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Obat Antianemia

Dr. dr. Lili Indrawati, MKes


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

Diminished production and or replacement of red


blood cells.

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 RBC’s Anemia's
 Microcytic anemia – deficiency of Fe
RBC’s 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 RBC’s 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)
Sites of action for EPO
Therapeutic Uses of EPO

 Anemia of end stage renal disease

 To treat AIDS anemia caused by azidotimidin’s


suppression of bone marrow

 Anemia related to cancer chemotherapy

 Others
 To increase RBC levels for autologous blood donation
 Anemia associated with rheumatoid arthritis
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.


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

 Malabsorption Syndrome
Pregnancy

 GI Bleeding due to:


Premature Babies  Ulcers
 Aspirin
 Excess consumption of
Blood loss 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
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 (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

 ABC’s supportive care

 Bicarbonate for acidosis

 Fluids for blood loss

 Ipecac or lavage

 Chelation with Deferoxamine


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 - 0.6-1.0mh/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.


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


Will’s 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.
 Digunakan utk tx anemia sideroblastik→ ditandai adanya defisiensi sintesis Hb &
akumulasi besi pd mitokondria sel prekursor eritroid yg disebut ringed sideroblasts.
 Piridoksin memperbaiki sintesis Hb
 Piridoksin (vit B6) terdapat dlm makanan & diabsorbsi dg mudah dr GIT. Rata2
kebutuhan minimum harian org dws: 2 mg
 Anemia sideroblastik yg herediter maupun dapatan berespon thd piridoksin, mskpn hy
yg herediter yg berespon baik
 Dibutuhkan 100 mg/hr utk menghaslkan efek positif
 Vitamin pd dasarnya tdk toksik, shg extensive trial (3 bln) cukup beralasan pd pasien
myelodisplasia yg memperlihatkan ringed sideroblasts pd ssm tulang
 Digunakan utk terapi anemia sickle cell, dimana hidroksiurea
meningkatkan hemoglobin fetus
 Dapat diselingi dgn eritropoietin
 Diberikan peroral dan scr cepat diabsorbsi, sebagian besar
diekskresi mll urin
 Dpt menyebabkan ES serius, tmsk depresi hematopoietik
general, yg mengakibatkan penurunan jml sel darah putih
 Overdosis dpt mengakibatkan netropeni berat & infeksi
sistemik
 Efektif mengkhelat besi & digunakan pd pasien dg anemia overload besi
 memp afinitas yg tinggi thd besi (btk ferri) & dpt mengambil besi dr
hemosiderin & ferritin, jg transferin.
 tdk mengkhelat besi dlm Hb
 Diabsorbsi scr lemah dr GIT, memp t1/2 15 mnt, & hrs diberikan dg
pompa SC
 Overload besi dpt disebabkan oleh hemokromatosis herediter, anemia
yg berhub dg eritropoiesis yg inefektif mis pd talasemia, anemia
sideroblastik, sindrom myelodisplastik, & anemia diseritropoietik
kongenital
 Overload besi juga ditemukan pada anemia hemolitik spt
sferositosis herediter, overload besi krn tranfusi, juga pada
anemia hemolitik berat
 Penelitian pada anak2 talasemia menunjukkan jika terapi
deferoksamin diberikan pd usia muda, efek samping overload
lbh sedikit, termsk penurunan insidensi DM, & fungsi hepar &
jantung lbh baik
 ES: dpt menyebabkan reaksi alergi, tetapi anafilaksis jarang;
neurotoksisitas pd terapi jangka panjang (efek visual &
auditori)