Drug Dose and Clinical Response - The Merck Veterinary Manual

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, K_D, 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 above). K_D is also the drug concentration at which receptor occupancy is half of maximum. Drugs with a high K_D (low affinity) dissociate rapidly from receptors; conversely, drugs with a low K_D (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 K_D).

Potency refers to the concentration (EC₅₀) or dose (ED₅₀) of a drug required to produce 50% of the drug’s maximal effect. EC₅₀ equals K_D 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 K_D 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. The ED₅₀ for a quantal dose-response relationship 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. In some tissues, agonists demonstrating high efficacy can result in a maximal effect, even when only a small fraction of the receptors are occupied. Efficacy is not linked to potency of a drug.

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 resulting in 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 E_max on a graded dose-response curve. E_max is derived from a quantitative dose-response relationship for a single animal and varies among individuals. The extrapolation of this value of E_max 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, in which case plotting plasma concentrations of a drug (abscissa) versus therapeutic effect (ordinate) in chronologic order displays the data as a loop. This phenomenon is referred to as hysteresis in the concentration-effect relationship. A counterclockwise hysteresis loop is observed for a drug such as digoxin, which distributes slowly to its site of action. 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.