Distribution of Intravenous Drugs

Intravenously administered anesthetic drugs are especially well suited to accomplish the first requirement of anesthetic management, rapid induction of unconsciousness. These compounds generally induce anesthesia within one or two circulation times after their administration because they rapidly achieve initial high concentration in the central nervous system (CNS). These drugs enter the brain because they are quite lipid soluble and consequently diffuse rapidly through all biological membranes, including the blood-brain barrier. In addition, since the brain tissue receives a large proportion of the cardiac output, a large proportion of an intravenously administered anesthetic will be distributed to the CNS. Tissues with lower blood flow per unit mass will receive and therefore remove proportionally less anesthetic during the initial phase of drug distribution. This concept is illustrated for thiopental in Fig. 25.1. All IV anesthetic drugs in use show this early pattern of distribution. The use of IV anesthetics permits the patient to pass rapidly through the initial stages of anesthesia, and sleep is induced quickly.

The initial unequal tissue-drug distribution cannot persist, however, because physicochemical forces tend to require an eventual establishment of concentration equilibria with other less well perfused organs. Therefore, as the drug continues to be removed from the blood by the less richly perfused tissues or eliminated by metabolism and excretion or both, plasma levels will fall, and the concentration of anesthetic in the brain will decline precipitously.

Tissues with an intermediate blood flow per unit of mass, such as skeletal muscle and skin, are among the first to participate in drug redistribution. In fact, it is the patient's skeletal muscle tissue groups that will contain the largest proportion of the initial dose of anesthetic when the patient awakens (Fig. 25.2). Most of the IV drugs used to induce anesthesia are slowly metabolized and excreted and depend on redistribution to terminate their pharmacological effects. The rate of initial redistribution following the administration of a single IV bolus of drug is defined by the half-life (t1/2a), and is generally about 8 minutes for most anesthetics. It can be said, therefore, that redistribution of IV anesthetics to skeletal muscle accounts for the return to consciousness after a single sleep dose of these agents. Patients generally awaken 15 to 30 minutes after a single IV injection of most of the commonly used IV anesthetics.

Poorly perfused tissues (adipose tissue, connective tissue, and bone) require hours to come into equilibrium with plasma drug concentrations (Fig. 25.1). Since the accumulation of anesthetic in body fat is relatively small soon after its IV administration, it is common clinical practice to calculate drug dosage on the basis of lean body mass rather than on total body weight. Thus, an obese patient may receive the same dose of IV anesthetic as a patient of normal body weight.

Since the distribution of blood flow is the dominant factor controlling both tissue drug levels and the accumulation of IV anesthetics, changes in cardiac output can be expected to influence the pharmacological effects of the IV anesthetics. Because blood flow to the brain is preserved, a greater proportion of the total dose of anesthetic will be delivered to the brain during times of diminished cardiac output, such as in congestive heart failure or hemorrhage. At such times, smaller

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