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).
- SourceAvailable from: physoc.orgThe Journal of Physiology 06/1906; 34(3):163-206. · 4.38 Impact Factor
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ABSTRACT: Beta-adrenoceptors are important regulators of cardiac function and their characteristics are known to change in human and canine diseased myocardium. This study aimed to determine the density and subtypes of beta-adrenoceptors in the normal and failing equine ventricular myocardium. Membrane preparations of the left papillary muscles were incubated with increasing concentrations of the nonselective beta-adrenoceptor antagonist [3H]-CGP12177. Saturable and reversible binding of [3H]-CGP12177 to myocardial membranes was demonstrated with Kd values (+/- s.d.) of 0.49 +/- 0.40 and 0.43 +/- 0.22 nmol/l and Bmax values of 93.4 +/- 20.5 and 110.0 +/- 21.2 and fmol/mg protein for normal (n = 19) and heart failure (n = 10) tissues, respectively. Heart failure had no significant effect on the density of ventricular beta-adrenoceptors. The cardiac beta-adrenoceptors were further characterised by studying displacement of [3H]-CGP12177 (0.6 nmol/l) with the beta1-selective antagonists CGP20712A and the beta2-selective antagonist ICI118.551. In normal ventricular muscle, CGP20712A was 26 times more potent than ICI118.551 (Ki values 30.4 +/- 24.8 and 814.1 +/- 485.2 nmol/l, respectively). In heart failure cases, CGP 20712A curves were monophasic with a Ki value of 45.6 +/- 39.7 nmol/l. ICI 118.551 curves were biphasic in 5 horses where 11-31% of the cardiac beta-adrenoceptors had a high affinity for ICI 118.551. These data suggest that the normal equine ventricular myocardium possesses predominately beta1-adrenoceptors, with no evidence for co-existence of a significant population of beta2-adrenoceptors. The density of beta-adrenoceptors did not appear to change in heart failure, but the appearance of receptors with a high affinity for ICI118.551 may suggest that, in some cases, heart failure increases the expression of beta2-adrenoceptors in equine ventricular myocardium. This study provides an insight into the role of the adrenergic system in heart disease in the horse. Further studies in this area are warranted.Equine Veterinary Journal 08/2002; 34(4):411-6. · 2.29 Impact Factor
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ABSTRACT: 5-hydroxytryptamine (5-HT) is a potent vasoconstrictor of equine digital arteries and veins which may play a role in the ischaemic disease, laminitis. The present investigation compared the properties of 5-HT1B/1D receptors in arteries with those in veins using isolated rings of equine digital blood vessels. The 5-HT1B/1D receptor-selective agonists, anpirtoline and sumatriptan were 17.9 and 10 times more potent and produced 4.1 and 5.6 times greater maximum contractions, respectively, in veins when compared to arteries. Other agonists tested were of equal potency and produced the same maximum responses in veins and arteries. Propranolol competitively inhibited 5-HT1B/1D receptor mediated responses in arteries, with a pKB of 6.7, but had no significant effects on responses in veins at 1 μM. Metergoline competitively inhibited 5-HT1B/1D receptor mediated responses in veins, with a pKB of 8.1, but had no significant effect in arteries at 0.1 μM. These data suggest that 5-HT1B/1D receptors mediating vasoconstriction in equine digital arteries are pharmacologically different to those found in digital veins.European Journal of Pharmacology 09/1998; · 2.59 Impact Factor