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BAG. FARMAKOLOGI FK.

UNUD
TOKSIKOLOGI

Ilmu yang mempelajari efek toksis bahan


kimia pd. organisme hidup

# Variasi dari keracunan


# Beraneka ragamnya bahan kimia

Merupakan ilmu pengetahuan yang sangat luas beragam


disiplin ilmu

Akhli Toksikologi Spesialisasi sesuai dengan bidang


tertentu
Aktivitas profesional akhli toksikologi terdiri dari
3 kategori :

1. Deskriftif
Melakukan testing toksisitas suatu bahan
pada : BINATANG

MANUSIA
Akhli toksikologi pd. industri kimia testing pada :
Manusia
Ikan
Burung
Tumbuhan
Faktor lain yang dapat mengganggu ekosistem
2. Mekanistik.
Menjelaskan ( mencari penjelasan )
bagaimana menerangkan terjadinya efek
toksik pd. organisme hidup.

Membantu dalam test prediksi yg. bermanfaat sebagai

informasi.

Membantu mengembangkan bahan-bahan kimia


yang lebih aman.

Membantu dalam terapi keracunan yang lebih rasional


3. “Regulatory”

Mengumpulkan data toksikologi ( dari akhli


toksikologi deskriftif

Apakah suatu bahan punya resiko tinggi /


rendah

Dipasarkan

menentukan level standar bahan-bahan kimia


pada :
Udara
Atmosfir industri
Air minum, dsb
Berdasarkan jenis zat & keadaan yang keracunan
bidang toksikologi :

1. Toksikologi obat
2. Toksikologi bahan yang menimbulkan
ketergantungan
3. Toksikologi bahan kimia
4. Toksikologi pestisida
5. Toksikologi industri
6. Toksikologi lingkungan
7. Toksikologi aksidental
8. Toksikologi perang
9. Toksikologi sinar
Reaksi toksis :
Fungsi konsentrasi bahan ( kimia, obat ) pada tempat
kerjanya

1. Sifat fisiko kimia dari bahan

2. Dosis, cara dan kecepatan pemberian bahan

Reaksi toksis 3. Kecepatan absorpsi, distribusi,


biotransformasi dan ekskresi bahan
4. Species yang diberikan
5. Berbagai variabel lain yang mempengaruhi
reaksi sistem biologis
# Melalui saluran cerna ( ingestion )

# Melaluii saluran nafas/ paru ( inhalation )


Masuknya racun
# Melalui kulit ( topical )

# Parenteral ( suntikan ) IM, IV, SC


I. peritoneal

# Lokal, kulit, mukosa saluran nafas,


mukosa saluran cerna
Tempat kerja
bahan toksis
# Sistemik

Sirkulasi sel / jaringan


Berdasarkan atas waktu terjadinya reaksi toksis
dibagi atas:

1. Reaksi toksis akut.


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

Biasanya oleh karena dosis tunggal /


pemberian tiba-tiba suatu bahan dalam
jumlah besar Depresi berat
fungsi fisiologis yg vital
Misalnya :
Keracunan akut barbiturat + 1-2 jam

Depresi pusat pernafasan diotak

Keracunan carbon monoksida + 5-6 ‘


Misl pd. Kebakaran bila terkurung udara
yang mengandung 1,5 % CO

Def. O2 dl. Darah ( afinitas CO ± 300 X dari


O2 pada. Hb )
Keracunan cyanide ( makan / menghirup gas

cyanide

Kematian dl. beberapa menit

Cyanide menghambat enzym- enzym yg


mempengaruhi penggunaan O2 oleh sel
2. Reaksi toksis subakut.
Terjadi karena pemberian dosis tak membahayakan
kalau diberikan sebagai dosis tunggal. Bisa timbul
dari dosis terapi suatu obat bila ada gangguan fungsi
mekanisme reaksi untuk menghilangkan efek obat

Misalnya

 Terapi dengan tetrasiklin ekskresi melalui ginjal


Ginjal gagal akumulasi obat keracunan

 Penyemprotan dengan insektisida


Tanpa proteksi
Diabsorpsi melalui kulit ( paru beberapa
saat keracunan
3. Reaksi toksis khronis

Terjadi karena pemberian berulang suatu bahan


dimana pemasukan melebihi kecepatan eliminasi

- Bisa terjadi pd. pemberian obat dg. waktu paruh


panjang / beberapa hari/ minggu – atau bulan

- Bisa juga terjadi pd. pemberian bahan secara


terus-menerus walaupun ekskresinya cepat

Setiap pemberian bahan kerusakan ringan


KERACUNAN KHRONIS
Misalnya : Campuran aspirine phenacetine
caffeine ( APC ) diminum > 1 tahun

Kerusakan ginjal yang irreversible


Cara penanggulangan efek toksik

1. Memperkecil absorpsi atau laju absorpsi


Membersihkan tubuh
Mengusahakan muntah
Dg. Penggunaan adsorbensia : mis. Karbon aktif
Pembilasan lambung
Mempercepat pengosongan lambung-usus
laksansia
Mempercepat pengeluaran melalui urine diuretika
2. Memperkecil kepekaan biologi ( obyek biologik
terhadap efek )

Menggunakan antidot khusus.

Org. fosfat Atropin

3. Meningkatkan eliminasi zat toksik /


pembentukan suatu kompleks zat tak aktif
Mengubah PH. Urine / diuresis
Laksansia

4.Terapi suportif
Konsep dasar pertolongan keracunan

Dikurangi Antidote Ditingkatkan

Obat / Absorpsi Eliminasi


Tempat kerja
zat kimia

Keracunan
Drugs used in the management of poisoning

Agents for general Agents for specific


management therapy
1. activated charcoal A. Metal antagonists
2. Syrup of ipecac 1. Dimerkaprol
3. Amonium chloride 2. Edetate calcium
4. Sodium bicarbonate 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
AGENTS FOR GENERAL MANAGEMENT

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
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 poisoning
Adverse 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 lead
poisoning (plumbism). The chelates
formed are water soluble, not easily
dissociated and readily excreted by the
kidney.
 EDTA is of questionable or unproved value
in poisoning caused by cadmium,
chromium, manganese, nickel, vanadium,
and zinc. It is ineffective in poisoning
caused by mercury, gold, or arsenic.
 Adverse reactions:
1. Pain at the site of i.m injection
2. Hypotension
3. Chills
4. Fever
5. Histamine-like reaction (sneezing, nasal
congestion and lacrimation)
Penicillamine
 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
metal antagonists for chelating copper and is
used primarily to remove excess copper in
patients with Wilson’s disease.
 Penicillamine chelates lead less effectively than
EDTA or dimercaprol but has been used in
asymptomatic patients with moderately elevated
blood levels because it is effective orally and
may enhance absorption of lead from
gastrointestinal tract.
Succimer (DMSA)
 This meso isomer of dimercaptosuccinic
acid is a significant addition to the
therapeutic choices of metal mobilizing
agents.

 Succimer produce lead diuresis similar to


that produce by EDTA
 Adverse Reactions:
1. Nausea/vomiting
2. Anorexia
3. Diarrhea
4. Pain in the back
5. Abdominal cramps
6. Chills
7. Headache
8. Skin rash
Misscelaneous Specific Antidote
 Naloxone Hydrochloride
- Naloxone is the drug of choice to treat
respiratory depression known or
suspected to be caused by opioid
overdose; it promptly increases the
respiratory rate and reverses coma.
- Adverse reactions:
Withdrawal syndrome in opioid-dependent
patient (hypertension, agitation)
 Naltrexone Hydrochloride
- Naltrexone resembles naloxone in its
ability to competitively antagonists opioid
drugs.
- An oral dose suppresses the
psychological and physical effect of
opioid for 48 to 72 hours.
Adverse reactions:
- Nausea
- Loss of energy
- Mental depression
- Dysphoria
- Hepatotoxicity (dose related)
 Cyanide Antidote
- Cyanide ion combines principally with
ferricytochrome oxidase to produce
hypoxia
- A cyanide antidote kit is available and
contains amyl nitrite for inhalation and
sodium nitrite and sodium thiosulphate
for intravenous injection
- Sodium thiosulphate increases the
biotransformation of cyanide to
thiocyanate more than thirtyfold.

Adverse reactions:
- Hypotension
 Physostigmine salicylate
- This drug is an anticholinesterase.
- Its ability to penetrate CNS is useful
adjunctively in the treatment of severe
central anticholinergic toxicity
characterized by anxiety, disorientation,
delirium, hyperactivity, hallucination,
illusions, impaired consciousness and
memory
Adverse reactions:
- Slight to moderate bradycardia
- Severe bradyarrhytmia
- Convulsion (rapid administration)
- Excessive salivation
- Bronchospasm
- Vomiting
- Urination
- Defecation
 Pralidoxime Chloride
- Pralidoxime is a cholinesterase
reactivator.
- Used primarily as an adjunct to atropine
in the treatment of severe poisoning
caused by pesticides that are
organophosphate cholinesterase inhibitors.
- Pralidoxime is particularly useful to reverse
muscular paralysis especially that of the
respiratory muscle
 Ethanol
- The toxicity of methanol is caused by the
metabolites of this compound. Methanol
are metabolized by the enzyme alcohol
dehydrogenase. Ethanol has a greater
affinity for this enzyme and retards the
rate of formation of toxic metabolites to
a level at which they can be eliminated
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
A.
1. ALKYLATING AGENTS
2. ANTIMETABOLITS
3. PLANT ALKALOIDS
4. ANTIBIOTICS

5. HORMONAL

6. MISCELLANEOUS ANTI Ca
B.
ANTI CANCER DRUGS

ACTION ON MITOTIC ACTION ON DNA ACTION ON STEROID


SPINDLE HORMONE RECEPTORS

AGONISTS ANTAGONISTS

DAMAGE DNA INHIBIT SYNTHESIS


OR FUNCTIONS

FREE RADICAL ALKYLATION ANTI TOPOISOMERASE


FORMATION METABOLITES INHIBITORS
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 KERJA
A. TITIK TANGKAP KERJA PADA SIKLUS CELL

G1 : FASE INTER MITOSIS


S : FASE SINTESIS DNA
G2 : FASE PRAMITOSIS
M : FASE MITOSIS
G0 : FASE ISTIRAHAT
CELL CYCLE SPECIFIC
( CCS )

TOKSISITAS SELEKTIF THD.


SEL YG. SEDANG BERPLORIFRASI
( TIDAK PADA G0 )
DITINJAU DARI
PERTUMBUHAN SEL

ANTI KANKER

CELL CYCLE NON SPESIFIC


( CCNS )
CELL CYCLE EFFECTS OF MAJOR OF
ANTICANCER DRUGS
CELL CYCLE NON SPECIFIC
CELL CYCLE SPECIFIC
( CCS ) AGENTS ( CCNS ) AGENTS

ANTIMETABOLITES ALKYLATING AGENTS


Capecitabine Busulfan
Cladribine Carmustine
Cytabine
Fludarabine
Cyclophosphamide
Fluorouracil Lomustine
Gemcitabine Mechloretamine
Mercaptopurine Melphalan
Methotrexate
Thioguanine ANTHRACYCLINES
ANTITUMOR ANTIBIOTICS
Daunorubicin
Bleomycin Doxorubicin
Epirubicin
EPIDOPHYLLOTOXINS
Etoposide ANTITUMOR ANTIBIOTICS
Teniposide Dactinomycin
TAXANES
Mitomycin
Dicetaxel
Paclitaxel CAMPTOTHECINS
Irinotecan
VINCA ALKALOIDS Topotecan
Vinblastine
Vincristine
Vinorelbine
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 DNA ( )
TRANSKRIPSI 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 Ca

Tujuan :
- Meningkatkan broad spectrum
- Menurunkan resistensi
- Efek sinergistik
- Menurunkan 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 :

- Obat-obat aktif kalau dipakai tunggal

- Obat-obat mempunyai mekanisme kerja yang


berbeda

- Obat-obat punya efek toksik yang berbeda

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


dipakai.
Contoh penggunaan kombinasi obat-obat anti
kanker :
1. Hodgkin’s disease
a. MOPP : Mechlorethamine,
Oncovin, Procarbazine
dan Prednison
b. ABVD : Adriamycin, Bleomycin,
Vinblastine, Dacarbazine

2. Non-Hodgkin’s Lymphoma
COP : Cyclophosphamide, Oncovin,
Prednison

3. Testicular Ca

PVB : Platinol ( Cisplatin ), Vinblastine,


Bleomycin
4. Breast Ca
CMF : Cyclophosphamide, Methotrexate,
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.
DACTINOMYCIN
KERJA : 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 DAUNORUBICINE
( ADRIAMYCIN ) ( 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

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