Agents Used in Anemias; Hematopoietic growth Factors

Anemia: a deficiency in oxygen-carrying erythrocytes Thrombocytopenia Neutropenia

Agents Used in Anemias

Iron Basic Pharmacology Iron-porphyrin heme ring

icrocytic hypochromic anemia

Pharmacokinetics

growing chi!dren pregnant women menstruating women

Heme iron in food Transport# storage# e!imination meat Nonheme iron in food che!ators comp!exing agent apotransferrin ferritin: !i"er sp!een bone p!asma transferrin receptor

Clinical Pharmacology I$ Indications for the use of iron : iron deficiency %$ Infants# especia!!y premature infants &$ 'hi!dren during rapid growth periods ($ )regnant and !actating women *$ +!ood !oss: menstruting women gastrointestina! b!eeding

II$ Treatment %$ ,ra! iron therapy Fai!ure to respond

&$ )arentera! iron therapy Iron dextran: ferric hydroxide and !ow mo!ecu!ar-weight dertran i$m$: !oca! pain# tissue staining i$"$ Hypersensit"ity Clinical Toxicity I$ Acute iron toxicity: young chi!dren necroti-ing gastroenterities shoc.# !ethargy# dyspnea# metabo!ic acidosis# coma# death Treatment: acti"ated charcoa!# deferoxamine

II$ 'hronic Iron Toxicity Hemochromatosis: heart# !i"er# pacreas and other organs inherited hemochromatosis: excessi"e iron absorption red ce!! transfusions o"er a !ong period of time Treatment: intermittent ph!ebotomy

/itamin +%&
0eficiency: anemia gastrointestina! symptoms neuro!ogic abnorma!ities due to abnorma! absorption of dietary /it +%& Chemistry prophyrin-!i.e ring 1 'o Acti"e form: 0eoxyadenosy!coba!amin ethy!coba!amin

Food: cyanocoba!amin hydroxycoba!amin microbia! synthesis anima!s or p!ants: not meat# eggs# dairy products extrinsic factor Pharmacokinetics intrinsic factor: g!ycoprotein secreted by the parieta! ce!! /it +%& 1 Intrinsci factor: receptoy-mediated transport system dista! i!eum

Pharmacodynamics

dT ): deoxythymidy!ate

Clinical Pharmacology %$ Neuro!ogic syndrome: degeneration of mye!in sheathdisruption of axon periphera! ner"es: paresthesia# spasticity centra! ner"ous system &$ ega!ob!astic anemia: "itamin +%& or fo!ic acid ($ )ernicious anemia: defecti"e secretion of intrinsic factor gastric atrophy partia! gastrectomy dista! i!eum: inf!ammation surgica! resection bacteria! o"ergrowth of the sma!! bowe! chronic pancreatitis and thyroid disease

*$ Treatment )arentera! in2ection: 'yanocoba!amin Hydroxocoba!amin: protein-bound ,ra! bone marrow: *3 hr reticu!ocytosis: second or third day hemog!obin: begins to increase in the first wee. and return to norma! by %-& months

Fo!ic Acid
Chemistry
po!yg!utamates

Pharmacokinetics the richest sources: !i"er# .idney# green "egetab!es una!tered fo!ic acid: proxima! 2e2unum dietary fo!ates: po!yg!utamate forms of N5-methy!tetrahydrofo!ate

Pharmacodynamics

Clinical Pharmacology %$ no neuro!ogic syndrome &$ Inade4uate dietary inta.e: e!der!y patients# poor patients# food faddist ($ 5i"er disease *$ )regnant women patient with hemo!ytic anemia 6$ Feta! neura! tube defect: spina bifida 7$ )henytoin# ora! contracepti"es# isonia-ide 8$ ethotrexate# trimethoprim# pyrimethamine dihydrofo!ate reductase High-ris. patient: pregnant women# a!coho!ics# patient with hemo!ytic anemia# !i"er disease rena! dia!ysis# certain s.in disease

Hematopoietic 9rowth Factors

:rythropoietin Chemistry & Pharmacokinetics %$ First human hematopoietic growth factor &$ the urine of patient with se"ere anemia ($ ;ecombinant 0NA techno!ogy *$ 9!ycosy!ated peptide Pharmacodynamics

Clinical Pharmacology %$ 'hronic rena! fai!ure iron deficiency fo!ate supp!ementation &$ )rimary bone marrow disorders and secondary anemias ap!astic anemia chronic inf!ammation ($ HI/ infection: <ido"udin )h!ebotomies *$ Ath!etes Toxicity hematocrit and hemog!obin hypertension and thrombotic comp!ication

ye!oid 9rowth Factors

9-'=F:granu!ocyte co!onystimu!ating factor

9 -'=F: granu!ocytemacrophage co!onystimu!ating factor

Chemistry and Pharmacokinetics Fi!grastim: 9-'=F =argramostim:9 -'=F Pharmacodynamics %$ receptor on "arious mye!oid progenitor ce!!s: tyrosine .inase in the >A?@=TAT pathway &$ 9-'=F: stimu!ate the production and function of neutrophi! mobi!i-e hematopoietic stem ce!!s

($ 9 -'=F: neutrophi! ear!y and !ate granu!ocytic progenitor ce!!s erythroid and mega.aryocyte progenitor T ce!! pro!iferation A1 I5-&B periphera! b!ood stem ce!! *$ =tem ce!! factor A='FB: ear!y p!uipotent progenitor ce!! Clinical Pharmacology %$Neutropenia : mye!osuppressio"e chemtherapy 9-'=F: prior episode of febri!e neutropenia 9 -'=F: itse!f can induce fe"er

&$ Acute mye!oid !eu.emia : postchemotherapy supporti"e care 9-'=F; 9 -'=F ($=econdary and primary neutropenia ap!astic anemia# congenita! neutropenia cyc!ic neutropenia# mye!odysp!asia *$ Auto!ogus stem ce!! transp!antation 6$ obi!i-e periphera! b!ood stem ce!! auto!ogus and a!!ogeneic transp!antation 9-'=F Toxicity 9 -'=F: more se"er side effect 9-'=F:bone pain

ega.aryocyte 9rowth factor Chemistry and Pharmacokinetics Inter!eu.in: fibrob!asts and stroma! ce!! in bone marrow ,pre!"e.in: recombinant Thrombopoietin: hepatocyte recombinant Pharmacodynamics I5-%%: primiti"e mega.aryocytic progenitors increases the number of periphera! p!ate!ets and neutrophi! Thrombopoietin: primiti"e mega.aryocytic progenitors mature mega.aryocytes

Clinical Pharmacology %$ I5-%% thrombocytopenia no effect on !eu.openia and neutropenia &$ Thrombopoietin: in"estigationa! agent Toxicity 'ardio"ascu!ar effect: anemia# dyspenia# transient atria! arrhythmia f!uid retention

,b2ecti"es %$ 0escribe the norma! mechanism of regu!ation or iron absorption and storage in the body$ &$ 5ist anemias for which iron supp!ementation is indicated and those for which it is contraindicated$ ($ 0escribe the acute and chronic toxicity of iron$ *$ =.etch the dT ) cyc!e and show fo!ic acid and "itamin +%& affect the cyc!e$ 6$ 0escribe the c!inica! app!ication of "itamin +%& and fo!ic acid$ 7$ 0escribe the ma2or ha-ard in"o!"ed in the use of fo!ic acid as so!e therapy for mega!ob!astic anemia$ 8$ Name the ma2or hematopoietic growth factors and describe their '!inica! uses$