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Drug Action and Pharmacodynamics


Pharmacodynamics is the study of the biochemical and physiologic effects of drugs and their mechanisms of action. It considers both drug action, which refers to the initial consequence of a drug-receptor interaction, and drug effect, which refers to the subsequent effects. The drug action of digoxin, for example, is inhibition of membrane Na+/K+-ATPase; the drug effect is augmentation of cardiac contractility.

Not all drugs exert their pharmacologic actions via receptor-mediated mechanisms. The action of some drugs—including inhalation anesthetic agents, osmotic diuretics, purgatives, antiseptics, antacids, chelating agents, and urinary acidifying and alkalinizing agents—is attributed to their physicochemical properties. Certain cancer and antiviral chemotherapeutic agents, which are analogs of pyrimidine and purine bases, elicit their effects when they are incorporated into nucleic acids and serve as suicide substrates for DNA or RNA synthesis. The effect of most drugs, however, results from their interactions with receptors. These interactions and the resulting conformational changes in the receptor initiate biochemical and physiologic changes that characterize the drug's response.

Drug Concentration and Effect

Drug therapy is intended to result in a particular pharmacologic response of desired intensity and duration while avoiding adverse drug reactions. The relationship between the administered dose and the clinical response has been investigated for some drugs using a pharmacokinetic/pharmacodynamic (PK/PD) modeling approach. For other drugs, a simpler relationship between the concentration and effect in an idealized in vitro system is modeled mathematically to conceptualize receptor occupancy and drug response. The model assumes that the drug interacts reversibly with its receptor and produces an effect proportional to the number of receptors occupied, up to a maximal effect when all receptors are occupied. The reaction scheme for the model is:

The relationship between effect and the concentration of free drug for the model can be written:

where E is the effect observed at concentration C, Emax is the maximal response that can be produced by the drug, and EC50 is the concentration of drug that produces 50% of maximal effect.

The above equation describes a rectangular hyperbola. It is generally more convenient to plot dose-response data as the drug effect (ordinate) against log dose or concentration (abscissa). The transformation yields a sigmoidal curve that allows the potency of different drugs to be readily compared. In addition, the effect of drugs used at therapeutic concentrations commonly falls on the portion of the sigmoidal curve that is approximately linear, ie, between 20% and 80% of maximal effect. This makes for easier interpretation of the plotted data.

Agonists and Antagonists

An agonist is a drug that binds to receptors and thereby alters (stabilizes) the proportion of receptors that are in the active conformation, resulting in a biologic response. A full agonist results in a maximal response by occupying all or a fraction of receptors. A partial agonist results in less than a maximal response even when the drug occupies all of the receptors. A partial agonist produces an effect if no full agonist is present, but acts as an antagonist in the presence of a full agonist. Concentration-effect curves of partial agonists resemble curves of full agonists in the presence of a noncompetitive antagonist.

An antagonist is a drug that blocks the response produced by an agonist. It interacts with the receptor or other component of the effector mechanism, but is devoid of intrinsic activity (ie, the ability to elicit a response upon binding to a receptor). A competitive antagonist results in reversible inhibition that can be overcome by increasing the concentration of agonist. The presence of a competitive antagonist causes a parallel shift of the log dose-effect curve to the right, without altering the Emax or EC50 of the agonist. A noncompetitive antagonist results in irreversible inhibition that generally prevents the agonist from producing a maximal effect (ie, Emax and EC50 are lowered). However, at low concentrations, a noncompetitive antagonist may cause a parallel shift of the log dose-effect curve to the right without reducing the maximal response of the agonist.

Agonists, but not antagonists, elicit an effect even when they bind to the same site on the same receptor. An explanation is provided by both structural and functional studies, which indicate that receptors exist in at least 2 conformations, active and inactive, and these are in equilibrium. Because agonists have a higher affinity for the receptor's active conformation, agonists drive the equilibrium to the active state, thereby activating the receptor. Conversely, antagonists have a higher affinity for the receptor's inactive conformation and push the equilibrium to the inactive state, producing no effect.

The concept of spare receptors is implicit in the definition of a noncompetitive antagonist; the latter effectively removes receptors irreversibly from the system. Yet low concentrations of a noncompetitive antagonist may result in a parallel shift of the log dose-effect curve to the right without reducing the maximal response of the agonist. This observation is attributed to a maximal response being elicited without all receptors being occupied, in which case the tissue is said to possess spare receptors. From a functional perspective, spare receptors are significant because they increase both the sensitivity and speed of a tissue's responsiveness to a ligand.

Structure–Activity Relationships

The chemical structure of a drug determines its affinity for the receptor and ability to elicit a response (ie, intrinsic activity). Structure-activity relationships are exploited in drug design; relatively minor modifications to drug structure may result in more favorable therapeutic profiles and/or pharmacokinetic properties.

Signal Transduction and Drug Action

Most receptors are proteins. The best characterized of these are regulatory proteins, enzymes, transport proteins, and structural proteins. Nucleic acids are also important drug receptors, particularly for cancer chemotherapeutic agents.

The receptors for several neurotrans-mitters modulate ion channel opening and closing through ligand gating or voltage gating. The nicotinic acetylcholine receptor is an example of a ligand-gated receptor, which allows Na+ to flow down its concentration gradient into cells, resulting in depolarization. Most of the clinically useful neuromuscular blocking drugs used by anesthetists compete with acetylcholine for the receptor but do not initiate ion-channel opening. Other ligand-gated ion channels include the receptors for the excitatory amino acids (glutamate and aspartate), the inhibitory amino acids (γ-amino butyric acid [GABA] and glycine), and certain serotonin (5-HT3) receptors. The sodium channel receptor is an example of a voltage-gated receptor; these are present in the membranes of excitable nerve, cardiac, and skeletal muscle cells. In the resting state, the Na+/K+-ATPase pump in these cells maintains an intracellular Na+ concentration much lower than that in the extracellular environment. Membrane depolarization causes channel opening and a transient influx of Na+ ions, followed by inactivation and return to the resting state. The action of local anesthetics is due to their direct interaction with voltage-gated Na+ channels.

Many transmembrane receptors are linked to guanosine triphosphate binding proteins, which activate second messenger systems. Two important second messenger systems are cyclic adenosine monophosphate (cAMP) and the phosphoinositides. In cAMP second messenger systems, binding of the ligand to the receptor increases or decreases adenylyl cyclase activity, which in turn regulates the formation of cAMP from adenosine triphosphate. The activation of protein kinase A by cAMP results in the phosphorylation of proteins and a physiologic effect. From a therapeutic standpoint, drug binding to β-adrenergic, histamine H2, or dopamine D1 receptors activates adenylyl cyclase, whereas binding to muscarinic M2, α2-adrenergic, dopamine D2, opiate μ and δ, adenosine A1, or GABA type B receptors inhibits adenylyl cyclase. In phosphoinositide second messenger systems, membrane phosphatidylinositol 4,5-biphosphate is hydrolyzed to 1,4,5-trisphosphate (IP3) and 1,2-diacylglycerol (DAG) by activation of a phospholipase C. Both IP3 and DAG activate kinases, and in the case of IP3, this involves the mobilization of calcium from intracellular stores. The action of numerous drugs is due to their interaction with receptors that rely on these second messengers, which include α1-adrenergic, muscarinic M1 or M2, serotonin 5-HT2, and thyrotropin-releasing hormone receptors.

Protein tyrosine kinase receptors are generally transmembrane enzymes that phosphorylate proteins exclusively on tyrosine residues, rather than on serine or threonine residues. They include endocrine hormone receptors for insulin and receptors for several growth hormones.

Intracellular receptors mediate the action of hormones such as glucocorticoids, estrogen, and thyroid hormone. These hormones, which regulate gene expression in the nucleus, are lipophilic and freely diffuse through the cell membrane to reach the receptor. Glucocorticoid receptors reside predominantly in the cytoplasm in an inactive form until they bind to the glucocorticoid steroid ligand. This results in receptor activation and translocation to the nucleus, where the receptor interacts with specific DNA sequences. Unlike glucocorticoid receptors, the receptors for estrogen and thyroid hormone reside in the nucleus.

Drug Dose and Clinical Response

To make rational therapeutic decisions, veterinarians must understand the fundamental concepts linking drug doses to clinical responses. The dose-response relationships for drugs may be graded or quantal. A graded dose-response curve can be constructed for responses that are measured on a continuous scale, eg, heart rate. Graded dose-response curves relate the intensity of response to the size of the dose, and hence are useful for characterizing the actions of drugs. A quantal dose-response curve can be constructed for drugs that elicit an all-or-none response, eg, presence or absence of epileptic seizures. For most drugs, the doses that are required to produce a specified quantal effect in a population are log normally distributed, so that the frequency distribution of responses plotted against log dose is a gaussian normal distribution curve. The percentage of the population requiring a particular dose to exhibit the effect can be determined from this curve. When these data are plotted as a cumulative frequency distribution, a sigmoidal dose-response curve is generated.

The equilibrium dissociation constant of the receptor-drug complex, KD, is the ratio of rate constants for the reverse (k2) and forward (k1) reaction between the drug and receptor and the drug-receptor complex (see Drug Concentration and Effect). KD is also the drug concentration at which receptor occupancy is half of maximum. Drugs with a high KD (low affinity) dissociate rapidly from receptors; conversely, drugs with a low KD (high affinity) dissociate slowly from receptors. These effects impact the rate at which biologic responses end.

The affinity of a drug for a receptor describes how avidly the drug binds to the receptor (ie, the KD). The chemical forces in drug-receptor interactions include electrostatic forces, van der Waal forces, and the forces associated with hydrogen bonds and hydrophobic bonds. Variation in the strength of these forces, and therefore the thermal energy in the system, determines the degree of association and dissociation of the drug and the receptor.

Potency refers to the concentration (EC50) or dose (ED50) of a drug required to produce 50% of the drug's maximal effect as depicted by a graded dose-response curve. EC50 equals KD when there is a linear relationship between occupancy and response. Often, signal amplification occurs between receptor occupancy and response, which results in the EC50 for response being much less (ie, positioned to the left on the abscissa of the log dose-response curve) than KD for receptor occupancy. Potency depends on both the affinity of a drug for its receptor, and the efficiency with which drug-receptor interaction is coupled to response. The dose of drug required to produce an effect is inversely related to potency. In general, low potency is important only if it results in a need to administer the drug in large doses that are impractical. Quantal dose-response curves provide information on the potency of drugs that is different from the information derived from graded dose-response curves. In a quantal dose-response relationship, the ED50 is the dose at which 50% of individuals exhibit the specified quantal effect.

Efficacy (also referred to as intrinsic activity) of a drug is the ability of the drug to elicit a response when it binds to the receptor. As discussed above, conformational changes in receptors as a result of drug occupancy initiate biochemical and physiologic events that characterize the drug's response. In some tissues, agonists demonstrating high efficacy can result in a maximal effect, even when only a small fraction of the receptors is occupied (the concept of spare receptors is discussed above).

The median inhibitory concentration or IC50 is the concentration of an antagonist that reduces a specified response to 50% of the maximal possible effect.

Selectivity refers to a drug's ability to preferentially produce a particular effect and is related to the structural specificity of drug binding to receptors. For example, propranolol (a β-blocker) binds equally well to β1- and β2-adrenoceptors; metoprolol (a cardioselective β-blocker) binds selectively to β1-adrenoceptors; and salbutamol (a β-agonist used for treating asthma) binds selectively to β2-adrenoceptors. The selectivity of salbutamol may be further enhanced by administering it directly to the lungs.

Specificity of drug action relates to the number of different mechanisms involved. Examples of specific drugs include atropine (a muscarinic antagonist), salbutamol (a β2-adrenoceptor agonist), phenoxybenzamine (an α-adrenergic blocking agent), and cimetidine (an H2-receptor antagonist). By contrast, nonspecific drugs result in drug effects through several mechanisms of action. A case in point is phenothiazine, which causes blockade of D2-dopamine receptors, α-adrenergic receptors, and muscarinic receptors.

The therapeutic index of a drug is the ratio of the dose that results in an undesired effect to that which results in a desired effect. The therapeutic index of a drug is usually defined as the ratio of LD50 to ED50, which indicates how selective the drug is in eliciting its desired effect. Values of LD50 and ED50 for this purpose are derived from quantal dose-response curves generated in animal studies.

The information obtained from dose-response curves is critically important when choosing between drugs and when determining the dose to administer. A drug is chosen largely on the basis of its clinical effectiveness for a particular therapeutic indication. In this context, the drug concentration at the receptor (determined by the pharmacokinetic properties of the drug) and the efficacy of the drug-receptor complex are the primary determinants of a drug's clinical effectiveness. The administered dose of a drug, by comparison, depends to a greater extent on potency than on maximal efficacy.

The maximal efficacy of the drug-receptor complex to result in a graded effect is Emax on a graded dose-response curve. Emax is derived from a quantitative dose-response relationship for a single animal and varies among individuals. The extrapolation of this value of Emax to a clinical case is only an estimate, but it facilitates a comparison of the maximal efficacy of drugs that result in a specified effect by identical receptors. A drug's potency (ie, EC50 or ED50) obtained from either graded or quantal dose-response curves is used to determine the dose that should be administered. The slope of the graded dose-response curve provides information concerning the dose range over which a drug elicits its effect. Other information concerning the selectivity of drug action and the therapeutic index is also obtained from the graded dose-response curve. When quantal effects are being considered, information concerning pharmacologic potency, selectivity of drug action, the margin of safety, and the potential variability of responsiveness among individuals is obtained from quantal dose-response curves.

An indication of the ability of drugs to reach the receptor is obtained from pharmacokinetic parameters that characterize the absorption, distribution, and clearance of a drug. There may not be a simple temporal correlation between plasma concentration of a drug and its therapeutic effect. Plotting plasma concentrations (abscissa) versus therapeutic effect (ordinate) in chronologic order displays the data as a loop for some drugs. This phenomenon is referred to as hysteresis in the concentration-effect relationship. A clockwise hysteresis loop is observed for cocaine and pseudo-ephedrine when tachyphylaxis develops (see below); a counterclockwise hysteresis loop is observed for digoxin, which distributes slowly to its site of action. The temporal correlation between plasma concentration and therapeutic effect also varies for the different classes of antagonists. For instance, the extent and duration of action of a competitive antagonist depends on its concentration in plasma, which depends (in part) on its rate of elimination. This requires that the dose be adjusted accordingly to maintain plasma concentrations in the therapeutic range. By contrast, the duration of action of an irreversible antagonist is relatively independent of its rate of elimination, and therefore plasma concentration, and more dependent on the rate of turnover of receptor molecules.

The density of most receptors is not constant with time, which has important therapeutic implications. Down-regulation of receptors may occur as a result of continual stimulation by an agonist, and manifests as the development of tachyphylaxis, which demonstrates a clockwise hysteresis loop in the concentration-effect relationship. Conversely, additional receptors can be synthesized in response to chronic receptor antagonism—a phenomenon known as up-regulation. Because more receptors are now available, a hyperreactive response occurs when the cell is exposed to an agonist.

Last full review/revision March 2012 by Philip T. Reeves, BVSc (Hons), PhD, FANZCVS

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