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CASE STUDY

CASE STUDY

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

The goal of therapeutics is to achieve a desired beneficial effect with minimal adverse effects. When a medicine has been selected for a patient, the clinician must determine the dose that most closely achieves this goal. A rational approach to this objective combines the principles of pharmacokinetics with pharmacodynamics to understand the dose-effect relationship (Figure 3–1). Pharmacodynamics governs the concentration-effect part of the relationship, whereas pharmacokinetics deals with the dose-concentration part (Holford & Sheiner, 1981). The pharmacodynamic concepts of maximum response and sensitivity determine the magnitude of the effect at a particular concentration (see Emax and C50, Chapter 2; C50 is also known as EC50). The pharmacokinetic processes of input, distribution, and elimination determine how rapidly and for how long the target organ will be exposed to the drug.

FIGURE 3–1

The relationship between dose and effect can be separated into pharmacokinetic (dose-concentration) and pharmacodynamic (concentration-effect) components. Concentration provides the link between pharmacokinetics and pharmacodynamics and is the focus of the target concentration approach to rational dosing. The three primary processes of pharmacokinetics are input, distribution, and elimination.

Figure 3–1 illustrates a fundamental hypothesis of pharmacology, namely, that a relationship exists between a beneficial or toxic effect of a drug and the concentration of the drug. This hypothesis has been documented for many drugs, as indicated by the target concentration column in Table 3–1. The target concentration is the concentration that reflects a balance between the beneficial and adverse effects. The apparent lack of such a relationship for some drugs does not weaken the basic hypothesis but points to the need to consider the time course of concentration at the actual site of pharmacologic effect (see below).

TABLE 3−1Pharmacokinetic and pharmacodynamic parameters for selected drugs in adults. (See Holford et al, 2013, for parameters in neonates and children.)

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