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KEY POINTS
Complex pharmacokinetic and pharmacodynamic variations occur in critically ill patients secondary to underlying illness and acute organ failures as well as the multiple supportive modalities employed.
Failure to appreciate variabilities in pharmacokinetic and pharmacodynamic characteristics may contribute to suboptimal dosing, adverse outcome, increased risk of medication errors and adverse drug reactions.
Altered drug absorption, plasma protein binding, volume of distribution, renal and hepatic clearance, and affinity of binding to target receptors in critically-ill patients can all affect the therapeutic response and clinical outcome.
For medications with monitoring parameters available and a fairly rapid onset of action, careful dose titration based on clinical observation is appropriate; many of the cardiovascular active agents fall into this category.
For medications with slower onset of action and dose-dependent pharmacology, proper loading and maintenance doses should be determined; changes in drug volume of distribution and clearance observed or measured in individual patients should be taken into consideration.
Therapeutic drug monitoring (TDM) is recommended for certain medications, including some antimicrobials, antiepileptics and cardiovascular agents. These tests are widely available with quick turnaround time for the results to assist in dose adjustment.
Different renal replacement regimens may have different impacts on the volume of distribution and clearance of each medication. Dosing need to be tailored to the dialysis modality utilized and delivered. In general, higher doses and more frequent dosing are necessary with continuous renal replacement therapy as compared to intermittent HD.
Other supportive modaltites, such as ECMO and plasmaphoresis, can also affect the pharmacology of some medications.
Polypharmacy is inevitable in critically ill and may contribute to adverse outcome secondary to drug interactions or toxicity; careful monitoring and patient assessment remains the key for optimal therapeutic outcome.
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Medication errors and adverse drug reactions (ADRs) occur more frequently in critically ill patients due to complex polypharmacy, frequent off-label drug use and multiorgan dysfunction. Requests to provide “STAT” doses during emergent situations further complicate this issue. Clinicians require an adequate knowledge of drug pharmacokinetics (PK) and pharmacodynamics (PD) to ensure safe and effective drug use in intensive care units (ICUs).
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PK describes the movement of a drug through the body including the processes of absorption, distribution, metabolism, and elimination. PD describes the physiologic effects once the drug reaches the site of action. Most PK data are derived from healthy volunteers or from stable patients with specific disease states and may not be applicable to critically ill patients. Failure to anticipate significant changes in PK and PD in critical illness may contribute to suboptimal patient management.
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PHARMACOKINETIC CONSIDERATIONS
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Volume of distribution (Vd) and clearance (CL) are the 2 most important PK parameters for appropriate drug dosing. Initial loading dose (LD) is determined by Vd whereas maintenance dosing (MD) is determined by CL. Alterations of Vd and CL can occur during critical illness. These changes may result in an increased pharmacologic ...