OBAT ANTIANEMIA

EVI SOVIA
 Anemia: penurunan konsentrasi sel darah
merah atau hemoglobin

Kriteria anemia:
Wanita: Hb < 12 g/dl atau hematokrit < 37%
Laki-laki:Hb < 14 g/dl atau hematokrit < 40%
 Anemia
2nd most presenting manifestation of disease, with
pain being the first.

It is defined as: low hemoglobin, low RBC count and

low RBC mass.

Usually presents with pallor, fatigability, weakness

and pale conjunctivae

In order to properly treat the anemia, you must

determine the cause.
 Causes of Anemia
1. Diminished production and or
replacement of red blood cells.

2. Excessive breakdown and loss of red blood

cells.

Hemodilution while not a cause of anemia, it

does cause an anemia-like effect.
 1. Diminished Production/Replacement of RBCs
Anemia's
Microcytic anemia deficiency of Fe
RBCs appear pale and smaller, and we see more reticulocytes
in circulation.
Can be caused by the chronic use of aspirin, which irritates
the stomach GI blood loss.

Normocytic anemia deficiency of Erythropoietin

Caused by compromised renal function.

Macrocytic Anemia- deficiency of folic acid and B12

Diminished cell division and release of larger cells in
circulation.
 2. Breakdown of RBCs Anemia
Bleeding: can be due to an ulcer or in females blood
loss due to their menstrual cycle

Use of drugs that irritate the GI tract (aspirin)

Hemolysis (Hemolytic Anemia) can be caused by:

Autoimmune disease
Mechanical (heart valves, microvascular disease)
Toxins (e.g., snake venom)
 Obat-obat Antianemia
Piridoksin
Untuk terapi anemia sideroblastik
Hidroksiurea
Untuk terapi sickle cell disease
Deferoksamin
Untuk mengkhelat besi pada iron loading anemia
Prednison
Untuk anemia hemolitik
 Siklosporin dan antitimosit globulin
Untuk anemia aplastik
Siklofosfamid dosis tinggi dan iradiasi seluruh
tubuh
Untuk anemia aplastik, sindroma mielodisplastik,
talasemia dan anemia sel sabit
Besi
Untuk anemia hipokrom mikrositer yang
berhubungan dengan defisiensi besi
 Vitamin B12 dan folat
Untuk anemia megaloblastik
Eritropoietin
Untuk anemia pada penyakit ginjal stadium akhir
dan anemia yang berhubungan dengan kanker
tertentu
 Besi (Fe)
Diberikan secara peroral atau parenteral pada
kasus yang berat
Pemberian preparat besi meningkatkan
kecepatan produksi sel darah merah sesuai
dengan jumlah besi yang tersedia dalam sel
eritroid sumsum tulang
 Iron Cycle
5 - 10% of ingested iron is
absorbed

Once ingested the acid in

the stomach:

1. Aids in ionization of
iron
2. Splits chelated food
iron from chelator
3. Maintains iron in
soluble form
4. Allows iron to
remain in the
absorbable form Fe3+
Mechanism of Iron Absorption
 Therapeutic uses of Iron
Iron Deficient Anemia Hookworn infestation

Pregnancy Malabsorption
Syndrome
Premature Babies
GI Bleeding due to:
Ulcers
Blood loss Aspirin
Excess consumption of
coffee
 Iron Preparations
Oral Iron
Ferrous Sulfate (Feosol) 300 mg tid
Side Effects are extremely mild:
Nausea, upper abdominal pain, constipation or diarrhea.
Cheapest form of Iron and one of the most widely used

Parenteral
Iron Dextran (Imferon) IM or IV
Indicated for patients who cannot tolerate or absorb oral
iron or where oral iron is insufficient to treat the condition
ie. Malabsorption syndrome, prolonged salicylate therapy,
dialysis patients
 Pemberian zat besi produksi sel darah
merah
ROA: p.o atau parenteral
Absorpsi meningkat bila diberikan bersama
ascorbate (mereduksi besi dari bentuk ferri
menjadi ferro)
Distribusi: plasma transferin protein
(glikoprotein)
 Overdosis Fe muntah, gastritis hemoragik,
hipotensi, letargi
Terapi gastrik lavage dengan sodium
bicarbonat dan pemberian deferoksamin
 Toxicity of Iron Overdose
5000 deaths/year in the US, usually in children

20% of children presenting with iron toxicity will die

1 to 2 grams are sufficient to cause death

At high doses, Iron is absorbed through passive

diffusion with no regulation
 Iron Clinical Effects
Early changes
Vomiting, diarrhea Blood Volume HR TPR (reflex)
Acidosis from Iron oxidation, Krebs cycle and
anaerobic metabolism citric acid and lactic acid

Intermediate changes
Improvement (short lived) profound shock and CV
Collapse Hepatic Failure, jaundice, pulmonary edema and
death

Late Stage
Intestinal scarring, fatty acid degeneration of liver, cirrhosis
and death.
 Treatment of Iron Overdose
Toxic levels
ALD 200-300mgkg, plasma iron > 300ug/dl

ABCs supportive care

Bicarbonate for acidosis

Fluids for blood loss

Ipecac or lavage

Chelation with Deferoxamine

 Vitamin B12 dan asam folat
Vitamin B12 dan asam folat diperlukan untuk
sintesis DNA dan protein
Defisiensi vitamin B12 atau asam folat
gangguan kecepatan dan keberlangsungan
maturasi inti sel dalam sumsum tulang
anemia megaloblastik
 Vitamin B12 ada dalam 2 bentuk koenzim:
MCB (metil B12) dan deoksiadenosilkobalamin
(deoksiadenosil B12)
MCB
 Vitamin B12
Absorpsi: memerlukan faktor intrinsik
(glikoprotein yang dihasilkan oleh sel parietal)
Anemia pernisiosa fungsi sel parietal (-)
Distribusi: terikat dengan plasma globulin
kemudian ditranspor ke jaringan (terutama hati)
dan disimpan sebagai koenzim
Siklus enterohepatik mempertahankan
konsentrasi vit B12
ESO: transient hipokalemia
 Vitamin B12
Source: In food, especially in liver and kidneys. GI
Microorganism synthesis, Vitamin Supplements
(Cyanocobalamin)

Necessary for normal DNA synthesis

Absorption of B12

1. Intrinsic Factor (low dose): a protein made by stomach parietal

cells that binds to B12 and delivers it from the ileum via a calcium
mediated event.

2. Mass Action (High dose): 1000mg/day, absorbed via passive

diffusion
 B12 Deficiency
A B12 deficiency will cause peripheral neuropathy
and a macrocytic anemia, a pernicious anemia.

Folic Acid administration can correct the macrocytic

anemia but will fail to correct the peripheral
neuropathy.

To treat the neuropathy, Vit B12 must be utilized.

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

Succinyl-CoA enters the Krebs cycles and goes into

nerves to make myelin.

If no Vitamin B12, methylmalonyl-CoA goes on to

form abnormal fatty acids and causes subacute
degeneration of the nerves. Only B12 can correct this
problem.
 Therapeutic Uses of B12
Daily Requirements - 0.6-1.0 mh/day; T1/2 ~ 1 year

Pernicious Anemia

Impaired GI absorption of B12

Gastrectomy

Corrosive Injury of GI mucosa

Fish tape worm: worm siphons off B12

Placebo abuse with B12, especially in elderly patients.

 Asam folat
Dalam makanan: polyglutamat
Dihidrolisis oleh karboksipeptidase, direduksi
menjadi dihidrofolat reduktase didalam intestin
Dimetilasi menjadi MTHF (methenyl
tetrahydrofolate) kemudian ditransport ke
jaringan
Siklus enterohepatik
 Folic Acid
Source in food yeast, egg yolk, liver and leafy vegetables

Folic Acid (F.A.) is absorbed in the small intestines.

F.A. is converted to tetrahydrofolate by dihydrofolate

reductase.

Folic Acid deficiency (F.A. Deficiency) is also called Wills

Disease.

Deficiency may produce megaloblastic anemia; neural tube

defect in fetus.
 Therapeutic Uses of Folic Acid
1. Megaloblastic Anemia due to inadequate dietary
intake of folic acid
Can be due to chronic alcoholism, pregnancy, infancy,
impaired utilization: uremia, cancer or hepatic disease.

2. To alleviate anemia that is associated with

dihydrofolate reductase inhibitors.
i.e. Methotrexate (Cancer chemotherapy), Pyrimethamine
(Antimalarial)

Administration of citrovorum factor (methylated folic acid)

alleviates the anemia.
 Therapeutic Uses of Folic Acid (cont)
3. Ingestion of drugs that interfere with intestinal
absorption and storage of folic acid.
Mechanism- inhibition of the conjugases that break off folic
acid from its food chelators.

Ex. phenytoin, progestin/estrogens (oral contraceptives)

4. Malabsorption Sprue, Celiac disease, partial

gastrectomy.

5. Rheumatoid arthritis increased folic acid demand or

utilization.
 Piridoksin (Vitamin B6)
Digunakan untuk anemia sideroblastik
(ditandai dengan inti sel darah merah yang
mengandung partikel besi) defisiensi
sintesis Hb dan akumulasi besi dalam
mitokondria sel prekursor eritroid yang
disebut cincin sideroblast
Sel terdiri dari SDM normal dan sel hipokrom
dan mikrositer
 Piridoksin memperbaiki defisiensi sintesis
asam yang diperlukan untuk sintesis
hemoglobin
Piridoksin terdapat dalam makanan
Diabsorpsi dengan baik pada pemberian
peroral
 Eritropoietin
Beberapa faktor humoral dan seluler berperan
dalam eritropoiesis, yang paling berperan
adalah eritropoietin
Eritropoietin merangsang proliferasi,
diferensiasi, dan maturasi stem sel menjadi sel
hematopoietik
90% erotropoietin disintesis dalam kortek
ginjal dan sisanya di ekstrarenal terutama sel
hati
 Hipoksia sekresi eritropoietin
Anemia, hipobaria, iskemia RBF
produksi eritropoietin
Diberikan IV atau SC
T1/2 = 8 jam
Konsentrasi puncak dicapai dalam 8-12 jam
setelah pemberian SC
Distribusi ke seluruh tubuh
Metabolisme di hepar
Sites of action for EPO
 Biological Actions of Other Hematopoietic
Growth Factors
1. Granulocyte/Macrophage Colony Stimulating Factor (GM-
CSF)- Sargramostim
Acts synergistically with IL-3 to stimulate the formation and
proliferation of colony forming cells: CFU-GEMM, BFU-E, CFU-
Meg, CFU-GM, CFU-M, CFU-E
Increases cytotoxic phagocytic activity of mature granulocytes

2. Interleukin 3 (IL-3)
Acts synergistically with GM-CSF to stimulate the formation of
granulocytes, macrophages, eosinophils and megakaryocytes.
Acts synergistically with EPO to stimulate formation of BFU-E
colonies
Induces CFU-S and leukemic blast cells into cell cycle
 More Hematopoietic Growth Factors
3. Colony stimulating Factor-1 (CSF-1 or M-CSF)
Acts synergistically with GM-CSF and IL-3 to stimulate
monocyte/macrophage colony formation and function

4. Granulocyte Colony Stimulating Factor (G-CSF)

- filgrastim
Acts synergistically with IL-3, GM-CSF and CSF-1 to stimulate
formation of megakaryocytes, granulocyte-macrophage and high
proliferative potential (HPP) colonies
Induces release of granulocytes from marrow
 More Hematopoietic Growth Factors
5. Thrombopoietin (TSF)
Increases the size and number of megakaryocytes.
(IL-11 also useful in stimulating production)

Increases the concentration of early megakaryocytes cells

(SACHE+cells) in bone marrow.

Produces an increase in megakaryocytes endomitosis.

Increases platelet size and number in plasma.

 Hidroksiurea
Digunakan untuk terapi anemia sel sabit,
dimana terjadi peningkatan sintesis fetal Hb
Mekanisme kerja belum jelas, tetapi
mempengaruhi ribonukleotida difosfat
reduktase tahap biosintesis DNA
menghancurkan pembentukan radikal bebas
tirosil dalam pusat katalitik enzim
 Absorpsi peroral baik
Konsentrasi puncak dicapai dalam 2 jam
ESO: menekan hematopoietik, neutropenia
 Deferoksamin
Deferoksamin efektif mengikat besi
digunakan untuk anemia dengan kelebihan
besi
Afinitas tinggi terhadap ion besi dan mengikat
besi dari hemosiderin dan feritin, juga dari
transferin
Deferoksamin tidak mengikat besi pada Hb
 Absorpsi peroral buruk
T1/2 15 menit
Diberikan melalui SC pump
ESO: reaksi alergi, neurotoksik (pada
penggunaan jangka panjang)
 Imunosupresan
Siklosporin dan antitimosit globulin digunakan
untuk anemia aplastik
 Antitimosit globulin
Diberikan secara IV setelah dilarutkan dalam
salin normal dan diberikan melalui infus pada
kateter intravena sentral
ESO: anafilaksis, serum sickness
 Farmakokinetik
Drugs ROA Notes

Recombinant IV, SC SC may be as

human effective as IV, T1/2
erythropoietin 8 hr
Iron Oral, IM,IV Absorpsi p.o ferrous
good, ferric poor, but
enhanced by
ascorbate; enteric
coated preparation
unreriable
 Farmakokinetik
Drugs ROA Notes

Asam folat Oral, IM, IV Absorpsi p.o good,

enterohepatic cycling
Vitamin B12 Oral, SC, IM Oral route ineffective
in malabsorption
disease;
enterohepatic cycling
Piridoksin Oral Absorpsi p.o good
 Farmakokinetik
Drugs ROA Notes

Hidroksiurea Oral Absorpsi p.o good

Prednison Oral or IV Absorpsi p.o good

Siklosporin Oral or IV Oral dose is 4x higher

than IV dose
Antitimosit IV Must be given IV with
globulin appropriate
premedication
 Farmakokinetik

Drugs ROA Notes

Deferoksamin SC or IV Absorpsi p.o poor,

must be given by
continuous pump
High dose IV Must be given IV
cyclophosphamide