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From protein binding alterations to frequent drug–drug interactions, from hypermetabolic states to anuria, there exists a multitude of reasons that the therapeutic interventions of choice must be individualized in a critically ill patient. The principles of clinical pharmacology provide the basis of optimizing a safe and effective drug regimen. The four major subdivisions of pharmacology include pharmacokinetics, pharmacodynamics, pharmacotherapeutics, and toxicology. Simply stated, pharmacokinetics and pharmacodynamics focus on what the body does to the drug and what the drug does to the body, respectively. The following pharmacokinetic and pharmacodynamics factors must be taken into consideration to optimize effectiveness and to minimize toxicity.