Pharmacodynamics

Pharmacodynamics starts where pharmacokinetics left off - it assumes that the drug has managed to reach its target, and looks at the principles that govern the interaction between the two. 

Almost all drugs will trigger their effects by binding to a receptor. In physiology, the term receptor is limited to the sites of action of hormones, neurotransmitters or cytokines. While many drugs do indeed bind to such receptors, in pharmacology the term is used in a more inclusive sense and is applied to other targets such as enzymes and cytoskeletal proteins as well. 

Drug receptors are mostly proteins. Most of these fall into 

Drug target sites that are not proteins include  

However, again, most drugs act directly on receptors that are proteins, and for the rest of this chapter we will deal with this major case only. 

Pharmacodynamics is the study to determine dose-response effects. We 

The response may be local or via a signal transduction process. The rate for the forward reaction of drug binding to receptor is proportional to the concentrations of both the drug and target. Conversely, the rate for the reverse reaction, i.e. dissociation of the drug-receptor complex, is proportional to concentration of the drug-receptor complex. At equilibrium, both forward and reverse reactions are equal. Mathematically we have  

When half the receptors are bound, we have [R] = [D R]. Substituting into Equation (2), Kd is equal to [D]. This means that Kd is the concentration of the drug that, at equilibrium, will bind to half the number of receptors. 

If we consider all the available receptors as 100% and [D R] are the occupied receptors with drug at the binding sites, then [R], which is the percentage of free, unoccupied receptors, can be substituted with 100 -[D R], Equation (2) can be re-written as  

Potency This is the dose required to generate an effect. A potent drug elicits an effect at a low dose. 

Pharmacodynamics relates to drugs binding to receptors and their effects, ironist A drug is called an agonist when binding to the receptor results in a response. 

Antagonist A drug is called an antt onist when binding to the receptor is not associated with a response. The drug has an effect only by preventing an agonist from binding to the receptor. 

Affinity ability of drug to bind to receptor, shown by the proximity of the curve to the y axis (if the curves are parallel) the nearer the y axis, the greater the affinity 

Efficacy a measure of how well a drug produces a response (effectiveness), shown by the maximal height reached by the curve 

More definitions. Pharmacodynamics is the term given to the properties of drug action on the body. The answer is (H). 

Pharmacokinetics is the general term that describes all of the body s actions on the drug. The answer is (I). 

The amount of active drug is reduced by excretion and metabolism, processes that are included in the term elimination. The answer is (B). 

First-pass effect is the term given to elimination of a drug before it enters the systemic circulation, ie, on its first pass through the liver. The answer is (D). 

The excretion of most drugs is determined by first-order kinetics. However, ethanol—and, in higher doses, aspirin and phenytoin— follow zero-order kinetics, ie, their elimination rates are constant regardless of blood concentration. The answer is (L). 

See Controlled release technology Drug delivery systems. 

Pharmacodynamics is the study of dmg action primarily in terms of dmg stmcture, site of action, and the biochemical and physiological consequences of the dmg action. The availabiUty of a dmg at its site of action is deterrnined by several processes (Fig. 1), including absorption, metaboHsm, distribution, and excretion. These processes constitute the pharmacokinetic aspects of dmg action. The onset, intensity, and duration of dmg action are deterrnined by these factors as well as by the avadabihty of the dmg at its receptor site(s) and the events initiated by receptor activation (see Drug delivery). 

For a large number of dmgs, including neurotransmitters, peptide and protein hormones (qv), and thein analogues and antagonists, the ceU membrane is the principal locus of action. Concepts of ceU membrane stmcture are derived from the original Davson-DanieUi Hpid bilayer hypothesis. 

The Federal Food, Dmg and Cosmetic (FDAC) Act defines dmgs as ...articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man... and articles (other than food) intended to affect the stmcture of any function of the body of man. In the United States and elsewhere, the introduction of a new dmg is subject to a sequence of weU-defined stages of development and approval (4). Each stage involves either scientific testing or submission and preparation of data and analysis review (Fig. 2). 

Kirk-Othmer Encyclopedia of Chemical Technology (4th Edition) 

PD is the study to determine dose-response effects. We are interested in finding out the effects of a drug on some particular response, such as heart rate, enzyme levels, antibody production, or muscle relaxation or contraction. When a drug binds to a receptor, the ensuing response is complex. The 

Very often, the dose-effect curve is redrawn using a logarithmic scale for the dose. This gives rise to a sigmoid curve, as shown in Fig. 5.2. It is a mathematical transformation, which shows an approximate linear portion for the 20-80% maximal effect scale, which is usually the dose level for a therapeutic drug. Doses above 80% provide very little increase in therapeutic effects but with a concomitant rise in the risk of adverse reactions. 

The effectiveness of drug targeting should be evaluated by taking into account not only pharmacokinetic aspects, but also the pharmacodynamic aspects. The latter include the concentration-effect relationship in the target tissue and at the sites where toxicity may occur [7,12]. The therapeutic effect of the drug and its toxic effect may be different with regard to their mechanisms, and hence their concentration-effect relationship may also be different, both qualitatively (different PD models) and quantitatively (different model parameters). 

PK models (Section 13.2.4), PD models (Section 13.2.5), and PK/PD models (Section 13.2.6) can be used in two different ways, that is, in simulations (Section 13.2.7) and in data analysis (Section 13.2.8). Simulations can be performed if the model structure and its underlying parameter values are known. In fact, for any arbitrary dose or dosing schedule the drug concentration profile in each part of the model can be calculated. The quantitative measures of the effectiveness of drug targeting (Section 13.4) can also be evaluated. If actual measurements have been performed in in-vivo experiments in laboratory animals or man, the relevant model structure and its parameter values can be assessed by analysis of plasma disappearance curves, excretion rate profiles, tissue concentration data, and so forth (Section 13.2.8). 

The desire to take medicine is perhaps the greatest feature which distinguishes men from the animals. 

Pharmacodynamics may be defined as the study of the actions and effects of drugs on organs, tissues, cellular, and subcellular levels. Therefore, pharmacodynamics provides us with information about the beneficial action of drugs and their side effects. 

Chapter 1, on pharmacokinetics, discussed the processes of absorption, binding, distribution, biotransformation, and excretion of drugs. These processes act efficiently to ensure that a sufficient quantity of drugs reach their receptor sites to elicit the desired therapeutic effects. 

Pharmacodynamics considers the sites, modes, and mechanisms of action of drugs. For example, if a patient with multiple fractures receives a subcutaneous injection of 10 to 15 mg of morphine sulfate (Papaver somniferum, Chapter 47), analgesia, sedation, respiratory depression, emesis, miosis, suppression of the gastrointestinal tract, and oliguria may ensue. These diversified effects occur at multiple peripheral and central sites through the action of numerous modes and mechanisms. 

Although the term is somewhat uncommon for vaccines, traditional investigations about their mode of action by assessing the type and duration of protective immune mechanisms under various conditions are based on a very similar approach. 

Protein Selectivity Studies Using CRID-MIFs 

In silico techniques have gained wide acceptance as a tool to support the drug discovery and optimization process. Binding mode predictions via docking, affinity predictions via QSAR and CoMFA, or the prediction of ADME(T) properties are routinely applied [1-3]. 

To complement the ligands view on affinity and selectivity, it would be desirable to use the information about the nature of the binding sites contained in the three-dimensional (3D) structures of the targets. Traditionally, this has been done by visual inspection of the protein structures. However, this is error prone, as it is too easy to overlook an important difference, or to identify a potential source of selectivity which cannot be confirmed experimentally. 

In the last few years, a number of publications have demonstrated that the GRID/PCA or GRID/CPCA methods can be successfully applied to characterize the structural differences between protein binding sites, and to identify differences in the protein-ligand interactions as well as the regions on the target enzymes which mediate highly selective interactions [4—17]. 

On the basis of the 3D structures of the proteins, the GRID/GPGA method analyzes the selectivity differences from the viewpoint of the target and is therefore independent of the availability of appropriate ligand binding data for a ligand-based QSAR analysis. 

Plots of dose (or log dose) versus response for drugs (agonists) that activate receptors can reveal the following characteristics of such drugs  

Affinity how well a drug and a receptor recognize each other. Notice the analogy to the Km value used in enzyme kinetic studies. 

Potency the quantity of drug required to achieve a desired effect. In D-R measurements, the chosen effect is usually 50% of the maximal effect. The primary determinant is the affinity of the drug for the receptor. Notice the analogy to the Km value used in enzyme kinetic studies. 

The distribution of a drug to its site of action and to other areas of the body affects therapeutic efficacy and adverse effects. Plasma concentrations of drugs may vary considerably in neonates and young infants and distribution, localisation and retention in organs and tissues may be unpredictable. The result may be a different efficacy or adverse effect profile from that expected. 

Although little is known about the effect of development on the interaction between drugs and receptors and the consequences of these interactions (pharmacodynamics), interesting evidence is emerging that 

2 Some common molecular patterns in pharmacodynamic drugs. 269 

The word pharmacodynamics, as used in this book, means the study of those examples of selective toxicity where the economic and uneconomic species are constituent cells in the one organism. Thus it stands in contrast to chemotherapy, where the uneconomic species is a different organism from the economic one. 

The beginnings of pharmacodynamics as a science is traceable to the efforts of Rudolf Buchheim (1820—1879), born in Saxony, the son of a physician. Four years after graduating in medicine, he was promoted to the rank of full professor at the (Baltic) University of Dorpat, where he established the World s first pharmacological laboratory and attracted many brilliant young men to work in it. In 1867, he transferred to a comparable position in Giessen (Germany), where he remained until his death from a stroke. 

Buchheim taught that the mode of action of drugs should be investigated by scientific means in order to introduce a more rational basis for therapy. This way of thinking was, at that time, revolutionary, yet he went on to write (Buchheim, 1872)  

Tf we translate our often obscure ideas about drug actions into an exact physiological language, this should without doubt be a considerable achievement. However, scientific recognition of the action of a given drug would imply our ability to deduce each of its actions from its chemical formula . 

Buchheim also pressed for the study of metabolism and of statistical methods to raise pharmacology to the level of an exact discipline, equal in status to chemistry and physiology. He placed special emphasis on experimentation with simple models. 

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Some specific thio-derivatives of thiazoles have been synthesized for pharmacodynamic, pesticidal, or rubber industry studies they are shown in Tables VII-13 and VII-14 described in Section III. Their chemistry has... 

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