toxic o kinetics

7/29/2019 Toxic o Kinetics

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Dosage Effects

Site

of

Action

Plasma

Concen.

Pharmacokinetic

Toxicokinetics

Pharmacodynamics

Toxicodynamics


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DISPOSITION OF CHEMICALS

The disposition of chemicals entering the body (from C.D. Klaassen, Casarett and Doulls Toxicology,5th ed., New York: McGraw-Hill, 1996).


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P

lasmaConce

ntration

Time

Plasma concentration vs. time profile of a single

dose of a chemical ingested orally


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Dose

PlasmaConcentratio

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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Bound Free Free Bound

LOCUS OF ACTION

RECEPTORS

TISSUE

RESERVOIRS

SYSTEMICCIRCULATION

Free Drug

Bound Drug

ABSORPTION EXCRETION

BIOTRANSFORMATION


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Transfer of Chemicals across

Membranes

Passive transport determined by:

- Permeability of surface

- Concentration gradient

- Surface area

Permeability depends on:

For cell membranes:

- Lipid solubility

- pH of medium

- pK of chemical

For endothelium

size, shape and charge of chemical

PASSAGE ACROSS

MEMBRANES

Passive

Facilitated

Active


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Weak Acids and Weak Bases

HA H+ + A- B + H+ BH+[ UI ] [ I ] [ UI ] [ I ]

pKa=pH+log(HA/A-) pKa=pH+log(BH+/B)

pKa = 4.5 (a weak acid)

100 = [ UI ] [ UI ] = 100

pH = 2 pH = 7.40.1 = [ I ] [ I ] = 9990

100.1 = total drug = 10090


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Factors Affecting Absorption

(G.I., lungs, skin) Determinants of Passive Transfer (lipid

solubility, pH, pK, area, concentration

gradient).

Blood flow to site.

Dissolution in the acqueous medium

surrounding the absorbing surface.


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Factors Affecting Absorption from

the GI Tract Disintegration of dosage form and dissolution of

particles

Chemical stability of chemical in gastric andintestinal juices and enzymes

Motility and mixing in GI tract

Presence and type of food

Rate of gastric emptying

Intestinal vs. gastric absorption

FIRST PASS EFFECT


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Absorption from the Lungs

For gases, vapors and volatile liquids,

aerosols and particles

In general: large surface area, thin barrier,

high blood flow rapid absorption

Blood:air partition coefficient

influence of respiratory rate and blood flow

Blood:tissue partition coefficient


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Absorption of Aerosols and

Particles:

1- Particle Size

2- Water solubility of thechemical present in the

aerosol or particle

REMOVAL OF

PARTICLES

Physical

Phagocytosis

Lymph

Absorption from the Lungs


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NasopharyngealR

egion

5-30 m

Trachea

Bronchi

Bronchioles

1-5 m

Alveolar Region

1 m

DEPOSITION OF PARTICLES IN

THE RESPIRATORY SYSTEM


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Absorption from the Skin

Must cross several cell layers (stratum

corneum, epidermis, dermis) to reach blood

vessels. Factors important here are:

lipid solubility

hydration of skin

site (e.g. sole of feet vs. scrotum)


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Other Routes of Exposure

Intraperitoneal

large surface area, vascularized, first pass

effect.

Intramuscular, subcutaneous, intradermal:absorption through endothelial pores into the

circulation; blood flow is most important +other factors

Intravenous


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Bioavailability

Definition: the fraction of the administered

dose reaching the systemic circulation

for i.v.: 100%

for non i.v.: ranges from 0 to 100%

e.g. lidocaine bioavailability 35% due todestruction in gastric acid and liver metabolism

First Pass Effect


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Bioavailability

Dose

Destroyed

in gut

Not

absorbed

Destroyed

by gut wall

Destroyed

by liver

to

systemiccirculation


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0

1 0

2 0

3 0

4 0

5 0

6 0

7 0

0 2 4 6 8 1 0

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 todetermine whether a certain exposure dose will

induce toxic effects or not. It will also explain

why the same dose may cause toxicity by oneroute 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 passtight 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 compoundsbone 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 interstitialfluid

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

chemicals1000 molecules

% bound

molecules free

99.9 90.0

1001


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Chemicals appear to distribute in the body as if itwere a single compartment. The magnitude of thechemicals 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 todistribute with a concentration equal to its

plasma concentration


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Drug L/Kg L/70 kg

Sulfisoxazole 0.16 11.2Phenytoin 0.63 44.1

Phenobarbital 0.55 38.5

Diazepam 2.4 168

Digoxin 7 490

Examples of apparent Vds for

some drugs


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K I D N Ef i l t r a t i o

s e c r e t i( r e a b s o r p t i

L I V E Rm e t a b o

e x c r e t i

L U N G

e x h a l a

O T H E

m o t h e r 's w e a t , s

E l i m i n a t i o n

o f c h e m i c a l s f r


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Elimination by the Kidney

Excretion - major1) glomerular filtration

glomerular 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

e 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 reactions

2) Function: change a lipid soluble to morewater 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 by

beta 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 andblood:air partition coefficient.

MOTHERS MILK

a) By simple diffusion mostly. Milk has high lipidcontent and is more acidic than plasma (traps alkalinefat soluble substances).

b) Important for 2 reasons: transfer to baby, transferfrom animals to humans.

OTHER SECRETIONS sweat, saliva, etc..

minor contribution


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CLINICAL

TOXICOKINETICS

Quantitative Aspects of

Toxicokinetics


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Dose

PlasmaConcentration

0 1 2 3 4 5 6 7 8 90

2

4

6

8

10

12

TOXIC RANGE

THERAPEUTIC RANGE

SUB-THERAPEUTIC

Influence of Variations in Relative Rates of Absorption


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02

4

6

8

10

12

14

0 5 10 15 20

TIME (hours)

Plasmaconce

ntration

Influence of Variations in Relative Rates of Absorption

and Elimination on Plasma Concentration of an Orally

Administered Chemical


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Elimination Zero order: constant rate of elimination

irrespective of plasma concentration.

First order: rate of elimination proportional toplasma concentration. Constant Fraction of drug

eliminated per unit time.

Rate of elimination = constant (CL) x

Conc.


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Zero Order Elimination

Pharmacokinetics of Ethanol Mild intoxication at 1 mg/ml in plasma

How much should be taken in to reach it?

42 g or 56 ml of pure ethanol (Vdx

Conc.)Or 120 ml of a strong alcoholic drink like whiskey

Ethanol has a constant rate of elimination of

10 ml/hour

To maintain mild intoxication, at what rate mustethanol be taken now?

at 10 ml/h of pure ethanol, or 20 ml/h of drink.

RARELY DONE DRUNKENNESS


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0

2

4

6

81 0

1 2

1 4

0 5 10 15 2 0

T IM E(hours)

Plasmaconcent

ration

Ct = Co e-Kel.t

lnCt = lnCo Kel .tlogCt = logCo - Kel . t

2.303

dC/dt = k

y = b a.x

First Order Elimination


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Time

PlasmaC

oncentratio

n

0 1 2 3 4 5 61

10

100

1000

10000

Zero Order Elimination

logCt = logCo - Kel . t

2.303


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Time

Plasma Concentration

0 1 2 3 4 5 6

1

10

100

1000

10000

C0

Distribution equilibrium

Elimination only

Distribution and Elimination

Plasma Concentration Profile

after a Single I.V. Injection


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lnCt = lnCo Kel.t

When t = 0, C = C0, i.e., the concentration at time

zero when distribution is complete and elimination

has not started yet. Use this value and the dose to

calculate Vd.

Vd = Dose/C0


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lnCt = lnCo Kel.t

When Ct = C0, then Kel.t = 0.693. This is the

time for the plasma concentration to reach half the

original, i.e., the half-life of elimination.

t1/2 = 0.693/Kel


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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 ofchemical 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 exposurestopped.


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Rate of elimination = Kel x Amount in body

Rate 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 moreslowly and reach a plateau, where:

rate ofadministration = rate of eliminationie. 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

plasmacon

c

Cumulation

Toxic level

Single dose


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Concentration due to a single dose

Concentration due to

repeated doses

The time to reach steady

state is ~4 t1/2s


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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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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

(AUC)


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0

1 0

2 0

3 0

4 0

5 0

6 0

7 0

0 2 4 6 8 1 0

Pla

smaconcentration

Time (hours)

Bioavailability (AUC)o(AUC)iv

=

i.v. route

oral route


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Daily Dose (mg/kg)

PlasmaD

rug

Concentratio

n(mg/L

)

0 5 10 150

10

20

30

40

50

60

Variability in Pharmacokinetics


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PRINCIPLEPRINCIPLE

The absorption, distribution andelimination of a chemical are

qualitatively similar in allindividuals. However, for severalreasons, the quantitative aspects

may differ considerably. Eachperson must be consideredindividually and treated accordingly.


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THE DOSE RESPONSE RELATIONSHIP


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THE DOSE-RESPONSE RELATIONSHIP

toxic o kinetics

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