Pharmacokinetic Principles
In general medicine, we give a drug to a patient at a recommended dose and anticipate a therapeutic response. Most Phase 3 clinical trials produce data that tell us what a ballpark dose should be for an average patient to achieve a usual effect, and if we
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Pharmacokinetic Principles David Brown and Mark Tomlin
Introduction In general medicine, we give a drug to a patient at a recommended dose and anticipate a therapeutic response. Most Phase 3 clinical trials produce data that tell us what a ballpark dose should be for an average patient to achieve a usual effect, and if we are lucky, what to expect in terms of side effects at usual doses or if doses are exceeded. We are sometimes surprised when the usual dose either fails to elicit any kind of response or produces side effects that, according to our evidence, should be observed only at much higher doses. Most drug effects are achieved by the interaction of a drug with receptors on the target organ. The intensity and duration of that effect are usually determined by the number of drug molecules present, their receptor site binding affinity, and their residence time at the receptor site(s). This pharmacodynamic aspect of drug therapy is discussed in detail in Chapter 1. After administration, by whatever route, the drug concentration at the target site is governed by the often tortuous route its takes to get there. Like any journey, it can be planned in terms of route directions, load, and time, and calculations can be used to show what load can be delivered at a particular speed over what terrain, and what hazards must be overcome to reach the destination successfully. This road map is the essence of pharmacokinetics – the study of time-dependent drug movement into, around and out of the body.
In a healthy population, there is a natural v ariation in the pharmacokinetic processes of absorption, distribution, metabolism, and excretion; that is why, average doses will produce average responses, and for many drugs with wide safety margins, this is sufficient. However, some drugs do not have wide safety margins and knowledge of clinical pharmacokinetics in the individual is vital to ensure that therapy with these drugs is effective and as safe as possible. It is also important to recognize that organ disease, particularly that of the liver and kidney, can affect pharmacokinetics profoundly and patients with such comorbidities should be monitored appropriately. Nowhere is this more important than in critical care where patient status may change rapidly with time, requiring a thorough knowledge of pharmacokinetics. To use the above analogy, the road map may be poorly defined, particularly for new drugs, and subject to frequent and sometimes misleading updates along the way. The following sections summarize the important aspects of pharmacokinetic first principles under the traditional headings of drug absorption, distribution, metabolism, and excretion. With their training in drug structure and action and knowledge of available formulations, pharmacists are in an excellent position to work with anesthetists in this area. As you will see, number crunching to arrive at a suitable solution to individualizing drug therapy is not always a prerequisite, but common sense and the ability to imagine what is happening to the drug
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