8/25/2008

pharmacokinetic

herni suprapti

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Pharmacokinetics

 the effects of biologic systems on drugs

 absorption, distribution, and elimination
and
 makes possible the calculation of loading
and maintenance doses

Effective Drug Concentration

 is the concentration of a drug at the receptor

site
 in contrast to drug concentrations that are
more readily measured, eg, in blood
 except for topically applied agents, this
concentration is usually proportionate to the
drug's concentration in the plasma or whole
blood

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The plasma concentration

is a function of
 the rate of input of the drug (by
absorption) into the plasma
 the rate of distribution to the peripheral
tissues (including the target organ), and
 the rate of elimination, or loss, from the
body.

The plasma concentration

 These are all functions of time; but if the rate of
input is known, the remaining processes are
well described by 2 primary parameters:
volume of distribution and clearance.
 These parameters are unique for a particular
drug in a particular patient but have average
values in large populations that can be used to
predict drug concentrations.

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VOLUME OF DISTRIBUTION (Vd)

 The volume of distribution relates the

amount of drug in the body to the plasma
concentration (Figure 3-
3-1) according to the
following equation :

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 The calculated parameter for the

apparent volume of distribution has no
direct physical equivalent.

 If a drug is avidly bound in peripheral

tissues, the drug's concentration in
plasma may drop to very low values
even though the total amount in the
body is large.

 As a result, the volume of distribution may

greatly exceed the total volume of the body.
For example, 50,000 liters is the Vd for the
drug quinacrine in a person whose physical
body volume is 70 liters.

 On the other hand, a drug that is completely

retained in the plasma compartment will have
a volume of distribution equal to the plasma
volume (about 4% of body weight).

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The volume of distribution of drugs that

are normally bound to plasma proteins
such as albumin can be altered by :

 liver disease (through reduced protein

synthesis) and
 kidney disease (through urinary protein
loss)

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CLEARANCE (CL)

 Clearance relates the rate of

elimination to the plasma concentration
:

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 For a drug eliminated with first-

first-order kinetics,
clearance is a constant, ie, the ratio of rate of
elimination to plasma concentration is the
same regardless of plasma concentration
(Figure 3-
3-2).

Clearance depends on :
 the drug and
 the condition of the organs of elimination in
the patient

HALF--LIFE (t 1/2)
HALF

 is a derived parameter, completely determined by

volume of distribution and clearance

 can be determined graphically from

 a plot of the blood level versus time (Figure 1-
1-3)
 or from the following relationship :

0.693 x Vd
t ½ = ------------
CL

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Bioavailability
 The bioavailability of a drug is the fraction (F) of the
administered dose that reaches the systemic
circulation.

 Bioavailability is defined as unity (or 100%) in the

case of intravenous administration.

 After administration by other routes, bioavailability is

generally reduced by
 incomplete absorption (or, in the intestine, expulsion of drug
by the intestinal P-
P-glycoprotein transporter),
 first­pass metabolism, and
 any distribution into other tissues that occurs before the
drug enters the systemic circulation.

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Extraction
 Removal of a drug by an organ can be specified as the
extraction ratio, or the fraction of the drug removed from the
perfusing blood during its passage through the organ (Figure 3-3-
5).

 After steady-
steady-state concentration in plasma has been achieved,
the extraction ratio is one measure of the elimination of the drug
by that organ.

 Drugs that have a high hepatic extraction ratio have a large

first--pass effect; the bioavailability of these drugs after oral
first
administration will be low.

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Skill keeper 2: first pass effect

 What route of administration is most

likely to have a large first-
first-pass effect
and therefore low bioavailability ?

Dosage regimens

 Maintenance dosage

 Loading dosage

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Dosage regimens

 A dosage regimen is a plan for drug administration

over a period of time.

 An appropriate dosage regimen results in the

achievement of therapeutic levels of the drug in the
blood without exceeding the minimum toxic
concentration.

 To maintain the plasma concentration within a

specified range over long periods of therapy, a
schedule of maintenance doses is used.

Dosage regimens

 If it is necessary to achieve the target plasma level

rapidly, a loading dose is used to "load" the volume of
distribution with the drug.

 Ideally, the dosing plan is based on knowledge of both

the minimum therapeutic and minimum toxic
concentrations for the drug, as well as its clearance
and volume of distribution.

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Maintenance dosage

 Because the maintenance rate of drug administration is

equal to the rate of elimination at steady state (this is
the definition of steady state), the maintenance dosage
is a function of clearance (from Equation 2).

Dosing rate =

Clearance x Desired plasma concentration

---------------------------------
Bioavailability

Loading dosage

 If the therapeutic concentration must be achieved

rapidly and the volume of distribution is large, a large
loading dose may be needed at the onset of therapy.
This is calculated from the following equation :

Loading dose =

Volume of distribution x Desired plasma concentration

--------------------------------------------------------
Bioavailability

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THERAPEUTIC WINDOW

 The therapeutic window is the safe "opening"

between the minimum therapeutic
concentration and the minimum toxic
concentration of a drug.

 The concept is used to determine the range of

plasma levels that is acceptable when
designing a dosing regimen.

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 Unfortunately, for some drugs the

therapeutic and toxic concentrations
vary so greatly among patients that it is
impossible to predict the therapeutic
window in a given patient.

 Such drugs must be titrated individually

in each patient

Adjustment of dosage when

elimination is altered by disease
 Renal disease or reduced cardiac output
often reduces the clearance of drugs that
depend on renal function

 Alteration of clearance by liver disease is

less common but may occur.

 Impairment of hepatic clearance occurs (for

high extraction drugs) when liver blood flow
is reduced, as in heart failure.

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 The dose in a patient with renal impairment

may be corrected by multiplying the average
dose for a normal person times the ratio of
the patient's altered creatinine clearance to
normal creatinine clearance (approximately
100 mL/min, or 6 L/h).

Corrected dose= Average dose x

Patient's creatinine clearance

-------------------------------
100 mL/min

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