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Propranolol, a β-adrenoceptor antagonist, is a useful antihy-pertensive agent because it reduces cardiac output and prob-ably vascular resistance as well. However, it also prevents β-adrenoceptor–induced bronchodilation and therefore may precipitate bronchoconstriction in susceptible individuals. Calcium channel blockers such as verapamil also reduce blood pressure but, because they act on a different target, rarely cause bronchoconstriction or prevent bronchodila-tion. An alternative approach in this patient would be to use a more highly selective adrenoceptor antagonist drug (such as metoprolol) that binds preferentially to the β1 subtype, which is a major βadrenoceptor in the heart, and has a lower affinity (ie, higher Kd) for binding the β2 subtype that mediates bronchodilation. Selection of the most appropriate drug or drug group for one condition requires awareness of the other conditions a patient may have and the receptor selectivity of the drug groups available.
Pharmacokinetics & Pharmacodynamics: Rational Dosing & the Time Course of Drug Action
Nicholas H. G. Holford, MB, ChB, FRACP is 1 ng/mL. Tablets of digoxin are available that contain 62.5 micrograms (mcg) and 250 mcg. What maintenance dose would you recommend? 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 con-centration of digoxin for the treatment of atrial fibrillation
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 clarify the dose-effect relationship (Figure 3–1). Pharmacodynamics governs the concentration-effect part of the interaction, whereas pharmacokinetics deals with the dose-concentration part (Holford & Sheiner, 1981). The pharmacokinetic processes of absorption, distribution, and elimination determine how rapidly and for how long the drug will appear at the target organ. 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).
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 and Toxic Concentration columns in Table 3–1.
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).
Knowing the relationship between dose, drug concentration, and effects allows the clinician to take into account the various pathologic and physiologic features of a particular patient that make him or her different from the average individual in responding to a drug. The importance of pharmacokinetics and pharmacodynamics in patient care thus rests upon the improvement in therapeutic benefit and reduction in toxicity that can be achieved by application of these principles.