By : MIvec Turbo // RALLY//ART

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

Alkylating agent, Antimetabolit,Mitotic inhibitor, Antibiotic

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

G1 to S Promoting Factor = GSPF

Catagories of Chemotherapy Drugs based on MOA

1. Stop the synthesis of pre DNA molecule building blocks
 methotrexate
 fluorouracil
 hydroxyurea
 mercaptopurine

2. Directly damage the DNA in the nucleus of the cell

 cisplatin
 daunorubicin
 doxorubicin
 etoposide
By : MIvec Turbo // RALLY//ART

3. Effect the synthesis or breakdown of the mitotic spindles

 Vinblastine
 Vincristine
 Pacitaxel

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

Treatment of Acute Limphoblastic Leukemia

• This treatment phase almost always includes the administration of

a glucocorticoid (prednisone, prednisolone, or dexamethasone),
vincristine, and at least one other agent (usually asparaginase, an
anthracycline, or both)
• Commonly used regimens for childhood ALL include high-dose
methotrexate with mercaptopurine, high-dose asparaginase given
for an extended period, and reinduction treatment.
• Chlorambucil should be still considered the standard treatment
• Purine analogues (pentostatin [2-deoxycoformycin],fludarabine,
and 2-chlorodeoxyadenosine) are highly active against CLL.
CLL = Chronic Limphocytic Leukemia
 Induction of remission
 daunorubicin and cytarabine
 daunorubicin is administered three times at a dose of 40 to
60 mg per square meter of body-surface area during each
course of chemotherapy.
 Daurubicin or mitoxantrone is more effective than
daunorubicin in younger patients, although both resulted in
more prolonged cytopenia.
 Postinduction Therapy
 Once remission is induced, further intensive treatment of
patients with AML is essential to prevent relapse.
 Three options are available for younger patients:
 allogeneic bone marrow transplantation from an
HLAmatched related or unrelated donor
 autologous bone marrow transplantation
 chemotherapy
 Ninety percent of patients who are treated with hydroxyurea or
busulfan have hematologic remissions.
By : MIvec Turbo // RALLY//ART

 Hydroxyurea is preferred to busulfan because the median duration

of the chronic phase and median survival were significantly better
in a comparative trial of long-term therapy to maintain the
neutrophilcount in the normal range
 Hydroxyurea is advantageous primarily because of its favorable
toxicity profile rather than because it has a specific effect on CML
cells.

By : MIvec Turbo // RALLY//ART

Blood Coagulation and AntiCoagulant

dr. Dwi Indria Anggraini

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

 Injectable, rapidly acting anticoagulant yang biasa digunakan

acutely(akut) untuk mengganggu pembentukan dari thrombin
 Chronic or intermitten administration of heparin can lead to a
reduction in AT III activity thus increasing the risk of thrombosis

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

 Rapidly and completely absorbed after oral adm

 99% bound to plasma albumin
 Not diffuse into the cerebrospinal fluid, urine, and breast milk,
 Rapidly crosser the placental barrier
 The product metabolism are inactive and after conjugation to glucoronic
acid are excreted in the urine and stool

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

 Vitamin B12 available for therapeutic uses

o Cyanocobalamin
o Hydroxycobalamin

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