Chapter 3

### INTRODUCTION

Anesthetic drug interactions exist when one anesthetic influences the behavior of another anesthetic. The combined effects can be enhanced or diminished, or a new effect may occur. New effects can be therapeutic, or they can be unwanted side effects. During anesthesia, clinicians make therapeutic decisions routinely involving multiple drugs and as such, anesthesiologists are confronted with anesthetic drug–drug interactions on a daily basis.

Anesthetic effects are achieved using either a single drug or combinations of drugs. Drugs in combination all contribute to the overall effect; most combinations decrease the dose of each individual anesthetic when compared to doses of individual drugs required to achieve an equivalent effect. Taking advantage of interaction may decrease the severity or incidence of adverse effects without hampering desired effects.

Despite years of training, clinicians may not appreciate the magnitude of drug interactions, and they may administer excessive doses of anesthetics, hamper recovery, or increase the risk of adverse effects. Recent work has described several anesthetic interactions, and new display technology has been developed to visualize these interactions at the bedside of the patient. These recent innovations may provide a more evidence-based approach to anesthetic drug administration.

This chapter consists of 3 sections and an appendix. The first section will review basic principles of drug interactions. The second section will review the available models for vapor–opioid, hypnotic–opioid, and hypnotic–hypnotic interactions. The third section will discuss methods for applying interaction models in clinical practice. The appendix will present the methodology used to develop interaction models for interested readers.

Two topics concerning interaction will not be covered in this chapter. First, anesthetic drugs are known to influence the pharmacokinetic profile of one another by altering distribution volumes or clearance. Although many studies have demonstrated the importance of such interactions, the ultimate goal in anesthesia practice is to control effect rather than concentration. Pharmacokinetic interactions eventually result in pharmacodynamic changes. Hence, this chapter will focus on the clinical observable expression of interactions rather than on the (more obscure) changes in plasma concentration. Second, the interaction between paralytic and anesthetic agents is not well defined. This is primarily because the interactions have not been well modeled.

### BASIC PRINCIPLES OF ANESTHETIC DRUG–DRUG INTERACTIONS

One of the main questions concerning interactions between drugs is the nature of the interaction. Three concepts of drug interaction can be distinguished: (1) additivity, (2) supra-additivity (or synergism), and (3) infra-additivity (or antagonism). For additive drugs with equal potency, the sum of the effects evoked by respectively doses (a) and (b) for drug A and drug B is equal to the effect obtained with a solitary administration of either drug A or B given in a dose (a) + (b). For synergistic interactions, the combination of drugs A and B will result in a more pronounced effect compared to additivity. For infra-additive ...

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