Chapter 40. Principles of Pharmacokinetics and Pharmacodynamics: Applied Clinical Pharmacology for the Practitioner

The ultimate goal of pharmacokinetic–pharmacodynamic study is the accurate prediction of the time course and magnitude of drug effect so the clinician can answer a very simple and important question: "What is the appropriate dosing scheme for my patient?"

Pharmacokinetics, often thought of as "what the body does to the drug," is the study of the relationship between the drug dose and the drug concentrations that are produced over time.

Pharmacodynamics, often thought of as "what the drug does to the body," is the study of the relationship between the drug concentration and the drug effects that are produced.

Pharmacokinetic–pharmacodynamic models can be constructed that characterize drug behavior. These models are mathematical expressions of the relationship between drug dose and concentration (pharmacokinetics) and drug concentration and effect (pharmacodynamics). The models are composed of individual parameters (eg, clearance, distribution volume, effective concentration for 50% of maximal effect). Because of the complex interaction of the parameters, it is difficult to draw conclusions about drug behavior from a single parameter.

Because it is a mathematically based discipline, pharmacokinetics–pharmacodynamics is a distinctly unpopular subject among clinical anesthesiologists. This unpopularity is ironic considering that there is no medical specialty for whom the accurate prediction of the time course and magnitude of drug effect is more important (anesthesiologists produce profound, potentially dangerous drug effects that must be "turned on and off" in a rapid fashion).

Fortunately, the clinical implications of pharmacokinetic–pharmacodynamic models can be easily understood and conveyed through the use of computer simulation. Using computer simulation, a proposed dosing scheme can be "input" into a pharmacokinetic–pharmacodynamic model, producing a "picture" of the drug levels and drug effects that are expected to occur. These pictures (ie, computer simulations) are intuitively understandable and are easily applied to clinical situations.

The "biophase" is the theoretical site of drug action or "effect site" (eg, the brain, the neuromuscular junction, the spinal cord). It is important to consider drug concentrations in the biophase (and not just the plasma) because most drugs do not exert their effect in the blood. Pharmacokinetic–pharmacodynamic models account for this problem by linking the concentrations in the blood to theoretical concentrations in the biophase.

Because anesthetics are rarely administered alone (ie, anesthesia is usually at least a 2-process consisting of an analgesic and a sedative), characterizing the interaction between drugs is also an important goal of pharmacokinetic-pharmacodynamic study. Most anesthetics commonly used in combination, such as fentanyl and propofol, interact in a profoundly synergistic way (eg, where 2 + 2 = 7 or more …) so that much less of each drug is required (compared with the doses necessary when the drugs are used alone). Drug interaction models using "response surface" methods can be used to visualize these synergistic interactions and identify optimal dosing regimens.

Anesthesiologists have long recognized the need to adapt their anesthetic to account for differences in demographic factors and disease processes that influence drug disposition or effect. Comorbidities such as obesity, blood loss, presence of opioid tolerance, and differences ...