Steady State Concentrations

Steady state is an important pharmacological concept for clinicians to understand if drug monitoring is employed. Steady state is that point, on a fixed dose, at which plasma concentrations of the drug reach a plateau. Steady state is achieved after five half-lives. At this point, the concentration of the drug should be 97% of the maximal concentration achieved for that dose. In fact, after three half-lives, the drug will have achieved about 87% of the steady-state concentration. If blood level monitoring is employed, a sample is drawn before the next dose is given, usually in the morning after the patient's level has reached a steady state. Steady-state drug concentrations should remain relatively stable as long as the dose is constant, the patient is compliant, and no interactive drugs are added.

The day-to-day biological variability of drug concentrations at steady state is not frequently described. In inpatients at steady state, the coefficient of variation (SD/mean) of desipramine is approximately 10%-15% (J. C. Nelson, unpublished data, 1985). In outpatients, this variability may increase. This means that if the average plasma concentration is 150 ng/mL, two-thirds of samples obtained will be ±10%, or between 135 ng/mL and 165 ng/mL. Research studies of drug concentrations usually employ an average of two or three plasma samples to reduce the effect of this variability. If only one sample is drawn, the clinician needs to remember that even if the laboratory error is low, there will be moderate biological variability. Single blood levels are better viewed as estimates than as precise measures.

When the drug concentration is measured, the total of both the free and bound drug is reported. Few laboratories are prepared to measure free levels, yet drug concentrations in the cerebrospinal fluid are proportional to the free levels. The free concentration is dependent on dose and hepatic clearance but is not affected by plasma protein binding (Greenblatt et al. 1998). The latter is often misunderstood. Factors that affect plasma proteins—malnutrition, inflammation—may lead to changes in the bound fraction, but the absolute free concentration is unaffected. If another drug affects binding, the absolute free concentration remains unaffected. In these instances, the free fraction may change because the bound portion declines, not because there is a change in the free concentration.

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