use of phenytoin
• H risk patients (FA supplementation) pregnancy,
  premature infants, hemolytic anemia, liver D,
  renal dialysis.

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• 4- Hematopoietic Growth Factors
• Glycoprotein hormones regulate ! proliferation
  differentiation of hematopoietic progenitor cells
  in Bone marrow.
• Produced by recombinant DNA technology.

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• Erythropietin Produced in ! Kidney
• 1- Epotein
• PK
• IV/ SC
• T1/2 4-13 hr
• Not cleared by dialysis.
• Given 2-3 times weekly.
• 2- Darbepoetin (a) glycosylate form, longer t1/2.

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• Pharmacodynamics
• 1- Stimulate erythroid proliferation
  differentiation by interacting with specific
  erythropoietin Rs on RBC progenitors.
• 2- Induces release of reticulocytes from bone
  marrow (BM)
• 3- Tissue hypoxia stimulate erythropoietin
  synthesis.

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• Clinical Pharm/ Uses
• 1- Anemia chronic renal failure
• Erythropoietin 50-150 IU/kg, IV/SC improve !
  hematocrit (in 10 days) Hg level (in 2-6 wk)
  eliminate ! need for transfusion
• Iron FA.
• 2- Anemia in HIV patients zidovudine (anti
  HIV).
• 3- Anemia in cancer patients.
• 4- Anemia due to BM disorders. As in patients
  with aplastic anemia other BM failure states,
  multiple myeloma.
• 5- Anemia associated with chronic inflammation
  (RA)
• 7- Anemia of prematurity
• 8- To accelerate erythropoiesis after
  phlebotomies.
• 9- Misused by athletes to increase O2 delivery
  performance.

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• Adverse effects Toxicity
• 1- Rapid increase of hematocrit Hg HTN
  thrombosis.
• 2- Seizure, headache
• 3- Transient influenza-like syndrome
• 4- Mild allergic reactions.