PHARMACOKINETICS

Pharmacokinetics
Dose-concentration relationship
Effects of the biologic system on drugs
Deals with the processes of absorption,
distribution, and elimination of drugs
Makes possible the calculation of loading
and maintenance doses
Effective Drug Concentration
Concentration of a drug at the receptor
site (in contrast to drug concentrations
that are more rapidly measured, eg,
blood)
Plasma Concentration
Rate of input of the drug (by absorption
into the plasma)
Rate of distribution to peripheral tissues
(including the target organ)
Rate of elimination, or loss, from the
body
2 Basic Parameters
Unique for a particular drug in a
particular patient
Average values in large populations that
can be used to predict concentrations
1. Volume of Distribution (Vd)
Measure of apparent space in the body
available to contain the drug (higher Vd,
higher dose needed)
Amount of drug in the body to the
plasma/serum concentration
Intracellular
and
extracellular
compartments
When a drug is avidly bound in
peripheral tissues, its concentration in
plasma may drop to very low values
even if the total amount in the body is
large: high volume of distribution (Vd)
When a drug is completely retained in
the plasma compartment, volume of
distribution is equal to the plasma
volume: low volume of distribution (Vd)
Vd = amount of drug in the body /
plasma drug concentration
(Units = volume)

Effect of Drug Binding in Volume Distribution

-

Drug A does not bind to macromolecules,

diffuses freely between 2 compartments
Drug B binds avidly to proteins in the
blood, diffusion is much more limited
In each case, the amount of the drug in
the body are the same, but the apparent
volume of distribution are different

2. Clearance (CL)
Rate of elimination compared to plasma
concentration
Depends on the drug and the organs of
elimination in the patient
CL = rate of elimination of drug/plasma
drug concentration
(Units = volume per unit time)
Drugs eliminated with first-order kinetics
- Clearance is a constant
- Elimination rate is equal to clearance
times plasma concentration
- Elimination will be rapid at first and slow
as the concentration decreases

Half-Life
T
Time it takes for the amount or
concentration of a drug to fall to 50% of
an earlier measurement
Drugs eliminated by first-order kinetics:
constant regardless of concentration
Drugs eliminated by zero-order kinetics:
particularly useful; not a constant
Derived parameter from the volumr of
distribution and clearance
Determined the rate at which blood
concentration rises during a constant
infusion and falls after administration is
stopped
t = (0.693 x Vd)/CL
o (Units = time)

PHARMACOKINETICS
-

Steady State Concentration

Rate of drug administration/input is equal
to rate of elimination
Dose in = dose out
Average total amount of drug in the body
does not change over multiple dosing
intervals
Condition in 3 to 4 t must elapse
before
checking
drug
blood
concentration

Rectal 50% probability of bypassing

the 1st-pass effect
Inhalation or nasal
Transdermal patches

Dependent on
- Extent of absorption
- 1st-pass effect
- Rate of absorption
- Site of administration (eg, topical drugs
(ointments) which have very slow rate of
absorption)
Bioavailability: Drugs are more absorbed in the
small intestines because it has a larger surface
area
Time Course of Drug Effects
1. Immediate Effect
- Directly related to concentration
- Eg, anticoagulant
2. Delayed Effect
- Due to distributional delay
- Delayed expression of the physiologig
substance needed for the effect
3. Cumulative Effects
- Constant infusion
- Aminoglycosides causes renal toxicity if
given constantly
- Intermittent dosing only

Bioavailability
Fraction of the administered dose of the
drug that reaches the systemic
circulation
Equal to the amount absorbed over the
amount administered
Intravenous administration: unity or
100%
Administration by Other Routes
- Reduced by incomplete absorption
- 1st-pass metabolism
- Distribution into other tissues before the
drug enters the systemic circulation
To offset low bioavailability
- Sublingual

Extraction
Fraction of the drug removed from the
perfusing blood during passage to the
organ
Measure of the elimination of the drug by
that organ
Drugs with high hepatuc extraction ratio
have large 1st-pass effect
Target Concentration
Desired therapeutic effects are produced
Dosage Regimens
Plan for drug administration over a
period of time
Achievement of therapeutic levels of the
drug in the body without exceeding the
minimum toxic concentration
Maintenance Dose
Dose needed to maintain a steady state
of concentration

PHARMACOKINETICS

Maintain plasma concentration within a

specified range over long periods of
therapy
Enough drugs to replace eliminated
drugs
Clearance is the most important
parameter in defining rational drug
dosage

Loading Dose
For drugs with long half-lives and longer
time to reach a steady state
Given to promptly raise the concentration
of the drug to the target concentration
If the therapeutic concentration must be
achieved rapidly and the volume of
distribution is large, a large loading dose
maybe needed at the onset of therapy
Volume of distribution (Vd) is important
Therapeutic Drug Monitoring
A. Pharmacokinetic Variables
1. Absorption
o Compliance of patient is important
o Variation in bioavailability are
usually due to variation in
metabolism during absorption
2. Clearance
o Most important parameter in
designing dosage regimen
o Creatinine clearance
Good indicator of renal function
Adjust the dosage of the drug
No reliable indicator for liver
function
3. Volume of Distribution
o Low Vd binding to plasma
proteins
o High Vd binding to tissues
o High Vd drug distributed to body
waters, extracellular accumulation
of body fluids
4. Half Life
o Clearance
and
volume
of
distribution
B. Pharmacodynamic Variables
1. Maximum Effect
o Emax
o No more increase in effect even if
the concentratin is increasing
2. Sensitivity

Increased, exaggerated response

to small doses

Plasma Binding Proteins

More highly protein bound drug will
displace the less protein bound drug
Inert
Eg:
A 90% protein bound
B 50% protein bound
o A will displace B
o More unbound drug to act on the
receptor site
Acidic drugs bind to albumin
Basic drugs bind to alpha 1 acid
glycoprotein
Most appropriate time to measure drug
concentration
Absorption is complete
2 hours after the dose
Therapeutic Window
Safe opening between the MEC
(minimum effective concentration) and
the MTC (minimum toxic concentration)
of the drug
Used to determine the range of plasma
levels that is acceptable when designing
a dosing regimen
Theophylline
o MEC = 7-10 mg/L
o MTC = 15-20 mg/L
o Therapeutic window = 8-17 mg/L
Peak and Trough Concentrations
MEC determines the desired trough
levels of a drug given intermittently
MTC determines the permissible peak
plasma concentration
Maximum
and
minimum
drug
concentrations in plasma or blood
measured during cycles of repeated
dosing
Drugs given intermittently are in steady
state of concentration