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INTRODUCTION

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Clinical pharmacokinetics is the discipline that applies pharmacokinetic concepts and principles in humans in order to design individualized dosage regimens that optimize the therapeutic response of a medication while minimizing the chance of an adverse drug reaction. Pharmacokinetics is the study of the absorption, distribution, metabolism, and excretion of drugs.1 When drugs are given extravascularly (eg, orally, intramuscularly, applied to the skin via a transdermal patch, etc), absorption must take place for the drug molecules to reach the systemic circulation. In order to be absorbed, the drug molecules must pass through several physiological barriers before reaching the vascular system. For example, when a medication is given orally, the drug dosage form must release drug molecules via dissolution, and the molecules must pass through the various layers of the gastrointestinal (GI) tract where they enter capillaries. Distribution occurs when drug molecules that have entered the vascular system pass from the bloodstream into various tissues and organs such as the muscle or heart. Metabolism is the chemical conversion of the drug molecule, usually by an enzymatically mediated reaction, into another chemical entity referred to as a metabolite. The metabolite may have the same, or different, pharmacological effect as the parent drug, or even cause toxic side effects. Excretion is the irreversible removal of drug from the body and commonly occurs via the kidney or biliary tract.

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Pharmacodynamics is the relationship between drug concentration and pharmacological response. It is extremely important for clinicians to realize that the change in drug effect is usually not proportional to the change in drug dose or concentration (Figure 1-1). For example, when a drug dose or concentration is increased from a baseline value, the increase in pharmacological effect is greater when the initial dose or concentration is low compared to the change in drug effect observed when the initial dose or concentration is high. Thus, the increase in pharmacological effect that one observes in a patient as the dose is incremented is subject to the law of diminishing returns and will eventually reach a maximum. The reason that most drugs follow this pattern is because their pharmacological effect is produced by forming a complex with a drug receptor. Once the drug-receptor complex is formed, the pharmacological effect is expressed. Often, toxic side effects of drugs follow the same type of dose- or concentration-response relationship, albeit shifted to the right on the dose or concentration axis. In clinical situations, patients may need to tolerate some drug side effects in order to obtain the maximal pharmacological effect of the agent.

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FIGURE 1-1

The relationship between drug concentration and response is usually a hyperbolic function: Effect = (Emax • C)/(EC50 + C), where Emax is the maximum effect and EC50 is the drug concentration where the drug effect equals Emax/2. After a dosage change is made and drug concentrations increase, the drug effect does ...

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