Katzung & Trevor's Pharmacology Examination and Board Review, 9th Edition

Chapter 2. Pharmacodynamics

Pharmacodynamics: Introduction

Pharmacodynamics deals with the effects of drugs on biologic systems, whereas pharmacokinetics (Chapter 3) deals with actions of the biologic system on the drug. The principles of pharmacodynamics apply to all biologic systems, from isolated receptors in the test tube to patients with specific diseases.

High-Yield Terms to Learn

Receptor A molecule to which a drug binds to bring about a change in function of the biologic system

Inert binding molecule or site A molecule to which a drug may bind without changing any function

Receptor site Specific region of the receptor molecule to which the drug binds

Spare receptor Receptor that does not bind drug when the drug concentration is sufficient to produce maximal effect; present when Kd > EC50

Effector Component of a system that accomplishes the biologic effect after the receptor is activated by an agonist; often a channel or enzyme molecule Agonist A drug that activates its receptor upon binding

Pharmacologic antagonist A drug that binds without activating its receptor and thereby prevents activation by an agonist

Competitive antagonist A pharmacologic antagonist that can be overcome by increasing the concentration of agonist

Irreversible antagonist A pharmacologic antagonist that cannot be overcome by increasing agonist concentration

physiologic antagonist A drug that counters the effects of another by binding to a different receptor and causing opposing effects

Chemical antagonist A drug that counters the effects of another by binding the agonist drug (not the receptor)

Allosteric agonist, antagonist A drug that binds to a receptor molecule without interfering with normal agonist binding but alters the response to the normal agonist

Partial agonist A drug that binds to its receptor but produces a smaller effect at full dosage than a full agonist

Graded dose-response curve A graph of increasing response to increasing drug concentration or dose

Quantal dose-response curve A graph of the fraction of a population that shows a specified response at progressively increasing doses

EC50, ED50, TD 50, etc In graded dose-response curves, the concentration or dose that causes 50% of the maximum effect or toxicity. In quantal dose-response curves, the concentration or dose that causes a specified response in 50% of the population under study

Kd The concentration of drug that binds 50% of the receptors in the system

Efficacy, maximal efficacy The maximum effect that can be achieved with a particular drug, regardless of dose

Receptors

Receptors are the specific molecules in a biologic system with which drugs interact to produce changes in the function of the system. Receptors must be selective in their ligand-binding characteristics (so as to respond to the proper chemical signal and not to meaningless ones). Receptors must also be modifiable when they bind a drug molecule (so as to bring about the functional change). Many receptors have been identified, purified, chemically characterized, and cloned. Most are proteins; a few are other macromolecules such as DNA. The receptor site (also known as the recognition site) for a drug is the specific binding region of the receptor macromolecule and has a relatively high and selective affinity for the drug molecule. The interaction of a drug with its receptor is the fundamental event that initiates the action of the drug, and many drugs are classified on the basis of their primary receptor affinity.

Effectors

Effectors are molecules that translate the drug-receptor interaction into a change in cellular activity. The best examples of effectors are enzymes such as adenylyl cyclase. Some receptors are also effectors in that a single molecule may incorporate both the drug-binding site and the effector mechanism. For example, a tyrosine kinase effector is part of the insulin receptor molecule, and a sodium-potassium channel is the effector part of the nicotinic acetylcholine receptor.

Graded Dose-Response Relationships

When the response of a particular receptor-effector system is measured against increasing concentrations of a drug, the graph of the response versus the drug concentration or dose is called a graded dose-response curve (Figure 2-1A). Plotting the same data on a semilogarithmic concentration axis usually results in a sigmoid curve, which simplifies the mathematical manipulation of the dose-response data (Figure 2-1B). The efficacy (Emax ) and potency (EC50 or ED50 ) parameters are derived from these data. The smaller the EC50 (or ED50 ), the greater the potency of the drug.

FIGURE 2-1

Graded dose-response and dose-binding graphs. (In isolated tissue preparations, concentration is usually used as the measure of dose.) A. Relation between drug dose or concentration (abscissa) and drug effect (ordinate). When the dose axis is linear, a hyperbolic curve is commonly obtained. B. Same data, logarithmic dose axis. The dose or concentration at which effect is half-maximal is denoted EC50, whereas the maximal effect is Emax. C. If the percentage of receptors that bind drug is plotted against drug concentration, a similar curve is obtained, and the concentration at which 50% of the receptors are bound is denoted Kd, and the maximal number of receptors bound is termed Bmax.

Graded Dose-Binding Relationship & Binding Affinity

It is possible to measure the percentage of receptors bound by a drug, and, by plotting this percentage against the log of the concentration of the drug, a graph similar to the dose-response curve is obtained (Figure 2-1C). The concentration of drug required to bind 50% of the receptor sites is denoted as Kd and is a useful measure of the affinity of a drug molecule for its binding site on the receptor molecule. The smaller the Kd, the greater the affinity of the drug for its receptor. If the number of binding sites on each receptor molecule is known, it is possible to determine the total number of receptors in the system from the Bmax .

Quantal Dose-Response Relationships

When the minimum dose required to produce a specified response is determined in each member of a population, the quantal dose-response relationship is defined (Figure 2-2). For example, a blood pressure-lowering drug might be studied by measuring the dose required to lower the mean arterial pressure by 20 mm Hg in 100 hypertensive patients. When plotted as the percentage of the population that shows this response at each dose versus the log of the dose administered, a cumulative quantal dose-response curve, usually sigmoid in shape, is obtained. The median effective (ED50), median toxic (TD 50), and (in animals) median lethal (LD50) doses are derived from experiments carried out in this manner. Because the magnitude of the specified effect is arbitrarily determined, the ED50 determined by quantal dose-response measurements has no direct relation to the ED50 determined from graded dose-response curves. Unlike the graded dose-response determination, no attempt is made to determine the maximal effect of the drug. Quantal dose-response data provide information about the variation in sensitivity to the drug in a given population, and if the variation is small, the curve is steep.

FIGURE 2-2

Quantal dose-response plots from a study of the therapeutic and lethal effects of a new drug in mice. Shaded boxes (and the accompanying bell-shaped curves) indicate the frequency distribution of doses of drug required to produce a specified effect, that is, the percentage of animals that required a particular dose to exhibit the effect. The open boxes (and corresponding sigmoidal curves) indicate the cumulative frequency distribution of responses, which are lognormally distributed.

(Modified and reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 11th ed. McGraw-Hill, 2009: Fig. 2-2.)

Efficacy

Efficacy—often called maximal efficacy—is the greatest effect (Emax) an agonist can produce if the dose is taken to very high levels. Efficacy is determined mainly by the nature of the drug and the receptor and its associated effector system. It can be measured with a graded dose-response curve (Figure 2-1) but not with a quantal dose-response curve. By definition, partial agonists have lower maximal efficacy than full agonists (see later discussion).

Potency

Potency denotes the amount of drug needed to produce a given effect. In graded dose-response measurements, the effect usually chosen is 50% of the maximal effect and the dose causing this effect is called the EC50 (Figure 2-1A and B). Potency is determined mainly by the affinity of the receptor for the drug and the number of receptors available. In quantal dose-response measurements, ED50, TD 50, and LD50 are also potency variables (median effective, toxic, and lethal doses, respectively, in 50% of the population studied). Thus, potency can be determined from either graded or quantal dose-response curves (eg, Figures 2-1 and 2-2), but the numbers obtained are not identical.

Spare Receptors

Spare receptors are said to exist if the maximal drug response (Emax) is obtained at less than maximal occupation of the receptors (Bmax). In practice, the determination is usually made by comparing the concentration for 50% of maximal effect (EC50) with the concentration for 50% of maximal binding (Kd). If the EC50 is less than the Kd, spare receptors are said to exist (Figure 2-3). This might result from 1 of 2 mechanisms. First, the duration of the activation of the effector may be much greater than the duration of the drug-receptor interaction. Second, the actual number of receptors may exceed the number of effector molecules available. The presence of spare receptors increases sensitivity to the agonist because the likelihood of a drug-receptor interaction increases in proportion to the number of receptors available. (For contrast, the system depicted in Figure 2-1, panels B and C, does not have spare receptors, since the EC50 and the Kd are equal.)

FIGURE 2-3

In a system with spare receptors, the EC50 is lower than the Kd, indicating that to achieve 50% of maximal effect, less than 50% of the receptors must be activated. Explanations for this phenomenon are discussed in the text.

Agonists, Partial Agonists, & Inverse Agonists

Modern concepts of drug-receptor interactions consider the receptor to have at least 2 states—active and inactive. In the absence of ligand, a receptor might be fully active or completely inactive; alternatively, an equilibrium state might exist with some receptors in the activated state and with most in the inactive state (Ra+Ri; Figure 2-4). Many receptor systems exhibit some activity in the absence of ligand, suggesting that some receptors are in the activated state. Activity in the absence of ligand is called constitutive activity. A full agonist is a drug capable of fully activating the effector system when it binds to the receptor. In the model system illustrated in Figure 2-4, a full agonist has high affinity for the activated receptor conformation, and sufficiently high concentrations result in all the receptors achieving the activated state (Ra-Da). A partial agonist produces less than the full effect, even when it has saturated the receptors (Ra-Dpa + Ri-Dpa), presumably by combining with both receptor conformations, but favoring the active state. In the presence of a full agonist, a partial agonist acts as an inhibitor. In this model, neutral antagonists bind with equal affinity to the Ri and Ra states, preventing binding by an agonist and preventing any deviation from the level of constitutive activity. In contrast, inverse agonists have a much higher affinity for the inactive Ri state than for Ra and eliminate any constitutive activity.

FIGURE 2-4

Upper: One model of drug-receptor interactions. The receptor is able to assume 2 conformations, Ri and Ra. In the Ri state, it is inactive and produces no effect, even when combined with a drug (D) molecule. In the Ra state, it activates its effectors and an effect is recorded, even in the absence of ligand. In the absence of drug, the equilibrium between Ri and Ra determines the degree of constitutive activity. Lower: A full agonist drug (Da) has a much higher affinity for the Ra than for the Ri receptor conformation, and a maximal effect is produced at sufficiently high drug concentration. A partial agonist drug (Dpa) has somewhat greater affinity for the Ra than for the Ri conformation and produces less effect, even at saturating concentrations. A neutral antagonist (Dant) binds with equal affinity to both receptor conformations and prevents binding of agonist. An inverse agonist (Di) binds much more avidly to the Ri receptor conformation, prevents conversion to the Ra state, and reduces constitutive activity.

(Modified and reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 11th ed. McGraw-Hill, 2009: Fig. 1-4.)

Antagonists

Competitive and Irreversible Pharmacologic Antagonists

Competitive antagonists are drugs that bind to, or very close to, the agonist receptor site in a reversible way without activating the effector system for that receptor. Neutral antagonists bind the receptor without shifting the Ra versus Ri equilibrium (Figure 2-4). In the presence of a competitive antagonist, the log dose-response curve for an agonist is shifted to higher doses (ie, horizontally to the right on the dose axis), but the same maximal effect is reached (Figure 2-5A). The agonist, if given in a high enough concentration, can displace the antagonist and fully activate the receptors. In contrast, an irreversible antagonist causes a downward shift of the maximum, with no shift of the curve on the dose axis unless spare receptors are present (Figure 2-5B). Unlike the effects of a competitive antagonist, the effects of an irreversible antagonist cannot be overcome by adding more agonist. Competitive antagonists increase the ED50; irreversible antagonists do not (unless spare receptors are present). A noncompetitive antagonist that acts at an allosteric site of the receptor (see Figure 1-1) may bind reversibly or irreversibly; a noncompetitive antagonist that acts at the receptor site binds irreversibly.

FIGURE 2-5

Agonist dose-response curves in the presence of competitive and irreversible antagonists. Note the use of a logarithmic scale for drug concentration. A. A competitive antagonist has an effect illustrated by the shift of the agonist curve to the right. B. An irreversible (or noncompetitive) antagonist shifts the agonist curve downward.

Physiologic Antagonists

A physiologic antagonist binds to a different receptor molecule, producing an effect opposite to that produced by the drug it antagonizes. Thus, it differs from a pharmacologic antagonist, which interacts with the same receptor as the drug it inhibits. A familiar example of a physiologic antagonist is the antagonism of the bronchoconstrictor action of histamine (mediated at histamine receptors) by epinephrine's bronchodilator action (mediated at adrenoceptors). Similarly, glucagon (acting at glucagon receptors) can antagonize the cardiac effects of an overdose of propranolol (acting at  receptors).

Chemical Antagonists

A chemical antagonist interacts directly with the drug being antagonized to remove it or to prevent it from binding to its target. A chemical antagonist does not depend on interaction with the agonist's receptor (although such interaction may occur). A common example of a chemical antagonist is dimercaprol, a chelator of lead and some other toxic metals. Pralidoxime, which combines avidly with the phosphorus in organophosphate cholinesterase inhibitors, is another type of chemical antagonist.

Skill Keeper: Allosteric Antagonists

(See Chapter 1)

Describe the difference between a pharmacologic antagonist and an allosteric antagonist. How could you differentiate these two experimentally?

Therapeutic Index & Therapeutic Window

The therapeutic index is the ratio of the TD 50 (or LD50) to the ED50, determined from quantal dose-response curves. The therapeutic index represents an estimate of the safety of a drug, because a very safe drug might be expected to have a very large toxic dose and a much smaller effective dose. For example, in Figure 2-2, the ED50 is approximately 3 mg, and the LD50 is approximately 150 mg. The therapeutic index is therefore approximately 150/3, or 50 in mice. Obviously, a full range of toxic doses cannot be ethically studied in humans. Furthermore, factors such as the varying slopes of dose-response curves make this estimate a poor safety index even in animals.

The therapeutic window, a more clinically useful index of safety, describes the dosage range between the minimum effective therapeutic concentration or dose, and the minimum toxic concentration or dose. For example, if the average minimum therapeutic plasma concentration of theophylline is 8 mg/L and toxic effects are observed at 18 mg/L, the therapeutic window is 8-18 mg/L. Both the therapeutic index and the therapeutic window depend on the specific toxic effect used in the determination.

Signaling Mechanisms

Once an agonist drug has bound to its receptor, some effector mechanism is activated. The receptor-effector system may be an enzyme in the intracellular space (eg, cyclooxygenase, a target of nonsteroidal anti-inflammatory drugs) or in the membrane or extracellular space (eg, acetylcholinesterase). The receptors for many drugs are neurotransmitter reuptake transporters (eg, the norepinephrine transporter, NET, and the dopamine transporter, DAT, targets for cocaine). Most antiarrhythmic drugs target voltage-activated ion channels in the membrane for sodium, potassium, or calcium. For the largest group of drug-receptor interactions, the drug is present in the extracellular space while the effector mechanism resides inside the cell and modifies some intracellular process. These represent the classic drug-receptor interactions and involve signaling across the membrane. Five major types of transmembrane-signaling mechanisms for receptor-effector systems have been defined (Figure 2-6).

FIGURE 2-6

Signaling mechanisms for drug effects. Five major signaling mechanisms are recognized: (1) transmembrane diffusion of the drug to bind to an intracellular receptor; (2) transmembrane enzyme receptors, whose outer domain provides the receptor function and inner domain provides the effector mechanism converting A to B; (3) transmembrane receptors that, after activation by an appropriate ligand, activate separate cytoplasmic tyrosine kinase molecules (JAKs), which phosphorylate STAT molecules that regulate transcription (Y, tyrosine; P, phosphate); (4) transmembrane channels that are gated open or closed by the binding of a drug to the receptor site; and (5) G protein-coupled receptors, which use a coupling protein to activate a separate effector molecule.

(Reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 11th ed. McGraw-Hill, 2009: Fig. 2-5.)

Receptors That Are Intracellular

Some drugs, especially more lipid-soluble or diffusible agents (eg, steroid hormones, nitric oxide), may cross the membrane and combine with an intracellular receptor that affects an intracellular effector molecule. The receptor and effector may or may not be the same molecule, but no specialized transmembrane signaling device is required.

Receptors Located on Membrane-Spanning Enzymes

Drugs that affect membrane-spanning enzymes combine with a receptor site on the extracellular portion of the molecule and modify its intracellular activity. For example, insulin acts on a tyrosine kinase that is located in the membrane. The insulin receptor site faces the extracellular environment, and the effector enzyme catalytic site is on the cytoplasmic side. When activated, such receptors dimerize and phosphorylate specific intracellular protein substrates.

Receptors Located on Membrane-Spanning Molecules That Bind Separate Intracellular Tyrosine Kinase Molecules

Like receptor tyrosine kinases, these receptors have extracellular and intracellular domains and form dimers. However, after receptor activation by an appropriate drug (often a cytokine) at the extracellular receptor site, associated but separate tyrosine kinase molecules (Janus kinases; JAKs) are activated, resulting in phosphorylation of STAT molecules (signal transducers and activators of transcription). STAT dimers (the effectors) then travel to the nucleus, where they regulate transcription.

Receptors Located on Membrane Ion Channels

Receptors that regulate membrane ion channels may directly cause the opening of the channel (eg, acetylcholine at the nicotinic receptor) or modify the ion channel's response to other agents (eg, benzodiazepines at the GABA-activated chloride channel). The channel molecule acts as both receptor and effector, and the result is a change in transmembrane electrical potential.

Receptors Linked to Effectors via G Proteins

A very large number of drugs bind to receptors that are linked by coupling proteins to intracellular or membrane-bound effectors. The best-defined examples of this group are the sympathomimetic drugs, which activate or inhibit adenylyl cyclase (formerly called adenylate cyclase) by a multistep process: activation of the receptor (located in the membrane with the binding site facing the extracellular side) by the drug results in activation of separate G proteins (located in the intracellular face of the membrane), which either stimulate or inhibit the cyclase. Thus, the receptor and effector are linked through the G-coupling protein. Many types of G proteins have been identified; 3 of the most important are listed in Table 2-1. When G-coupled receptors bind agonist, the G protein is activated. This process involves replacement of the GDP that is bound to the protein with GTP and subsequent dissociation of the trimeric G protein complex into a GTP-alpha moiety and a beta-gamma moiety. The GTP-alpha portion is the primary player in most interactions with effector molecules, but in some, the beta-gamma moiety is the activator.

TABLE 2-1 Examples of receptors that are coupled to their effectors by G proteins.

Receptor Regulation

Receptors are dynamically regulated in number, location, and sensitivity. Changes can occur over short times (minutes) and longer periods (days).

Frequent or continuous exposure to agonists often results in short-term diminution of the receptor response, sometimes called tachyphylaxis. Several mechanisms are responsible for this phenomenon. First, intracellular proteins may block access of a G protein to the activated receptor molecule. For example, the molecule -arrestin has been shown to bind to an intracellular loop of the  adrenoceptor when the receptor is continuously activated. Beta-arrestin prevents access of the Gs-coupling protein and thus desensitizes the tissue to further  agonist activation within minutes. Removal of the  agonist results in removal of -arrestin and restoration of the full response after a few minutes or hours.

Second, agonist-bound receptors may be internalized by endocytosis, removing them from further exposure to extracellular molecules. The internalized receptor molecule may then be either reinserted into the membrane (eg, morphine receptors) or degraded (eg,  adrenoceptors, epidermal growth factor receptors). In some cases, the internalization-reinsertion process may actually be necessary for normal functioning of the receptor-effector system.

Third, continuous activation of the receptor-effector system may lead to depletion of some essential substrate required for downstream effects. For example, depletion of thiol cofactors may be responsible for tolerance to nitroglycerin. In some cases, repletion of the missing substrate (eg, by administration of glutathione) can reverse the tolerance.

Long-term reductions in receptor number (downregulation) may occur in response to continuous exposure to agonists. The opposite change (upregulation) occurs when receptor activation is blocked for prolonged periods (usually several days) by pharmacologic antagonists or by denervation.

Skill Keeper Answer: Allosteric Antagonists

Allosteric antagonists do not bind to the agonist receptorsitethey bind to some other region of the receptor molecule that results in inhibition of the response to agonists (see Figure 1-1). They do not prevent binding of the agonist. In contrast, pharmacologic antagonists bind to the agonist site and prevent access of the agonist. The difference can be detected experimentally by evaluating competition between the binding of radioisotopically labeled antagonist and the agonist. High concentrations of agonist displace or prevent the binding of a pharmacologic antagonist but not an allosteric antagonist.

Checklist

When you complete this chapter, you should be able to:

 Compare the efficacy and the potency of 2 drugs on the basis of their graded dose-response curves.

 Predict the effect of a partial agonist in a patient in the presence and in the absence of a full agonist.

 Name the types of antagonists used in therapeutics.

 Describe the difference between an inverse agonist and a pharmacologic antagonist.

Specify whether a pharmacologic antagonist is competitive or irreversible based on its effects on the dose-response curve and the dose-binding curve of an agonist in the presence of the antagonist.

 Give examples of competitive and irreversible pharmacologic antagonists and of physiologic and chemical antagonists.

 Name the coupling and effector proteins usually activated by muscarinic receptors (M1, M2, M3); 1 and 2 receptors; and  receptors.

 Name 5 transmembrane signaling methods by which drug-receptor interactions exert their effects.

 Describe 2 mechanisms of receptor regulation.

Chapter 2 Summary Table

Major Concept Description

Graded vs quantal responses Responses are graded when they increment gradually (eg, heart rate change) as the dose of drug increases; they are quantal when they switch from no effect to a specified effect at a certain dose (eg, from arrhythmia to normal sinus rhythm)

Graded vs quantal dose response curves Graded dose response curves plot the increment in physiologic or biochemical response as dose or concentration is increased.Quantal dose response curves plot the increment in the percent of the population under study that responds as the dose is increased

Efficacy vs potency Efficacy represents the ability of a drug to accomplish a specified effect, whereas potency reflects the amount of drug (the dose) required to cause an effect. A drug may have high efficacy but low potency or vice versa

Agonism and antagonism Because a receptor may have multiple binding sites, different drugs may have very different effects on it. The effect may be to activate, partially activate, or inhibit the receptor's function. In addition, the binding may be at the site of the usual endogenous ligand at that receptor, or at a different site

Transmembrane signaling Many drugs act on intracellular functions but reach their target tissue in the extracellular space. On reaching the target, some drugs diffuse through the cell membrane and act on intracellular receptors. Most act on receptors on the extracellular face of the cell membrane and modify the intracellular function of those receptors by transmembrane signaling

Receptor regulation Receptors are in dynamic equilibrium, being synthesized in the interior of the cell, inserted into the cell membranes, sequestered out of the membranes, and degraded at various rates. These changes are noted as upregulation or downregulation of the receptor numbers. Receptors may also be reversibly inhibited by biochemical modification.



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