First-order pharmacokinetics : Most drugs are metabolized via processes that obey first-order kinetics, meaning that the rate of drug metabolism is proportional to the concentration of the drug (see Fig. 3.1). The rate of elimination is usually described in terms of the drug’s half time, which is the time in which metabolism and excretion reduce the plasma concentration of the drug to 50 % of its starting value. As further time progresses, the process continues as detailed in Table 3.1. Note that after 5 half-times have passed, 96.9 % of the drug has been eliminated, and for practical purposes, the drug has been fully eliminated.

Clearance: The clearance of a drug is defined as the theoretical volume of blood that is completely cleared of drug per unit time. It is analogous to the creatinine clearance rate of the kidneys. Different pathways of clearance for a drug (i.e. renal and hepatic) are additive, and a decrease in a major pathway of clearance will prolong the effect of drugs that use that pathway for elimination (e.g., administration of a drug that is mainly cleared by the kidneys to a patient with impaired renal function will result in a relatively long duration of action).

Context-sensitive half-time : As discussed above, some drugs are eliminated from the plasma by redistribution to adipose tissue. As the adipose tissue acquires more drug, the diffusion gradient from plasma to tissue decreases, and the rate of redistribution decreases. This leads to the phenomenon of context-sensitive half-times, in which the time to 50 % reduction in drug concentration increases with increasing total doses of the drug or duration of infusion. Drugs that are highly redistributed but metabolized relatively slowly, such as thiopental, are affected more than drugs with rapid metabolism, such as sufentanil. The context sensitive half-times as a function of duration of drug infusion are shown in Fig. 3.2.