Pharmacokinetic and Pharmacodynamic Principles

Abstract

This chapter summarizes the pharmacokinetic principles that are essential in everyday clinical practice: Whenever initiating a dosage, changing a dosage, or upon cessation of a treatment, the new steady state of the medication (including its de facto elimination) is not reached before 4 elimination half-lives. Many neuropsychiatric medications have elimination half-lives around 24 h, so the clinician has to wait at least 4 days until the new effect intensity can be expected. On pharmacologic principle, medications with longer elimination half-lives should be preferred because their concentrations fluctuate less, producing less variation in effect strength and carrying a lower risk of adverse drug reactions (ADRs). With respect to pharmacodynamics, clinical studies in psychiatric institutions have been notoriously poor in demonstrating a relationship between the concentration of the prescribed medication and its effect on psychiatric symptoms. This chapter identifies the very likely reasons for this shortcoming of clinical trials: Concentration-effect relationships becomes less and less clear-cut as one proceeds from simple outcomes that are very much upstream in the biologic chain of events, for example, receptor occupancy or prolactin blood concentration, to a multifactored outcome such as symptom improvement. Investigators have to contend with “signal noise” contributed by placebo responders, placebo deteriorators, and nonresponders, especially as one moves from single center to multicenter trials. This chapter ends with a study design checklist to improve clinical trials investigating concentration-effect relationships of neuropsychiatric medications. With respect to the pharmacologic targets of neuropsychotropic medications (receptors, monoamine transporters, etc.), the reader is referred to the chapter “Adverse Drug Reactions, Intoxications and Interactions of Neuropsychotropic Medications”