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• W2077895837 abstract "Don't despair. The title of this editorial is not intended to suggest that all our training in pharmacokinetics was in error. However, many principles taught at medical school are flawed when applied to the practice of anesthesia. Remember that most drugs are given orally and chronically and have a slow onset of effect. As a result, the vast majority of pharmacokinetic studies focus on events after days or weeks of oral drug administration when plasma drug concentrations are changing relatively slowly and concentrations throughout the body are changing at similar rates. This contrasts to many drugs used in anesthesia in which administration is limited to a period of several hours, route of administration is typically intravenous (or inhaled), and effect changes rapidly during periods of rapidly changing plasma concentration. Consider, for example, the typical assumption that, after bolus drug administration, arterial plasma concentration can be described by the sum of two or more exponential terms (Figure 1). If the first plasma sample is not obtained until 2 or more minutes after drug administration (as in many pharmacokinetic studies), then drug concentration will decrease monotonically over time, consistent with the proposed model. However, plasma samples obtained frequently during the first minute would reveal an initial increase, followed by oscillations, eventually followed by the expected monotonic decrease [1,2]. The polyexponential model misspecifies the early time course of drug concentration because it assumes the body to be homogeneous rather than a complicated system of organs in series and parallel. Although the polyexponential model is well accepted, and probably sufficient for most nonanesthetic drugs, we now recognize its limitation when applied to bolus administration of anesthetic drugs, particularly those that attain maximum effect in <2 min.Figure 1: After bolus drug administration, arterial plasma concentrations are traditionally assumed to decrease monotonically (solid line) and the plasma concentration (Cp) versus time profile can be described by the sum of exponential terms, e.g., Cp = Ae-alpha t + Be-beta t. However, recent studies demonstrate that this model is flawed and that arterial plasma concentrations actually increase during the initial 30-60 s, then oscillate (dashed line) before decreasing monotonically.Another area in which traditional pharmacology has misled is its focus on the term half-life. Often when we discuss pharmacology in the operating room, my residents ask me what is the half-life of a drug. I respond which half-life-distribution (rapid or slow), elimination, terminal, mean residence, etc.? The focus on half-life probably originated with the (somewhat flawed) concept that dosing intervals and time to steady state could be predicted from the elimination half-life. However, anesthetic drugs are rarely given for sufficient duration to attain steady state, limiting the importance of elimination half-life. Consider repeated intravenous administration of an anesthetic drug or adjunct, either by bolus or infusion. At the conclusion of anesthesia, the issue of importance to the clinician is how soon the plasma concentration decreases 50% (or perhaps 80%) to a concentration that permits the patient to awaken, to breathe, or to be strong, rather than the slope of the plasma concentration-time curve when the elimination phase is reached many hours later. Instead of focusing on elimination half-life, we should embrace the concept of context-sensitive half-time. Hughes et al. [3] used pharmacokinetic data for several drugs to determine the rapidity with which plasma concentration decreases twofold after drug administration of varying periods. Similar simulations on opioids by Shafer and Varvel [4] suggested that, despite sufentanil's elimination half-life being longer than alfentanil's, its pharmacokinetic profile (rapid distribution clearance) favored more rapid recovery after procedures <6 h in duration. These studies illustrate the limited utility of elimination half-life. Another seminal investigation challenged the assumption that drug effect should relate to its plasma concentration, even for rapidly acting drugs for which the drug rather than a metabolite is active. One minute after bolus administration of cisatracurium [a muscle relaxant with a relatively slow onset [5]], arterial plasma concentration is decreasing (the oscillatory peaks mentioned earlier having passed) but effect (and presumably concentration at the effect site) is increasing. Sheiner et al. [6] proposed that effect should not be related to plasma drug concentration but rather to drug concentration in a hypothetical effect compartment (not necessarily one of the tissue compartments determined in a pharmacokinetic analysis), linked to plasma with a rate constant keo. This approach reconciled the obviously erroneous observation that, 1 min after drug administration, plasma drug concentrations were quite high yet most drugs demonstrated no obvious, and certainly not maximal, effect. Effect compartment modeling is now well accepted in most areas of pharmacology and has provided numerous insights into the time course of onset and offset of drugs. A final example of the new pharmacokinetics involves a new muscle relaxant, the pharmacology of which is examined in the present issue of this journal by Kisor et al. [7]. Cisatracurium, like atracurium, is eliminated by Hofmann degradation [8], a pathway that does not depend on the usual organs of elimination (liver and kidney). This pathway presumably results in cisatracurium being eliminated from both plasma (central compartment) and tissue (peripheral compartment). As a result, the traditional pharmacokinetic model in which drugs are eliminated only from the central compartment must be flawed if applied to cisatracurium. This type of flaw was first noted in 1984 by Hull [9] in an editorial in which he described a similar problem with atracurium [10]. To address this problem, Sheiner and I [11] recognized that the pharmacokinetic characteristics of atracurium could be determined only if one estimated the rate constant for nonorgan pathways-Hofmann degradation (and ester hydrolysis for atracurium). These estimates were obtained in vitro by replicating physiologic conditions (maintaining physiologic pH and temperature) as atracurium decayed in blood. Kisor et al. use a similar approach to determine the pharmacokinetics of cisatracurium. The major difference in design between the present study and our work with atracurium is that we performed both in vitro and in vivo analyses in the same subjects, whereas Kisor et al. estimated in vitro half-life and in vivo half-lives in different groups of subjects. Results for the two drugs differ markedly, presumably because of differences between drugs rather than differences in study design. Whereas 61% of atracurium's elimination was via organs [11], Kisor et al. report that only 23% of cisatracurium's elimination is via organs. Thus, the original intent of the chemists at Burroughs Wellcome (now merged into Glaxo Wellcome)-to develop a drug depending minimally on the kidney and liver for elimination [12]-has finally succeeded. What do we learn by applying this more complicated model to determine the pharmacokinetics of cisatracurium? First, clearance is identical regardless of the model by which it is determined (and can be estimated by dividing drug dose administered by the area under the plasma concentration versus time curve). However, the fraction of clearance that results from organ-based versus non-organ-based elimination can only be estimated using an appropriate model. Second, the traditional pharmacokinetic model that does not account for elimination of drug from tissue compartments (in this case by Hofmann degradation) underestimates volume of distribution at steady state. Thus, Kisor et al.'s application of our model to cisatracurium should improve accuracy of their estimate of volume of distribution at steady state compared with that obtained from the traditional (and inappropriate) model [13]. However, the approach used by Kisor et al. remains slightly erroneous (as was ours) because of a remaining incorrect assumption that organ-based and non-organ-based elimination occur entirely in parallel. In fact, all drug entering the liver and kidney is subject to elimination by Hofmann degradation (and possibly ester hydrolysis). As a result, the correct model for drugs having both organ and nonorgan elimination pathways must account for both serial and parallel elimination. The complicated approach used by Kisor et al. is necessary in order to estimate the relative contribution of organ and nonorgan pathways to the elimination of cisatracurium. Knowing that most of cisatracurium's elimination results from Hofmann degradation, a chemical process not dependent on the liver or kidney, suggests that, like atracurium, its time course should be altered minimally by organ dysfunction. Clinical studies of cisatracurium in patients with renal failure [5] and end-stage liver disease [14] support this finding. The study by Kisor et al. is another example of how the traditional approach to pharmacokinetic modeling was limited or flawed. Consider one final example. Mivacurium, another muscle relaxant, is cleared from plasma extremely rapidly by plasma cholinesterase. In vitro, its half-life in plasma is 40 s (unpublished data from our laboratory), less than the time it takes blood to circulate through the body. Thus, while blood courses through the arterial and venous circulations, mivacurium's concentration decreases constantly (so that, at steady state, blood sampled from the proximal aorta should differ in concentration from blood sampled from the pedal artery or from that in a peripheral vein). When a drug has been infused to steady state, we typically assume that arterial concentrations throughout the body are identical and that peripheral venous concentrations can be used as surrogates for arterial values, thereby simplifying sampling in pharmacokinetic studies. This assumption must be flawed for mivacurium, for which, at steady state, concentrations must decrease constantly and significantly during the course of each circulation. In turn, clearance (calculated as infusion rate divided by the measured plasma concentration) should vary markedly as a function of sampling site. As the pharmaceutical industry develops other drugs with extremely rapid clearance (so as to permit the rapid onset and offset desired of anesthetic drugs), we will need to rethink traditional pharmacokinetic concepts. Fortunately, pharmacokinetic/pharmacodynamic modeling continues to evolve and thereby aids the clinician in understanding the response to anesthetic drugs." @default.
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• W2077895837 title "(Almost) Everything You Learned About Pharmacokinetics Was (Somewhat) Wrong!" @default.
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