The duration of effect following administration of sedatives will obviously be related to the decline in serum concentration. However, there is a mistaken belief that drug elimination is the principal factor that accounts for this decline, and a drug having a longer elimination half-life will provide a longer duration of sedation. To correct this misconception we need to better appreciate the pharmacokinetics of distribution and elimination.
The so-called “two-compartment model” is conventionally used to describe the pharmacokinetics of drug distribution and elimination. When drug is administered it enters the bloodstream or central compartment. From this location it can undergo elimination or it can distribute into body tissues, the peripheral compartment. However, this peripheral compartment is very large and consists of all body tissues, each having varied degrees of volume and perfusion. For this reason a “three-compartment model” is more accurate because it divides the peripheral compartment into a “shallow” or highly perfused compartment and a vast “deep” compartment that is less perfused. This concept is illustrated in .
Figure 5. 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 (more ...)
Drug half-life (T1/2) is a general term representing the time required for plasma concentration to diminish by 50%. Unlike that following PO and IM administration, the decline in serum concentration following an IV bolus injection occurs in 2 major phases. The initial decline is rapid and is attributed to drug distribution, not elimination. The rate for this decline is designated distribution half-life (T1/2α) and is relevant only for drugs administered intravenously. (Following PO and IM administration, drug distribution proceeds simultaneously with absorption as illustrated in .) Once distribution is completed, further decline in serum concentration becomes more gradual and is identical to that following PO and IM administration. This rate of decline is attributed to drug elimination and is designated elimination half-life (T1/2β). For example, the T1/2β for the drug illustrated in is approximately 3 hours, but its distribution half-life (T1/2α) is only 30 minutes.
Before the duration of drug effect is discussed any further, we need to clarify the significance of elimination half-life. This value provides 2 clinical correlates, neither of which relate to duration of sedation in clinical practice. The first of these is that a drug may be considered completely eliminated following 4 half-lives and, secondly, steady state drug concentrations can be achieved following 4 half-lives provided the drug is administered at a consistent dose and schedule.8
These principles are illustrated in .
Figure 6. 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 (more ...)
Although elimination half-life provides insight regarding the length of time a drug continues to circulate within the bloodstream, it does not identify the point at which the concentration falls below that required to sustain an adequate drug level in the target tissues. Following repeated administration, serum levels will become higher but a steady state will not occur unless dosing is consistent for a total of 4 half-lives. This consideration is more relevant for chronic drug therapy, not when drugs are administered for procedural sedation.
The duration of sedation is more dependent on drug distribution and redistribution because these processes generally proceed well before elimination comes into play. Revisit and imagine that a serum concentration of 35 ng/mL is required to provide adequate sedation. Notice that the process of distribution accounts for a drop below this level, not elimination. Therefore,the duration of sedation more closely correlates with distribution half-life (T1/2α) than elimination half-life (T1/2β).
Again consider diazepam (Valium) and lorazepam (Ativan) as examples. The elimination half-life for diazepam and its active metabolites ranges from 40–50 hours, while that for lorazepam is 15–20 hours. Yet the duration of sedation is significantly shorter for diazepam despite its longer elimination half-life. This is because diazepam has far greater lipid solubility. Even though adipose tissue is poorly perfused, highly lipid soluble drugs will distribute to this compartment more rapidly and account for a more rapid decline in the serum concentration. As this occurs, drug that initially distributed rapidly to brain will redistribute back into the blood stream reducing the degree of sedation. Therefore, high lipid solubility not only provides fast onset but accounts for shorter duration (). This principle has been confirmed by Greenblatt et al following intravenous administration of diazepam and lorazepam9
and following PO administration of triazolam (Halcion) and zolpidem (Ambien).10
Figure 7. 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 (more ...)
As serum levels rise following repeated doses, the duration of sedation may increase somewhat because tissue depots become more saturated and processes of elimination begin to come into play. During IV sedation using midazolam or diazepam, the duration of sedation following the first few increments may last only 10–15 minutes, which corresponds to the distribution half-lives for these drugs. During more lengthy appointments, however, subsequent IV increments may lead to progressively longer durations of sedation before additional increments are needed.
In summary, it is important to distinguish the relative significance of distribution versus elimination. While distribution and redistribution determine duration of sedation during treatment, drug elimination must be considered at discharge. Residual serum concentrations may not be profoundly sedative but can have an impact on subsequent psychomotor recovery. Furthermore, one cannot entertain the time for drug elimination until peak serum concentration has been achieved. This issue is of extreme importance following repeated PO or sublingual drug administration. Also, when considering drug elimination, attention must be given to any active metabolites of the parent drug. For example, normeperidine is an active metabolite of meperidine that acts as a CNS stimulant and has an elimination half-life of approximately 16 hours compared to only 2–3 hours for the parent drug.