Page 55 - Basic _ Clinical Pharmacology ( PDFDrive )

C H A P T E R

Pharmacokinetics & 3

Pharmacodynamics:

Rational Dosing &

the Time Course

of Drug Action

Nicholas H. G. Holford, MB, ChB, FRACP

C ASE STUD Y

An 85-year-old, 60-kg woman with a serum creatinine of is 1 ng/mL. Tablets of digoxin are available that contain
1.8 mg/dL has atrial fibrillation. A decision has been made to 62.5 micrograms (mcg) and 250 mcg. What maintenance
use digoxin to control the rapid heart rate. The target con- dose would you recommend?
centration of digoxin for the treatment of atrial fibrillation

The goal of therapeutics is to achieve a desired beneficial effect with The apparent lack of such a relationship for some drugs does not
minimal adverse effects. When a medicine has been selected for a weaken the basic hypothesis but points to the need to consider the
patient, the clinician must determine the dose that most closely time course of concentration at the actual site of pharmacologic
achieves this goal. A rational approach to this objective combines effect (see below).
the principles of pharmacokinetics with pharmacodynamics to Knowing the relationship between dose, drug concentration,
clarify the dose-effect relationship (Figure 3–1). Pharmacodynam- and effects allows the clinician to take into account the various
ics governs the concentration-effect part of the interaction, whereas pathologic and physiologic features of a particular patient that
pharmacokinetics deals with the dose-concentration part (Holford make him or her different from the average individual in respond-
& Sheiner, 1981). The pharmacokinetic processes of absorption, ing to a drug. The importance of pharmacokinetics and pharma-
distribution, and elimination determine how rapidly and for how codynamics in patient care thus rests upon the improvement in
long the drug will appear at the target organ. The pharmacody- therapeutic benefit and reduction in toxicity that can be achieved
namic concepts of maximum response and sensitivity determine by application of these principles.
the magnitude of the effect at a particular concentration (see E max
and C , Chapter 2; C is also known as EC ).
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50
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Figure 3–1 illustrates a fundamental hypothesis of pharmacol- PHARMACOKINETICS
ogy, namely, that a relationship exists between a beneficial or toxic
effect of a drug and the concentration of the drug. This hypothesis The “standard” dose of a drug is based on trials in healthy
has been documented for many drugs, as indicated by the Target volunteers and patients with average ability to absorb, distribute,
Concentration and Toxic Concentration columns in Table 3–1. and eliminate the drug (see Clinical Trials: The IND & NDA
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