2. Phase II reactions are known as conjugation or synthetic reactions. Similar to the cytochrome P450 system, the enzymes that catalyze phase II reactions are inducible.

3. Genetic Variations in Drug Metabolism. Drug metabolism varies substantially among individuals because of variability in the genes controlling the numerous enzymes responsible for biotransformation.

4. Chronologic Variations in Drug Metabolism. The activity and capacity of the CYP enzymes increase from subnormal levels in the fetal and neonatal period to reach normal levels at about 1 year of age. Neonates have a limited ability to perform phase II conjugation reactions, but after normalizing phase II activity over the initial year of life, advanced age does not affect the capacity to perform phase II reactions.

C. Renal Drug Clearance. The primary role of the kidneys in drug elimination is to excrete into urine the unchanged hydrophilic drugs and the hepatic derived metabolites from phase I and II reactions of lipophilic drugs. In patients with acute and chronic causes of decreased renal function, including advanced age, low cardiac output states, and hepatorenal syndrome, drug dosing must be altered to avoid accumulation of parent compounds and potentially toxic metabolites (Table 7-2).

D. Hepatic Drug Clearance. Drug elimination by the liver depends on the intrinsic ability of the liver to metabolize the drug and the amount of drug available to diffuse into the liver (hepatic blood flow) (Table 7-3).

IV. PHARMACOKINETIC MODELS. The concentration of drug at its tissue site or sites of action is the fundamental determinant of a drug’s pharmacologic effects.

A. Physiologic versus Compartment Models

1. Awakening after a single dose of thiopental is primarily a result of redistribution of thiopental from the brain to the muscle with little contribution by distribution to less well-perfused tissues or drug metabolism; this fundamental concept of redistribution applies to all lipophilic drugs.

2. Drug concentrations in the blood are used to define the relationship between dose and the time course of changes in the drug concentration.

B. Pharmacokinetic Concepts

1. Rate Constants and Half-Lives. The disposition of most drugs follows first-order kinetics. A first-order kinetic process is one in which a constant fraction of the drug is removed during a finite period of time regardless of the drug’s amount or concentration. Rather than using rate constants, the rapidity of pharmacokinetic processes is often described with half-lives, which is the time required for the concentration to change by a factor of 2. After five half-lives, the process is almost 97% complete (Table 7-4). For practical purposes, this is essentially 100%, so there is a negligible amount of drug remaining in the body.

2. Volume of distribution quantifies the extent of drug distribution (overall capacity of tissues versus the capacity of blood for that drug). If a drug is extensively distributed, then the concentration will be lower relative to the amount of drug present, which equates to a larger volume of distribution. The apparent volume of distribution is a numeric index of the extent of drug distribution that does not have any relationship to the actual volume of any tissue or group of tissues. In general, lipophilic drugs have larger volumes of distribution than hydrophilic drugs.

3. Elimination half-life is the time during which the amount of drug in the body decreases by 50%. Although elimination of drug from the body begins the moment the drug is delivered to the organs of elimination, the rapid termination of effect of a bolus of an IV agent is attributable to redistribution of drug from the brain to the blood and subsequently other tissue (muscle). Therefore, the effects of most anesthetics have waned long before even one elimination half-life has been completed. Thus, the elimination half-life has limited utility in anesthetic practice.

C. Effect of Hepatic or Renal Disease on Pharmacokinetic Parameters. Diverse pathophysiologic changes preclude precise prediction of the pharmacokinetics of a given drug in individual patients with hepatic or renal disease.

1. When hepatic drug clearance is reduced, repeated bolus dosing or continuous infusion of such drugs as benzodiazepines, opioids, and barbiturates may result in excessive accumulation of drug as well as excessive and prolonged pharmacologic effects.

2. Because recovery from small doses of drugs such as thiopental and fentanyl is largely the result of redistribution, recovery from conservative doses is minimally affected by reductions in elimination clearance.

V. COMPARTMENTAL PHARMACOKINETIC MODELS

A. One-Compartment Model. Although the one-compartment model is an oversimplification for most drugs, it does serve to illustrate the basic relationships among clearance, volume of distribution, and the elimination half-life (Fig. 7-1).

B. Two-Compartment Model. There are two discrete phases in the decline of the plasma concentration (Fig. 7-2). To account for this biphasic behavior, one must consider the body to be made up of two compartments, a central compartment, which includes the plasma, and a peripheral compartment.

C. Three-Compartment Model. After IV injection of some drugs, the initial, rapid distribution phase is followed by a second, slower distribution phase before the elimination phase becomes evident.

D. In general, the model with the smallest number of compartments or exponents that accurately reflects the data is used.

VI. PHARMACODYNAMIC PRINCIPLES. Pharmacodynamic studies focus on the quantitative analysis of the relationship between the drug concentration in the blood and the resultant effects of the drug on physiologic processes.

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