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Antianemeic drugsAgents 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 drugsIn 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;

< 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 β 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 liverNormal 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,, IMOr 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 DHFRase>> dihydroFA >>HFA (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: poConverted 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 (α): 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 failureErythropoietin 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 prematurity8- 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.