Relationship Between Drug Concentration Receptor Occupancy and Response

The relationship between the interaction of an agonist with a receptor to produce a response was initially described by A. J. Clark (1937) using mass action principles [59]. According to Clark, an agonist drug, D, would interact with a receptor, R, forming a drug receptor complex [DR]. At equilibrium, the rate of drug-receptor complex formation would be equal to the rate of dissociation of the complex. The agonist, after binding to the receptor, would produce a conformational change in it, which would initiate the sequence of events that culminate in a biological response. The relationship between the concentration of agonist and the response reflected the mass action principles used to describe the interaction between two chemicals e.g. the drug and the receptor. The reversible interaction of a drug (D) and a receptor (R) to form a drug-receptor (DR) complex was represented as:

At equilibrium and according to mass action principles:

Kd represents the dissociation constant of the drug-receptor complex.

While the relationship between receptor occupancy and the response was not known, Clark [59] assumed that the ratio of the intensity of the drug effect (E) as a fraction of the maximum effect was proportional to the fraction of receptors occupied. He further assumed that when all the receptors were occupied, the maximal effect of the drug would be produced and there were no spare receptors, refer to Ruffolo [60]. If Emax is defined as the maximum effect that can be produced by the drug, this relationship between response and effect which may apparently resemble Michaelis-Menten postulate for enzyme substrate plot.

However, there are important differences between these two types of reactions. While the interaction between substrate and enzyme leads to the formation of product, the drug-receptor interaction initiates a series of molecular events that eventually culminate in a physiological response. Thus, the drug-induced response reflects the amplification of a series of chemical reactions that are initially triggered by the formation of the drug-receptor complex. These differences in drug-receptor interaction become important when attempts are made to determine the affinity of the drug for the receptor based on measuring a distant parameter called the response to the drug.

As indicated above, the concentration-response curve produced by an agonist will indicate EC50 values as well as a concentration which will produce a maximal drug effect. These response parameters to the percentage of receptors occupied by a drug. Thus, the EC50 of a drug should be produced when 50% of the receptors are occupied, and the maximum response should occur when the drug occupies all the receptors. Furthermore, differences in the EC50 among several drugs should reflect their affinity differences for the receptor being studied.

However, it has been found that the relationship between the effect of a drug, as a percentage of the maximal effect, and the percentage of receptors occupied by the drug is frequently not linear as expected from the assumptions underlying the kinetic parameters [60,61]. The problem is that equations derived by Clark [59] do not take into account several factors. For example, it is clear that receptor occupation by a drug is necessary but not sufficient to induce a response, since competitive antagonists can occupy receptors without inducing physiological responses. Thus, in order for a drug to produce a response, the receptor must not only be occupied by the drug but also be activated. That is, after receptor occupation, the conformation of the receptor has to be altered in a specific way in order to initiate the subsequent events that lead to the response. Drugs can show marked differences in their ability to activate the receptor and produce a response. Thus, many drugs can bind to the receptor, but the maximum response is lower than that produced by a full agonist. In practical terms, any drug that produces a maximum response that is 95% or less than that produced by a full agonist can be considered a partial agonist. The maximum response produced by a partial agonist may vary depending upon the number of spare receptors in a given tissue. For example, pilocarpine produces about 80% of the maximum response produced by carbachol when tested in the human iris, whereas it produces only 11% of maximum when tested in rabbit iris (Figure 5). These data are consistent with a greater proportion of spare receptors or second messenger systems that contribute to the functional reserve in the human iris compared to the rabbit iris.

The partial agonist concept, which encompasses an agonist whose degree of activity is lower than that produced by a full agonist, can be added to the initial reaction described for drug-receptor interaction as follows:

Figure 5. Effect of carbachol and pilocarpine in human (A) and rabbit (B) iris. Note that the effects of carbachol and pilocarpine are different in the two irides. Carbachol, a full agonist, appears to be more potent in the human iris than in the rabbit iris. Pilocarpine, a partial agonist, produces in the human iris a maximum response, which was 80% of that produced by carbachol. In contrast, the maximum response for pilocarpine in the rabbit iris was only 11% of that for carbachol. Figure is reproduced from Akesson et al. [62] with permission from Springer Verlag.

Figure 5. Effect of carbachol and pilocarpine in human (A) and rabbit (B) iris. Note that the effects of carbachol and pilocarpine are different in the two irides. Carbachol, a full agonist, appears to be more potent in the human iris than in the rabbit iris. Pilocarpine, a partial agonist, produces in the human iris a maximum response, which was 80% of that produced by carbachol. In contrast, the maximum response for pilocarpine in the rabbit iris was only 11% of that for carbachol. Figure is reproduced from Akesson et al. [62] with permission from Springer Verlag.

This reaction illustrates that after the drug (either agonist o partial agonist) binds to the receptor forming the drug-receptor complex (DR), the receptor becomes activated (forming DR*). The activated receptor then provides the stimulus that can trigger the subsequent intracellular steps leading to the response. According to this model, partial agonists differ from full agonists in that they are less able to convert the drug-receptor complex (DR) into the "activated drug-receptor complex" (DR*) and, therefore, produces a weaker effect.

The existence of drugs with partial agonist activity indicates that the effect produced by an agonist depends not only on the number of receptors occupied by the drug but also on the ability of the drug receptor complex to produce a significant conformational change in the receptor triggering a receptor mediated response. This latter effect has been termed intrinsic activity by [63] and has also been given the symbol a. If intrinsic activity (a) is expressed in the dose-response equation, the ratio of the effect (E) of the drug to the maximum effect (Emax) that can be produced is:

This equation indicates that the effect of the drug is equal to the product of the proportion of receptors occupied and the intrinsic activity. Rt represents total receptors in the organ. Substituting for Rt:

As shown previously, the curve produced by plotting the response to an agonist as a fraction of the maximal response against a log concentration of the agonist is sigmoidal. The curve for a partial agonist would be similar to that for a full agonist except that the maximum response would be smaller. That is, when the partial agonist occupies 100% of receptors, the response that it produces would be less than the full tissue response. The intrinsic activity (a) of a partial agonist is evaluated as the ratio of the maximal response of a full agonist. For full agonists, a equals 1, while for partial agonists, 0 < a < 1. For antagonists, which can bind to the receptor but do not produce any response and, therefore, have no intrinsic activity, a equals 0.

The concept of intrinsic activity is based on the assumption that the intensity of the drug-induced response is proportional to the percentage of the receptors occupied and that the maximum response to a full agonist will be produced when all the receptors are occupied. Thus, this equation does not take into account the existence of spare receptors, which are present in many tissues [61]. This concept will be discussed below.

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