B. To avoid excessive levels of sedation, drugs should be titrated in increments rather than administered in larger doses according to predetermined notions of efficacy.

C. Continuous infusions (e.g., propofol) are superior to intermittent bolus dosing because they produce less fluctuation in drug concentration, thus reducing the number of episodes of inadequate or excessive sedation and contributing to a more prompt recovery (Fig. 29-1).

V. DISTRIBUTION, ELIMINATION, ACCUMULATION, AND DURATION OF ACTION. After administration of IV drugs, the immediate distribution phase causes a rapid decrease in plasma levels as the drug is quickly transported to the vessel-rich group of rapidly equilibrating tissues. Accumulation of drug in poorly perfused tissues during prolonged IV infusion may contribute to delayed recovery when the drug is released back into the central compartment after drug administration is discontinued.

A. Elimination half-life is often cited as a determinant of a drug’s duration of action, when it is actually often difficult to predict the clinical duration of action from this value.

1. The elimination half-life represents a single-compartment model in which elimination is the only process that can alter drug concentration.

2. Most drugs used by anesthesiologists for MAC are lipophilic and much more suited to multicompartmental modeling than single-compartment modeling. In multicompartmental models, the metabolism and excretion of some IV drugs may make only a minor contribution to changes in plasma concentration compared with the effects of intercompartmental distribution.

B. Context-sensitive half-time is the time required for the plasma drug concentration to decline by 50% after an IV infusion of a particular duration is terminated. It is calculated by computer simulation of multicompartmental pharmacokinetic models of drug disposition.

1. The context-sensitive half-time increases as the duration of the infusion increases (particularly for fentanyl and thiopental).

a. This confirms that thiopental is not an ideal drug for continuous infusion during ambulatory procedures.

b. The context-sensitive half-time of propofol is prolonged to a minimal extent as the infusion duration increases. (After the infusion ends, the drug that returns to the plasma from the peripheral compartments is rapidly cleared by metabolic processes and is therefore not available to slow the decay in plasma levels.)

2. The context-sensitive half-times of drugs bear no constant relationship to their elimination half-times.

C. How Does the Context-Sensitive Half-Time Relate to the Time to Recovery? The context-sensitive half-time does not directly describe how long it will take for the patient to recover from sedation/analgesia but rather how long it will take for the plasma concentration or drug to decrease by 50%. The time to recovery depends on how far the plasma concentration must decrease to reach levels compatible with awakening (Fig. 29-2).

D. Effect site equilibration describes the time from rapid IV administration of a drug until its clinical effect is manifest. (A delay occurs because the blood is not usually the site of action but is merely the route via which the drug reaches its effect site.)

1. Thiopental, propofol, and alfentanil have a short effect site equilibration times compared with midazolam, sufentanil, and fentanyl. This is an important consideration when determining bolus spacing of doses.

FIGURE 29-2. The time to awakening is determined by the duration of infusion (context-sensitive half-time), the difference in the plasma concentration at the end of the procedure, and the plasma concentration below which awakening will occur.

2. A distinct time lag between the peak serum fentanyl concentration (which is an important consideration when determining bolus spacing of doses) and the peak electroencephalographic (EEG) slowing can be seen, but after administration of alfentanil, the EEG spectral edge changes closely parallel serum concentrations. If an opioid is required to blunt the response to a single, brief stimulus, alfentanil might represent a more logical choice than fentanyl.

VI. DRUG INTERACTIONS IN MONITORED ANESTHESIA CARE

A. No one inhaled or IV drug can provide all the components of MAC. Patient comfort is usually maintained by a combination of drugs that act synergistically to enable reductions in the dose requirements of individual drugs.

B. It is likely that a rapid recovery in the ambulatory setting can be achieved by using an opioid in combination with other drugs (especially a benzodiazepine) rather than using an opioid as the sole anesthetic.

1. Opioid and benzodiazepine combinations are frequently used to achieve the components of hypnosis, amnesia, and analgesia.

2. The opioid–benzodiazepine combination displays marked synergism in producing hypnosis. This synergism also extends to unwanted effects of these drugs. (Whereas midazolam alone produces no significant effects on ventilation, the combination with fentanyl produces apnea in many patients.)

3. The advantage of synergy between opioids and benzodiazepines should be carefully weighed against the disadvantages of the potential adverse effect of this drug combination on the cardiovascular system and breathing.

VII. SPECIFIC DRUGS USED DURING MONITORED ANESTHESIA CARE (Table 29-2)

A. Propofol has many of the ideal properties of a sedative–hypnotic for use in sedation/analgesia.

TABLE 29-2 DOSE RANGES FOR DRUGS USED TO PRODUCE SEDATION/ANALGESIA

IM = intramuscular; IV = intravenous; PO = per os.

1. The context-sensitive half-time of propofol remains short even after prolonged IV infusions (in contrast to midazolam), and the short effect site equilibration time makes propofol an easily titratable drug that has an excellent recovery profile.

2. The prompt recovery combined with a low incidence of nausea and vomiting make propofol well suited to ambulatory sedation/analgesia procedures.

3. Propofol in typical sedation/analgesia doses (25–75 μg/kg/min IV) has minimal analgesic properties and does not reliably produce amnesia.

B. Fospropofol is a prodrug of propofol. The resulting active metabolite of propofol has a C_max (maximum plasma concentration) value of 4 minutes, which is longer than that of propofol. At present, the safety and efficacy of fospropofol for short procedures requiring MAC is unclear.

C. Benzodiazepines are commonly used during sedation/analgesia for their anxiolytic, amnestic, and hypnotic properties.

1. Midazolam has many advantages over diazepam and is the most commonly used benzodiazepine for sedation/analgesia (Table 29-3).

a. Despite a short elimination half-time, there is often prolonged psychomotor impairment after sedation/analgesia techniques using midazolam as the main component.

TABLE 29-3 COMPARISON OF THE IMPORTANT PROPERTIES OF MIDAZOLAM AND DIAZEPAM