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Pharmacokinetic-Pharmacodynamic Correlations of Anesthetic Agents
Published in Hartmut Derendorf, Günther Hochhaus, Handbook of Pharmacokinetic/Pharmacodynamic Correlation, 2019
Virginia D. Schmith, Keith T. Muir
Levy developed the first PK/PD model describing the offset of drug effects and applied the model to data collected after administration of the depolarizing NMB agent, succinylcholine. Spontaneous recovery (in the 10 to 90% block range) from succinylcholine-induced neuromuscular block was described by a linear model in which the slope was related to the pharmacokinetics and to the steepness of the dose-response curve.1 This was the first report to provide support for the theory that the kinetics of pharmacologic effects can be adequately described by appropriate mathematical expressions. The linear model described has since been applied to other NMB agents such as doxacurium, a nondepolarizing NMB agent.4 Neuromuscular block data collected in patients receiving doxacurium during phase II/III clinical trials were described using this linear model. The slope was shallower in elderly patients and in obese patients than in young nonobese patients; in addition, the slope was steeper in patients receiving N2O/O2/opioid anesthesia than in patients receiving N2O/O2/inhalational anesthesia. Thus, the use of Levy’s model allowed for the detection of special patient populations that may require dose adjustments.4 Levy’s model has also been expanded and used to determine the half-life of atracurium, a nondepolarizing NMB agent, from neuromuscular block data alone.5
Effect of cardiopulmonary bypass on cytochrome P450 enzyme activity: implications for pharmacotherapy
Published in Drug Metabolism Reviews, 2018
Santosh Kumar Sreevatsav Adiraju, Kiran Shekar, John F. Fraser, Maree T. Smith, Sussan Ghassabian
On the other hand, drugs that are not metabolized by liver are affected to a smaller extent compared with the previous group. Vancomycin, rocuronium, doxacurium, and alcuronium are drugs with low plasma protein binding (30–70% to albumin) and that are eliminated from the body unchanged in the urine (vancomycin (Zhao et al. 2014), teicoplanin (Roberts et al. 2014), daptomycin (Dvorchik et al. 2003)) or urine and bile (alcuronium (Miller et al. 1997), rocuronium (Khuenl-Brady and Sparr 1996), doxacurium (Cook et al. 1991; Asokumar et al. 1998)). A 20% increase in vancomycin CL with no change in t½β (Ortega et al. 2003) was underpinned by a 30% decrease in vancomycin renal CL during CPB which returned to the pre-CPB levels after CPB termination (Klamerus et al. 1988). Similarly, a 38% decrease in doxacurium t½β1/2 in hypothermic compared with normothermic CPB has been reported (Asokumar et al. 1998). The impact of CPB on the renal CL of drugs can be explained by two opposing factors: reduced kidney perfusion and reduced plasma protein binding. Teicoplanin and daptomycin are eliminated by the kidney (Dvorchik et al. 2003; Roberts et al. 2014), but have high plasma protein binding (Lee et al. 1991; Yano et al. 2007; Beer et al. 2009) with both factors potentially affected by initiation of CPB therapy. Altered plasma protein binding of important drugs is thought to be underpinned by changes in acid-base balance during CPB (Gedney and Ghosh 1995). Tranexamic acid is a drug with only 3% plasma protein binding and small metabolism (McCormack 2012) and its PK was not affected during cardiac surgery using CPB (Table 1).