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)

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:
Blood loss

Ulcers
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

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 812 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 MCSF)
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, granulocytemacrophage 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
Drug
s
Rec
ombi
nant
hum
an
eryt
hrop
oieti
n
Iron

RO Notes
A
IV, SC
SC may
be as
effecti
ve as
IV,
T1/2 8
hr
Ora Absor
l,
psi p.o
IM,I ferrou

Farmakokinetik
Dru
gs
Asa
m
folat

RO
A
Oral
,
IM,
IV

Notes

Absor
psi p.o
good,
entero
hepati
c
cyclin
g
Vita Oral Oral
min ,
route
B12 SC, ineffec
IM tive in

Farmakokinetik
Dru R
gs O
A
Hidr Or
oksi al
ure
a
Pre Or
dnis al
on or
IV
Sikl Or
osp al

Notes
Absorp
si p.o
good
Absorp
si p.o
good
Oral
dose is

Farmakokinetik
Drugs R
O
A
Defer S
oksa C
min
or
IV

Notes
Absor
psi
p.o
poor,
must
be
given
by
contin
uous