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In the previous chapters, pharmacokinetics was used to develop dosing regimens for achieving therapeutic drug concentrations for optimal safety and efficacy. The interaction of a drug molecule with a receptor causes the initiation of a sequence of molecular events, resulting in a pharmacodynamic or pharmacologic response. The term pharmacodynamics refers to the relationship between drug concentrations at the site of action (receptor) and pharmacologic response. Pharmacodynamics includes the biochemical and physiologic effects that result from the interaction of the drug with the receptor. Early pharmacologic research demonstrates that the pharmacodynamic response produced by the drug depends on the chemical structure of the drug molecule and the affinity of the drug at the receptor site. The drug affinity for the receptor site and the resultant pharmacodynamic response is referred to as the intrinsic activity of the drug. Drug receptors interact only with drugs of specific chemical structure, and the receptors are classified according to the type of pharmacodynamic response induced. Drugs may be considered a full agonist, partial agonist, or antagonist, depending upon the type of drug interaction with the receptor and the resulting pharmacodynamic response (see discussion below).

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Drug Receptor and Occupancy Concept

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Drugs may react with receptors to form covalent or noncovalent bonds. Drugs that form covalent bonds with the receptor produce a nonreversiblepharmacodynamic response. Most pharmacologic responses are due to weak, noncovalent bonds (eg, hydrogen bonding, ionic electrostatic bonds, van der Waals forces) between the drug and the receptor. These interactions between drug and receptor are assumed to be reversible and to conform to the law of mass action. One or more drug molecules may interact simultaneously with the receptor to produce a pharmacologic response. Typically, a single drug molecule interacts with a receptor with a single binding site to produce a pharmacologic response, as illustrated below.

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where the brackets [ ] denote molar concentrations.

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This scheme illustrates the occupation theory for the interaction of a drug molecule with a receptor molecule. More recent schemes consider a drug that binds to macromolecules as a ligand. Thus, the reversible interaction of a ligand (drug) with a receptor may be written as (Neubig et al, 2003).

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where L is generally referred to as ligand concentration (since many drugs are small molecules) and LR is analogous to the [drug–receptor complex]. LR* is the activated form which results in the effect.

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The last step is written to accommodate different modes of how LR leads to a drug effect. For example, the interaction of a subsequent ligand with the receptor may involve a conformation change of the receptor or simply lead to an additional effect. In this chapter, effect and response are used interchangeably.

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This model makes the following assumptions:

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  1. The drug molecule combines with the receptor molecule as a bimolecular association, and ...

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