toksikologi kuliah ke-3
DESCRIPTION
TOKSIKOLOGI KULIAH KE-3TRANSCRIPT
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Toksisitas
• Tujuan utama studi toksisitas adalah untuk mengetahui efek toksis zat/senyawa kimia pada makhluk hidup sekaligus mengetahui derajat amannya.
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Pengelompokan bahan toksis bisa berdasarkan: - organ targetnya (hati, jantung, ginjal, dll), • penggunaannya (pestisida, solven, aditif
makanan, dll), • sumbernya (toksin tanaman, hewan), • efeknya (kanker, mutasi gen, kerusakan hati,
dll)• berdasarkan fisiknya (gas, debu, cair), • keperluan labelnya (mudah meledak, mudah
terbakar, oksidiser), • kandungan kimianya (aromatik, hidrokarbon,
dll) • tindak mekanisme biologinya (sulfhidril
inhibitor, produser methemoglobin,dll)
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Untuk mengetahui toksisitas bahan kimia perlu diketahui :
• efek yang ditimbulkan,
• dosis yang diperlukan,
• informasi tentang bahan kimia tersebut,
• lama pemaparan
• kondisi subyek.
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• Faktor penting dalam pemaparan adalah frekuensi pemberian.
• Suatu dosis tunggal bahan toksik akan menimbulkan efek segera, namun bila dosis tadi dibagi dua dan diberikan berulang akan menimbulkan efek yang kurang, bahkan tidak menimbulkan efek bila diberikan dalam dosis 1/10 dalam waktu beberapa hari.
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Terjadinya efek yang terpecah-pecah tersebut karena biotransformasi atau eksresi terjadi dalam dosis berikutnya atau kerusakan yang timbul bisa diperbaiki sebagian atau seluruhnya sebelum diberikan dosis berikutnya.
Efek toksik kronik terjadi bila bahan toksik terakumulasi dalam sistem biologis (absorbsi melebihi biotransformasi dan atau ekskresi), atau menghasilkan efek toksik yang tidak dapat pulih kembali atau tidak cukup waktu bagi sistem biologis untuk melakukan pemulihan dari kerusakan dalam interval frekuensi pemaparan.
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Efek dari dua bahan toksik yang diberikan secara bersamaan akan menghasilkan respon :
• aditif dari respon individual bahan toksik • lebih besar/ lebih kecil dari efek yang terjadi.
Efek aditif adalah efek gabungan dari dua bahan kimia sama dengan jumlah dari efek masing-masing bahan (misal 2 + 3 = 5).
• Contohnya bila dua insektisida organofosfat diberikan secara bersamaan, terjadi aditif hambatan cholin esterase.
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• Efek sinergistik adalah efek gabungan dari dua bahan kimia melampoi jumlah efek masing-masing bahan toksik (misal 2 + 3 = 20).
• Karbon tetraklorida dan etanol adalah hepatotoksik, kalau diberikan secara bersamaan akan menimbulkan kerusakan hati yang parah.
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• Efek potensiasi adalah salah satu bahan kimia tidak mempunyai efek toksik, namun bila ditambahkan pada bahan kimia lain, bahan kimia kedua tersebut menjadi jauh lebih toksik (misal 0 + 2 = 10).
• Isopropanol tidak hepatotoksik, namun bila isopropanol diberikan disamping pemberian karbon tetraklorida, efek hepatotoksik dari karbon tetraklorida jauh lebih tinggi dibanding efek hepatotoksik karbontetraklorida sendiri.
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• Antagonisme adalah situasi dimana dua bahan kimia diberikan bersamaan, efeknya saling mempengaruhi, atau satu bahan kimia mempengaruhi bahan kimia lainnya. (misal 4 + 6 = 8, 4 + 0 = 1, 4 + (-4) = 0).
• Efek antagonisme merupakan efek yang dikehendaki dalam toksikologi dan merupakan dasar berbagai antidot.
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• Perpindahan bahan toksik dari lingkungan (sumbernya) ke dalam organisme melalui tahap penyerapan zat, perpindahan bahan toksik di dalam badan, perubahan bahan toksik di dalam badan dan dikeluarkan melalui ekskresi. Tahapan tersebut dikenal dengan istilah adsorbsi – distribusi – transformasi – ekskresi.
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DISPOSITION OF CHEMICALS
The disposition of chemicals entering the body (from C.D. Klaassen, Casarett and Doull’s Toxicology, 5th ed., New York: McGraw-Hill, 1996).
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Dose
Pla
sma
Co
nce
ntr
atio
n
0 1 2 3 4 5 6 7 8 90
2
4
6
8
10
12
TOXIC RANGE
THERAPEUTIC RANGE
SUB-THERAPEUTIC
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• Setelah bahan toksik masuk kedalam badan, bahan toksik tersebut beredar keseluruh tubuh mengikuti aliran darah, sistem getah bening dan aliran intraseluler sitoplasma. Sebelum mencapai reseptor (organ target), bahan toksik bisa diadsorpsi oleh komponen tubuh, seperti protein plasma dan jaringan tubuh. Dengan demikian, waktu tinggal bahan tersebut di dalam tubuh menjadi lebih lama.
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• Ikatan bahan toksik dengan protein plasma berarti bahwa transpot bahan toksik ke reseptor menjadi lebih cepat. Adsorpsi bahan toksik pada jaringan tertentu dapat pula mengakibatkan jumlah molekul yang mencapai reseptor menjadi lebih kecil.
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Bioavailability
Dose
Destroyed in gut
Notabsorbed
Destroyed by gut wall
Destroyedby liver
tosystemiccirculation
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0
10
20
30
40
50
60
70
0 2 4 6 8 10
Plasma concentration
Time (hours)
i.v. route
oral route
Bioavailability
(AUC)o
(AUC)iv
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PrinciplePrinciple
For chemicals taken by routes other than the i.v. route, the extent of absorption and the
bioavailability must be understood in order to determine whether a certain exposure dose will induce toxic effects or not. It will also explain why the same dose may cause toxicity by one
route but not the other.
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• Plasma 3.5 liters. (heparin, plasma expanders)
• Extracellular fluid 14 liters.
(tubocurarine, charged polar compounds)
• Total body water 40 liters. (ethanol)
• Transcellular small. CSF, eye, fetus (must pass tight junctions)
Distribution into body compartments
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Distribution
• Rapid process relative to absorption and elimination
• Extent depends on - blood flow
- size, M.W. of molecule- lipid solubility and
ionization - plasma protein binding - tissue binding
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Distribution
• Initial and later phases:
initial determined by blood flow
later determined by tissue affinity
• Examples of tissues that store chemicals:
fat for highly lipid soluble compounds
bone for lead
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Distribution
• Blood Brain Barrier – characteristics:
1. No pores in endothelial membrane
2. Transporter in endothelial cells
3. Glial cells surround endothelial cells
4. Less protein concentration in interstitial fluid
• Passage across Placenta
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100-fold increase in free pharmacologically active concentration at site of action.
NON-TOXIC TOXIC
Alter plasma binding of chemicals
1000 molecules
% bound
molecules free
99.9 90.0
100 1
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Chemicals appear to distribute in the body as if it were a single compartment. The magnitude of
the chemical’s distribution is given by the apparent volume of distribution (Vd).
Amount of drug in bodyConcentration in Plasma
Vd =
PRINCIPLEPRINCIPLE
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Volume of Distribution
Volume into which a drug appears to distribute with a concentration equal to its plasma concentration
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Drug L/Kg L/70 kg
Sulfisoxazole 0.16 11.2
Phenytoin 0.63 44.1
Phenobarbital 0.55 38.5
Diazepam 2.4 168
Digoxin 7 490
Examples of apparent Vd’s for some drugs
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KID N EYf iltra tion
secretion(reab sorp tion )
LIVERm etabolism
excretion
LU N GSexhalation
OTH ER Sm other's m ilk
sw eat, sa liva etc .
Elim inationof chem icals from the body
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• Organ ekskresi yang merupakan jalan pembuangan sisa hasil pertukaran zat dalam tubuh. Zat kimia yang beredar dalam darah biasanya cepat dibuang melalui air seni dengan cara ultrafiltrasi dalam ginjal. Contohnya zat antibiotika. Dalam darah, sebagian zat antibiotika dialirkan ke ginjal untuk dibuang melalui air seni. Contoh lain, trikloretilen yang masuk tubuh melalui jalur inhalasi, mengalami transformasi pada ginjal dan bentuk metabolitnya ( trikloretanol dan asam triklorasetat) dibuang melalui air seni.
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• Selain ginjal, jalur ekskresi lain adalah hati – empedu – feses. Hati dan ginjal merupakan sistem ekskresi untuk asam dan basa organik dan beberapa logam berat.
• Beberapa zat toksik yang mudah menguap dan masuk ke paru-paru, secara keseluruhan atau sebagian meninggalkan tubuh melalui jalur yang sama. Contohnya adalah karbonmonoksida dan bermacam bahan pelarut.
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Elimination by the Kidney
• Excretion - major1) glomerular filtrationglomerular structure, size constraints, protein binding 2) tubular reabsorption/secretion- acidification/alkalinization,- active transport,
competitive/saturable, organic acids/bases -protein binding
• Metabolism - minor
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Nephron Structure
The structure of the nephron (from A.C. Guyton, Textbook of Medical Physiology, Philadelphia, W.B. Saunders Co.; 1991
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Elimination by the Liver
• Metabolism - major
1) Phase I and II reactions2) Function: change a lipid soluble to
more water soluble molecule to excrete in kidney
3) Possibility of active metabolites with same or different properties as parent molecule
• Biliary Secretion – active transport, 4 categories
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The enterohepatic shunt
Portal circulation
Liver
gall bladder
Gut
Bile
duct
Drug
Biotransformation;glucuronide produced
Bile formation
Hydrolysis bybeta glucuronidase
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EXCRETION BY OTHER ROUTES• LUNG - For gases and volatile liquids by diffusion.
Excretion rate depends on partial pressure of gas and blood:air partition coefficient.
• MOTHER’S MILK a) By simple diffusion mostly. Milk has high lipid content and is more acidic than plasma (traps alkaline fat soluble substances). b) Important for 2 reasons: transfer to baby, transfer from animals to humans.
• OTHER SECRETIONS – sweat, saliva, etc.. minor contribution
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• Pada hewan menyusui, sekresi susu kadang-kadang dianggap sebagai jalan ekskresi. Contohnya adalah pestisida klorhidrokarbon seperti DDT, aflatoksin B1 (aflatoksin M1).
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PrinciplePrinciple
Elimination of chemicals from the body usually follows first
order kinetics with a characteristic half-life (t1/2) and fractional rate constant (Kel).
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First Order Elimination
• Clearance: volume of plasma cleared of chemical per unit time.Clearance = Rate of elimination/plasma conc.
• Half-life of elimination: time for plasma conc. to decrease by half.
Useful in estimating: - time to reach steady state concentration.
- time for plasma conc. to fall after exposure stopped.
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Rate of elimination = Kel x Amount in bodyRate of elimination = CL x Plasma Concentration
Therefore,Kel x Amount = CL x Concentration
Kel = CL/Vd
0.693/t1/2 = CL/Vd
t1/2 = 0.693 x Vd/CL
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PrinciplePrinciple
The half-life of elimination of a chemical (and
its residence in the body) depends on its
clearance and its volume of distribution
t1/2 is proportional to Vd
t1/2 is inversely proportional to CL
t1/2 = 0.693 x Vd/CL
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Multiple dosing
• On continuous steady administration of a chemical, plasma concentration will rise fast at first then more slowly and reach a plateau, where:
rate of administration = rate of elimination ie. steady state is reached.
• Therefore, at steady state:Dose (Rate of Administration) = clearance x plasma
conc.or
steady state conc. = Dose/clearance
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0
1
2
3
4
5
6
7
0 5 10 15 20 25 30
Time
pla
sma
con
c
Cumulation
Toxic level
Single dose
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Pharmacokinetic parameters
• Vol of distribution V = DOSE / Co
• Plasma clearance Cl = Kel .Vd
• plasma half-life (t1/2) t1/2 = 0.693 / Kel or directly from graph
• Bioavailability (AUC)x / (AUC)iv
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Concentration due to a single dose
Concentration due to repeated doses
The time to reach steady state is ~4 t1/2’s
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But Conc. x dt = small area under the curve. For total amount eliminated (which is total given or the
dose if i.v.), add all the small areas = AUC. Dose = CL x AUC and Dose x F = CL x AUC
dX/dt = CL x Conc.
dX = CL x Conc. x dt
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0
10
20
30
40
50
60
70
0 2 4 6 8 10
Pla
sma
con
cen
trat
ion
Time (hours)
Bioavailability (AUC)o
(AUC)iv=
i.v. route
oral route
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Daily Dose (mg/kg)
Pla
sma
Dru
gC
on
cen
trat
ion
(m
g/L
)
0 5 10 150
10
20
30
40
50
60
Variability in Pharmacokinetics
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PRINCIPLEPRINCIPLE
The absorption, distribution and elimination of a chemical are
qualitatively similar in all individuals. However, for several reasons, the quantitative aspects
may differ considerably. Each person must be considered
individually and treated accordingly.