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For practical purposes, the results of this study would suggest that remifentanil and alfentanil are essentially equivalent in terms of latency to peak effect that is, both drugs should be regarded as rapid-onset agents. Thus, remifentanil's pharmacokinetic profile, in addition to its T 1/2k e0, contributes to its rapid latency to peak effect. If central compartment concentrations decline rapidly, peak effect-site concentration will be reached quickly, albeit at a lower peak. Drugs that manifest an extremely rapid decline in plasma concentration after termination of drug administration inevitably exhibit a short time to peak effect, because effect-site concentrations are driven by the central compartment concentration gradient. Because T 1/2k e0 is only one of many factors that contribute to drug onset time, the finding is not surprising. The implication of the first simulation may not appear to be consistent with the fact that alfentanil's T 1/2k e0is shorter than remifentanil's. The simulations depicted in Figure 4contrast the short, time-independent context-sensitive half-time of remifentanil with the longer, time-dependent context-sensitive half-time of alfentanil (80% decrement times are also included in Figure 5). Defined as the time required to achieve a 50% decrease in concentration after termination of a continuous infusion targeting a constant concentration, context-sensitive half-times are a method of providing some clinically interpretable meaning to what can be a confusing table of pharmacokinetic parameters. In this case, the "context" is the duration of a continuous infusion. Using concepts developed by Shafer and Varvel, these simulations are an attempt to provide context-sensitive half-times, as proposed by Hughes et al. The context-sensitive half-time simulations based on the NONMEM population parameters are perhaps the most clinically interpretable way of illustrating the pharmacokinetic differences between remifentanil and alfentanil. The optimal k e0is used to calculate the apparent effect-site concentrations and thus identify the "pseudosteady-state" concentration-effect relationship. The algorithm is thus an iterative process in which the hysteresis loops determined by numeric convolution of the measured drug concentrations with a potential k e0are successively "collapsed" until a k e0that results in minimal hysteresis is found. Potential k e0values are sequentially tested until the optimal estimate of k e0is obtained. The optimal k e0value minimizes the area of the hysteresis loop formed by plotting the apparent effect-site concentration versus effect.
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In summary, this k e0-estimating technique performs a numeric convolution of the measured drug concentrations with a candidate k e0value to calculate the apparent effect-site concentrations. The theoretical foundation of this technique is that, in the effect site, there should be no delay or hysteresis between changes in drug concentration and changes in pharmacologic effect. K e0was estimated using a hysteresis loop minimization technique. The aim of this study was to contrast the clinical pharmacology of remifentanil and alfentanil in healthy, adult male volunteers by constructing a detailed pharmacokinetic/pharmacodynamic model for each drug using an open-label, randomized, crossover study design. Preliminary evidence from volunteer and patient studies suggests that remifentanil may constitute the first true ultrashort-acting opioid for use as a supplement to general anesthesia. As an ester, remifentanil is susceptible to hydrolysis by blood and tissue nonspecific esterases, resulting in rapid metabolism to essentially inactive compounds. Although chemically related to the fentanyl family of short-acting 4-anilidopiperidine derivatives commonly used as supplements to general anesthesia, remifentanil is structurally unique among currently available opioids because of its ester linkages. REMIFENTANIL (hydrochloride salt of 3-1-piperidine]propanoic acid, methyl ester), formerly known as GI87084B, is a synthetic opioid that exhibits classic micro-agonist pharmacologic effects.