Chapter 3

### INTRODUCTION

Pharmacodynamics is the study of the biochemical and physiological effects of drugs and their mechanisms of action. Understanding pharmacodynamics can provide the basis for the rational therapeutic use of a drug and the design of new and superior therapeutic agents. Simply stated, pharmacodynamics refers to the effects of a drug on the body. In contrast, the effects of the body on the actions of a drug are pharmacokinetic processes (Chapter 2), and include absorption, distribution, metabolism, and excretion of drugs (often referred to collectively as ADME). Many adverse effects of drugs and drug toxicities can be anticipated by understanding a drug's mechanism(s) of action, its pharmacokinetics, and its interactions with other drugs. Thus, both the pharmacodynamic properties of a drug and its pharmacokinetics contribute to safe and successful therapy. The effects of many drugs, both salutory and deleterious, may differ widely from patient to patient due to genetic differences that alter the pharmacokinetics and the pharmacodynamics of a given drug. This aspect of pharmacology is termed pharmacogenetics and is covered in Chapter 7.

### PHARMACODYNAMIC CONCEPTS

The effects of most drugs result from their interaction with macromolecular components of the organism. These interactions alter the function of the pertinent component and initiate the biochemical and physiological changes that are characteristic of the response to the drug. The term drug receptor or drug target denotes the cellular macromolecule or macromolecular complex with which the drug interacts to elicit a cellular response, i.e., a change in cell function. Drugs commonly alter the rate or magnitude of an intrinsic cellular response rather than create new responses. Drug receptors are often located on the surface of cells, but may also be located in specific intracellular compartments such as the nucleus. Many drugs also interact with acceptors (e.g., serum albumin) within the body. Acceptors are entities that do not directly cause any change in biochemical or physiological response. However, interactions of drugs with acceptors such as serum albumin can alter the pharmacokinetics of a drug's actions.

From a numerical standpoint, proteins form the most important class of drug receptors. Examples include the receptors for hormones, growth factors, transcription factors, and neurotransmitters; the enzymes of crucial metabolic or regulatory pathways (e.g., dihydrofolate reductase, acetylcholinesterase, and cyclic nucleotide phosphodiesterases); proteins involved in transport processes (e.g., Na+,K+-ATPase); secreted glycoproteins (e.g., Wnts); and structural proteins (e.g., tubulin). Specific binding of drugs to other cellular constituents such as DNA is also exploited for therapeutic purposes. For example, nucleic acids are particularly important drug receptors for certain cancer chemotherapeutic agents and antiviral drugs.

#### Physiological Receptors

A major group of drug receptors consists of proteins that normally serve as receptors for endogenous regulatory ligands. These drug targets are termed physiological receptors. Many drugs act on physiological receptors and are particularly selective because physiological receptors have evolved to recognize and respond ...

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