Page 60 - Basic _ Clinical Pharmacology ( PDFDrive )

46 SECTION I Basic Principles

concentration of drug that is achieved (Table 3–1). Capacity- 100
limited elimination is also known as mixed-order, saturable,
dose- or concentration-dependent, nonlinear, and Michaelis- 75 Accumulation
Menten elimination.
Most drug elimination pathways will become saturated if the Plasma concentration (% of steady state) 50
dose and therefore the concentration are high enough. When Elimination
blood flow to an organ does not limit elimination (see below), 25
the relation between elimination rate and concentration (C) is 0
expressed mathematically in equation (5): 0 1 2 3 4 5 6 7 8
Time (half-lives)
(5) FIGURE 3–3 The time course of drug accumulation and elimina-
tion. Solid line: Plasma concentrations reflecting drug accumula-
tion during a constant-rate infusion of a drug. Fifty percent of the
The maximum elimination capacity is V max , and K is the drug steady-state concentration is reached after one half-life, 75% after
m
concentration at which the rate of elimination is 50% of V max . At two half-lives, and over 90% after four half-lives. Dashed line: Plasma
concentrations that are high relative to the K , the elimination concentrations reflecting drug elimination after a constant-rate infusion
m
rate is almost independent of concentration—a state of “pseudo- of a drug had reached steady state. Fifty percent of the drug is lost
zero order” elimination. If dosing rate exceeds elimination capac- after one half-life, 75% after two half-lives, etc. The “rule of thumb” that
ity, steady state cannot be achieved: The concentration will keep four half-lives must elapse after starting a drug-dosing regimen before
on rising as long as dosing continues. This pattern of capacity- full effects will be seen is based on the approach of the accumulation
limited elimination is important for three drugs in common use: curve to over 90% of the final steady-state concentration.
ethanol, phenytoin, and aspirin. Clearance has no real meaning
for drugs with capacity-limited elimination, and AUC should not
be used to calculate clearance of such drugs.
Half-life is useful because it indicates the time required to
B. Flow-Dependent Elimination attain 50% of steady state—or to decay 50% from steady-state
In contrast to capacity-limited drug elimination, some drugs are conditions—after a change in the rate of drug administration.
Figure 3–3 shows the time course of drug accumulation during a
cleared very readily by the organ of elimination, so that at any constant-rate drug infusion and the time course of drug elimina-
clinically realistic concentration of the drug, most of the drug in the tion after stopping an infusion that has reached steady state.
blood perfusing the organ is eliminated on the first pass of the drug Disease states can affect both of the physiologically related
through it. The elimination of these drugs will thus depend primar- primary pharmacokinetic parameters: volume of distribution and
ily on the rate of drug delivery to the organ of elimination. Such clearance. A change in half-life will not necessarily reflect a change
drugs (see Table 4–7) can be called “high-extraction” drugs since in drug elimination. For example, patients with chronic renal fail-
they are almost completely extracted from the blood by the organ. ure have both decreased renal clearance of digoxin and a decreased
Blood flow to the organ is the main determinant of drug delivery, volume of distribution; the increase in digoxin half-life is not as
but plasma protein binding and blood cell partitioning may also
be important for extensively bound drugs that are highly extracted. great as might be expected based on the change in renal function.
The decrease in volume of distribution is due to the decreased
renal and skeletal muscle mass and consequent decreased tissue
+
+
Half-Life binding of digoxin to Na /K -ATPase.
Many drugs will exhibit multicompartment pharmacokinetics
Half-life (t ) is the time required to change the amount of drug (as illustrated in Figures 3–2C and 3–2D). Under these condi-
1/2
in the body by one-half during elimination (or during a constant tions, the “half-life” reflecting drug accumulation, as given in
infusion). In the simplest case—and the most useful in designing Table 3–1, will be greater than that calculated from equation (6).
drug dosage regimens—the body may be considered as a single
compartment (as illustrated in Figure 3–2B) of a size equal to
the volume of distribution (V). The time course of drug in the Drug Accumulation
body will depend on both the volume of distribution and the Whenever drug doses are repeated, the drug will accumulate in the
clearance:
body until dosing stops. This is because it takes an infinite time
(in theory) to eliminate all of a given dose. In practical terms, this
(6) means that if the dosing interval is shorter than four half-lives,

accumulation will be detectable.
Because drug elimination can be described by an exponential Accumulation is inversely proportional to the fraction of the
process, the time taken for a twofold decrease can be shown to be dose lost in each dosing interval. The fraction lost is 1 minus
proportional to the natural logarithm of 2. The constant 0.7 in the fraction remaining just before the next dose. The fraction
equation (6) is an approximation to the natural logarithm of 2. remaining can be predicted from the dosing interval and the