ABSTRACT
The therapeutic benefits of any drug therapy and the risks of toxicity depend on the relationship between the delivery of the drug to the patient (dose and dose interval), the disposition of the drug to determine drug concentration at the effector site (pharmacokinetics), and the drug's action at the effector site and the end response (pharmacodynamics). Intersubject variations in response, and specifically variations in therapeutic outcome among adults and children of varying ages, are a consequence of the balance among these variables. It is clear that a child is not simply a small adult, and that physiologic differences in any of the determinants of kinetics and dynamics will influence this balance. There are numerous examples of what appears to be a true difference in the dynamic response to a given plasma concentration. These include drugs where higher doses can be achieved with less toxicity (such as digoxin), 1 where therapeutic levels in adults can be associated with toxicity or even sudden death in children (such as the tricyclic antidepressants), 2 or where lower plasma levels are required to achieve a desired therapeutic effect (for example, haloperidol). 3 In addition, child maturation results in sequential changes in a number of physiologic determinants of drug disposition. Thus there is a need to identify both the pharmacokinetic and pharmacodynamic interrelationships for each drug. The physiologic determinants of drug disposition will be discussed in greater detail in this chapter, while individual kinetic–dynamic interrelationships will be discussed with respect to individual drugs in later chapters.
