Principles of pharmacodynamics and their applications in veterinary pharmacology
ABSTRACT Pharmacodynamics (PDs) is the science of drug action on the body or on microorganisms and other parasites within or on the body. It may be studied at many organizational levels – sub-molecular, molecular, cellular, tissue/organ and whole body – using in vivo, ex vivo and in vitro methods and utilizing a wide range of techniques. A few drugs owe their PD properties to some physico-chemical property or action and, in such cases, detailed molecular drug structure plays little or no role in the response elicited. For the great majority of drugs, however, action on the body is crucially dependent on chemical structure, so that a very small change, e.g. substitution of a proton by a methyl group, can markedly alter the potency of the drug, even to the point of loss of activity. In the late 19th century and first half of the 20th century recognition of these facts by Langley, Ehrlich, Dale, Clarke and others provided the foundation for the receptor site hypothesis of drug action. According to these early ideas the drug, in order to elicit its effect, had to first combine with a specific ‘target molecule’ on either the cell surface or an intracellular organelle. It was soon realized that the ‘right’ chemical structure was required for drug–target site interaction (and the subsequent pharmacological response). In addition, from this requirement, for specificity of chemical structure requirement, developed not only the modern science of pharmacology but also that of toxicology. In relation to drug actions on microbes and parasites, for example, the early work of Ehrlich led to the introduction of molecules selectively toxic for them and relatively safe for the animal host.
In the whole animal drugs may act on many target molecules in many tissues. These actions may lead to primary responses which, in turn, may induce secondary responses, that may either enhance or diminish the primary response. Therefore, it is common to investigate drug pharmacodynamics (PDs) in the first instance at molecular, cellular and tissue levels in vitro, so that the primary effects can be better understood without interference from the complexities involved in whole animal studies.
When a drug, hormone or neurotransmitter combines with a target molecule, it is described as a ligand. Ligands are classified into two groups, agonists (which initiate a chain of reactions leading, usually via the release or formation of secondary messengers, to the response) and antagonists (which fail to initiate the transduction pathways but nevertheless compete with agonists for occupancy of receptor sites and thereby inhibit their actions). The parameters which characterize drug receptor interaction are affinity, efficacy, potency and sensitivity, each of which can be elucidated quantitatively for a particular drug acting on a particular receptor in a particular tissue. The most fundamental objective of PDs is to use the derived numerical values for these parameters to classify and sub-classify receptors and to compare and classify drugs on the basis of their affinity, efficacy, potency and sensitivity.
This review introduces and summarizes the principles of PDs and illustrates them with examples drawn from both basic and veterinary pharmacology. Drugs acting on adrenoceptors and cardiovascular, non-steroidal anti-inflammatory and antimicrobial drugs are considered briefly to provide a foundation for subsequent reviews in this issue which deal with pharmacokinetic (PK)–PD modelling and integration of these drug classes. Drug action on receptors has many features in common with enzyme kinetics and gas adsorption onto surfaces, as defined by Michaelis–Menten and Langmuir absorption equations, respectively. These and other derived equations are outlined in this review. There is, however, no single theory which adequately explains all aspects of drug–receptor interaction. The early ‘occupation’ and ‘rate’ theories each explain some, but not all, experimental observations. From these basic theories the operational model and the two-state theory have been developed. For a discussion of more advanced theories see Kenakin (1997).
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- "Pharmacodynamics is the study of the biochemical and physiological effects of drugs on the body as well as the mechanisms of drug action and the relationship between drug concentration and its effect. One particular example may be drug-receptor interactions. Biological rhythms at the cellular and subcellular levels can provoke significant dosing-time differences in the pharmacodynamics of medications that are unrelated to their pharmacokinetics. "
ABSTRACT: For many decades, researchers are aware of the importance of circadian rhythm in physiological/biochemical properties and drug metabolism. Chronopharmacology is the study of how the effects of drugs vary with biological timing and endogenous periodicities. It has been attaching substantial attention in the last years. Chronopharmacodynamics mainly deals with the biochemical and physiological effects of drugs on the body, the mechanisms of drug action, the relationship between drug concentration and effect in relation to circadian clock. In this review, we will focus on mammalian circadian pharmacodynamics and discuss new chronotherapy approaches. Moreover, we will try to highlight the chronopharmacodynamics of cardiovascular drugs, anti-cancer drugs, analgesics and non-steroidal anti-inflammatory drugs (NSAIDs) and give some practical concerns for clinical pharmacists and pharmacy practitioners, concerning this issue.Journal of Pharmacy Practice and Research 10/2012; 1(2):41-7. DOI:10.4103/2279-042X.108369
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- "The ligand receptor binding process is governed by mass action kinetic laws  which determine the rate at which the overall reaction occurs. The reaction equations below describe how this process occurs and how the kinetic laws are applied. "
ABSTRACT: Systems biology has developed considerably in the past decade combining the different disciplines of mathematical modelling, computational simulation and biological experimentation facilitating the quantitative analysis of biological systems. This is often severely hampered by the lack of time-resolved data which ultimately leads to problems in validating any models created. To address the inherent complexity in biological systems, a recent trend in systems biology is exploring multi-scale modelling and simulation methodologies. We consider the Bile Acid and Xenobiotic System (BAXS) as a typical example of a multi-scale system. In the absence of dynamic data from biological experimentation the models we have developed are based on artificial data which enables us to explore multi-scale modelling and validation techniques and the integration of individual models. The outcome of this study will direct further research into multi-scale modelling methodology and ultimately will produce a novel framework for validation in the absence of dynamic data.
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- "For further discussion and a glossary of terms used in pharmacodynamics see Neubig et al. (2003) and Lees et al. (2004a). "
ABSTRACT: In veterinary drug development procedures, pharmacokinetic (PK) and pharmacodynamic (PD) data have generally been established in separate, parallel studies to assist in the design of dosage schedules for subsequent evaluation in clinical trials. This review introduces the concept of PK/PD modelling, an approach in which PK and PD data are generated in the same study, and used to derive numerical values for PD parameters based on drug plasma concentrations. The PD parameters define the efficacy, potency and slope (sensitivity) of the concentration-effect relationship. It is proposed that the parameters derived from PK/PD modelling may be used as an alternative and preferred approach to dose titration studies for selecting rational dosage regimens (both dose and dosing interval) for further evaluation in clinical trials. In PK/PD modelling, the explicative variable for effect is the plasma concentration profile. The PK/PD approach provides several advantages over dose-titration studies, including determination of a projected dosage regimen by investigation of a single dose, in contrast to dose-ranging studies which by definition require testing of multiple dosage. Implementation of PK/PD modelling in the veterinary drug development process is currently constrained by the limited number of veterinary studies performed to date, and the consequently limited understanding of PK/PD concepts and their absence from regulatory authority guidelines. Nevertheless, PK/PD modelling has major potential for rational dosage regimen determination, as it considers and quantifies the two main sources of interspecies variability (PK and PD). It is therefore applicable to interspecies extrapolation and to multiple species drug development. As well as the currently limited appreciation of PK/PD principles in the veterinary scientific community, a further constraint in implementing PK/PD modelling is the need to validate PK/PD approaches and thereby gain confidence in its value by pharmaceutical companies and regulatory authorities.Journal of Veterinary Pharmacology and Therapeutics 01/2005; 27(6):467-77. DOI:10.1111/j.1365-2885.2004.00613.x · 1.19 Impact Factor