PharmacologyAgents Used in Anemias (katzung)19 February 08Agents Used in Anemias; Hematopoietic Growth FactorsHematopoiesis The roduction !rom undi!!erentiated stem cells o! circulating erythrocytes" latelets" and leukocytes# $esides rimarily in the bone marro% in adults $e&uires a constant suly o! three essential nutrients ' iron" vitamin B12 and folic acid ' as %ell as the resence o! hematopoietic growth factors, roteins that regulate the roli!eration and di!!erentiation o! hematooietic cells (nade&uate sulies o! either the essential nutrients or the gro%th !actors result in de!iciency o! !unctional blood cells) Anemia, Thromboctopenia and !e"tropenia#AG#!T$ U$#% &! A!#'&A$&()! (ron de!iciency is the most common cause o! chronic anemia# *eadstoallor" !atigue" dizziness" e+ertional dysnea" and other generalized symtoms o! tissue hyo+ia# The cardio,ascular adatations to chronic anemia-tachycardia" increased cardiac outut" ,asodilation-can %orsen the condition o! atients %ith underlying cardio,ascular disease# (n theabsenceo! ade&uateiron" small erythrocytes %ith insu!!icient hemoglobin are !ormed" gi,ing rise to microctic hpochromic anemia*+HA('A,)-&!#T&,$A# Absortion .uodenum and ro+imal /e/unum 0emeironinmeat hemoglobinandmyoglobincanbe absorbed intact 1onheme iron and iron in inorganic iron salts and comle+es must be reduced to !errous iron (Fe23) be!ore it can be absorbed 4+cess iron can be stored in mucosal cell as ferritin" a %ater solublecomle+ consistingo! acoreo!ferric hdro.ideco,eredbyashell o! asecializedstorage rotein called apoferritin#5# Transort (ron is transorted in the lasma bound to transferrin, a 6-globulin that seci!ically binds t%o molecules o! !errous iron7# 8torage (ron is stored" rimarily as ferritin" in intestinal mucosal cells" macrohages in the li,er" sleen" and bone" and in arenchy mal li,er cells .# 4limination 91mg:day (!eces" bile" s%eat" urine),/&!&,A/ +HA('A,)/)G0A# (ndications !or the Use o! (ron Treatment or re,ention o! iron de!iciency anemia (ncreased iron re&uirements)o (n!ants" eseciallyrematurein!ants; childrenduring raidgro%theriods;regnant andlactating %omen; and atients %ith chronic kidney disease (nade&uate iron absortiono Post-gastrectomy; and se,ere small bo%el disease5# Treatment )ral &ron Therapo Ferrous sul!ate" !errous gluconate" and !errous !umarateo 200- months a!ter correction o! iron losso A.$) ?( s+ +arenteral &ron Therapo 8hould be reser,ed !or atients %ith documented iron de!iciency%hoareunabletotolerateorabsorboral iron and !or atients %ith e+tensi,e chronic blood loss %ho cannot be maintained %ith oral iron alone# - ostgastrectomy conditions and re,ious small bo%el resection" (5. in,ol,ing the ro+imal small bo%el" malabsortion syndromes" and ad,anced chronic renal disease including hemodialysis and treatment %ith erythrooietin#o &ron de.tran- Astablecomle+o! !errichydro+ideandlo%-molecular-%eight de+trancontaining@0mgo! elemental iron er m* o! solution#- (A or (B# (B most common#- A.$) hyersensiti,ity and anahyla+is- A small test dose o! iron de+tran should al%ays be gi,en be!ore !ull (A or (B doses are gi,eno &ron1s"crosecomple.and&ronsodi"mgl"conate comple.- (B- *ess likely to cause hyersensiti,ity reactionso Periodicallymonitor ironstoragele,elstoa,oidthe serious to+icity associated %ith iron o,erload#o (ronstorescanbeestimatedonthebasiso!ser"m concentrations of ferritinand thetransferrin sat"ration"%hich is theratioo! thetotalserum iron concentration to the total iron-binding caacity (T(57)#,/&!&,A/ T)2&,&T0A* Ac"te &ron To.icit 8een almost e+clusi,ely in young children %ho accidentally ingest iron tablets 1ecrotizing gastroenteritis" %ith ,omiting" abdominal ain" andbloodydiarrhea!ollo%edbyshock" lethargy" and dysnea# T+) 3hole bowel irrigation %efero.amine' a otent iron-chelating comound" can be gi,en systemically to bind iron that has already been absorbed and to romote its e+cretion in urine and !ecesB* ,hronic &ron To.icit Also kno%n as hemochromatosis $esults%hene+cessironisdeositedintheheart" li,er" ancreas" and other organs# (t Aost commonly occurs in atients %ith inherited hemochromatosis" a disorder characterized by e+cessi,e iron absortion" and in atients %ho recei,e manyredcell trans!usionso,eralongeriodo! time (eg" atients %ith thalassemia ma/or)# 7hronic iron o,erload in the absence o! anemia is most e!!iciently treated by intermittent phlebotom# Elyu, Brim & Virns 1 of 4Pharmacology Agents Used in Anemias; Hematopoietic Growth Factors by Katzung Page 2 o! < %eferasiro.' an oral iron chelator aro,ed !or treatment o! iron o,erload#4&TA'&! B12 Aco!actor !or se,eral essential biochemical reactions in humans# .e!iciencyleadstoanemia"gastrointestinal symtoms"and neurologic abnormalities# 7onsistso! aorhyrin-likering%ithacentral cobalt atom attached to a nucleotide %eo.adenoslcobalaminandmethlcobalaminarethe acti,e !orms o! the ,itamin in humans# ,anocobalaminandhdro.ocobalaminand other cobalamins !ound in !ood sources are con,erted to the acti,e !orms# The ultimate source o! ,ita min 5(2 is !rom microbially deri,ed ,itamin 512in meat (esecially li,er)" eggs" and dairy roducts# Bitamin 512 is sometimes called e+trinsic !actor#+HA('A,)-&!#T&,$ 8tored rimarily in the li,er %ith a total storage ool o! =000-@000 mcg# Cnly trace amounts are normally lost in urine and stool# 1ormal daily re&uirements are only about 2 mcg Bitamin5l2inhysiologicamounts is absorbedinthedistal ileum only a!ter it comle+es %ith intrinsic !actor Bitamin 5l2de!iciency inhumans most o!ten results !rom malabsortiono! ,itamin5l2dueeither tolacko! intrinsic !actor or tolossor mal!unctiono! theseci!ic absorti,e mechanism in the distal ileum# 1utritional de!iciency is rare but may be seen in strict ,egetariansa!ter manyyears%ithout meat" eggs" or dairy roducts# Cnce absorbed" ,it# 5(2is transorted to the ,arious cells o! the body bound to a lasma glycorotein" transcobalamin &+HA('A,)%0!A'&,$ T%o essential enzymatic reactions in humans re&uire ,itamin 5l2 )1. Aethylcobalamin ser,es as an intermediate in the trans!er o! a methyl grou !rom1@ -methyltetrahydro!olate to homocysteine" !orming methionine# - Dithout,itamin5l2con,ersiono!the ma/ordietary andstorage!olate" 1@-methyltetrahydro!olate" to tetrahydro!olate" therecursor o! !olateco!actors" cannot occur# - The deletion o! tetrahydro!olate re,ents synthesis o! ade&uate sulies o! the deo+ythymidylate (dTAP)andurinesre&uired!or.1Asynthesisin raidly di,iding cells#- Theaccumulationo! !olateas1@-methyltetrahydro!olate and the associated deletion o! tetrahydro!olateco!actors in,itamin5l2de!iciency ha,e been re!erred to as the Emethlfolate trap#E 2. (somerization o! methylmalonyl-7oA to succinyl7oA by the enzyme methylmalonyl-7oA mutase - (n ,itamin 5(2 de!iciency" this con,ersion cannot take lace" and the substrate" methylmalonyl# 7oA" accumulates# ,/&!&,A/ +HA('A,)/)G0 Bitamin 5l2 is used to treat or re,ent de!iciency 'egaloblastic Anemia o The most characteristic clinicalmani!estation o! ,itamin 5l2 de!iciency o 7linical !indings) macrocytic anemia" o!ten %ith associated mild or moderate leukoenia or thrombocytoenia (or both)" and a characteristic hyercellular bone marro% %ith an accumulation o! megaloblastic erythroid and other recursor cellso Theneurologic syndromeassociated%ith ,itamin512 de!iciency usually begins %ith aresthesias and %eakness in eriheral ner,es and rogresses to sasticity" ata+ia" and other central ner,ous system dys!unctions# $chilling test" %hich measures absortion and urinary e+cretion o! radioacti,ely labeled ,itamin 512can be used to !urther de!inethemechanismo! ,itamin512malabsortion %henthis is !oundtobethecauseo! themegaloblastic anemia# Aost commoncauseso! ,itamin512de!iciency) ernicious anemia" artial or total gastrectomy" and conditions that a!!ect the distal ileum" such as malabsortion syndromes" in!lammatory bo%el disease" or small bo%el resection# +ernicio"s anemiaresults !rom de!ecti,e secretion o! intrinsic!actor bythegastric mucosal cells# Patients %ith erniciousanemiaha,egastricatrohyand!ail tosecrete intrinsic !actor (as %ell as hydrochloric acid)# Cther rare causes o! ,itamin 5l2de!iciency include bacterial o,ergro%tho! thesmall bo%el" chronic ancreatitis" and thyroid disease# $arecaseso! ,itamin5l2de!iciencyinchildrenha,ebeen !oundtobesecondarytocongenital de!iciencyo! intrinsic !actor and congenital selecti,e ,itamin 5l2 malabsortion due to de!ects o! the recetor sites in the distal ileum#T(#AT'#!T Parenteral in/ections o! Bitamin 512 The underlying disease should be treated a!ter initial treatment Bitamin 5l2 !or arenteral in/ection is a,ailable as cyanocobalamin or hydro+ocobalamin# o Hdro.ocobalaminis re!erred because it is more highly rotein-bound and there!ore remains longer in the circulation# (nitial theray should consist o! 100-1000 mcg o! ,itamin 512 intramuscularlydailyor e,eryother day!or 1-2%eeksto relenish body stores# Aaintenance theray consists o! 100-1000 mcg intramuscularly once a month !or li!e# (! neurologic abnormalities are resent" maintenance theray in/ectionsshouldbegi,ene,ery1-2%eeks!or >months be!ore s%itching to monthly in/ections# Cral doses o! 1000mcgo! ,itamin512dailyareusually su!!icient to treat atients %ithpernicio"s anemia%ho re!use or cannot tolerate the in/ections# o A!ter ernicious anemia is in remission !ollo%ing arenteral ,itamin 512theray" the ,itamin can be administered intranasally as a sray or gel#Pharmacology Agents Used in Anemias; Hematopoietic Growth Factors by Katzung Page 5 o! >1 &N 7H3 ;:N3 9ARR:CF :prelve2ino Recombinant form of &l"