Chapter 2. Pharmacodynamics

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.

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. Some authorities consider enzymes as a separate category; for the purposes of this book, enzymes that are affected by drugs are considered receptors. 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 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.

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.

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 dose-binding 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 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.

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 (TD50), 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.

Efficacy—often called maximal efficacy—is the greatest effect (Emax) an agonist can produce if the dose is taken to the highest tolerated level. 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 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 concentration or dose causing this effect is called the EC50 or ED50 (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, TD50, 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, respectively), but the numbers obtained are not identical.

Spare receptors are said to exist if the maximal drug response (Emax) is obtained at less than 100% 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.)

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 fraction of the receptors are always 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 decrease or abolish any constitutive activity.

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.

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. Familiar examples of physiologic antagonists are the antagonism of the bronchoconstrictor action of histamine by epinephrine's bronchodilator action and glucagon's antagonism of the cardiac effects of propranolol.

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). Common examples of chemical antagonists are dimercaprol, a chelator of lead and some other toxic metals, and pralidoxime, which combines avidly with the phosphorus in organophosphate cholinesterase inhibitors.

See Chapter 1.

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

The therapeutic index is the ratio of the TD50 (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.

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). Neurotransmitter reuptake transporters (eg, the norepinephrine transporter, NET, and the dopamine transporter, DAT, are receptors for many drugs, eg, antidepressants and 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, whereas the effector mechanism resides inside the cell and modifies some intracellular process. These classic drug-receptor interactions involve signaling across the membrane. Five major types of transmembrane-signaling mechanisms for receptor-effector systems have been defined (Figure 2–6, Table 2–1).

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 molecules may block access of a G protein to the activated receptor molecule. For example, the molecule β-arrestin has been shown to bind to an intracellular loop of the β adrenoceptor when the receptor is continuously activated. Beta-arrestin prevents access of the Gs-coupling protein and thus desensitizes the tissue to further β-agonist activation within minutes. Removal of the β agonist results in removal of β-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, β 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.

Allosteric antagonists do not bind to the agonist receptor site; they 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.

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 5 transmembrane signaling methods by which drug-receptor interactions exert their effects.
• □ Describe 2 mechanisms of receptor regulation.