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Drugs in Leukemia
dr. Asep
3 Tujuan/Goal Anticancer
1. Damage the DNA of the affected cancer cells
2. Inhibit Synthesis of new DNA strands to stop the cell from
replicating
3. Stop mitosis or the actual splitting of the original cell into two new
cells
By : MIvec Turbo // RALLY//ART
Transisi G0 ke G1
Aktivasi tirosin kinase reseptor autofosforilasi dan fosforilasi
protein kinase (serin threonin kinase)
Protein kinase : faktor pemicu dan penekanan siklus sel
– Faktor pemicu : gena siklin, CDK, RNA polimerase, DNA
helikase, dan DNA polimerase
– Faktor penekanan faktor represi transkripsi : Rb, p107, p53
(Rb menghambat ekspresi c-fos, c-myc, TGF-, dan Dhfr)
Transisi G1 ke S
Aktivasi transisi : aktifitas fosforilasi siklin G1-Cdc kinase
• Fosforilasi protein H1 (Histon-1) : kromatin menjadi
nukleosom
• Fosforilasi protein Rb : terlepasnya E2f
Terlepasnya E2f RNA polimerase berikatan dgn promotor
Aktifasi faktor2 transkripsi dan aktifator transkripsi + RNA
polimerase RNA primer di daerah oriR replikasi DNA
Transisi G2 ke M
• Protein Lamin (A,B,C) : ikatan antara kromosom dan membran
nukleolus akan pecah (Lamin A,C) serta terjadi fragmentasi
membran nukleolus (Lamin B)
• Protein perancah/scaffold (topoisomerase) : konformasi kromosom
seperti perancah
• Kaldesmon : kelasi ion kalsium kadar ion Ca+2 sinyal untuk
polimerasi tubulin dari MOC atau sentrosom
• Microtubule associated protein kinase (MAPK) : fosforilasi
mikrotubul
By : MIvec Turbo // RALLY//ART
Methotrexate
Methotrexate inhibits folic acid reductase which is responsible for the
conversion of folic acid to tetrahydrofolic acid.
Tetrahydrofolic acid itself is synthesized in the cell from folic acid with the
help of an enzyme, folic acid reductase.
Methotrexate looks a lot like folic acid to the enzyme, so it binds to it
thinking that it is folic acid.
Methotrexate looks so good to the enzyme that it binds to it quite
strongly and inhibits the enzyme, Thus DNA synthesis cannot proceed
because the coenzymes needed for one-carbon transfer reactions are not
produced from tetrahydrofolic acid because there is no tetrahydrofolic
acid.
5-Fluorouracil
5-Fluorouracil is an effective pyrimidine antimetabolite. Fluorouracil is
synthesized into the nucleotide, 5-fluoro-2-deoxyuridine.
This product acts as an antimetabolite by inhibiting the synthesis of 2-
deoxythymidine because the carbon - fluorine bond is extremely stable
and prevents the addition of a methyl group in the 5-position.
The failure to synthesize the thymidine nucleotide results in little or no
production of DNA.
Two other similar drugs include: gemcitabine and arabinosylcytosine
By : MIvec Turbo // RALLY//ART
Hydroxyurea
Hydroxyurea blocks an enzyme which converts the cytosine nucleotide
into the deoxy derivative.
In addition, DNA synthesis is further inhibited because hydroxyurea
blocks the incorporation of the thymidine nucleotide into the DNA
strand.
Mercaptopurine
Mercaptopurine, a chemical analog of the purine adenine, inhibits the
biosynthesis of adenine nucleotides by acting as an antimetabolite.
6-MP ribonucleotide is a potent inhibitor of the conversion of a
compound called inosinic acid to adenine . Without adenine, DNA cannot
be synthesized.
Thioguanine
Thioguanine is an antimetabolite in the synthesis of guanine nucleotides.
Mitotic Disrupters
• Plant alkaloids like vincristine prevent cell division, or mitosis.
• During metaphase, the cell pulls duplicated DNA chromosomes to
either side of the parent cell in structures called "spindles".
• These spindles ensure that each new cell gets a full set of DNA.
• Spindles are microtubular fibers formed with the help of the protein
"tubulin". Vincristine binds to tubulin, thus preventing the
formation of spindles and cell division.
By : MIvec Turbo // RALLY//ART
Alkylating Agents
Alkylating agents involve reactions with guanine in DNA.
This in turn inhibits their correct utilization by base pairing and causes a
miscoding of DNA.
first mechanism an alkylating agent attaches alkyl groups to DNA bases
second mechanism by which alkylating agents cause DNA damage is the
formation of cross-bridges, bonds between atoms in the DNA.
The third mechanism of action of alkylating agents causes the mispairing
of the nucleotides leading to mutations.
There are six groups of alkylating agents: nitrogen mustards;
ethylenimes; alkylsulfonates; triazenes; piperazines; and nitrosureas.
Antibiotics
anthracyclines, dactinomycin, bleomycin, adriamycin, mithramycin, bind
to DNA and inactivate it Thus the synthesis of RNA is prevented.
General properties of these drugs include: interaction with DNA in a
variety of different ways including intercalation (squeezing between the
base pairs), DNA strand breakage and inhibition with the enzyme
topoisomerase II.
Intercalating Agents
• The intercalated drug molecules affect the structure of the DNA,
preventing polymerase and other DNA binding proteins from
functioning properly.
• The result is prevention of DNA synthesis, inhibition of transcription
and induction of mutations.
• Examples include: Carboplatin and Cisplatin
By : MIvec Turbo // RALLY//ART
Blood Coagulation
1. Extrinsic System
Diinisiasi oleh aktifasi dari
Clotting F VII oleh tissue factor
(thromboplastin)
2. Intrinsic System
Triggered by the activation
of Clotting F XII
Anticoagulant
1. Heparin
2. Warfarin
By : MIvec Turbo // RALLY//ART
Heparin
Heparin mempercepat inaktifasi dair
koagulasi factor by antithrombin
AE’s and CI
Bleeding complications hypersensitivity reactions thrombocytopenia
CI : hypersensitive; have bleeding disorders; alcoholics; had surgery of the
brain, eye or spinal cord
By : MIvec Turbo // RALLY//ART
Warfarin
The coumarin anticoagulants
(warfarin and dicumarol)
have ability to antagonize the
cofactor function of vit K
Widely employed clinically as
an oral anticoagulant (MCI
and hip arthroplasty)
By : MIvec Turbo // RALLY//ART
AE’s
Bleeding disorders
CI
In pregnancy (teratogenic and cause abortion)
By : MIvec Turbo // RALLY//ART
AntiAnemic Drugs
dr. Novita Carolia
Anemia
1. Decrease Hemoglobin Concentration
2. Decrease Hematocrite
3. Decrease Erytrosite Count
Classification of Morfology
1. Hipokrom Mikrositik
MCV < 80 fl
MCH < 27 pg
2. Normokromic Normositik
MCV 80 – 95 / fl
MCh 27 – 34 pg
3. Makrositik
MCV > 95 fl
AntiAnemic drugs
Drugs effective in iron deficiency and other hypochromic anemias
1. Iron
2. Pyridoxine, Riboflavin
3. Copper
Drugs effective in megaloblastic anemia
1. Vitamin B12
2. Folic Acid
Hematopoietic growth factors
1. Erythropoietin
By : MIvec Turbo // RALLY//ART
Iron Cycle
5 – 10% of ingested iron is
absorbed
once ingested the acid in the
stomach
o Aids in ionization of iron
o Splits chelated food iron
from chelator
o Maintains iron in soluble
form
o Allows iron to remain in
the absorbable from FE3+
Preparation
Oral
Ferrous Sulphate
Ferrous Gluconate
Ferrous Fumarate
Parenteral
Iron Dextran i.m or i.v
Iron Sorbitol i.m only
By : MIvec Turbo // RALLY//ART
Farmakokinetik
Absorbsinya bergantung pada
Kebutuhan
iron stores
Ferrous (Fe++) / Ferric (Fe+++) form
pH
Vitamin C
CHelators or complexing agents
Malabsorbtion syndrome
Distribusi
Transferin
A beta – globulin, transport iron in plasma,
Specifically bind ferric iron
Excretion
Tidak ada mekanisme untuk ekskresi dari besi
Small amount lost by exfoliation of
intestinal mucosal cells into stool
Indikasi
Kehamilan, laktasi, atau menstruasi
Growing children & adolescence
Infants, especially premature infants
Malabsorption Gastrectomy
Severe small bowel disease
Occult G.I. bleeding GI cancer
Dietary deficiency
By : MIvec Turbo // RALLY//ART
Efek Samping
Abdominal pain
Nausea
Ulkus gaster
Diare dan konstipasi
Toxicity
20% anak mati karena toksisitas besi
1 – 2 gram besi dapat menyebabkan kematian
At high dose, iron is absorbed through passive diffusion with no
regulation
Clinical Effect
Early Changes
Vomiting, diare
acidosis karna iron oxidation
Intermediate changes
improvement Profound shock and CV collapse hepatic failure, jaundice,
pulmonary edema and death
Late stage
Intestinal scarring, fatty acid degeneration of liver, sirosis dan kematian
Vitamin B12
Porphyrin-like ring with a central cobalt atom & nucleotide
Cobalamins = various organic groups covalently bound tocobalt atom
Active forms of vitamin B12 in human
o Deoxyadenosylcobalamin
o Methylcobalamine
By : MIvec Turbo // RALLY//ART
Farmakokinetik
Absorbsi
Intrinsic Factor (IF) a glycoprotein
Secreted by parietal cells of gastric mucosa
IF Vit B12 complex absorbed by
Active transport in the distal ileum
Distribusi
Transported in plasma bound to the glycoprotein transcobalamin II
Stored in hepatosit
Metabolisme
Not significantly metabolized
Eliminasi
Pass into bile
Enterohepatic circulation
Excreted via kidney
Folic Acid
Source in food, yeast, egg yolk, liver and leafy vegetables
Folic Acid (FA) Is absorbed in the small intestines
FA is converted to tetrahydrofolate by dihydrofolate reductase
Functions: required for synthesis of Amino Acids, purines, pyrimidines, & DNA;
& therefore in the cell division
Defisiensi may produce megaloblastic anemia; neural tube defect in fetus
By : MIvec Turbo // RALLY//ART
Therapeutic Uses
Megaloblastic anemia due to inadequate dietary intake of folic acid
o can be due to chronic alcoholism, pregnancy, infancy, impaired
utilization : uremia, cancer or hepatic disease
To alleviate anemia that is associated with dihydrofolate reductase
inhibitors
o Methrotrexate (Cancer Chemotherapy), Pyrimethamine
(Antimalarial),
o Administration of citrovorum factor ( methylated folic acid)
alleviates the anemia
Ingestion of drugs that interfere with intestinal absorption and storage
of folic acid
o Mechanism – inhibition of the conjugases that break off folic acid
from its food chelators.
o Phenytoin, progestin/estrogens(oral contraceptives)
Malabsorption sprue, celiac disease, partial gastrectomy,
Rheumatoid arthritis increased folic acid demand or utilization
Farmakokinetik
Rute administrasi biasanya oral
Absorption must be converted to Monoglutamyl form
Absorbed mostly in proximal jejunum
Clinical Uses
Dietary insufficiency
Pregnancy & laktasi
to prevent congenital malformation neural tube defect (spina bifida)
Premature infant
Malabsorbtion syndrome
By : MIvec Turbo // RALLY//ART
Erythropoietin (EPOTEIN)
A glycoprotein Hormone
Produce : 90% by peritubural cells in kidney and remainder – by
liver and other tissue
Essential for normal reticulosit produksi
Synthesis is stimulated by hypoxia
Synthesized for clinical use by recombinan DNA technology
Farmakokinetik
Rute administrasi S.C atau I.V
Plasma T1/2 4 – 13 jam pada pasien dengan kegagalan renal kronik
Not cleared by dialysis
Mechanism Of Action
1. Increases rate of stem cell differentiation
2. inscreases rate of mitosis in red cell precursors, blast-forming units,
colony forming cells
3. Increases release of reticulocyte from marrow
4. Increases Hb synthesis
5. its action requires adequate stores of iron
By : MIvec Turbo // RALLY//ART
Clinical Uses
Anemia associated with chronic renal failure
Premature infants
Anemia during chemotherapy of cancer
Anemia of AIDS (which is exacerbated by zidovudine treatment)
To increase the yield of autologous blood before donation
Anemia of chronic inflammatory conditions such as rheumatoid arthritis
MISUSED by sports people
Adverse Effects
Transient influenza – like symptoms chills & myalgias
Iron deficiency
Transient increases in platelet count
Hyperkalemia
Skin Rashes
Pure red cell aplasia discontinue the drug
antibodies to epoetins
Precautions/Kontraindikasi
Hipertensi harus dikontrol dgn baik
Seizures
Thrombocytosis
Ischemic Vascular disease
Iron, Folic Acid, Vit B12 supplements may be
Needed heparin during dialysis