Page 65 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 3 Pharmacokinetics & Pharmacodynamics: Rational Dosing & the Time Course of Drug Action 51

25

20
Plasma concentration (mg/L) 15

10

0 5
0 8 16 24 32 40 48 56 64 72 80 88 96
Time (h)

FIGURE 3–6 Relationship between frequency of dosing and maximum and minimum plasma concentrations when a steady-state theoph-
ylline plasma level of 10 mg/L is desired. The smoothly rising black line shows the plasma concentration achieved with an intravenous infusion
of 28 mg/h. The doses for 8-hour administration (orange line) are 224 mg; for 24-hour administration (blue line), 672 mg. In each of the three
cases, the mean steady-state plasma concentration is 10 mg/L.

concentration (Figure 3–6). To match the peak steady-state
(12) concentration, the loading dose can be calculated from
equation (13):

Loading dose = Maintenance dose (13)
For the theophylline example given in the box, Example: × Accumulation factor
Maintenance Dose Calculations, the loading dose would be
350 mg (35 L × 10 mg/L) for a 70-kg person. For most drugs, TARGET CONCENTRATION
the loading dose can be given as a single dose by the chosen
route of administration. INTERVENTION: APPLICATION
Up to this point, we have ignored the fact that some drugs OF PHARMACOKINETICS &
follow more complex multicompartment pharmacokinetics, eg, PHARMACODYNAMICS TO DOSE
the distribution process illustrated by the two-compartment INDIVIDUALIZATION
model in Figure 3–2. This is justified in the great majority of
cases. However, in some cases the distribution phase may not be The basic principles outlined above can be applied to the interpre-
ignored, particularly in connection with the calculation of loading tation of clinical drug concentration measurements on the basis
doses. If the rate of absorption is rapid relative to distribution (this of three major pharmacokinetic variables: absorption, clearance,
is always true for rapid intravenous administration), the concen- and volume of distribution (and the derived variable, half-life). In
tration of drug in plasma that results from an appropriate loading addition, it may be necessary to consider two pharmacodynamic
dose—calculated using the apparent volume of distribution—can variables: maximum effect attainable in the target tissue and the
initially be considerably higher than desired. Severe toxicity may sensitivity of the tissue to the drug. Diseases may modify all of
occur, albeit transiently. This may be particularly important, eg, these parameters, and the ability to predict the effect of disease
in the administration of antiarrhythmic drugs such as lidocaine, states on pharmacokinetic parameters is important in properly
where an almost immediate toxic response may occur. Thus, adjusting dosage in such cases. (See Box: The Target Concentra-
while the estimation of the amount of a loading dose may be quite tion Strategy.)
correct, the rate of administration can sometimes be crucial in pre-
venting excessive drug concentrations, and slow administration of Pharmacokinetic Variables
an intravenous drug (over minutes rather than seconds) is almost
always prudent practice. A. Input
When intermittent doses are given, the loading dose calcu- The amount of drug that enters the body depends on the patient’s
lated from equation (12) will only reach the average steady- adherence to the prescribed regimen and on the rate and extent of
state concentration and will not match the peak steady-state transfer from the site of administration to the blood.