Toxicology Part 1 2012

7/27/2019 Toxicology Part 1 2012

1/43

u an o, ., ., . .

Budhijanto, 2009


2/43

IntroductionToxicology:

a subject concerned with the study of the

living systems

Xenobiotics substances foreign to living

, . . , Normal body constituents at toxic levels

. . ,

Budhijanto, 2009


3/43

IntroductionParacelsus (14931541):

that is not a poison. The right dose

no observable effect and another, higher

,

Budhijanto, 2009


4/43

IntroductionIntoxication:

interaction between a chemical poison and

sustains life

1. Exposure to the chemicals

2. Disposition3. Toxic response

Budhijanto, 2009


5/43

IntroductionExposure to the chemicals:.

gastrointestinal tract.

3. Inhalation exposure via respiratory

4. Parenteral exposure by injection

. er rou es

Budhijanto, 2009


6/43

IntroductionDisposition:

a. Absorption The chemicals must cross cell membranes

Cell membranes composed of long-chain

phospholipids bilayer studded with andpenetrated by bands of protein

Budhijanto, 2009


7/43

Introductiona. Absorption

Budhijanto, 2009


8/43


Budhijanto, 2009


9/43

Introductiona. Absorption Membranes are selectivel ermeable

Physicochemical characteristics of, . .

a. size/shape

.

c. structural similarity to endogenous

d. charge/polarity.

Budhijanto, 2009


10/43

Introductiona. Absorption Forei n com ounds ma ass across

membranes by:.

2. Passive diffusion

.

4. Facilitated diffusion

5. agocytos s p nocytos s.

Budhijanto, 2009


11/43

Introductiona. Absorption1. Filtration:

diffusion through pores in the membrane

Foreign compounds: small, hydrophilic, . . ,

urea

such as sodium will not pass through pores

pores. Budhijanto, 2009


12/43

Introductiona. Absorption1. Filtration:

Pore sizes vary between cells and tissues,.

molecules with MW of several thousand

ma ass it2. Passive diffusion:

Budhijanto, 2009


13/43

Introductiona. Absorption2. Passive diffusion:

Requirement:. .across the membrane

. .soluble

. . -

Budhijanto, 2009


14/43


2.1. There must be a concentration gradient

Ficks Law:

= t e sur ace areaC2 = the concentration of compound on the

outside of the membrane

Budhijanto, 2009


15/43



C1 = the concentration of compound on the

d = is the thickness of the membrane

= t e us on coe c ent, a constant afunction of lipophilicity, size, shape, etc.

Budhijanto, 2009


16/43



biological systems are dynamic the

maintained thus passive diffusion is not asaturable rocess

Budhijanto, 2009


17/43



the concentration on the inside of the

as a result of ionization, metabolism , andremoval b distribution into othercompartments such as via blood flow

Budhijanto, 2009


18/43


2.2. The foreign compound must be lipid

Lipophilicity: the ability of a substance to

Lipid solubility: an intrinsic property of a

,denoted by the partition coefficient, KP (or

Budhijanto, 2009


19/43



Clipid = concentration of compound in the lipid

Cwater= concentration of compound in thewa er p ase

Budhijanto, 2009


20/43



Drugs % absorbed through

intestinal

wall

Kchloroform

Thiopental 67 100

Aniline 54 26,4

Acetanilide 43 7,6

Acetylsalicylic

acid 21 2,0Barbituricacid 5 0,008

Mannitol


21/43


2. Passive diffusion:


The larger the partition coefficient the

Although there is often a good correlation

through membranes, very lipophilic

membrane Budhijanto, 2009


22/43

Introduction (AKHIR KULIAH 1)

a. Absorption


2.3. The compound must be non-ionized

Budhijanto, 2009


23/43




Budhijanto, 2009


24/43




Budhijanto, 2009


25/43


3. Active trans ort:

Important features:. .required

,protein carriers:

. . .actively or passively transport one molecule.

Budhijanto, 2009


26/43



I3.1.2. Symports involve the transport of two

3.1.3. Antiports involve the transport of two

Budhijanto, 2009


27/43



3.2. Metabolic energy is necessary to operate

Active transport requires a source of energy,

carrier protein, or the co-transport of ionssuch as Na+ or H+ down their

electrochemical gradients

Budhijanto, 2009


28/43



3.3. Transport occurs against a concentration

3.4. The process may be inhibited by metabolic

3.5. The process may be saturated at high

3.6. Substrates may compete for uptake.

Budhijanto, 2009


29/43


4. Facilitated diffusion:

Important features:. .molecule

. .competitively inhibited.

. .a concentration gradient

. . ere s no requ remen or me a o c

energy. Budhijanto, 2009


30/43


5. Pha oc tosis/ inoc tosis:

forms of endocytosis (a process of cellular

folds inward to bring substances into the

cell involve the invagination of the membrane to

enclose a article or dro let res ectivel

The process requires metabolic energy and

molecules, such as ions, in the surroundingmedium. Budhijanto, 2009


31/43


5. Pha oc tosis/ inoc tosis:

The result is the production of a vesicle

become a secondary lysosome in which the

enz mes ma di est the macromolecule In some cases a particular part of the

lasma membrane with s ecific rece tors

binds the macromolecule and theninvaginates

Budhijanto, 2009


32/43


a.1. Absor tion throu h skin:

Budhijanto, 2009


33/43


a.1. Absor tion throu h skin:

by passive diffusion mainly through the.

Compounds are generally lipophilic, e.g.

, Lipophilicity is not always a prerequisite for

necessarily a good correlation

Budhijanto, 2009


34/43


a.2. Absor tion throu h lun s:

Budhijanto, 2009


35/43



Usually rapid and efficient

The solubility in the blood is a major factor in.

For compounds with low solubility the rate of

dependent on blood flow (perfusion limited)

Budhijanto, 2009


36/43



For compounds with high solubility in the,

blood will be mainly dependent on

res iration rate ventilation limiteda.3. Absorption through gastrointestinal tract:

gastrointestinal tract varies throughout its

Budhijanto, 2009


37/43


a.3. Absor tion throu h astrointestinal tract:

the lining of the mouth (buccal cavity), the,

alkaline in some other species, e.g rat.

,certain other mammals.

, .

Budhijanto, 2009


38/43



Budhijanto, 2009


39/43



Lipid soluble, nonionized compounds may

Ionizable substances will generally only be

non-ionized at the pH of the particular siteand are also li id soluble

Budhijanto, 2009


40/43



e.g. pKa of benzoic acid = 4,202; pKa of aniline= ,

Budhijanto, 2009


41/43



Budhijanto, 2009


42/43



The absorption from the gastrointestinal tract

compounds so absorbed are transported

directl to the liver. Extensive metabolism inthe liver may alter the structure of thecompound, making it more or less toxic.

Little of the parent compound reaches thesystemic circulation in these circumstances.

Budhijanto, 2009


43/43



It may lead to different toxicity after.

.

Through bloodstream

Budhijanto, 2009

Toxicology Part 1 2012

Documents

Transcript of Toxicology Part 1 2012