Agents Used in Anemias;Agents Used in Anemias;Hematopoietic Growth Factors

Tri Widyawati-Zulkarnain Rangkutyy g y

Blok HIS, Senin, 13 April 2009

IntroductionIntroductionAnemia : a deficiency in oxygen-carrying

erythrocytes.

Hematopoietic machinery residesHematopoietic machinery resides primarily in the bone marrow, requires a constant supply of :constant supply of :

- Iron- Vitamin B- Vitamin B12- Folic acid

And : hematopoietic growth factorAnd : hematopoietic growth factor.

Agents Used in Anemias

• Iron• Vitamin B12• Folic acid

Iron : Basic Pharmacology

• Iron form the nucleus of the iron porphyrin heme ring t th ith l bi h i h l bitogether with globin chains hemoglobin

• Hb reversibly binds O2 and provides the critical mechanism for O2 delivery from the lungs to other 2 y gtissues

Iron Distribution in normal adultsIron Distribution in normal adults

Iron content (mg)Men Women

H l biHemoglobin 3050 1700Myoglobin 430 300Enzymes 10 8Enzymes 10 8Transport (transferrin) 8 6Storage (ferritin and other forms) 750 300Storage (ferritin and other forms) 750 300

Total 4248 2314

Estimated Dietary Iron RequirementsAbsorbed iron requirement mg/day

Daily food iron requirement* mg/day

Normal men and non menstruating women

0,5-1 5-10

Menstruating women 0,7-2 7-20g ,

Pregnant women 2-4,8 20-48#

Adolescent 1-2 10-20

Children 0,4-1 4-10

Infants 0,5-1,5 1,5mg/kg**

* Assuming 10% absorption# This amount of iron can’t be derived from diet and should be met by iron supplementation in the latter half of pregnancy** To a maximum of 15 mg

Iron Requirements for Pregnancyg y

Average(mg)

Range (mg)( g) ( g)

External iron loss 170 150-200

Expansion of red-blood-cell mass 450 200-600

Fetal iron 270 200-370

Iron in placenta and cord 90 30-170

Blood loss at delivery 150 90-310-Total requirement *-Cost of pregnancy #

980680

580-1340440-1050

* Blood loss at delivery not included# Expansion of red-cell mass no included

Iron : PharmacokineticIron : Pharmacokinetic• Absorption

N ll i d d d i l j j- Normally in duodenum and proximal jejunum.- Usually absorption ± 5-10% of average diet daily.- In menstruating women : ↑ to 1-2 mg/day and 3-4 mg/day in

pregnant women.• Iron in:

- meat protein easily absorbed.meat protein easily absorbed.- vegetables & grain tightly bound to phytates or other complexing agents less available for absorption.

• Non heme iron in foods and Iron in organic iron salts and• Non heme iron in foods and Iron in organic iron salts and complexes :

must be reduced to ferrous (Fe2+) before absorbedcan be inhibited b chelatorscan be inhibited by chelatorsincreased by HCl and vit. C.

Iron : PharmacokineticIron : Pharmacokinetic• Transport

I i t t d i th l b d t t f i ( β l b li- Iron is transported in the plasma bound to transferrin (a β-globulin that specially binds ferric iron).- The transferrin-ferric iron complex enters maturing erythroid

ll b ifi t h i (t f i t )cells by a spesific receptor mechanism (transferrin receptors)- The transferrin and transferrin receptors are then recycled → incorporating iron into hemoglobin in developing red blood cells

• Storage- Iron binds avidly to a protein, apoferritin → form the complex ferritin

- Iron stored as ferritin in: intestinal mucosal cells and in the macrophages in the liver, spleen, and bone.

- Apoferritin synthesis is regulated by the levels of free iron.p y g y

Iron : PharmacokineticIron : Pharmacokinetic• EliminationElimination

- small amounts : exfoliation of intestinal mucosal cells into the stool- trace amounts : bile, urine, and sweat. - 0 5 – 1 mg/day0,5 1 mg/day

Iron Therapy : OralIron Therapy : OralPreparation Tablet size Elemental iron per Usual adult

(mg) tablet (mg) dosage (tablets per day)

Ferrous sulfate, h drated

325 65 3-4hydratedFerrous sulfate, desiccated

200 65 3-4

F l t 325 36 3 4Ferrous gluconate 325 36 3-4Ferrous fumarate 200 66 3-4Ferrous fumarate 325 106 2-3

• 200-400 mg of elemental iron should be given daily to correct iron deficiency

• 3-6 months

Iron Therapy: ParenteralIron Therapy: Parenteral

• anemic patients unable to tolerate oral therapyanemic patients unable to tolerate oral therapy.• extensive chronic blood loss

Preparation

• Iron dextran 5% (IM/IV): ferric hydroxide and low-molecular-weight dextran ( 50 mg of elemental iron/ml solution)

• Iron sucrose complex.• Iron sodium gluconate complexIron sodium gluconate complex.

Dosage : 1-2 g of replacement iron,or 20-40 mL of iron dextran

Iron : Adverse Effect

• Oral: nausea epigastric discomfortOral: nausea, epigastric discomfort, abdominal cramps, constipation, diarrhea, black stoolsblack stools

• Parenteral: local pain, tissue staining, headache fever arthralgia nauseaheadache, fever, arthralgia, nausea, vomiting, back pain, flushing, urticaria, bronchospasm and rarely anaphylaxis andbronchospasm and rarely anaphylaxis and death.

Iron : Acute ToxicityIron : Acute Toxicity• Usually in ChildrenUsually in Children

ingested iron tablets → necrotizing gastroenteritis :g- Vomitting.- Abdominal painAbdominal pain.- Bloody diarrhealethargy shock & dyspnealethargy, shock & dyspnea.

Iron : Acute ToxicityIron : Acute Toxicity• TreatmentTreatment

- Charcoal ineffective because does not bind iron.- Deferoxamine potent iron-chelating.- Supportive therapySupportive therapy.

Iron : Chronic ToxicityIron : Chronic Toxicity

• HemochromatosisHemochromatosis• In patients with :

I h it d h h t i ( i- Inherited hemochromatosis (excessive iron absorption)- too many blood, transfusion over a long period of time.

• Treatment : intermittent phlebotomy

Vitamin B12Vitamin B12

• Cofactor for several essential biochemicalCofactor for several essential biochemical reactions.

• Deficiency of vit B12 :• Deficiency of vit. B12 :anemiagastrointestinal symptomsneurologic abnormalitiesg

Vitamin B12Vitamin B12• Chemistry :Chemistry :- Porphyrin – like ring with a central cobalt atom

attached to a nucleotide.• In human : active form → - deoxyadenosylcobalamine→ deoxyadenosylcobalamine

- methylcobalamin• Therapeutic use: cyanocobalamin and• Therapeutic use: cyanocobalamin and

hydroxycobalamin

Vitamin B12 : PharmacokineticsVitamin B12 : Pharmacokinetics

• Stored in the liver (3000-5000 μg)Stored in the liver (3000 5000 μg)• Normal daily requirement ± 2 μg• Vit B12 in food bind to intrinsic factor ( aVit. B12 in food, bind to intrinsic factor ( a

glycoprotein secreted by the parietal cells of the gastic mucosa) absorbed in distal ileum by g ) yhighly specific receptor mediated transport system.

Vitamin B12 : PharmacokineticsVitamin B12 : Pharmacokinetics• After absorption :p

- Transported to the various organ cells bound to plasma glycoprotein → transcobalamin II (beta globulin)globulin) - Excess vit. B12 stored in the liver

• Metabolism : hati ⇒ hydroxycobalamin and y ycyanocobalamin → coenzim B12

Vitamin B12 : PharmacokineticsVitamin B12 : Pharmacokinetics• Excretion : empedup

urin (bentuk tdk terikat protein)• 80-95% diretensi tubuh sampai dosis 50 mcg

K it ik t t i d i h ti j i d• Kapasitas ikatan protein dari hati, jaringan dan darah jenuh ⇒ dikeluarkan melalui urin

• Vitamin B12 dapat melewati sawar uriVitamin B12 dapat melewati sawar uri• Vit. B12 deficiency often results from :- Malabsorption of Vit. B12 due to ⇒ Lack of intrinsic factor⇒ Malfunction of specific absorptive mechanism.

Vitamin B12 : Pharmacodynamics

• Methylfolate trap: def Vit B12 corrected : folic acid• Neurologic manifestations : def vit B12

Vit i B12 Cli i l Ph lVitamin B12 : Clinical Pharmacology

• Vitamin B12 is used to treat or prevent deficiency megaloblastic anemiadeficiency megaloblastic anemia (macrocytic anemia)

Preparation

• Tablet : oral • Solution : par enteral (IM/SK) → lebih baik

1. sol. Cyanocobalamin 10-1000 mcg/mlJ i b lk k i l i⇒ Jarang menimbulkan reaksi alergi

2. sol. Eksrak hati dalam air⇒ Sering reaksi alergi⇒ Sering reaksi alergi

3. suntikan depot vit. B12⇒Mengurangi frekuensi pemberian ⇒ e gu a g e ue s pe be a• Solution : hidroxycobalamin 100 mcg : efek

lebih lama

Folic AcidFolic AcidPrecursors for the synthesis

f i id i dof amino acids, purines, and DNADNA

Folic Acid

Folic Acid : PharmacokineticsFolic Acid : Pharmacokinetics

• The average diets : 500-700 μg daily ⇒The average diets : 500 700 μg daily ⇒50-200 μg of which is usually absorbed

• Sources :• Sources : - plant and animal tissues- richest : yeast, liver, kidney and green vegetables

• Normally : 5 – 20 mg stored in the liver and other tissues

Folic Acid : PharmacokineticsFolic Acid : Pharmacokinetics

• Excreted : urine and stoolExcreted : urine and stool destroyed by catabolism

F li id d fi i d l bl ti• Folic acid deficiency and megaloblastic anemia : develop within 1-6 months after th i t k f li id tthe intake folic acid stops

Folic Acid : TherapyFolic Acid : Therapy

• Oral : - well absorbedOral : well absorbed- 1 mg/day for anemia megaloblastic

C ti d til th d l i f⇒ Continued until the underlying cause of deficiency is removed or corrected

• Parenteral : rarely

Hematopoietic Growth FactorsE h i iErythropoietin

E th i ti• Erythropoietin :- Glycoprotein- a growth hormone- a growth hormone

• stimulates erythroid proliferation and differentiation by interacting with spesificdifferentiation by interacting with spesific eryhropoietin receptors on red cell progenitors

• induces release of reticulocytes from the boneinduces release of reticulocytes from the bone marrow

ErythropoietinErythropoietin

• Recombinant human erythropoietin used in clinic.

• Epoitin alfa : - I.V t ½ 4-13 hrs in CRF- Not cleared by dialysis.y y

• Darbopoietin alfa : - Glycosylated form of erythropoietiny y y p- t ½ 2-3 x epoitin.

ErythropoietinErythropoietinI di ti• Indication :

- Anaemia in chronic renal failure → can maintained a hematocrit of 35% with erythropoietin 50-150 IU/kg I.V. or S C 3 x a weekS.C. 3 x a week.

• Anaemia in :- Bone marrow disorders.

Ch i i fl ti- Chronic inflammation- AIDS- CancerSid ff t rapid increase in hematocrit & Hb• Side effect : rapid increase in hematocrit & Hb

- hypertension- thrombotic complication.

Vitamin B12 : PharmacokineticsVitamin B12 : Pharmacokinetics• Absorption :

- B12-FIC (Faktor intrinsik Castle)- Langsung : mass action effect- cyanocobalamin : IM/SK ⇒ well absorptioncyanocobalamin : IM/SK ⇒ well absorption

Cmax (IM): 1 hour- hydroxycobalamin : lebih lambat ~ ikatan protein kuat

oral : lambat (Cmax: 8 12 jam)- oral : lambat (Cmax: 8-12 jam)• Sekresi FIC ↑ : obat kolinergik, histamin, ACH,

coricoseroid, hormon tiroid → B12 absorption ↑B12 b ti ↓ k l k l i d bit l• B12 absoprtion ↓ : pengkela kalsium dan sorbitol

Metabolisme ferrum di dalam tubuh

ABSORBSI TRANSPORT KEBUTUHAN Simpan

apoferritin → ferritin

Oral Ferrum

pHati, lien, sumsum tulang

Ferrum

TransferinPlasma, protein

Eritropoesis(120 h )

Lambung → HCL → ferro

Plasma, protein ( )

Pe cah

D d f iti f iti

Darah plasmaprotein

Duodenum, apoferritin → ferritin

Hemosiderin

The great majority of iron in the body is found in red cells where it is incorporated into hemoglobin tocells where it is incorporated into hemoglobin to function as an oxygen carrier. Smaller amounts are incorporated into myoglobin (muscle) and cytochromes (all tissues). As red cells turnover incytochromes (all tissues). As red cells turnover in the spleen, iron is recycled back to the bone marrow where it is re-incorporated into hemoglobin. Iron is transported through the plasma bound to transferrin

d t k b ll i th t f i tand taken up by cells via the transferrin receptor. Iron is concentrated and stored within the cell encased by ferritin. Excess iron is stored primarily in the macrophages of the liver spleen and bonethe macrophages of the liver, spleen and bone marrow Very little iron is lost except through bleeding and menstruation. Therefore, homeostasis of total body iron is maintained by regulatingof total body iron is maintained by regulating intestinal iron absorption.