Foundations in Pharmacokinetics

Foundations in Pharmacokinetics Adam M. Persky, PhD All Rights Reserved, Copyright 2015 © Adam M. Persky 1 About This Book This book was written to acclimatize the pharmacy student or other healthcare student or professional to the discipline of pharmacokinetics. Typically, the pharmacokinetics curriculum in most schools of pharmacy is less well “appreciated” by students compared to other classes. This “lack of appreciation” or disinterest is likely attributable, in part, to the mathematical nature of the subject. Another contributing factor may be the fact that memorization-based learning strategies do not fare well in pharmacokinetics. As in many other disciplines, memorization of some basic principles is necessary; however, the ability to appropriately apply these basics under a variety of contexts is paramount to success. Thus, application of critical thinking and reasoning skills is the best method to learn pharmacokinetics. The goal of this book is to assist the reader in developing an appropriate level of comfort with relevant mathematical formulae and techniques in order to provide a foundation for progression to more advanced therapeutic concepts. How to learn pharmacokinetics using this book A complete mastery of the field of pharmacokinetics cannot be accom- plished in one semester, one year, or even one lifetime. This book is intended to supplement the concepts discussed in the classroom by both providing an overview of the essential ideas and offering general guidance for dealing with clinical situations you may encounter. Simply reading about pharmacokinetics will not be sufficient to develop an understanding of the topic. This book is only one component of your pharmacokinetics education. You must spend time thinking about concepts discussed in the classroom and in this book. Ask questions of yourself, your classmates, and your instructors. Identify areas in which you have difficulty, and ask questions (preferably before exams). Merely talking about pharmacokinetics is beneficial, thus you may also benefit from forming discussion groups. Since not all students learn effectively by the In the margin same mechanisms, one aim of this book is to approach problems from a are important variety of angles, and to accommodate different types of learning styles. highlights! Each chapter includes learning outcomes, highlights of important concepts in the margins, and a summary of new equations, symbols and skills obtained. Special thanks to Gary M. Pollack, PhD, Jeannie Padowski, PhD, and Kerri A. McEnroe for help in putting this book together and all editorial comments. Special thanks for all the student-pharmacists who offered input on making the book better. Finally, a special thanks to Gunther Hochhaus, PhD for daring me to write a book. 2 The SQ4R Method of Reading The SQ4R method of reading is based on some well-established principles of learning from cognitive psychology. Numerous studies indicate using the SQ4R method can make a significant difference in the amount of information recalled at a later time point (like examinations). SQ4R leads to a more active learning environment and deeper processing of information. Most students use a rather passive learning strategy. Pas- sively reading your notes may lead to the 'labor in vain' effect, where you work very hard, but remember very little. SURVEY Take a look at the material: skim the chapter headings and the boldface words, and read the learning objectives. Studies show that subjects who read a summary recalled the material better, particularly when they read the summary first. This is why this book starts with a chapter “In Brief”. QUESTIONS Make up questions about the things you found in the preview and from the learning objectives. Often you can just transform a section heading into a question. For example, the section heading might be Zero-order vs. First-order kinetics, and you could then develop a question that states “What is the difference between zero-order and first-order kinetics?” This simple technique could double the amount you can remember. READ As you read, try to answer the questions you developed. Make notes as you read. Understand the vocabulary. It is extremely important that any notes you make are in your own words and not merely duplicating the exact wording used in the text. RECITE Say the material over to yourself; put it into your own words. Answer the questions you developed. One form of recitation is to try to write your own study guide - write out the ideas in your own words, using your own organization. Another form is to try to explain the ideas to somebody else; imagine explaining perceptual maps to your mother. Or perhaps you can invent mnemonics to help remember terms. If you can’t recall enough, reread sections you had trouble remembering. 3 WRITE (or RECALL) Write down summaries in your own words. Recall information as much as possible as if you are taking a quiz or assessment. Practice recall, practice problem solving, then practice some more. Practicing recall can be more effective than simply re-reading the material. REVIEW Try to recall the material and test yourself. Study partners can help here. Making up a quiz for yourself as part of recitation and then taking it as review is a good way to study. You should review several times during your studying so you know what to concentrate on. Again, try answering the questions you made up. 4 Table of Contents About This Book .................................................................................... 2 The SQ4R Method of Reading .............................................................. 3 Table of Contents .................................................................................. 5 1) Introduction .................................................................................... 6 2) Pharmacokinetic Tools ................................................................. 11 3) Distribution Phenomenon ............................................................. 25 4) Clearance Concepts .................................................................... 36 5) Intravenous Bolus ........................................................................ 47 6) Extravascular Administration ........................................................ 57 7) Intravenous Infusion ..................................................................... 80 8) Multiple Dosing ............................................................................ 95 9) Hepatic Clearance ..................................................................... 127 10) Metabolite Kinetics ................................................................. 149 11) Renal Clearance ..................................................................... 154 12) Multi-Compartment Models .................................................... 176 13) Nonlinear Pharmacokinetics ................................................... 194 14) Pharmacodynamic Basics ...................................................... 214 Appendix A: Math Basics .................................................................. 237 Appendix B: Common Pharmacokinetic Terms and Their Units........ 245 Appendix C: Useful Equations .......................................................... 246 Appendix D: Method of Residuals ..................................................... 248 Index ................................................................................................. 252 5 1) Introduction Goal To develop a definition of the term “pharmacokinetics” and to understand how this field of study impacts the health care system, including the pharmaceutical industry, pharmacists, patients, and researchers. Objectives By the end of this chapter, you should be able to: Describe the differences between pharmacokinetics, biopharmaceu- tics and pharmacodynamics Describe the role of pharmacokinetics in the treatment of patients and in the pharmaceutical industry Explain the implications of therapeutic drug monitoring and discuss the role pharmacokinetics plays in this process In Brief This chapter defines pharmacokinetics (i.e., what the body does to the drug) and pharmacodynamics (i.e., what the drug does to the body). It discusses the importance of pharmacokinetics and dynamics for patient care and describes therapeutic drug monitoring – the monitoring of medications typically with low therapeutic indexes (the ratio between the tox- ic and therapeutic effects). For patient care, pharmacokinetics can help facilitate decisions for dose amount and frequency or the impact of drug interactions. Within the pharmaceutical industry, pharmacokinetics helps determine the appropriate dose and adds to labeling information. In the hospital setting, we have direct and measurable information to inform our pharmacokinetic analysis (e.g., serum creatinine, blood concentra- tions of drug, pharmacodynamic effects like INR). In the community setting, we often do not have these direct and measurable information, but we have context clues. Understanding the patient (e.g., elderly, obese, pregnant) and their medications (e.g., which are renal cleared) are important in counseling and medication selection. Introduction Pharmacokinetics: I nput Pharmacokinetics (PK) is the study of how a drug behaves in the body. T ransfer In other words, pharmacokinetics is the study of “what the body does to E limination a drug.” Most textbooks use the acronym ADME to refer to four pro- What the body does to cesses relevant to pharmacokinetics,

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