HAEMATINICSHAEMATINICS

Agents Used In Agents Used In AnemiasAnemias

By the end of lecture students should By the end of lecture students should be able to:be able to:

Know various types of anemias Know various types of anemias Know aetiology of anemiasKnow aetiology of anemias Know drugs used for treatment of Know drugs used for treatment of

anemiasanemias Explain pharmacokinetics and Explain pharmacokinetics and

pharmacodynamics of Iron pharmacodynamics of Iron Know acute and chronic toxicities of ironKnow acute and chronic toxicities of iron Know the management of overdose of Know the management of overdose of

ironiron

HaematopoiesisHaematopoiesis

200 billion new blood cells are 200 billion new blood cells are produced per day in normal personproduced per day in normal person

Process occur in bone marrow in Process occur in bone marrow in adults adults

Essential nutrients: iron, vitamin BEssential nutrients: iron, vitamin B1212, , folic acid, pyridoxine, ascorbic acid folic acid, pyridoxine, ascorbic acid and riboflavinand riboflavin

Hematopoietic growth factors Hematopoietic growth factors

Erythropoiesis is controlled by a feedback Erythropoiesis is controlled by a feedback system in which a sensor in the kidney system in which a sensor in the kidney detects changes in oxygen delivery to detects changes in oxygen delivery to modulate the erythropoietin secretionmodulate the erythropoietin secretion

AnemiaAnemia

Decrease in haemoglobin level below Decrease in haemoglobin level below normalnormal

Deficiency in oxygen-carrying erythrocytesDeficiency in oxygen-carrying erythrocytes SymptomsSymptoms

Features of tissue hypoxiaFeatures of tissue hypoxia

Pallor, fatigue, dizziness, exertional Pallor, fatigue, dizziness, exertional dyspnoeadyspnoea

CVS adaptations to anemia (tachycardia, CVS adaptations to anemia (tachycardia, increased cardiac output, vasodilation)increased cardiac output, vasodilation)

ANEMIAS:ANEMIAS:

Microcytic hypochromic anemia- iron Microcytic hypochromic anemia- iron deficiency most deficiency most

Most common cause of chronic anemia is Most common cause of chronic anemia is iron deficiency iron deficiency

Macrocytic anemias- Vit B12 deficiencyMacrocytic anemias- Vit B12 deficiency

Folic acid deficiencyFolic acid deficiency

Drugs used for the correction of Drugs used for the correction of

anemiasanemias Include:Include: IronIron Folic acidFolic acid Vit B12Vit B12 Hematopoietic growth factorsHematopoietic growth factors

IRONIRON

Iron forms the nucleus of the iron-Iron forms the nucleus of the iron-porphyrin heme ring, which together with porphyrin heme ring, which together with globin chains forms haemoglobinglobin chains forms haemoglobin

Increased iron requirementIncreased iron requirement

Growing childrenGrowing children

PregnancyPregnancy

Increased losses of iron (menstruating Increased losses of iron (menstruating women) women)

Iron containing heme is also an Iron containing heme is also an essential component of essential component of

Myoglobin Myoglobin Cytochromes Cytochromes Catalase Catalase Peroxidase Peroxidase Metalloflavoprotein enzymes Metalloflavoprotein enzymes Xanthine oxidaseXanthine oxidase Mitochondrial enzymes Mitochondrial enzymes

Sources:Sources: Natural Natural Meat, green vegetables, grainMeat, green vegetables, grain SyntheticSynthetic Iron preparationsIron preparations In bodyIn body catalysis of hemoglobin in catalysis of hemoglobin in

senescent or damaged erythrocytessenescent or damaged erythrocytes

PharmacokineticsPharmacokinetics

Average diet contain 10-15 mg of elemental Average diet contain 10-15 mg of elemental iron dailyiron daily

Total iron absorption can increase to 3-4 Total iron absorption can increase to 3-4 mg/day in pregnant womanmg/day in pregnant woman

Iron in meat is absorbed as such Iron in meat is absorbed as such (hemoglobin and myoglobin)(hemoglobin and myoglobin)

Nonheme iron in foods is reduced by Nonheme iron in foods is reduced by ferroreductase to ferrous formferroreductase to ferrous form

A peptide hepcidin produced by liver cells-A peptide hepcidin produced by liver cells-key central regulator of the systemkey central regulator of the system

AbsorptionAbsorption:: Duodenum and Proximal jejunumDuodenum and Proximal jejunum

as Feas Fe+2+2

BY:BY: Active transport by DMT1 (divalent Active transport by DMT1 (divalent

metal transporter)metal transporter) Iron complexed with heme Iron complexed with heme Iron absorption increases when iron stores

are depleted regulated by mucosal iron stores

Absorption…..Absorption…..

The absorbed iron is actively The absorbed iron is actively transported into the blood across the transported into the blood across the basolateral membrane by transporter basolateral membrane by transporter ferroportin ferroportin and oxidized to ferric iron and oxidized to ferric iron by by ferroxidase hephaestinferroxidase hephaestin

DISTRIBUTIONDISTRIBUTION Bound to Bound to Transferrin (Transferrin (ββ –globulin) –globulin) bind two molecules of ferric ironbind two molecules of ferric iron

The transferrin-iron complex enters maturing The transferrin-iron complex enters maturing erytthoid cells erytthoid cells

Transferrin receptors, Transferrin receptors, transferrin iron transferrin iron complex is internalized in erythroid cells by complex is internalized in erythroid cells by endocytosisendocytosis

Storage Storage

As ferritin in liver, spleen and bone and As ferritin in liver, spleen and bone and in parenchymal liver cellsin parenchymal liver cells

Ferroportin is storage protein level is Ferroportin is storage protein level is regulated by hepcidin regulated by hepcidin Low hepcidin lead to release of iron Low hepcidin lead to release of iron from storage sitesfrom storage sites Ferritin level is checked in serum to Ferritin level is checked in serum to estimate total body iron stores.estimate total body iron stores.

EliminationElimination

Small amount lost in faeces by Small amount lost in faeces by exfoliation of intestinal mucosal cellsexfoliation of intestinal mucosal cells

Trace amounts in bile, urine and Trace amounts in bile, urine and sweatsweat

1 mg of iron is lost from body per day1 mg of iron is lost from body per day

Therapeutic uses of IronTherapeutic uses of Iron

Iron Deficient Iron Deficient AnemiaAnemia

Treatment and preventionTreatment and prevention PregnancyPregnancy Lactation Lactation Growing childrenGrowing children Premature BabiesPremature Babies Patents with chronic Patents with chronic

kidney diseasekidney disease Blood lossBlood loss

Inadequate iron absorptionInadequate iron absorption

GastrectomyGastrectomy

Malabsorption SyndromeMalabsorption Syndrome GI Bleeding due to:GI Bleeding due to:

UlcersUlcers AspirinAspirin Excess consumption of coffeeExcess consumption of coffee Hookworm infestationHookworm infestation

Oral preparations of ironOral preparations of iron

Oral IronOral Iron Ferrous SulphateFerrous Sulphate Ferrous GluconateFerrous Gluconate Ferrous FumarateFerrous Fumarate

Treatment with oral iron should be continued for 3-6 Treatment with oral iron should be continued for 3-6 months after correction months after correction of cause of iron loss.

Oral Iron TherapyOral Iron Therapy

Dosage:Dosage: 200- 400 mg/ day for 3- 6 months200- 400 mg/ day for 3- 6 months

Adverse effects:Adverse effects: nausea, epigastric discomfort, nausea, epigastric discomfort,

abdominal cramps, constipation, abdominal cramps, constipation, diarrhea, black stoolsdiarrhea, black stools

To overcome adverse effectsTo overcome adverse effects Lower daily dose of ironLower daily dose of iron Take iron with foodTake iron with food Change iron preparation.Change iron preparation.

PARENTRAL IRON THERAPYPARENTRAL IRON THERAPY

Indications:Indications: Patients unable to tolerate oral ironPatients unable to tolerate oral iron

Patients with extensive blood lossPatients with extensive blood loss

Malabsorptive statesMalabsorptive states Patients with advanced chronic renal Patients with advanced chronic renal

diseases.diseases.

I/M and I/v use:I/M and I/v use: Iron dextranIron dextran

(ferric oxyhydroxide and dextran (ferric oxyhydroxide and dextran polymers) 50 mg /mlpolymers) 50 mg /ml

I/V only:I/V only: Iron sucrose complexIron sucrose complex Sodium ferric gluconate complexSodium ferric gluconate complex

Dose calculationDose calculation

Total iron deficit (TID)Total iron deficit (TID) Body wt (Kg) ˟ (Target Hb-Actual Hb Body wt (Kg) ˟ (Target Hb-Actual Hb

g/dl) ˟ 2.4 + depot iron (mg) g/dl) ˟ 2.4 + depot iron (mg) Total amount of venofer to be Total amount of venofer to be

administered in ml = administered in ml = TID mgTID mg

200 mg/ml200 mg/ml

Ratio of total serum iron concentration Ratio of total serum iron concentration and TIBCand TIBC

Adverse EffectsAdverse Effects

i)i) Local pain & tissue stainingLocal pain & tissue staining

ii)ii) Headache, giddiness, flushingHeadache, giddiness, flushing

iii)iii) Fever, Arthralgia, BackacheFever, Arthralgia, Backache

iv)iv) Nausea, VomitingNausea, Vomiting

v)v) UrticariaUrticaria

Rarely Anaphylaxis & death.Rarely Anaphylaxis & death.

Test dose of iron dextran is given.Test dose of iron dextran is given.

Clinical ToxicityClinical Toxicity

Acute Iron ToxicityAcute Iron Toxicity Seen in young children, who accidently Seen in young children, who accidently

ingest ingest Iron tablets.Iron tablets. 10 tablets in children10 tablets in children

Symptoms:Symptoms: vomiting, necrotizing vomiting, necrotizing

gastroenteritis causing abdominal pain, gastroenteritis causing abdominal pain, bloody diarrhea followed by metabolic bloody diarrhea followed by metabolic acidosis, dyspnea, coma & deathacidosis, dyspnea, coma & death

RRxx

i)i) Gastric Aspiration Gastric Aspiration Gastric lavage, with carbonate solution to Gastric lavage, with carbonate solution to form insoluble Iron.form insoluble Iron.

whole bowel irrigationwhole bowel irrigationii)ii) Deferoxamine - potent iron chelating Deferoxamine - potent iron chelating compound given intravenously compound given intravenously iii)iii) Supportive TherapySupportive Therapy

Chronic Iron ToxicityChronic Iron Toxicity Hemochromatosis (excess iron is Hemochromatosis (excess iron is

deposited in the heart, liver, pancreas, and deposited in the heart, liver, pancreas, and other organs)other organs)

Cause is inherited hemochromatosis and Cause is inherited hemochromatosis and patient receiving many blood transfusionspatient receiving many blood transfusions

RxRx– Intermittent Phlebotomy (1 unit of blood Intermittent Phlebotomy (1 unit of blood

is removed every week) is removed every week) – Iron. Chelation therapy (Deferoxamine, Iron. Chelation therapy (Deferoxamine,

deferasirox is oral iron chelator)deferasirox is oral iron chelator)

Vit B 12Vit B 12

CofactorCofactor for several essential biochemical for several essential biochemical reactions in humansreactions in humans

Deficiency lead to megaloblastic anemia, Deficiency lead to megaloblastic anemia, GIT symptoms and neurologic GIT symptoms and neurologic abnormalitiesabnormalities

Cyanocobalamine Cyanocobalamine HydroxocobalamineHydroxocobalamine

Source: microbial synthesis from meat, Source: microbial synthesis from meat, eggs and dairy products eggs and dairy products (microorganisms grow in soil, sewage, (microorganisms grow in soil, sewage, water or in intestinal lumen of animals)water or in intestinal lumen of animals)

Chemistry: porphyrin like ring with a Chemistry: porphyrin like ring with a central cobalt atom attached to central cobalt atom attached to nucleotidenucleotide

Structure…….Structure…….

Various organic groups may be Various organic groups may be covalently bound to cobalt atom covalently bound to cobalt atom forming different cobalaminesforming different cobalamines

DeoxyadenosylcobalamineDeoxyadenosylcobalamine Methylcobalamine Methylcobalamine

active form of vitamins in humansactive form of vitamins in humans

Pharmacokinetics Pharmacokinetics

Vitamin BVitamin B1212 is absorbed only after it is absorbed only after it complexes with intrinsic factor complexes with intrinsic factor (glycoprotein)(glycoprotein)

This complex of vit B12 and intrinsic This complex of vit B12 and intrinsic factor is absorbed in distal ileumfactor is absorbed in distal ileum

Transported to various cells by binding Transported to various cells by binding with transcobalamin I, II and IIIwith transcobalamin I, II and III

Excess is transported to liver for Excess is transported to liver for storage.storage.

PharmacodynamicsPharmacodynamics

Deficiency of vit B 12 also cause Deficiency of vit B 12 also cause ‘folate trap’‘folate trap’

Methyltetrahydrofolate is not Methyltetrahydrofolate is not converted into other intracellular converted into other intracellular forms of folic acidforms of folic acid

Clinical usesClinical uses

Treat or prevent deficiency Treat or prevent deficiency Megaloblastic, macrocytic anemiaMegaloblastic, macrocytic anemia

mild or moderate leukopenia or mild or moderate leukopenia or thrombocytopenia.thrombocytopenia.

Neurologic syndrome (paresthesias in Neurologic syndrome (paresthesias in peripheral nerves, weakness.peripheral nerves, weakness.

Progresses to spasticity, ataxia and Progresses to spasticity, ataxia and CNS dysfunction.CNS dysfunction.

Mechanism for Peripheral Mechanism for Peripheral NeuropathyNeuropathy

Cobalamin is a cofactor for the enzyme Cobalamin is a cofactor for the enzyme Methylmalonyl-CoA mutase which converts Methylmalonyl-CoA mutase which converts methylmalonyl-CoA to succinyl-CoAmethylmalonyl-CoA to succinyl-CoA. .

Succinyl-CoA enters the Krebs cycles and Succinyl-CoA enters the Krebs cycles and goes into nerves to make myelin. goes into nerves to make myelin.

If no Vitamin BIf no Vitamin B1212, methylmalonyl-CoA goes , methylmalonyl-CoA goes on to form on to form abnormal fatty acidsabnormal fatty acids and and causes subacute degeneration of the causes subacute degeneration of the nerves. Only Bnerves. Only B1212 can correct this problem. can correct this problem.

Diagnosis Diagnosis

Serum levels of vitamins (Vit B12 and Serum levels of vitamins (Vit B12 and Folic acid)Folic acid)

Schilling test (measures absorption Schilling test (measures absorption and urinary excretion of radioactively and urinary excretion of radioactively labelled vitamin B12) labelled vitamin B12)

Common causes of vit B12 Common causes of vit B12 deficiencydeficiency

Pernicious anemiaPernicious anemia

Defective secretion of intrinsic Defective secretion of intrinsic factorfactor

Partial and total gastrectomyPartial and total gastrectomy Malabsorption syndromeMalabsorption syndrome Inflammatory bowel diseaseInflammatory bowel disease Small bowel resectionSmall bowel resection

Treatment Treatment

If the cause is malabsorption, If the cause is malabsorption, Parenteral injections of vit BParenteral injections of vit B1212

cyanocobalamine or cyanocobalamine or hydroxocobalamine.hydroxocobalamine.

vitamin B12 can be administered vitamin B12 can be administered intranasally as a spray or gel. intranasally as a spray or gel.

Parenteral therapyParenteral therapy Inj Cyanocobalamin or hydroxcobalaminInj Cyanocobalamin or hydroxcobalamin Initial therapyInitial therapy

100 – 1000 µg – I/M-D or on alternate days 100 – 1000 µg – I/M-D or on alternate days for 1-2 weeks for 1-2 weeks

Maintenance therapyMaintenance therapy100 – 1000 µg – I/M- once a month100 – 1000 µg – I/M- once a month

Folic Acid Folic Acid Essential for normal DNA synthesisEssential for normal DNA synthesisSource Source Plant and animal (liver, Plant and animal (liver, kidney kidney & green & green vegetables. vegetables. Chemistry Chemistry Pteroylglutamic acidPteroylglutamic acid p-aminobenzoic acid and glutamic p-aminobenzoic acid and glutamic acidacid

Pharmacokinetics of Folic AcidPharmacokinetics of Folic Acid Site of absorption:Site of absorption:

Proximal jejunum Proximal jejunum Polyglutamates monoglutamatePolyglutamates monoglutamate αα- - 1 glutamyl transferase (conjugase) 1 glutamyl transferase (conjugase)

PHARMACODYNAMICS:PHARMACODYNAMICS:

Tetrahydrofolate cofactor participate Tetrahydrofolate cofactor participate in one-carbon transfer reactions in one-carbon transfer reactions

dTMP DNA synthesisdTMP DNA synthesis

Required for the synthesis of :Required for the synthesis of :

Amino acidsAmino acids

purinespurines

DNADNA

dTMP synthesis cycledTMP synthesis cycle

dTMP synthase, dihydrofolate dTMP synthase, dihydrofolate reductase and serine reductase and serine transhydroxymethylase transhydroxymethylase

Synthesis of methionine from Synthesis of methionine from homocystinehomocystine

Donate one carbon for synthesis of Donate one carbon for synthesis of essential purinesessential purines

Folic Acid Deficiency Seen inFolic Acid Deficiency Seen in

i)i) Inadequate dietary intake of folates Inadequate dietary intake of folates

ii)ii) Prolong cookingProlong cooking

iii)iii) In alcholics & in pt with liver diseasesIn alcholics & in pt with liver diseases

iv)iv) PregnancyPregnancy

v)v) Hemolytic AnemiasHemolytic Anemias

vi)vi) Malabsorption SyndromeMalabsorption Syndrome

vii)vii) Drugs Methotrxate , trimethoprim and Drugs Methotrxate , trimethoprim and pyrimethaminepyrimethamine

Treatment of Folic Acid Treatment of Folic Acid DeficiencyDeficiency

parentral administ rarely needed.parentral administ rarely needed.

Oral therapy:Oral therapy:DoseDose

1mg/d – continued until cause is 1mg/d – continued until cause is corrected or removed.corrected or removed.

Hematopoietic Growth Hematopoietic Growth FactorsFactors

Glycoproteins hormonesGlycoproteins hormones Erythropoietin Erythropoietin G-CSFG-CSF GM-CSFGM-CSF Interlukin-IIInterlukin-II RomiplostimRomiplostim

Erythropoietin Erythropoietin

Source: Recombinant DNA Source: Recombinant DNA technologytechnology

I/V administration I/V administration Dose calculated in IU.Dose calculated in IU. Epoetin alfa and epoetin beta Epoetin alfa and epoetin beta Half life is 4-13 hrsHalf life is 4-13 hrs Darbepoetin alfa is heavily Darbepoetin alfa is heavily

glycosylated (longer half life)glycosylated (longer half life)

Pharmacodynamics Pharmacodynamics

Erythropoietin receptors on red cell Erythropoietin receptors on red cell progenitors (JAK/STAT) progenitors (JAK/STAT)

Increased production of RBCs in bone Increased production of RBCs in bone marrow if marrow if

No nutritional deficiency is presentNo nutritional deficiency is present No primary bone marrow disorderNo primary bone marrow disorder No bone marrow suppression from No bone marrow suppression from

drugs drugs

Clinical uses Clinical uses

Anemia due to chronic renal diseaseAnemia due to chronic renal disease

After treatment increase in After treatment increase in reticulocyte count is observed in 10 reticulocyte count is observed in 10 days days

Increase in Hb in 2-6 weeksIncrease in Hb in 2-6 weeks Anemia due to zidovudine treatment Anemia due to zidovudine treatment

in HIV patientsin HIV patients Reduce the need of transfusions in high Reduce the need of transfusions in high

risk patients risk patients

Toxicity Toxicity

Hypertension Hypertension Thrombotic complicationsThrombotic complications Allergic reactions are rareAllergic reactions are rare

Erythropoieitin is banned by Erythropoieitin is banned by International Olympic Committee International Olympic Committee

Myeloid Growth factorsMyeloid Growth factors

FilgrastrimFilgrastrim SargramostimSargramostim Pegfilgrastim Pegfilgrastim Leograstim Leograstim

used for cancer chemotherapy induced used for cancer chemotherapy induced NeutropeniaNeutropenia

Congenital neutropeniaCongenital neutropenia

Cyclic neutropeniaCyclic neutropenia

Myelodysplasia Myelodysplasia

Aplastic anemia Aplastic anemia

Toxicity Toxicity

Bone painBone pain Fever, malaise, arthralgia, myalgiaFever, malaise, arthralgia, myalgia