BAG. FARMAKOLOGI FK. UNUD

TOKSIKOLOGITOKSIKOLOGI

Ilmu yang mempelajari efek toksis bahan Ilmu yang mempelajari efek toksis bahan kimia pd. organisme hidup kimia pd. organisme hidup

# # Variasi dari Variasi dari keracunankeracunan # # Beraneka Beraneka ragamnya ragamnya

bahan bahan kimiakimia

Merupakan ilmu pengetahuan yang sangat luas Merupakan ilmu pengetahuan yang sangat luas beragam beragam disiplin ilmu disiplin ilmu

Akhli Toksikologi Spesialisasi sesuai dengan bidang Akhli Toksikologi Spesialisasi sesuai dengan bidang tertentu tertentu

Aktivitas profesional akhli toksikologi Aktivitas profesional akhli toksikologi terdiri dariterdiri dari 3 kategori : 3 kategori :

1. Deskriftif1. Deskriftif Melakukan testing toksisitas suatu bahan Melakukan testing toksisitas suatu bahan pada : BINATANG pada : BINATANG

MANUSIA MANUSIAAkhli toksikologi pd. industri kimia testing pada :Akhli toksikologi pd. industri kimia testing pada :

ManusiaManusia

IkanIkan

BurungBurung

TumbuhanTumbuhan

Faktor lain yang dapat mengganggu ekosistemFaktor lain yang dapat mengganggu ekosistem

2. Mekanistik.2. Mekanistik. Menjelaskan ( mencari penjelasan ) Menjelaskan ( mencari penjelasan ) bagaimana menerangkan terjadinya efek bagaimana menerangkan terjadinya efek

toksik pd. organisme hidup. toksik pd. organisme hidup.

Membantu dalam test prediksi yg. bermanfaat Membantu dalam test prediksi yg. bermanfaat sebagai sebagai informasi. informasi.

Membantu mengembangkan bahan-bahan kimia Membantu mengembangkan bahan-bahan kimia yang lebih aman. yang lebih aman.

Membantu dalam terapi keracunan yang lebih Membantu dalam terapi keracunan yang lebih rasional rasional

3. “Regulatory”3. “Regulatory”

Mengumpulkan data toksikologi ( dari akhliMengumpulkan data toksikologi ( dari akhli toksikologi deskriftif toksikologi deskriftif

Apakah suatu bahan punya resiko tinggi / Apakah suatu bahan punya resiko tinggi / rendah rendah

DipasarkanDipasarkan

menentukan level standar bahan-bahan menentukan level standar bahan-bahan kimiakimia pada : pada :

UdaraUdaraAtmosfir industriAtmosfir industriAir minum, dsbAir minum, dsb

Berdasarkan jenis zat & keadaanBerdasarkan jenis zat & keadaan yang yang keracunan keracunan bidang toksikologi : bidang toksikologi :

1.1. Toksikologi obatToksikologi obat

2.2. Toksikologi bahan yang menimbulkan Toksikologi bahan yang menimbulkan ketergantungan ketergantungan

3.3. Toksikologi bahan kimiaToksikologi bahan kimia

4.4. Toksikologi pestisidaToksikologi pestisida

5.5. Toksikologi industriToksikologi industri

6.6. Toksikologi lingkungan Toksikologi lingkungan

7.7. Toksikologi aksidentalToksikologi aksidental

8.8. Toksikologi perangToksikologi perang

9.9. Toksikologi sinarToksikologi sinar

Reaksi toksis :Reaksi toksis : Fungsi konsentrasi bahan ( kimia, obat ) pada Fungsi konsentrasi bahan ( kimia, obat ) pada tempat tempat kerjanyakerjanya

Reaksi toksis

1. Sifat fisiko kimia dari bahan

2. Dosis, cara dan kecepatan pemberian bahan

3. Kecepatan absorpsi, distribusi, biotransformasi dan ekskresi bahan

4. Species yang diberikan

5. Berbagai variabel lain yang mempengaruhi reaksi sistem biologis

Masuknya racun

# Melalui saluran cerna ( ingestion )

# Melaluii saluran nafas/ paru ( inhalation )

# Melalui kulit ( topical )

# Parenteral ( suntikan ) IM, IV, SC I. peritoneal

Tempat kerja bahan toksis

# Lokal, kulit, mukosa saluran nafas, mukosa saluran cerna

# Sistemik

Sirkulasi sel / jaringan

Berdasarkan atas waktu terjadinya reaksi Berdasarkan atas waktu terjadinya reaksi

toksis dibagi atas:toksis dibagi atas: 1. Reaksi toksis akut.1. Reaksi toksis akut.

Apabila gejala yang membahayakan individu Apabila gejala yang membahayakan individu terjadi segera setelah pemberian bahan ( 24 terjadi segera setelah pemberian bahan ( 24 jam atau kurang ) jam atau kurang )

Biasanya oleh karena dosis tunggal / Biasanya oleh karena dosis tunggal / pemberian tiba-tiba suatu bahan dalam pemberian tiba-tiba suatu bahan dalam jumlah besar Depresi berat jumlah besar Depresi berat fungsi fisiologis yg vital fungsi fisiologis yg vital

Misalnya :Misalnya :

Keracunan akut barbiturat + 1-2 jamKeracunan akut barbiturat + 1-2 jam

Depresi pusat pernafasan diotak Depresi pusat pernafasan diotak

Keracunan carbon monoksida + 5-6 ‘Keracunan carbon monoksida + 5-6 ‘ Misl pd. Kebakaran bila terkurung udara Misl pd. Kebakaran bila terkurung udara yang mengandung 1,5 % CO yang mengandung 1,5 % CO

Def. O Def. O22 dl. Darah ( afinitas CO ± 300 X dari dl. Darah ( afinitas CO ± 300 X dari

O O22 pada. Hb ) pada. Hb )

Keracunan cyanide ( makan / menghirup Keracunan cyanide ( makan / menghirup gas gas cyanide cyanide

Kematian dl. beberapa menitKematian dl. beberapa menit

Cyanide menghambat enzym- enzym yg Cyanide menghambat enzym- enzym yg mempengaruhi penggunaan O mempengaruhi penggunaan O22 oleh sel oleh sel

22. . Reaksi toksis subakut.Reaksi toksis subakut. Terjadi karena pemberian dosis tak Terjadi karena pemberian dosis tak membahayakanmembahayakan kalau diberikan sebagai dosis tunggal. Bisa kalau diberikan sebagai dosis tunggal. Bisa timbultimbul dari dosis terapi suatu obat bila ada gangguan dari dosis terapi suatu obat bila ada gangguan fungsifungsi mekanisme reaksi untuk menghilangkan efek mekanisme reaksi untuk menghilangkan efek obatobat MisalnyaMisalnya

Terapi dengan tetrasiklin ekskresi melalui ginjalTerapi dengan tetrasiklin ekskresi melalui ginjal

Ginjal gagal akumulasi obat keracunanGinjal gagal akumulasi obat keracunan

Penyemprotan dengan insektisidaPenyemprotan dengan insektisida

Tanpa proteksi Tanpa proteksi

Diabsorpsi melalui kulit ( paru beberapa Diabsorpsi melalui kulit ( paru beberapa saat keracunan saat keracunan

3. Reaksi toksis khronis3. Reaksi toksis khronis

Terjadi karena pemberian berulang suatu bahanTerjadi karena pemberian berulang suatu bahan dimana pemasukan melebihi kecepatan eliminasi dimana pemasukan melebihi kecepatan eliminasi

- Bisa terjadi pd. pemberian obat dg. waktu paruh- Bisa terjadi pd. pemberian obat dg. waktu paruh panjang / beberapa hari/ minggu – atau bulan panjang / beberapa hari/ minggu – atau bulan

- Bisa juga terjadi pd. pemberian bahan secara - Bisa juga terjadi pd. pemberian bahan secara terus-menerus walaupun ekskresinya cepat terus-menerus walaupun ekskresinya cepat

Setiap pemberian bahan kerusakan ringan Setiap pemberian bahan kerusakan ringan KERACUNAN KHRONIS KERACUNAN KHRONIS

Misalnya : Campuran aspirine phenacetine Misalnya : Campuran aspirine phenacetine

caffeine ( APC ) diminum > 1 tahun caffeine ( APC ) diminum > 1 tahun

Kerusakan ginjal yang irreversibleKerusakan ginjal yang irreversible

Cara penanggulangan efek Cara penanggulangan efek toksiktoksik

1.1. Memperkecil absorpsi atau laju absorpsiMemperkecil absorpsi atau laju absorpsi Membersihkan tubuhMembersihkan tubuh

Mengusahakan muntahMengusahakan muntah

Dg. Penggunaan adsorbensia : mis. Karbon aktifDg. Penggunaan adsorbensia : mis. Karbon aktif

Pembilasan lambungPembilasan lambung

Mempercepat pengosongan lambung-usus Mempercepat pengosongan lambung-usus laksansialaksansia

Mempercepat pengeluaran melalui urine Mempercepat pengeluaran melalui urine diuretikadiuretika

2. Memperkecil kepekaan biologi ( obyek 2. Memperkecil kepekaan biologi ( obyek biologik terhadap efek )biologik terhadap efek )

Menggunakan antidot khusus.Menggunakan antidot khusus.

Org. fosfat AtropinOrg. fosfat Atropin

33. . Meningkatkan eliminasi zat toksik / Meningkatkan eliminasi zat toksik / pembentukan suatu kompleks zat tak aktifpembentukan suatu kompleks zat tak aktif

Mengubah PH. Urine / diuresisMengubah PH. Urine / diuresis

LaksansiaLaksansia

4.Terapi suportif4.Terapi suportif

Konsep dasar pertolongan keracunan

Tempat kerjaObat / zat kimia

Absorpsi Eliminasi

Dikurangi Antidote Ditingkatkan

Keracunan

Drugs used in the management of poisoning

Agents for general management 1. activated charcoal 2. Syrup of ipecac 3. Amonium chloride 4. Sodium bicarbonate

Agents for specific therapy A. Metal antagonists 1. Dimerkaprol 2. Edetate calcium

dosodium (EDTA) 3. Penisillamine 4. Succimer (DMSA) 5. Deferoxamine mesylate B. Miscellaneous specific antidotes 1. Naloxone hydrochloride 2. Naltrexone hydrochloride 3. Cyanide antidote 4. Physostigmine salicylate 5. Pralidoxime chloride 6. Ethanol

Activated charcoal - It is known to reduce the gastro intestinal absorption of drugs that commonly cause poisoning, such as analgesics (salicylate, acetaminophen, propoxyphen) anti antianxiety agents, hipnotic as and tricyclic antidepresants. Does not affect the absorption of mineral acid in organic salts aliphatic hidrocarbons and drugs that are in soluble in aqueous acidic solution - Charcoal is midly constipating

Syrup of ipecac Ipecac alkaloids act locally on the gastric mucosa and centrally on the chemoreceptor trigger zone to induce vomiting. Vomiting occurs within 30 minutes. Emesis may be more effective, altought not more rapid, if water is taken immediately after administration of the syrup.

Adverse reactions : - Drowsines - Diarrhea - Coughing or choking

AGENTS FOR GENERAL MANAGEMENT

Amonium chloride. Ammonium chlorida reduce unrinary pH, which increases the degree of ionization of organic bases, and impedes of the renal tubular reabsorption of these bases, which enhances their urinary excretion.

Adverse reactions : - Gastric irritation. - Nausea - Vomiting

Contra indication : - Impaired hepatic or renal function - Convulsions or prolonged coma

Sodium bicarbonate Sodium bicarbonate is used to treat metabolic acidosis. It also is used to alkalize the urine, which increases the degree of ionization organic acid (eg. Aspirin, phenobarbital), and interferes which renal tubular reabsorption, which enhances their excretion.

Adverse reactions : - Tetany - Cardiac arrhythmia

AGENTS FOR SPECIPIC THERAPY Deferoxamine mesylate A potent and highly iron chelating agent. It ready complexes with ferric ion to form ferrioxamine, a stable, water soluble chelate

Adverse reactions - rapid i.v injection : hypotension, tachycardia, erythema, and urticaria - In some patients : histamine-like reaction or induration following s.c administration.

Dimercaprol - Dimercaprol antagonizes the toxic effect of arsenic, mercuri and gold by forming helates or complexes - Therapy in most effective when begun within 1 0r 2 hours after ingestion. - Efficacy is reduced after six hours, thus dimercaprol is used only in acute mercury poisoningAdverse reactions. - Pain at site of injection - Sometimes sterile abscesses - Nausea / vomiting - Headache - Conjuctivitis - Lacrimation

- Rhinorrhea- Salivation- Burning sensation in the lips, month & throat- Feeling constriction or pain in the throat, chest or hand- Tingling or burning paresthesias in the hand and penis- Sweating- Abdominal pain- Increases systolic and diastolic blood pressure accompanied by tachycardia- Induce metabolic acidosis- Induce hemolysis in patient with glucose-6-phosphate dehydrogenase deficiency

Contra incation - Impaired lever function

Edetate calcium disodium (EDTA)

This drug is used primarily to treat This drug is used primarily to treat lead poisoning (plumbism). The lead poisoning (plumbism). The chelates formed are water soluble, chelates formed are water soluble, not easily dissociated and readily not easily dissociated and readily excreted by the kidney.excreted by the kidney.

EDTA is of questionable or unproved EDTA is of questionable or unproved value in poisoning caused by value in poisoning caused by cadmium, chromium, manganese, cadmium, chromium, manganese, nickel, vanadium, and zinc. It is nickel, vanadium, and zinc. It is ineffective in poisoning caused by ineffective in poisoning caused by mercury, gold, or arsenic.mercury, gold, or arsenic.

Adverse reactions:Adverse reactions:

1. Pain at the site of i.m injection1. Pain at the site of i.m injection

2. Hypotension2. Hypotension

3. Chills3. Chills

4. Fever4. Fever

5. Histamine-like reaction (sneezing, 5. Histamine-like reaction (sneezing, nasalnasal

congestion and lacrimation)congestion and lacrimation)

PenicillaminePenicillamine It combines with copper, iron, mercury, lead,

gold, and arsenic to form soluble complexes that are readily excreted by the kidneys.

This orally effective agents is superior to other This orally effective agents is superior to other metal antagonists for chelating copper and is metal antagonists for chelating copper and is used primarily to remove excess copper in used primarily to remove excess copper in patients with Wilson’s disease.patients with Wilson’s disease.

Penicillamine chelates lead less effectively than Penicillamine chelates lead less effectively than EDTA or dimercaprol but has been used in EDTA or dimercaprol but has been used in asymptomatic patients with moderately elevated asymptomatic patients with moderately elevated blood levels because it is effective orally and blood levels because it is effective orally and may enhance absorption of lead from may enhance absorption of lead from gastrointestinal tract. gastrointestinal tract.

Succimer (DMSA)Succimer (DMSA)

This meso isomer of This meso isomer of dimercaptosuccinic acid is a dimercaptosuccinic acid is a significant addition to the therapeutic significant addition to the therapeutic choices of metal mobilizing agents.choices of metal mobilizing agents.

Succimer produce lead diuresis Succimer produce lead diuresis similar to that produce by EDTAsimilar to that produce by EDTA

Adverse Reactions:Adverse Reactions:

1. Nausea/vomiting1. Nausea/vomiting

2. Anorexia2. Anorexia

3. Diarrhea3. Diarrhea

4. Pain in the back4. Pain in the back

5. Abdominal cramps5. Abdominal cramps

6. Chills6. Chills

7. Headache7. Headache

8. Skin rash8. Skin rash

Misscelaneous Specific Misscelaneous Specific AntidoteAntidote

Naloxone HydrochlorideNaloxone Hydrochloride

- Naloxone is the drug of choice to - Naloxone is the drug of choice to treat treat

respiratory depression known or respiratory depression known or

suspected to be caused by opioid suspected to be caused by opioid

overdose; it promptly increases the overdose; it promptly increases the

respiratory rate and reverses coma.respiratory rate and reverses coma.

- Adverse reactions:- Adverse reactions:

Withdrawal syndrome in opioid-Withdrawal syndrome in opioid-dependent patient (hypertension, dependent patient (hypertension, agitation)agitation)

Naltrexone HydrochlorideNaltrexone Hydrochloride

- Naltrexone resembles naloxone in its - Naltrexone resembles naloxone in its

ability to competitively antagonists ability to competitively antagonists opioidopioid

drugs.drugs.

- An oral dose suppresses the - An oral dose suppresses the

psychological and physical effect of psychological and physical effect of

opioid for 48 to 72 hours.opioid for 48 to 72 hours.

Adverse reactions:Adverse reactions:

- Nausea- Nausea

- Loss of energy- Loss of energy

- Mental depression- Mental depression

- Dysphoria- Dysphoria

- Hepatotoxicity (dose related)- Hepatotoxicity (dose related)

Cyanide AntidoteCyanide Antidote

- Cyanide ion combines principally with - Cyanide ion combines principally with

ferricytochrome oxidase to produce ferricytochrome oxidase to produce

hypoxiahypoxia

- A cyanide antidote kit is available and - A cyanide antidote kit is available and

contains amyl nitrite for inhalation and contains amyl nitrite for inhalation and

sodium nitrite and sodium thiosulphate sodium nitrite and sodium thiosulphate

for intravenous injectionfor intravenous injection

- Sodium thiosulphate increases the Sodium thiosulphate increases the biotransformation of cyanide to biotransformation of cyanide to thiocyanate more than thirtyfold.thiocyanate more than thirtyfold.

Adverse reactions:Adverse reactions:- HypotensionHypotension

Physostigmine salicylatePhysostigmine salicylate

- This drug is an anticholinesterase.- This drug is an anticholinesterase.

- Its ability to penetrate CNS is useful - Its ability to penetrate CNS is useful

adjunctively in the treatment of severe adjunctively in the treatment of severe

central anticholinergic toxicity central anticholinergic toxicity

characterized by anxiety, disorientation,characterized by anxiety, disorientation,

delirium, hyperactivity, hallucination, delirium, hyperactivity, hallucination,

illusions, impaired consciousness and illusions, impaired consciousness and

memorymemory

Adverse reactions:Adverse reactions:- Slight to moderate bradycardia- Slight to moderate bradycardia- Severe bradyarrhytmia- Severe bradyarrhytmia- Convulsion (rapid administration)- Convulsion (rapid administration)- Excessive salivation- Excessive salivation- Bronchospasm- Bronchospasm- Vomiting- Vomiting- Urination- Urination- Defecation- Defecation

Pralidoxime ChloridePralidoxime Chloride- Pralidoxime is a cholinesterase - Pralidoxime is a cholinesterase reactivator. reactivator. - Used primarily as an adjunct to atropine- Used primarily as an adjunct to atropine in the treatment of severe poisoning in the treatment of severe poisoning

caused by pesticides that are caused by pesticides that are organophosphate cholinesterase organophosphate cholinesterase inhibitors.inhibitors.- Pralidoxime is particularly useful to - Pralidoxime is particularly useful to reversereverse muscular paralysis especially that of the muscular paralysis especially that of the respiratory muscle respiratory muscle

EthanolEthanol

- The toxicity of methanol is caused by - The toxicity of methanol is caused by thethe

metabolites of this compound. Methanol metabolites of this compound. Methanol

are metabolized by the enzyme alcohol are metabolized by the enzyme alcohol

dehydrogenase. Ethanol has a greater dehydrogenase. Ethanol has a greater

affinity for this enzyme and retards the affinity for this enzyme and retards the

rate of formation of toxic metabolites to rate of formation of toxic metabolites to

a level at which they can be eliminateda level at which they can be eliminated

safely. safely.

TERAPI KANKER

1. OPERASI

2. RADIOTERAPI

3. KHEMOTERAPI

4. TERAPI GEN

5. TERAPI ENDOKRIN

6. IMUNOTERAPI

TUJUAN KHEMOTERAPI

MEMBUNUH SEL KANKER LOKAL MAUPUN YANG SUDAH METASTASE JAUH

PENGGOLONGAN OBAT-OBAT ANTI Ca

1. ALKYLATING AGENTS

2. ANTIMETABOLITS

3. PLANT ALKALOIDS

4. ANTIBIOTICS

5. HORMONAL

6. MISCELLANEOUS ANTI Ca

A.

B.ANTI CANCER DRUGS

ACTION ON DNAACTION ON MITOTIC SPINDLE

ACTION ON STEROIDHORMONE RECEPTORS

DAMAGE DNA INHIBIT SYNTHESIS OR FUNCTIONS

AGONISTS ANTAGONISTS

ALKYLATIONFREE RADICALFORMATION

ANTI METABOLITES

TOPOISOMERASEINHIBITORS

1. ALKILATOR

- MUSTARD NITROGEN # MEKLORETAMIN # SIKLOFOSFAIND # MUSTAR URASIL # KLORAMBUSIL

- DERIVAT ETILINIMIN # TRIENTILIN MELAMIN # TRIETLENTIO FOSFORAMID

- ALKIL SULFONAT # BUSULFAN

- NITROSO UREA # KARMUSTIN # LOMUSTIN # SEMUSTIN

2. ANTI METABOLIT- ANALOG PIRIMIDON # 5-FLUORO URASIL # SITARABIN

- ANALOG PURIN # 6-MERKAPTOPURIN # 6-TIOGUANID

- ANALOG FOLAT # METOTREKSAT

3. VINCA ALKALOID- VINKRISTIN - VINBLASTIN

4. ANTIBIOTIKA

- DAKTINOMISIN- MITOMISIN- ANTRASIKLIN # DAUNORUBISIN # DOKSORUBISIN- MITRAMISIN - BLEOMISIN

5. HORMON - ADRENOKORTIKOSTEROID # PREDNISON - PROGESTIN # HIDROKSI PROGESTERON ASETAT # MEGESTROL ASETAT- ESTROGEN & ANDROGEN

6. LAIN-LAIN - ASPARGINASE- METOTANE, DSB

MEKANISME KERJAA. TITIK TANGKAP KERJA PADA SIKLUS CELL

G1 : FASE INTER MITOSIS S : FASE SINTESIS DNAG2 : FASE PRAMITOSIS M : FASE MITOSISG0 : FASE ISTIRAHAT

DITINJAU DARI PERTUMBUHAN SEL

ANTI KANKER

CELL CYCLE SPECIFIC ( CCS )

TOKSISITAS SELEKTIF THD. SEL YG. SEDANG BERPLORIFRASI( TIDAK PADA G0 )

CELL CYCLE NON SPESIFIC ( CCNS )

CELL CYCLE EFFECTS OF MAJOR OF ANTICANCER DRUGS

CELL CYCLE SPECIFIC( CCS ) AGENTS

ANTIMETABOLITES Capecitabine Cladribine Cytabine Fludarabine Fluorouracil Gemcitabine Mercaptopurine Methotrexate Thioguanine

ANTITUMOR ANTIBIOTICS Bleomycin

EPIDOPHYLLOTOXINS Etoposide Teniposide

TAXANES Dicetaxel Paclitaxel

VINCA ALKALOIDS Vinblastine Vincristine Vinorelbine

CELL CYCLE NON SPECIFIC( CCNS ) AGENTS

ALKYLATING AGENTS Busulfan Carmustine Cyclophosphamide Lomustine Mechloretamine Melphalan ANTHRACYCLINES Daunorubicin Doxorubicin Epirubicin

ANTITUMOR ANTIBIOTICS Dactinomycin Mitomycin

CAMPTOTHECINS Irinotecan Topotecan

PLATINUM ANALOGS Carboplatin Cisplatin

B. MEKANISME KERJA PD. PROSES DLM. SEL

1. ALKILATOR # ALKILASI ASAM NUKLEAT TERUTAMA PADA DNA

# ALKILASI SENYAWA NUKLEOFILIK SPT. ASAM AMINO KARBOKSIL. DLL

MOL. DNA PECAH

REPLIKASI DNATRANSKRIPSI RNA

TAK. TERJADI MITOSIS

( )

2. ANTIMETABOLITS # Menghambat enzym-enzym asam nukleat

efek lebih toksis pada sel-sel yang sedang berproliferasi

3. PLANT ALKALOIDA ( VINCA ALKALOIDA ) # Menghambat mitosis ( Spindle poisons )

mempengaruhi mikrotubulus yang berperan dalam proses mitosis

4. ANTIBIOTIKA. Actinomycin D

- Dosis kecil menghambat sintesa RNA - Dosis besar menghambat sintesa DNA

Adriamycin dan Daunorubicin - Berikatan dengan DNA - Menghambat sintesa DNA dan RNA

Bleomycin - Terutama menghambat sintesis DNA

5. HORMON ? Kenyataan bahwa beberapa kanker adalah “ hormon dependent “

Mekanisme terjadinya resistance

1. Increase DNA repair

2. Formation of trapping agents

3. Change in target enzymes

4. Decreased activation of prodrugs

5. Inactivation of anticancer drugs

6. Decreased drug accumulation

Kombinasi Anti CaKombinasi Anti Ca

Tujuan :Tujuan :- Meningkatkan broad spectrumMeningkatkan broad spectrum- Menurunkan resistensiMenurunkan resistensi- Efek sinergistikEfek sinergistik- Menurunkan efek sampingMenurunkan efek samping

Misalnya dikenal berbagai kombinasi :

ABVD : Doxorubicin ( adriamycin ), bleomycin, vinblastin, dacarbazine.

CHOP : Cyclophospamide, doxorubicin ( hydroxydaunorubicin ), vincristin ( oncovin ), prednison

CMF : Cyclophospamide, methotrexate, fluorouracil

COP : Cyclophosphamide, Vincristine ( oncovin ), prednisone

FAC : Fluorouracil, doxorubicin ( adriamycin ), cyclophosphamide

FEC : Fluorouracil, epirubicin, cyclophosphamide

IFL : Irinotecan, Fluorouracil, leucovorin.

MP : Melphalan, prednison.

MOPP : Mechlorethamine, vincristine ( oncovin ), procarbazine, prednisone

PCV : Procarbazine, lomustine, vincristine

Syarat :Syarat :

- Obat-obat aktif kalau dipakai tunggalObat-obat aktif kalau dipakai tunggal

- Obat-obat mempunyai mekanisme kerja yang Obat-obat mempunyai mekanisme kerja yang berbedaberbeda

- Obat-obat punya efek toksik yang berbedaObat-obat punya efek toksik yang berbeda

- Tak ada “ cross-resistance “ antara obat-obat Tak ada “ cross-resistance “ antara obat-obat yang dipakai.yang dipakai.

Contoh penggunaan kombinasi obat-obat Contoh penggunaan kombinasi obat-obat anti kanker :anti kanker :

1.1. Hodgkin’s diseaseHodgkin’s disease

a. MOPP : Mechlorethamine, a. MOPP : Mechlorethamine, Oncovin, Procarbazine Oncovin, Procarbazine dan Prednison dan Prednison

b. ABVD : Adriamycin, Bleomycin, b. ABVD : Adriamycin, Bleomycin, Vinblastine, Dacarbazine Vinblastine, Dacarbazine

2.2. Non-Hodgkin’s LymphomaNon-Hodgkin’s Lymphoma

COP : Cyclophosphamide, Oncovin, COP : Cyclophosphamide, Oncovin, Prednison Prednison

3.3. Testicular CaTesticular Ca

PVB : Platinol ( Cisplatin ), Vinblastine,PVB : Platinol ( Cisplatin ), Vinblastine, Bleomycin Bleomycin

4.4. Breast Ca Breast Ca CMF : Cyclophosphamide, Methotrexate, CMF : Cyclophosphamide, Methotrexate, Fluorouracil. Fluorouracil.

EFEK SAMPING

TERUTAMA PD. JAR. YG. BERPROLIFRASI # SUMSUM TULANG # KULIT # MUKOSA SALURAN CERNA

TERAPI KERACUNAN

# LEUCOVORIN

VINCRISTINE

KERJA: “SPINDLE POISON”

MENGHENTIKAN MITOSIS

PENGGUNAAN KLINIK

# UNTUK LEUKEMIA AKUT PD. ANAK

DIKOMBINASI DG. PREDNISONE

HASIL CUKUP BAIK

KERACUNAN : # AREFLEKSIA, FERIFERAL NEURITIS, ILIUS PARALITIK & DEPRESI SUMSUM TULANG.

DACTINOMYCINKERJA : BERIKATAN DG. DOUBLE- HELIC DNA

BEKERJA MENGHAMBAT PROLIFRASI SEL.

FARMAKOKINETIK.# PO. KURANG KUAT DIBANDINGKAN PARENTERAL# HALF LIFE : 36 JAM # METABOLISME MINIMAL# TAK MENEMBUS SAWAR DARAH OTAK.

EKSKRESI : # EMPEDU # URINE

KERACUNAN

# ANOREKSIA # NAUSEA & VOMITING # SUPRESI SISTEM HEPOPOITIK# DEPRESI SUMSUM TULANG # PROKTITIS, DIARE, GLOSITIS, CHEILITIS, ULCUC MUKOSA MULUT# ALOPESIA, DESQUAMASI KULIT, DSB.

ANTRASIKLIN

DOXORUBICIN( ADRIAMYCIN )

DAUNORUBICINE( SERUBIDIN )

MEKANISME KERJA

1. BERIKATAN DG DNA MELALUI INTERKALASI

MENGHAMBAT SINTESIS DNA & RNA

2. BERIKATAN DG. MEMBRAN SEL MENGUBAH KEPEKATAN DAN TRANSPORT ION-ION

3. MENGHASILKAN SEMI QUINON RADIKAL BEBAS DAN OKSIGEN RADIKAL MLL PROSES REDUKSI OLEH SITOKROM P450

FARMAKOKINETIK

# PEMBERIAN SECARA IV.

# KADAR PUNCAK TERCAPAI SETELAH 30 MENIT DAN BERTAHAN LEBIH KURANG 20 JAM

# DIMETABOLISME DALAM HATI DAN DIKELUARKAN SEBAGIAN BESAR MELALUI EMPEDU DAN SEDIKIT MELALUI URINE