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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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One Compartment IV Bolus
Pharmacokinetic Model
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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One Compartment IV Bolus
Pharmacokinetic Model
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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One Compartment IV Bolus
Pharmacokinetic Model
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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One Compartment IV Bolus
Pharmacokinetic Model
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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One Compartment IV Bolus
Pharmacokinetic Model
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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One Compartment IV Bolus
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
Pharmacokinetic Model
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