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PHARMACOLOGY OF DRUGS FOR ANEMIA

Dr.Datten Bangun MSc.SpFK Dept.Farmakologi & Therapetik Fak.Kedokteran UHN MEDAN

ANEMIA
Anemia can be defined as a reduction in the hemoglobin,hematocrit or red cell number.

In physiologic terms an anemia is any disorder in which the patient suffers from tissue hypoxia due to decreased oxygen carrying capacity of the blood

Hematinics
These are drugs used to treat anemia Iron Vitamin B12, Cyanocobalamin Folic acid Erythropoietin

TYPES OF ANEMIA
Various classifications: Examples: Iron deficiency anemia ---microcytic , hypochromic Megaloblastic anemia ---macrocytic , normochromic due to Vit. B12 or Folic Acid deficiency Anemia due to decreased Erythropoietin as in chronic renal failure
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Causes of Anemia
1. Diminished production and or replacement of red blood cells.

2. Excessive breakdown and loss of red blood cells. Hemodilution while not a cause of anemia, it does cause an anemia-like effect.

1. Diminished Production/Replacement of RBCs Anemia's


Microcytic anemia deficiency of Fe
RBCs appear pale and smaller, and we see more reticulocytes in circulation. Can be caused by the chronic use of aspirin, which irritates the stomach GI blood loss.

Normocytic anemia deficiency of Erythropoietin


Caused by compromised renal function.

Macrocytic Anemia- deficiency of folic acid and B12


Diminished cell division and release of larger cells in circulation.

2. Breakdown of RBCs Anemia


Bleeding: can be due to an ulcer or in females blood loss due to their menstrual cycle Use of drugs that irritate the GI tract (aspirin) Hemolysis (Hemolytic Anemia) can be caused by:
Autoimmune disease Mechanical (heart valves, microvascular disease) Toxins (e.g., snake venom)

Anti anaemic Drugs


Haematopoiesis: it is the production of erythrocytes, platelets, and leukocytes from undifferentiated stem cells. The haematopoietic machinary reside in the bone marrow in adults. It requires a constant supply of essential nutrients iron, vit B12, folic acid and presence of hematopoietic growth factors

ANTI-ANEMIC DRUGS
Drugs effective in iron deficiency and other hypochromic anemias: Iron Pyridoxine , Riboflavin , Copper Drugs effective in megaloblastic anemia: Vitamin B12 Folic Acid Hematopoietic growth factors: Erythropoietin
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IRON FACTS
All body cells need iron. It is crucial for oxygen transport, energy production, and cellular growth and proliferation. The human body contains an average of 3.5 g of iron (males 4 g, females 3 g). The typical daily normal diet contains 1020 mg of iron. Only about 10% of dietary iron is absorbed (12 mg/day).

Anti anaemic Drugs


Iron: Total quantity of iron in the body is 4-5G, 65-70% in the form of Hb in RBC, 4% in myoglobin, 1% in various heme compound, 15-30% stored in the form of ferritin and hemosiderin in RE system, liver, spleen, intestinal mucosa and bone marrow

IRON
Preparations: Oral: Ferrous sulphate Ferrous gluconate Ferrous fumarate , etc. Parenteral: Iron dextran ---- i.m or i.v Iron Sorbitol ----- i.m only.
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Pharmacokinetics

Absorption ---- depends on requirements iron stores Ferrous (Fe++) / ferric (Fe+++) form pH Vitamin C Chelators or complexing agents Malabsorption syndrome
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Iron transport
Most absorbed iron is transported in the bloodstream bound to the glycoprotein transferrin. Transferrin is a carrier protein that plays a role in regulating the transport of iron from the site of absorption to virtually all tissues. Transferrin binds only two iron atoms. Normally, 2045% of transferrin binding sites are filled (measured as percent transferrin saturation [TS]).

Iron transport

Ferritin molecules store thousands of iron atoms within their mineral core. When excess dietary iron is absorbed, the body responds by producing more ferritin to facilitate iron storage.

Importance of Iron
Iron forms the nucleus of the iron-porphyrin heme ring, This with globin chains forms hemoglobin. Function of Haemoglobin:

Reversibly binds oxygen and provides the critical Mechanism for oxygen delivery from the lungs to other tissues. In the absence of adequate iron, small erythrocytes with insufficient hemoglobin are formed, giving rise to Microcytic hypochromic anemia

Acute Oral toxicity (overdose ; poisoning) Necrotizing gastroenteritis with ---vomiting, abdominal pain, bloody diarrhea Shock , lethargy & dyspnea Severe metabolic acidosis Coma Death

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Acute Oral toxicity (overdose ; poisoning): (Contd.)


Treatment: Whole bowel irrigation Desferrioxamine (Deferoxamine) orally --- for Unabsorbed iron Parenteral ( i.m. , i.v. ) --- for iron absorbed Desferrioxamine + ferric iron Ferrioxamine --- excreted in urine and bile.
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Chronic iron toxicity (iron overload): (Contd.)


Hemosiderosis: a focal or general increase in tissue iron stores without associated tissue damage Hemochromatosis: associated with tissue damage

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Chronic iron toxicity (iron overload) (Contd.) Treatment: Intermittent Venesection (Phlebotomy)---when there is no anemia Chelation (Desferrioxamine) ---for transfusional overload

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Adverse effects of Parenteral iron therapy Local pain & tissue staining (brown discoloration of tissue overlying the injection site). Headache , light-headedness , fever , arthralgias, nausea , vomiting , back pain , flushing , urticaria, bronchospasm , & , Rarely anaphylaxis & death
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VITAMIN B12
Chemistry Porphyrin-like ring with a central cobalt atom & nucleotide. Cobalamins = various organic groups covalently bound to cobalt atom Cyanocobalamine hydroxycobalamin & other cobalamins (found in food sources) are converted to active forms Deoxyadenosylcobalamin &methylcobalamin
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Active forms of vitamin B12 in human: Deoxyadenosylcobalamin Methylcobalamin Vitamin B12 available for therapeutic uses: Cyanocobalamin Hydroxycobalamin
Hydroxycobalamin --- is preferred because it is highly protein-bound & therefore remains longer in the circulation.
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Pharmacokinetics
Absorption: Intrinsic factor (IF) --- a glycoprotein , secreted by parietal cells of gastric mucosa IF-Vit.B12 Complex --- absorbed by active transport in the distal ileum Transported in plasma bound to the glycoprotein transcobalamin II & is taken up by tissues where required & stored in hepatocytes
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Pharmacokinetics (Contd.)
Route of administration Mostly ------ Parenteral ---- i.m.

Oral
Aerosol

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Pharmacokinetics (Contd.)
Elimination: not significantly metabolized

pass into bile


Enterohepatic circulation Excreted via kidney
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Features of Vitamin B12 deficiency


Impairment of DNA synthesis affects all cells but most apparently RBCs. Megaloblastic Anemia GI symptoms neurologic abnormalities
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Features Vitamin B12 deficiency (Contd.)


Neurological abnormalities : Degeneration of brain and spinal cord (Subacute combined degeneration ) and peripheral nerves. Symptoms may be psychiatric & physical. Paresthesia & weakness in peripheral nerves spasticity, ataxia, & other CNS dysfunction

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Uses
Pernicious (addisonian) anemia After partial or total gastrectomy Malabsorption syndromes Insufficient dietary intake Hydroxycobalamin (Not cyanocobalamin) Tobacco Amblyopia Cyanide toxicity
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Adverse effects
Allergic hypersensitivity reactions Antibodies to hydroxycobalamin-transcobalamin II complex Arrhythmias secondary to hypokalemia

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FOLIC ACID (PTEROYLGLUTAMIC ACID; VITAMIN B9) Is inactive Active form is ---- tetrahydrofolic acid

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Pharmacokinetics
Route of administration ----- usually oral In diet ---- Polyglutamate form For absorption ---- must be converted to --Mono-glutamyl form Absorbed mostly --- in proximal jejunum

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Functions
Is required for synthesis of Amino acids , purines, pyrimidines, & DNA ; & therefore in the cell division

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Features of folic acid deficiency


Mitotically active tissues such as erythroid tissues are markedly affected.

Anemia Congenital malformations --neural tube defects ( e.g., spina bifida) Vascular disease
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Vitamin C
Vitamin C deficiency can cause megaloblastic anemia

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Uses
Prevention & treatment of folic acid deficiency Dietary insufficiency (e.g. in elderly) Pregnancy & lactation to prevent --- Congenital malformations --neural tube defects ( e.g., spina bifida) High red cell turn over --- e.g. in hemolytic anemias --Premature infants Malabsorption syndromes
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Uses (contd.)
Drugs Antiepileptics ---- enzyme inducers Phenytoin Primidone Phenobarbitone Antimalarials pyrimethamine Methotrexate FOLINIC ACID (not folic acid)

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Uses (contd.)
Myelofibrosis Exfoliative dermatitis Rheumatoid arthritis Malignant disease , e.g., lymphoma Chronic hemodialysis

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Adverse effects
Generally well tolerated Rarely -- G.I. Disturbances hypersensitivity reactions Status epilepticus may be precipitated

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ERYTHROPOIETIN (EPOTEIN)
a glycoprotein hormone produced : 90% --- by peritubular cells in kidney remainder --- by liver and other tissues is essential for normal reticulocyte production synthesis is stimulated by hypoxia synthesized for clinical use ---- by --recombinant DNA technology
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Pharmacokinetics
Route of administration --- S.C. or I.V. Plasma t1/2 ---- 4 - 13 hrs in patients with chronic renal failure. Not cleared by dialysis

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Mechanism of action
increases rate of stem cell differentiation increases rate of mitosis in red cell precursors, blast-forming units, colony forming cells. increases release of reticulocyte from marrow increases Hb synthesis its action requires adequate stores of iron

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Uses
Anemia associated with chronic renal failure premature infants Anemia during chemotherapy of cancer Anemia of AIDS (which is exacerbated by zidovudine treatment) to increase the yield of autologous blood before donation Anemia of chronic inflammatory conditions such as rheumatoid arthritis MISUSED --- by sports people

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Adverse effects
Usually due to excessive increase in hematocrit increase blood pressure thrombosis seizures headache hypertensive crises with encephalopathy-like symptoms clotting in dialyser
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Adverse effects
Transient influenza-like symptoms -----chills & myalgias iron deficiency transient increases in platelet count hyperkalemia skin rashes pure red cell aplasia --- discontinue the drug antibodies to epoetins
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Precautions / contraindications
hypertension should be well controlled seizures thrombocytosis ischemic vascular disease iron , folic acid , vit. B12 supplements may be needed heparin during dialysis
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Monitor
hematocrit blood pressure platelet count serum potassium

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