Basic Principles and Pharmacodynamics

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Chapter 1 Basic Principles and Pharmacodynamics

The term pharmacology is derived from the Greek words pharmakon, meaning drug, and logos, meaning rational discussion or study. Thus pharmacology is the rational discussion or study of drugs and their interactions with the body. Classically there are two major divisions of pharmacology: pharmacodynamics and pharmacokinetics. Pharmacodynamics is the study of actions of drugs on the body—what effects a drug has on the patient, including mechanisms of action, beneficial and adverse effects of the drug, and the drug’s clinical applications. Pharmacokinetics is the inverse: the study of actions of the body on drugs—the absorption, distribution, storage, and elimination of a drug. An emergent third division is pharmacogenomics: the study of how genetic makeup affects pharmacodynamics and pharmacokinetics and thus affects drug selection and application to individual patients.

There is no precise uniformly accepted definition for the term drug. However, it is commonly accepted that a drug is any exogenous non-nutritive substance that affects bodily function. Drugs may influence bodily functions via several general mechanisms, including physical interactions (e.g., antacids), by affecting enzymatic activity (e.g., increasing or decreasing), or by binding to molecular structures on or in the cell that affect cellular function (e.g., antihistamines).

Drug Nomenclature

Several names refer to the same drug, which can be a source of confusion for students and practitioners alike.

Drug-Receptor Interactions

Although some notable exceptions exist, a fundamental principle of pharmacology is that drugs must interact with a molecular target to exert an effect. Drug interaction with molecular targets is the initiating event in a multistep process that ultimately alters tissue function. For the purposes of current discussion, the target will be referred to as a receptor. An in-depth discussion of molecular targets and a description of these processes will be presented later in this chapter (see the discussion of molecular mechanisms of drug action). Let us first consider the relationship between drug binding to its target receptors and the ultimate response of the tissue.

At its most fundamental level, the interaction of drug and receptor follows the law of mass action. The law of mass action dictates that:

Factors Affecting Drug-Target Interactions

Two basic properties of the drug-receptor interaction contribute importantly to drug responses: the ability of the drug to bind to its receptor, and the ability of the drug to alter the activity of its receptor.

Drug Binding

At the molecular level, a number of factors contribute to the interaction between drug and receptor and control the strength, duration, and type of the drug-receptor interaction. Collectively these factors dictate the strength with which the drug forms a complex with its receptor, also known as the affinity:

It is important to recognize that, in most cases, binding of drug to target molecules involves weaker bonds. Accordingly, the drug-receptor complex is not static, but rather there is continuous association and dissociation of the drug with the receptor as long as drug is present. A measure of the relative ease with which the association and dissociation reactions occur is the equilibrium dissociation constant (KD). Each drug-receptor combination will have a characteristic KD value. Drugs with high affinity for a given receptor display a small value for KD, and vice versa. In Figure 1-1, A and B, Drug A has a higher affinity for the receptor than Drug B. KD also represents the concentration of drug needed to bind 50% of the total receptor population. These concepts are important in the study of basic pharmacologic data regarding different compounds with affinity for the same receptor. In general, drugs with lower KD values will require lower concentrations to achieve sufficient receptor occupancy to exert an effect.

Selectivity of Drug Responses

Another important and desirable facet of pharmacologic responses is selectivity of drug action, determined by drug molecules exhibiting preferential affinity for receptors, as follows:

It is important to note that selectivity of drug action is a key concept. Few drugs are entirely specific for one receptor. Rather, drugs exhibit selectivity toward different receptors based on their relative affinities. Thus, selectivity is also relative. As the concentration of a drug increases, the drug will combine with receptors for which it has lower affinity and may generate off-target effects.

Activation of the Molecular Target

The relationship between the drug-receptor binding event and the ultimate biologic effect is complex. Quite often in experimental settings, the KD (concentration causing 50% receptor occupancy) does not correspond to a 50% maximal response from the test tissue or organism. In fact, in many cases half-maximal tissue responses are obtained at drug concentrations below the KD, suggesting that amplification of drug response occurs. Amplification of drug responses is discussed in a later section. This observation suggests that other factors, in addition to affinity and receptor occupancy, determine the strength of response. Accordingly, an additional modifier termed intrinsic activity was proposed. Intrinsic activity indicates the ability of receptor-bound drug to activate the receptor and initiate downstream events, leading to an effect. Drugs are categorized based on their intrinsic activity at a given receptor:

Thus, the ultimate action of a drug will depend on both its affinity and its intrinsic activity. It is important to remember that affinity and intrinsic activity are distinct properties. A weak partial agonist, which by definition activates a receptor only minimally, may have very high affinity for a receptor. In this case the drug will be able to effectively compete for the receptor and will usually out-compete the endogenous agonist for receptor occupancy and inhibit the endogenous response.

Quantifying Drug-Target Interactions: Dose-Response Relationships

Ultimately, to make informed clinical decisions regarding drug treatment, it is necessary to understand the relationship between the amount of drug given and the anticipated effect in the patient. This relationship is described quantitatively by the dose-response curve. There are two basic types of dose-response curves—graded and quantal—and each provides useful information for therapeutic decisions.

Graded Dose-Response Curves

image Have a sigmoidal shape similar to the drug receptor occupancy curves shown in Figure 1-2, because the biologic response to a drug is determined by the interaction of a drug with a receptor or molecular target.

The ED50 and Emax are useful parameters to assess drugs. In Figure 1-2, A, Drug A is more potent than Drug B or Drug C, whereas Drugs B and C have equal potency. Potency is sometimes used incorrectly as a measure of therapeutic effectiveness. In fact, in most cases potency is secondary to Emax in drug selection. However, in situations in which the absorption of drug is very poor, such that only small quantities of the drug reach the target, potency can be a critical consideration. Drugs with higher Emax values have higher pharmacologic efficacy.

In Figure 1-2, A, Drug B has the greatest efficacy, followed by Drug C, whereas Drug A, despite being the most potent, has the least efficacy. Drug C is equipotent with Drug B but has less efficacy. Thus, potency and efficacy can vary independently. It is important not to confuse the pharmacologic usage of efficacy with the more general usage. Pharmacologic efficacy is a measure of the strength of effect produced by the maximum dose of drug. By definition, antagonists do not activate their receptors after binding and therefore have an intrinsic activity and efficacy of 0. Nevertheless, an antagonist may be very clinically “efficacious” or beneficial because it blocks activation of the receptor by endogenous agonist.

These variables can be useful in determining how much of a drug to administer. For example, knowledge of the ED50 concentration for blood pressure lowering can be used to determine the dose of antihypertensive agent to administer to achieve a certain magnitude of blood pressure reduction. However, the astute clinician recognizes that ED50 values are derived from the average of a great many patients and thus should be used only as initial guidelines. Because of interindividual variability, each patient may respond in ways that differ from the average. The second type of dose-response curves, quantal dose-response curves, provide an estimate of this variability.

Quantal Dose-Response Curves

Quantal dose-response curves do the following:

image Represent a cumulative frequency distribution for a given response.

image Can be plotted for therapeutic, toxic, and lethal effects to obtain: