Potency and Relative Efficacy

In general, the drug-receptor interaction is characterized first by binding of drug to receptor and second by generation of a response in a biological system. The first function is governed by the chemical property of affinity, ruled by the chemical forces that cause the drug to associate reversibly with the receptor.

This simple relationship, permits an appreciation of the reliance of the interaction of drug (D) with receptor (R) on both the forward or association rate (k^) and the reverse or dissociation rate (k2). At any given time, the concentration of agonist-receptor complex [DR] is equal to the product of kj[D][R] minus the product k2[DR]. At equilibrium (i.e., when S[DR]/Sr = 0), kj[D][R] = k2[DR]. The equilibrium dissociation constant (KD) is then described by ratio of the off-rate and the on-rate (k2/kj).

The affinity constant is the reciprocal of the equilibrium dissociation constant (affinity constant = Kd = 1/Ka). A high affinity means a small KD. As a practical matter, the affinity of a drug is influenced most often by changes in its off-rate (k2) rather than its on-rate (k1). Although a number of assumptions are made in this analysis, it is generally useful for considering the interactions of drugs with their receptors. Using this simple model of Equation 1-17 permits us to write an expression of the fractional occupancy f) of receptors by agonist:

CHAPTER 1 Pharmacokinetics and Pharmacodynamics 23 This can be expressed in terms of KA (or KD) and [D]:

Thus, when [D] = KD, a drug will occupy 50% of the receptors present. Potent drugs are those which elicit a response by binding to a critical number of a particular receptor type at low concentrations (high affinity) compared with other drugs acting on the same system and having lower affinity and thus requiring more drug to bind to the same number of receptors.

The generation of a response from the drug—receptor complex is governed by a property described as efficacy. Where agonism is the information encoded in a drug's chemical structure that causes the receptor to change conformation to produce a physiological or biochemical response when the drug is bound, efficacy is that property intrinsic to a particular drug that determines how "good" an agonist the drug is. Historically, efficacy has been treated as a proportionality constant that quantifies the extent of functional change imparted to a receptor-mediated response system on binding a drug. Thus, a drug with high efficacy may be a full agonist eliciting, at some concentration, a full response, whereas a drug with a lower efficacy at the same receptor may not elicit a full response at any dose. When it is possible to describe the relative efficacy of drugs at a particular receptor, a drug with a low intrinsic efficacy will be a partial agonist.

QUANTIFYING AGONISM When the relative potency of two agonists of equal efficacy is measured in the same biological system, downstream signaling events are the same for both drugs, and the comparison yields a relative measure of the affinity and efficacy of the two agonists (Figure 1-9A). It is convenient to describe agonist response by determining the half-maxi-mally effective concentration (EC50) for producing a given effect. Thus, measuring agonist potency by comparison of EC50 values is one method of measuring the capability of different agonists to induce a response in a test system and for predicting comparable activity in another. Another method of estimating agonist activity is to compare maximal asymptotes in systems where the agonists do not produce maximal response (Figure 1-9B). The advantage of using maxima is that this property depends solely on efficacy, whereas potency is a mixed function of both affinity and efficacy.

QUANTIFYING ANTAGONISM Characteristic patterns of antagonism are associated with certain mechanisms of blockade of receptors. One is straightforward competitive antagonism, whereby a drug that lacks intrinsic efficacy but retains affinity competes with the agonist for the binding site on the receptor. The characteristic pattern of such antagonism is the concentration-dependent production of a parallel shift to the right of the agonist dose-response curve with no change in the maximal response (Figure 1-10A). The magnitude of the rightward shift of the curve depends on the concentration of the antagonist and its affinity for the receptor.

FIGURE 1-9 Two ways of quantifying agonism. A. The relative potency of two agonists (drug x, gray line; drug y, blue line) obtained in the same tissue is a function of their relative affinities and intrinsic efficacies. The halfmaximal effect of drug x occurs at a concentration that is one-tenth the half-maximally effective concentration of drug y. Thus, drug x is more potent than drug y. B. In systems where the two drugs do not both produce the maximal response characteristic of the tissue, the observed maximal response is a nonlinear function of their relative intrinsic efficacies. Drug x is more efficacious than drug y; their asymptotic fractional responses are 100% (drug x) and 50% (drug y).

Log [Agonist] Log [Agonist]

FIGURE 1-9 Two ways of quantifying agonism. A. The relative potency of two agonists (drug x, gray line; drug y, blue line) obtained in the same tissue is a function of their relative affinities and intrinsic efficacies. The halfmaximal effect of drug x occurs at a concentration that is one-tenth the half-maximally effective concentration of drug y. Thus, drug x is more potent than drug y. B. In systems where the two drugs do not both produce the maximal response characteristic of the tissue, the observed maximal response is a nonlinear function of their relative intrinsic efficacies. Drug x is more efficacious than drug y; their asymptotic fractional responses are 100% (drug x) and 50% (drug y).

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