k7 distribution

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Pharmacokinet ics

DISTRIBUTION

Dr. Yun ita Sari Pane, MSiDepartment of Pharmacology and Therapy

Universitas Sumatera Utara


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DISTRIBUTION

The transport of a drug in the

body by the bloodstream to itssite of action


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Distribution

Absorbed drugs leave capillary wall

quickly and freely (via filtration

and diffusion) to enter interstitial

fluid; blood flow being important

in the regional distribution ofdrugs


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Drug Distribution

Drug transfer to var ious t issues

-- depends on drug l ipoph i lic i ty and blood f low

Drug barr iers

-- e.g. blood -brain barrier, placenta

Drug binding to plasma pro teins

-- bounddrugs are pharmacolog ically inact ive

-- unbound drug s are free to distr ibu te to target t issues

-- dif ferent drug s may com pete for bind ingto plasma

proteins and displace each other from bind ing si tes


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Binding to plasma proteins (mostlyto albumin and, for basic drugs,

1-

acid glycoprotein)major distribution site

highest drug concentrations usuallyfound in blood; serve as drug depots,thus prolonging half-life of drugs

pharmacologic effects and toxic

manifestations affected byhypoalbuminemia and copresence ofother drugs also bound effectively toalbumin


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Central nervous system:permeable to lipid-soluble drugs

only; limited permeability to

water-soluble drugs when inflamed Placental transfer: limited by

blood flow, not by a "barrier"


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Fat tissue: depot for thiopental and

chlorinated hydrocarbon insecticides(e.g., DDT)

Sites for metabolism and excretion:liver, kidney, intestine, lungs

Redistribution: especially importantfor IV injection of lipophilic drugs


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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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Saturat ion o f Pro tein B ind ing Sites


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Drug disp lacement from

pro tein bind ing s i tes


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Plasma Protein B ind ing

an increase in free drug concentrat ion of

the displaced drug

an inc rease in drug effect(be caut ious when u sing a drug of low T.I.)

a decrease in the du rat ion of act ion of the

disp laced drug because more free drugs

are avai lable fo r el imin at ion

con sequence of drug disp lacement


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Time Course of Drug Action

General rules

Compartment models

Single-compartment

Multiple-compartment

Exceptions to general rules


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First-order process:

dC/dT = kC (constant fraction)

Zero-order process:

dC/dT = k (constant amount)

Capacity limited process:

low C, first-order; high C, zero-order


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One Compartment IV Bolus

Pharmacokinetic Model

Assumpt ions

drug is m ixed instantaneously in blood

drug in the blood is in rapid equ i l ibr iumwi th drugin the extravascular t issues

drug el im inat ion fo l lows f i rst order kinet ics


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Single compartment model: no

absorption, f irst-order elimination


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rate of concentrat ion change at each t ime po int :

dCp=k Cp

d t

. (1)

Cp: plasma drug concnetration

k : el iminat ion rate con stant


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Ct

= C0

e k t

. (2)

Ct: plasma con centrat ion at t ime t

C0: plasma concentrat ion at t ime 0


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k t

log Ct= log C0. (3)

2.303

Ct: plasma con centrat ion at t ime t

C0: plasma concentrat ion at t ime 0


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Vd = X/C = Div/Co(iv) = F.Doral/Co (oral)

X = amount of drug in the body

C = drug levels in plasma or serum

Div = drug dose on intravenous administration

Doral = dose of the drug on oral administration

F = fraction of oral dose reaching the systemic

blood circulation in active form

= bioavailability oral

Co = levels of plasma or serum at time t = 0


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Vd amount determined by the size and bodycomposition, CV function, the ability of

drug molecules into various body

compartments, and the degree of drug

binding to plasma proteins and with various

networks. Drugs that accumulate in the

tissues, so levels of drug in plasma is very

low, but has a very large Vd (eg digoxin)


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DOSE

Vd= . (4)

C0

su bs tit ut e (4) to (3), I.e. Ct= C0 ek t

DOSE

Ct = ek t . (5)

Vd


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Half-Lif e of Elim ination ( t 1/2)

t ime taken for the plasma concentrat ion to fal l to

half i ts or iginal value

0.693

t 1/2= . (6)k


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One-compartment pharmacokinetics (single dose, IV)

Cp= plasma drug concentration C0= plasma concentration at time zero

k el = elimination constant elimination half-life t 1/2= t 2- t 1


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Pharmacokinetic ModelBioavailabi l i t y ( F )

measures the extent of absorp t ion o f a given

drug , usually expressed as fract ion of the

adm inistered dose

in t ravenous inject ion , by def in i t ion , has a

bioavailabi l i ty o f 100%

AUC CLF = .. (8)

DOSE

AUC: area und er the con c.-t ime cu rve


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Combined Infusion and Bolus Administration

to achieve a therapeut ic co ncentrat ion more

qu ickly is to give a loading do se by rapid IV

in ject ion and then star t the slower

maintenance infusion

Loading dose = CssVd ........... (9)

Maintenance dose = CL Cp t. (10)


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Drug disappearance

usually follows first-order kinetics(exponential decay), with a constantfraction (not amount)of drug beingeliminated per unit of time

the process is independent of thekind and amount of drug

half-life (T1/2), not dose, is theprimary factor in prolonging drugeffects


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Multicompartment models

combine kinetics of redistribution and

elimination

provide best description of drugs with highlipid solubility and drugs given

intravenously


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Redistribution of thiopental afterintravenous injection


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Multi-compartment


the drug appears to distr ibu te between 2 or

mo re compartments

the drug is no t instantaneously equ i l ibrated in

var ious t issues

rapid ly perfused t issues often belong to the

central com partment

slow ly perfused t issues belong to the

per ipheral compartment


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Two-compartment pharmacokinetics (single dose, IV)

central compartment (rapid) t 1/2

peripheral compartment (slow) t 1/2


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DRUGS DISTRIBUTION

Factors influence drug distribution-Drugs with large Vd have the following properties

High protein binding

High lipid solubility

High affinity to other tissues such as bone & liver


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DRUGS DISTRIBUTION

Factors influence drug distribution4-Rate of blood flow to tissues

- Skeletal muscles have high blood flow

5-Regional pH

- breast milk more acidic than blood: Weak base drugs

accumulate in breast milk

6-Tissues mass


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ended

k7 distribution

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