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W, Zuppa AF, Feudtner C Epidemiology of polypharmacy and potential drug-drug interactions among pediatric patients in ICUs of U.S Children’s hospitals Pediatr Crit Care Med 2016;17(5):e218-e228 e5 Abstract: In the pharmacologic treatment of critically ill children, clinicians must understand that the basics of drug disposition are governed by pharmacokinetics and pharmacodynamics, which include the processes of absorption, distribution, metabolism, and elimination These processes influence the clinical pharmacokinetic parameters of drugs, such as clearance, volume of distribution, half-life, and bioavailability—which, in turn, influence the choice of drug, dose, route, and dosing interval Choosing a safe and efficacious dosing strategy in critically ill children entails recognizing and applying these developmental and diseasedependent changes to therapeutic decision-making Key words: pharmacokinetics, pharmacodynamics, ontogeny, absorption, distribution, metabolism, elimination 123 Molecular Mechanisms of Drug Actions KEVIN WATT Optimizing drug response is a challenging task that clinicians confront on a daily basis This is particularly true for those caring for critically ill patients, in whom many factors influencing drug response are being more commonly recognized These include reduced absorption, variable drug distribution, decreased metabolism and elimination, as well as alterations in drug receptors, signaling mechanisms, and effectors.1–3 Advances in molecular pharmacology have shed more light on the processes that transduce extracellular signals into intracellular messages that control cell function This has led to the elucidation of multiple points at which modulation of signal transduction, by either pharmacologic agents or diseases, can occur Also, there has been an ongoing recognition of the role of inheritance in the individual variation of drug response with the identification of polymorphisms in genes encoding drug-metabolizing enzymes, drug targets (e.g., receptors, enzymes), and proteins involved in signal transduction.4–6 This chapter provides an overview of how drugs work at the molecular level and how this complex system is influenced by genetic factors, developmental changes, disease processes, and the environment (Fig 123.1) Ultimately, the objective is to help pediatric intensive care providers better tailor the pharmacotherapy that they use—to choose the right drug, or combination of drugs, for the right patient to achieve maximal efficacy with the least toxicity This chapter does not address signaling pathways involved in diseases per se 1446 • • • Receptors play a central role in determining the nature of the pharmacologic effects produced by a drug Most drugs and endogenous compounds (e.g., hormones, neurotransmitters) exert their action by binding to a receptor or by modulating an ion channel G proteins are a superfamily of proteins that allow transduction between an activated receptor (by an agonist) and different intracellular effectors, such as enzymes or ion channels, relaying signals from more than 1000 receptors G protein–coupled receptors are complex signaling machines that participate in most physiologic and pathophysiologic processes and represent the target, directly or indirectly, of approximately 40% of all current therapeutic agents • • • • PEARLS Continued exposure of a receptor to an agonist often results in progressive loss of receptor responsiveness, with a diminished receptor-mediated response over time This is called desensitization Two main superfamilies of membrane transporters provide the active transport of drugs to their target receptors in specific organs and tissues: the adenosine triphosphate–binding cassette superfamily and the solute carrier family Calcium is critically important as a regulator of cell function It exerts its control on cellular function through its ability to regulate the activity of many different proteins, such as channels, transporters, and transcription factors An individual’s genetic makeup can modify the efficacy of drug treatment and the risk of adverse reactions Targets for Drug Action The initial step in the cascade of biochemical events resulting in drug action mostly consists in the binding of drugs to specific cellular targets These can be broadly divided into four categories: (1) receptors, (2) ion channels, (3) enzymes, and (4) carrier proteins (Fig 123.2) The majority of important drugs act on one of these types of proteins Table 123.1 shows the targets of some pharmacologic agents commonly used in the pediatric intensive care unit (ICU) Receptors Receptors are the most frequent drug target They can be defined as the sensing elements in the system of chemical communication that coordinate the function of all of the different cells in the body, the chemical messengers being the various hormones, neurotransmitters, other mediators, or drugs Clark’s theory of receptor occupancy posits that the drug effect is directly proportional to the number of occupied receptors.7 While not always true, this concept is useful in illustrating the concepts of selectivity, affinity, and efficacy (Fig 123.3A) Selectivity refers to the preference of a drug for one receptor over another (Fig 123.3B) A perfect drug binds only to its target receptor In reality, drugs also bind to other receptors and can result in off-target “side” effects Even drugs with very high selectivity can result in off-target effects if they ... enzymes), and proteins involved in signal transduction.4–6 This chapter provides an overview of how drugs work at the molecular level and how this complex system is influenced by genetic factors,... processes that transduce extracellular signals into intracellular messages that control cell function This has led to the elucidation of multiple points at which modulation of signal transduction, by... KEVIN WATT Optimizing drug response is a challenging task that clinicians confront on a daily basis This is particularly true for those caring for critically ill patients, in whom many factors influencing