Download Anti-anemic agent

Anti-anemic agents
Anemia ---a deficiency in erythrocytes or hemoglobin.
Types of anemia
 Iron-deficiency anemia
 megaloblastic anemia
 aplastic anemia
 hemolytic anemia
Agents used in anemias
 Iron
 Vitamin B12
 Folic acid
Iron
Iron deficiency
 most common nutritional cause of anemia
 result from inadequate iron intake, malabsorption, blood loss, or an increased
requirement, as with pregnancy
Iron Cycle
 5 - 10% of ingested iron is absorbed
 Once ingested the acid in the stomach:
 1. Aids in ionization of iron
 2. Splits chelated food iron from chelator
 3. Maintains iron in soluble form
 4. Allows iron to remain in the absorbable form Fe3+
Iron Preparations
Oral Iron
 Ferrous Sulfate (Feosol) – 300 mg tid
 Side Effects are extremely mild:
 Nausea, upper abdominal pain, constipation or diarrhea.
 Cheapest form of Iron and one of the most widely used
Parenteral
 Iron Dextran (Imferon) – IM or IV
 Indicated for patients who cannot tolerate or absorboral iron or where oral iron is
insufficient to treat the condition ie. Malabsorption syndrome, prolonged
salicylate therapy, dialysis patients
P’kinetic
Absorption: Fe2+
Increase: Vitamin C, amino acid, gastric acid
Decrease:
phosphorus, calcium，Tannic acid, Antacids, H2-receptor blockers, Proton pump inhibitors,
Tetracyclines
 Transfer: transferrin
 Utilization:
transferrin-R on proliferating erythroid cells.
 Storage:
ferritin(Fe3+) in intestinal mucosal cells and in macrophages in the liver, spleen, and bone.
Pharmacological actions:
 Iron is part of hemoglobin, the oxygen-carrying component of the blood. Iron-deficient
people tire easily because their bodies are starved for oxygen.
 Iron is also part of myoglobin. Myoglobin helps muscle cells store oxygen.
Uses
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Iron Deficient Anemia
Pregnancy
Premature Babies
Blood loss
Hookworn infestation
Malabsorption Syndrome
GI Bleeding due to:
Ulcers
Aspirin
Excess consumption of coffee
Adverse effects
 Nausea
 Epigastric discomfort
 Abdominal cramps
 Constipation
 Diarrhea
Clinical toxicity
 Acute iron toxicity
 Necrotizing gastroenteritis
 Vomiting, abdominal pain, bloody diarrhea
 Followed by shock, lethargy, dyspnea
 Severe metabolic acidosis, coma, death
 Chronic iron toxicity (hemochromatosis)
 Deposit of iron in the heart, liver, pancreas
 Can lead to organ failure and death
Toxicity of Iron Overdose
 5000 deaths/year in the US, usually in children
 20% of children presenting with iron toxicity will die
 1 to 2 grams are sufficient to cause death
 At high doses, Iron is absorbed through passive diffusion with no regulation
Treatment of Iron Overdose
 Toxic levels
 ALD – 200-300mgkg, plasma iron > 300ug/dl
 Bicarbonate for acidosis
 Fluids for blood loss
 Ipecac or lavage
 Chelation with Deferoxamine
Folate deficiency
 Nutritional
 Malabsorption
 Drug related – impaired absorption (eg. Anticonvulsants) folate antagonists (eg.
methotrexate)
 Increased Folate Requirements
Folic Acid
 Folic acid (pteroylglutamic acid) is composed of a heterocycle (pteridine), paminobenzoic acid, and glutamic acid.
 Folic acid is required for the synthesis of amino acids, purines, and DNA.
 Megaloblastic anemia of folate deficiency is microscopically indistinguishable from B12
deficiency.
 Folate deficiency does not cause neuropathy.
Folic acid
 Process in body
FA → FH2 → FH4 → 5-CH3-FH4
 Machinism: One carbon unit carrier
 ☆ Reduction of folic acid →
↓dTMP →↓ DNA→megaloblastic anemia
↓amino acid biosynthesis
P’kinetic
 Only 5-20 mg of folates are stored in the liver.
 Folates elimination is high, so serum levels fall within a few days when intake is
diminished.
 Megaloblastic anemia can develop within 1-6 months after the intake of folic acid stops.
Pharmacology
 Deficiency
 result in megaloblastic anemia
 Often caused by inadequate dietary intake
 Pregnant woman has increased folate requirement
 A dose of 1 mg is sufficient
 Folic acid deficiency is seen in:
 Alcohol dependence and liver disease (poor diet and diminished hepatic storage)
 Pregnancy and hemolytic anemia (increased folate requirement)
 Malabsorption syndromes
 Renal dialysis (dialysis removes folates)
 Some drug ingestion: methotrexate, trimethoprim and pyrimethamine (inhibit
dihydrofolate reductase)
Uses
 1. Megaloblastic Anemia due to inadequate dietary intake of folic acid
 Can be due to chronic alcoholism, pregnancy, infancy, impaired
utilization: uremia, cancer or hepatic disease.
 2. To alleviate anemia that is associated with dihydrofolate reductase inhibitors.
 i.e. Methotrexate (Cancer chemotherapy), Pyrimethamine (Antimalarial)
 Administration of citrovorum factor (methylated folic acid) alleviates the
anemia.
 3. Ingestion of drugs that interfere with intestinalabsorption and storage of folic acid.
 Mechanism- inhibition of the conjugases that break off folic acid from its
food chelators.
 Ex. – phenytoin, progestin/estrogens (oral contraceptives)
 4. Malabsorption – Sprue, Celiac disease, partial gastrectomy.
 5. Rheumatoid arthritis – increased folic acid demand or utilization.
B12 Deficiency
 A B12 deficiency will cause peripheral neuropathy and a macrocytic anemia, a pernicious
anemia.
 Folic Acid administration can correct the macrocytic anemia but will fail to correct the
peripheral neuropathy.
 To treat the neuropathy, Vit B12 must be utilized.
Vitamin B12
 Vitamin B12 deficiency causes:
 Megaloblastic anemia, thrombocytopenia and/or leukopenia
 GI and neurologic abnormalities.
 Deficiency of B12 in older adults due to inadequate absorption is a common and easily
treated disorder.
 Deoxyadenosylcobalamin and methylcobalamin are the active forms of the B12 in
humans.
 Cyanocobalamin and hydroxocobalamin (available for therapeutic use) are converted to
the active forms.
 The dietary source of vitamin B12 is meat (especially liver), egg, and dairy products.
 The ultimate source of B12is microbial synthesis; B12 is not synthesized by animals or
plants.
 Vitamin B12 is also called extrinsic factor.
P’kinetic
 B12 is stored in the liver with a storage pool of 3000-5000 mcg.
 Daily requirements are 2 mcg, it would take 5 years for megaloblastic anemia to develop.
 B12 is absorbed only in complex with intrinsic factor (IF) secreted by the parietal cells of
the stomach.
 The IF-B12 complex is absorbed in the distal ileum.
 It is transported in the blood by transcobalamin II.
Relation to Folic Acid
 Methylfolate trap is the biochemical step whereby B12 and folic acid are linked.
 That is why the anemia of B12 deficiency can be partially corrected by folic acid.
 Folic acid will not prevent neuropathies of B12 deficiency.
Fig. below = Enzymatic reactions that use vitamin B .21
Mechanism for Peripheral Neuropathy
 Cobalamin is a cofactor for the enzyme Methylmalonyl-CoA mutase which converts
methylmalonyl-CoA to succinyl-CoA.
 Succinyl-CoA enters the Krebs cycles and goes into nerves to make myelin.
 If no Vitamin B12, methylmalonyl-CoA goes on to form abnormal fatty acids and causes
subacute degeneration of the nerves. Only B12 can correct this problem.
Pharmacology
 The most common causes of vitamin B12 deficiency are:
 Pernicious anemia
 Partial or total gastrectomy
 Abnormality in the distal ileum (malabsorption syndromes, IBD, small bowel
resection).
 Pernicious anemia results from defective secretion of intrinsic factor.
 Patients have gastric atrophy and fail to secrete intrinsic factor and hydrochloric acid.
 Treat or prevent deficiency
 Megaloblastic anemia
 Neurologic syndrome
 Degeneration of myelin sheaths
 Disruption of axons in the dorsal and lateral horns of spinal cord and in
peripheral nerves
Clinical uses:
1. Megaloblastic anemia
2 .Pernicious anemia
3 .Nervous system diseases
4. Hepatopathy
Hematopoietic growth factors
Erythropoietin (EPO)
Granulocyte colony-stimulating
factor (G-CSF)
Granulocyte-macrophage colony-
stimulating factor (GM-CSF)
Erythropoietin (EPO)
source: produced by the kidney in response to tissue hypoxia.
Pharmacological effects:
 stimulates erythroid proliferation and differentiation
 Stimulates maturation of red blood cell
 also induces release of reticulocytes from the bone marrow
Clinical uses:
 patients with chronic renal failure
 patients with aplastic anemia
 anemias associated with chronic inflammation, AIDS, and cancer
Adverse reaction:
 a rapid increase in hemoglobin
 hypertension and thrombotic complications.
Granulocyte colony-stimulating factor (G-CSF)
Pharmacological effects:
 stimulates proliferation and differentiation of progenitors to neutrophils
 Increase release of neutrophils from bone marrow
 activatesthe phagocytic activity of mature neutrophils and prolongs their survival in the
circulation.
Clinical uses: neutropenia
Granulocyte-macrophage colony - stimulating factor (GM-CSF)
Pharmacological effects:
 stimulates proliferation and differentiation of early and late granulocytic progenitor cells
as well as erythroid and megakaryocyte progenitors
 stimulates the function of mature neutrophils
 Clinical uses: neutropenia
 Adverse reaction: fevers, malaise, arthralgias, myalgias, peripheral edema and pleural or
pericardial effusions, allergic reactions