Academic literature on the topic 'Pharmacokinetics. Pharmacology. Models, statistical'

Differences in pharmacokinetics and pharmacodynamics are important in small children. This chapter provides an overview of essential pharmacokinetic parameters and developmental aspects. Intravenous anaesthetic agents, including total intravenous anaesthesia models, are described. An overview of commonly used inhalational anaesthetic agents, sedatives, and neuromuscular blockers is given. The analgesic sections describe opioids, simple analgesics, and local anaesthetic agents. Paediatric indications, common side effects, and dosing are included for each agent. A fundamental understanding of developmental differences is key to the safe and effective use of anaesthetic drugs in children.

Pharmacology, the study of agents and their actions, can be divided into two branches. Pharmacodynamics is concerned with the effects of a drug on the body and, therefore, encompasses dose–response relationships as well as the molecular mechanisms of drug activity. Pharmacokinetics, on the other hand, is concerned with the effect of the body on the drug. Drug metabolism, transport, absorption, and elimination are components of pharmacokinetic analysis. Physiology influences the distribution of drugs within the body; overall distribution depends on rates of drug uptake, rates of distribution between tissue compartments, and rates of drug elimination or biotransformation. Each of these phenomena potentially involves aspects of drug diffusion, permeation through membranes, and fluid movement that were introduced in the previous sections. The goal of pharmacokinetics is synthesis of these isolated basic mechanisms into a functional unit; this goal is most often achieved by development of a mathematical model that incorporates descriptions of the uptake, distribution, and elimination of a drug in humans or animals. This model can then be used to predict the outcome of different dosage regimens on the time course of drug concentrations in tissues. The development of a complete pharmacokinetic model for any given drug is a substantial undertaking, since the fate of any compound introduced into a whole organism is influenced by a variety of factors, and is usually complicated—in ways that are difficult to predict—by the presence of disease. In this section, pharamacokinetics will be introduced by first considering the simplest situation: an agent is introduced into a single body compartment from which it is also eliminated. While quite sophisticated compartmental models can be developed from this basic construct, it is frequently difficult to relate model parameters (such as the volume of specific compartments or the rate of transfer between compartments) to physiological or anatomical parameters. To avoid this difficulty, physiological pharmacokinetic models are frequently employed; in these models, the kinetics of drug uptake, distribution, and elimination from local tissue sites are predicted by constructing anatomically and biochemically accurate models of the tissue environment.

This chapter outlines an introduction to the neuromuscular junction. It covers anatomy and physiology (including presynaptic physiology and pharmacology, postsynaptic physiology and pharmacology, and margin of safety of neurotransmission), paralytics, reversal agents, the mechanisms of action of muscle relaxants (and their structure-activity relationship, intrinsic activity at the neuromuscular junction, effects on acetylcholine receptors of the CNS/ANS, the carotid body, bronchial smooth muscle, and histamine release and anaphylaxis by relaxants), and the acetylcholinesterase enzyme. The chapter furthermore discusses pre-clinical pharmacology and pharmacological variables of neuromuscular block, pharmacokinetics (models and parameters, factors influencing pharmacokinetics of relaxants, and their elimination and metabolism), clinical pharmacology of succinylcholine and nondepolarizing neuromuscular blocking drugs, factors confounding the clinical pharmacology of relaxants, reversal agents (including the cholinesterase inhibitors Neostigmine and Pyridostigmine) as well as the selective relaxant binding agent sugammadex), and special considerations in neuroanaesthesia and neurocritical care.

Pharmacology is defined as the study of the effects of drugs on the function of a living organism. It is an inte­grative discipline that tackles drug/ compound behaviours in varied physiological systems and links these to cellular and molecular mechanisms of action. As a scientific endeavour, pharmacology evolved from the early identification of therapeutic properties of nat­ural compounds, with herbal medicines and relatively complex pharmacopoeias widely used in early cultures. Despite this, lack of understanding of the physio­logical, pathological, and chemical processes governing the human body prevented the early establishment of pharmacology as a scientific discipline. Since then, pharmacology has progressed to be considered a fully developed integrative science that employs techniques and theories from various disciplines, such as chemistry, biochemistry, genomics, medicinal chemistry, physi­ology, and cellular and molecular biology. Collectively, these are applied to study disease causality and the rele­vant mechanistic action of compounds, to establish new treatments. In the last 100 years, the importance of clinical pharmacology has increased in line with the scientific and technological advances in biomedical research. Benefits gained from molecular and cellular approaches have enabled a more comprehensive analysis of drugs and their actions in functional context. Now, clinical pharmacology and therapeutics encompass the dis­covery, development, regulation, and application of drugs in a process that integrates scientific research with clinical practice to better treat illness and preserve health. Within this textbook the principles of pharmacology are discussed by therapeutic area so that the reader can link disease pathophysiology, drug mechanism, and modern prescribing behaviours for conditions commonly seen in clinical practice. There are, however, fundamental concepts that are universal in understanding the interaction between drugs and their ‘targets’, including receptor pharmacology, genomic pharmacology, and pharmacokinetics. The pharmacological receptor models preceded by many years the knowledge of the receptor as an entity. It was not until the last 150 years that a series of contributions from many notable biologists and chemists established the principles that founded modern day pharmacology. They produced a significant paradigm shift in therapeutics, where empirical descriptors of the activities observed (heating, cooling, moistening, emetic, etc.) were replaced by the concept of a ‘target’. After more than a century, the basic receptor concept is still the foundation of biomed­ical research and drug discovery.