Abstract

Pharmacokinetic considerations. The concentration of drug at the target tissue is determined by combined influences of absorption, metabolism, distribution, and elimination (excretion). Notice obstacles to bioavailability (serum concentration) following oral and intramuscular administration compared to those following intravenous administration.

Time-concentration curves for meperidine. This graph illustrates time-concentration curves for identical doses of meperidine following 3 routes of administration. Following intravenous (IV) administration the concentration drops rapidly during the first 30 minutes due to distribution. The decline then becomes more gradual as drug is eliminated. Following intramuscular (IM) and oral (PO) administration the serum level rises gradually as drug is absorbed and distributed simultaneously. The peak is lower than that following IV administration as initial drug absorbed undergoes distribution and possible elimination before final amounts are absorbed. Compared to IM administration, the time until peak concentration following a PO dose is longer due to slower absorption, and the peak is lower due to more factors hindering bioavailability, eg, first-pass metabolism. Notice that once the processes of absorption and distribution are completed, elimination of drug occurs at an identical rate regardless of the route by which it was administered; elimination T_1/2 is identical (adapted from Stambaugh et al2).

Repeated sublingual doses. This graph illustrates time-concentration curves following 1 to 3 doses of triazolam, 0.25 mg administered sublingually. Notice that a single dose (1 Dose) results in a conventional peak time of 1 hour and then declines as drug is eliminated. However, a second dose results in a peak concentration 1.5 hours later (2 Doses). Finally, the peak following a third dose occurs 2.5 hours later (3 Doses). Although a single dose achieves peak serum concentration in 1 hour, the peak following additional increments becomes progressively longer. Precise serum concentrations are approximated and adapted from Pickrell et al.4

Circulation and distribution. Drug (D) circulating in the bloodstream can distribute easily through systemic capillaries into most body tissues. Distribution through central nervous system capillaries (blood-brain barrier) requires lipid solubility. Notice that a portion of the total drug circulating may be temporarily bound to plasma protein but readily dissociates to distribute into tissues. See text for further explanation.

Pharmacokinetic compartments. Following an intravenous bolus, drug introduced into the bloodstream (central compartment) distributes into peripheral tissues (peripheral compartment). In the three-compartment model these tissues are divided into those highly perfused (shallow) and less perfused (deep). As the serum concentration declines due to distribution or elimination, drug in the peripheral compartments will equilibrate by redistribution into the central compartment. The time-concentration curve illustrates the decline in serum concentration attributable to rapid distribution into highly perfused tissues, intermediate distribution to less perfused tissues, and a slow decline due to drug elimination.

Elimination half-life: steady state and elimination. The following time-concentration curves are for a drug having an elimination half-life of 2 hours. The doses have been determined by the manufacturer to provide a therapeutic serum level of approximately 10 µg/mL. The solid line represents the drug administered by continuous intravenous infusion at a constant rate of 25 mg/h. Notice that a steady state serum concentration of 10 µg/mL is achieved in 8 hours or 4 half-lives. At this point the amount of drug administered is equal to the amount being eliminated. A drug administered intermittently orally cannot produce a perfect steady state but one that is approximate. The dashed line represents the same drug administered as 200 mg orally every 4 hours (q4h). Notice that in 8 hours (4 half-lives) a relative steady state is reached when both peak and trough (lowest) levels are the same following each dose. If larger doses were given, the steady-state concentration would be greater (>10 µg/mL), but it would still not be achieved until 4 half-lives (8 hours) have passed. Notice that when administration is discontinued, the drug is completely eliminated in 4 half-lives, eg, 8 hours (#1–4).

Onset and duration of sedation. Following absorption, serum concentrations are high and drug distributes to tissues in proportion to their degree of perfusion; brain, muscle, and finally adipose tissues. As distribution proceeds, serum level declines and high concentrations in brain redistribute into the bloodstream. These processes occur more rapidly with highly lipid soluble drugs and account for rapid onset but shortened duration of sedation. Drug elimination follows subsequently.

Representative context-sensitive half-times. The following graph compares the time required for serum concentrations to decline by 50% upon discontinuation of varied durations of continuous infusions. With the exception of remifentanil, the context-sensitive half-times increase following greater durations of infusion. Continuous infusions of diazepam and vfentanyl result in an unacceptable time for recovery. Data are adapted from Hughes et al12 and Egan et al.13