Pharmacodynamics fundamentals

The therapeutic efficacy of a dmg is generally measured in terms of ED q or ID q which represent the concentration of dmg which produces 50% of the maximum effect or 50% of maximum inhibition. LD q represents the concentration of dmg that produces 50% fataUties in test animals. The therapeutic index is the ratio of the ED q versus LD q. Detailed descriptions of the terminology and fundamental principles of pharmacology are available (32) (see Pharmacodynamics). 

The fundamental relationship between the pharmacodynamics of a drug (i.e. the drug) is expressed by Equation 1 ... 

The inability of R77975 to show a therapeutic effect is more likely due to poor pharmacodynamics rather than a fundamental inability for this compound to inhibit an established infection. The pharmacodynamic problem was witnessed in the R77975 study, which showed that administration intranasally 3 times a day did not yield prophylactic protection. Yet if administered 6 times daily the prophylaxis occurs. Therefore if more potent and metabolically stable compounds are found, more positive clinical results would be expected. 

Editor s Note Tile following references have been selected to provide the interested reader wiLli more detail on the pharmacologic complexities of anticoagulants Tile article by Edwin W. Salzman, M.D. is a short, but excellent summary of the status of antithrombotic drugs as of early 1992. The article on heparin by Jack Hirsh, MD. and the article on warfarin by the same author proride important fundamental background information on the pharmacokinetics and pharmacodynamics of the most widely used anticoagulant drugs, Brandjes. D.P.M., et al. Acenocoumarol and Heparin Compared with Acenocoumarol. Alone in the Initial Treatment of Proximal-Vein Thrombosis," N. Eng. J. Med., 1485 (November 19, 1992). 

Before discussing the specific pharmacokinetics and pharmacodynamics of each class of antineoplastic agents, several fundamental concepts and therapeutic objectives will be considered first. 

It was noted in the previous section that both pharmacokinetics and pharmacodynamics are concerned with relationships over time. One illustration of the fundamental importance of the rates of these processes can be seen in the plasma concentration-time profile (also known as the plasma-concentration curve) for an administered drug. This was introduced in Section 4.2.1, along with several quantitative pharmacokinetic terms used to describe and quantify aspects of the plasma concentration-time profile ... 

An important outcome of these studies is the opportunity that it offers to discuss the implications of the presence of nonlinear dynamics in processes such as the secretion of cortisol. Based on the aforementioned discussion it is evident that the concepts of deterministic nonlinear dynamics should be adopted in pharmacodynamic modeling when supported by experimental and physiologic data. This is valid not only for the sake of more detailed study, but mainly because nonlinear dynamics suggest a whole new rationale fundamentally different from the classical approach. Moreover, the clinical pharmacologist should be aware of the limitations of chaotic models for long-term prediction, which is contrary to the routine use of classical models. 

Hydrogenation of the double bond in position 9-10 of the lysergic acid moiety results in fundamental changes in the pharmacodynamic action, as a comparison of the activity spectra of ergotamine (Fig. 7a) and dihydroergotamine (Fig. 7c) makes evident. The vasoconstrictor and uterotonic effects of the dihydrogenated derivative have been markedly attenuated, as has the stimulation of central structures, so that these effects are hardly elicited by therapeutic doses. On the other hand the adrenolytic effect and the central inhibition of the vasomotor centers are markedly enhanced. This is manifested clinically in vasodilatation, hypotension, and a certain sedative action. 

Although the main goal of Phase II clinical trials is the determination of efficacy toward the disease indication, PK is a fundamental part of this determination because to understand the clinical use of the new drug candidate, it is necessary to determine the temporal relationship between the plasma levels and the pharmacodynamics of the beneficial effect (PK/PD). A secondary PK goal in Phase II is to determine if the disease state affects the PK of the candidate drug compared with the PK observed in healthy subjects. 

Absorption/distribution/metabolism/excretion/ pharmacodynamics are considered fundamental data, as are mutagenicity tests (e.g., Ames test, in vivo... 

The fundamental principle of toxicology is the concept that the sixteenth century physician Paracelsus articulated in the 1500s sola dosis facit venenum or the dose makes the poison . The modem version of this observation is the dose-response relationship, which is experimentally and theoretically supported through pharmacokinetic and pharmacodynamic experimentation. Pharmacokinetics is concerned with the study of the time course of the disposition of drugs, specifically absorption, distribution, metabolism and elimination, often referred to as ADME. In non-technical terms it can be thought of as what the body does to the chemical. An understanding of the pharmacokinetic (in the case of dmgs) or toxicokinetic (all chemicals) profile is critical to estimate the... 

Pharmacodynamics most directly concerns actions of the drug on the body and thus drug effects. This chapter covered fundamental terms that pharmacologists use to describe drug effects and ways to depict them graphically. 

The chemical properties and hence the chemical structure of a compound definitely determine its participation in the partial processes making up the various phases of action. The relationship of structure to action is therefore a fundamental characteristic of the action of pharmaca. The apparent absence of such a relationship can only be due to deficient methods of investigation and to the multiplicity and complexity of the processes involved. The structure-action relationship will be found to emerge more clearly if it is studied with regard to particular part-processes such as those involved in pharmacon metabolism, in pharmacon distribution, and in pharmacodynamics. Such a study involves the use of simple, isolated test systems. 

It should be noted that almost all fundamental types of adverse event have been described, including those mentioned above. These include agonist-antagonist interaction, protein-binding competition, metabolic adaptation and pharmacodynamic synergy. 

Although drug volatility can provide fundamental information about the inhalation potential for drugs of abuse, it is only one of many factors necessary for producing a pharmacological effect. Pharmacokinetic and pharmacodynamic considerations have considerable bearing on a drug s ability to produce an effect. 

Fig. 1. Overview of pharmacology. Pharmacokinetics (PK) relates to the effect of the body on the drug and principally includes bioavailability, distribution, and clearance. Pharmacodynamics (PD) relates to drug concentration and receptor availability. The response to drug concentrations may be therapeutic, subtherapeutic, or toxic, depending on considerations involving both PK and PD principles. From Linder MW, Valdes R Jr. Pharmacogenetics fundamentals and applications. Therapeutic drug monitoring and toxicology. AACC 1999 20(l) 10 with permission.)...

Fig. 6. Pharmacogenetics establishes the functional basis of pharmacokinetics and pharmacodynamics. (From Linder MW, Valdes R Jr. Pharmacogenetics fundamentals and applications. Therapeutic drug monitoring and toxicology. AACC 1999 20(l) 9 with permission.)...

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