Chapter 103

• Critical care therapeutics should be individualized to maximize therapeutic effect while minimizing the potential for adverse drug reactions.
• The appropriate loading dose is determined primarily by the volume of distribution of the drug in the patient.
• The maintenance dose is proportional to the clearance and the desired steady-state plasma concentration.
• Elimination half-life is inversely proportional to clearance and directly proportional to volume of distribution.
• Steady-state conditions are obtained after the passage of three to five half-lives.
• Prospective consideration of possible drug-patient, drug-disease, and drug-drug interactions minimizes the potential for undertreatment or adverse drug reactions.
• Therapeutic drug monitoring may follow purely pharmacodynamic parameters or additionally use plasma levels to calculate pharmacokinetic parameters.
• Systemwide changes in management of critically ill patients, including physician order entry systems and dedicated intensivists and pharmacists, can potentially decrease the incidence of adverse drug reactions.

Individualization of critical care therapeutics through the application of pharmacologic principles is intended to reconcile important features of ICU management including polypharmacy, altered drug disposition, and cost considerations, in the design of a rational drug regimen. Critically ill patients routinely receive multiple medications, and the potential for adverse drug reactions (ADRs), particularly drug-drug interactions, increases in proportion to the number of agents received. Furthermore, physiologic changes resulting from critical illness may alter several aspects of drug disposition in a manner that is often difficult to predict based on available information. Finally, rational critical care therapeutics is a major component of providing cost-effective critical care, because of the substantial fraction of the average hospital pharmacy budget consumed by critical care therapeutic agents.

Individualization of pharmacotherapy attempts to avoid ADRs caused by drug overdosage or undertreatment, including ADRs caused by drug-disease, drug-drug, and drug-patient interactions. Correct drug dosing is frequently complicated in critical illness by alterations in bioavailability, volume of distribution, and elimination.1 Errors in choosing a therapeutic regimen are frequently poorly tolerated by these patients; rapid efficacy may be necessary for survival, but physiologic reserve may also be inadequate to withstand the effects of drug intoxication. Concentrating efforts on optimal dosing of drugs that have a low therapeutic index (low ratio of toxic to therapeutic plasma level) is therefore particularly important. Consideration of pharmacokinetic (PK) and pharmacodynamic (PD) principles, and their application to design an approximate patient model for individualized therapeutics, should precede addition of any new drug to an ICU patient's regimen. Furthermore, the dynamic physiology of these patients mandates frequent reassessment of the accuracy of this model, updating drug regimens as required. Therapeutic drug monitoring is used to titrate therapy with drugs that have both a low therapeutic index and readily measurable plasma concentrations that are proportional to drug effects (therapeutic and toxic). Finally, any change in the status of an ICU patient must be considered to be potentially the result of an adverse drug reaction, especially in the absence of a clear-cut ...

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