Computer simulation is required to meaningfully interpret dosing and to accurately devise new dosing regimens.

1. Rise to Steady-State Concentration. The drug concentration versus time profile for the rise to steady state is the mirror image of its elimination profile.
2. Infusion Dosing Schemes. Based on a one-compartment pharmacokinetic model, a stable steady-state plasma concentration (Cpss) can be maintained by administering an infusion at a rate that is proportional to the elimination of drug from the body.
3. Isoconcentration Nomogram. To make the calculations of the various infusion rates required to maintain a target plasma concentration for a drug that follows multicompartment pharmacokinetics, a clinician needs access to a basic computer and the software to perform the appropriate simulations.
4. Context-Sensitive Decrement Times. During an infusion, drug is taken up by the inert peripheral tissues. After drug delivery is terminated, recovery occurs when the effect site concentration decreases below a threshold concentration for producing a pharmacologic effect.
5. Target-Controlled Infusions. By linking a computer with the appropriate pharmacokinetic model to an infusion pump, it is possible for the physician to enter the desired target plasma concentration of a drug and for the computer to nearly instantaneously calculate the appropriate infusion scheme to achieve this concentration target in a matter of seconds.
6. Time to Maximum Effect Compartment Concentration (T_max). By simultaneously modeling the plasma drug concentration versus time data (pharmacokinetics) and the measured drug effect (pharmacodynamics), an estimate of the drug transfer rate constant between plasma and the putative effect site can be estimated.
7. Volume of Distribution at Peak Effect (V_dpe). It is possible to calculate a bolus dose that will attain the estimated effect site concentration at T_max without overshoot in the effect site.
8. Front-end pharmacokinetics refers to the intravascular mixing, pulmonary uptake, and recirculation events that occur in the first few minutes during and after IV drug administration. These kinetic events and the drug concentration versus time profile that results are important because the peak effect of rapidly acting drugs occurs during this temporal window.
9. Closed-Loop Infusions. When a valid and nearly continuous measure of drug effect is available, drug delivery can be automatically titrated by feedback control. Such systems have been used experimentally for control of blood pressure, oxygen delivery, blood glucose, neuromuscular blockade, and depth of anesthesia.
   1. Closed-loop systems for anesthesia are the most difficult systems to design and implement because the precise definition of anesthesia remains elusive, as does a robust monitor for anesthetic depth.
   2. Because modification of consciousness must accompany anesthesia, processed electroencephalographic (EEG) parameters that correlate with level of consciousness, such as the bispectral index, EEG entropy, and auditory evoked potentials, make it possible to undertake closed-loop control of anesthesia.
10. Response Surface Models of Drug–Drug Interactions. During the course of an operation, the level of anesthetic drug administered is adjusted to ensure amnesia to ongoing events, provide immobility to noxious stimulation, and blunt the sympathetic response to noxious stimulation. To limit side effects, an opioid and a sedative–hypnotic are often administered together (synergistic for most pharmacologic effects).

Basic Principles of Clinical Pharmacology

1. Pharmacokinetic Principles: Drug Absorption and Routes of Administration
2. Drug Distribution
3. Drug Elimination
4. Pharmacokinetic Models
5. Compartmental Pharmacokinetic Models
6. Pharmacodynamic Principles
7. Drug–Receptor Interactions
8. Drug Interactions
9. Clinical Applications of Pharmacokinetic and Pharmacodynamics to the Administration of IV Anesthetics