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American Journal of Respiratory and Critical Care Medicine Vol 165. pp. 1353-1358, (2002)
© 2002 American Thoracic Society

Pulmonary Perspective

ß-Agonist Intrinsic Efficacy

Measurement and Clinical Significance

Nicola A. Hanania, Amir Sharafkhaneh, Roger Barber and Burton F. Dickey

Section of Pulmonary and Critical Care Medicine, Department of Medicine, Baylor College of Medicine and the Houston Veterans Administration Medical Center; and Department of Integrative Biology, Pharmacology and Physiology, University of Texas-Houston Health Sciences Center, Houston, Texas

Correspondence and requests for reprints should be addressed to Nicola A. Hanania, M.D., Pulmonary and Critical Care Medicine, Baylor College of Medicine, 1504 Taub Loop, Houston, TX 77030. E-mail: Hanania{at}bcm.tmc.edu

ß2-Adrenoceptor agonists (ß-agonists) are the most powerful known bronchodilators, and numerous agents of differing pharmacologic properties are available for clinical use (1–4). Clinicians typically base their choice of a particular agent on the parameters of receptor selectivity and duration of action, but rarely consider intrinsic efficacy. However, a major pharmacologic difference between the long-acting ß-agonists salmeterol and formoterol is the dramatic difference in their intrinsic efficacies. Thus, rational choice between these two agents depends on understanding the clinical significance of this difference. More broadly, possible deleterious effects of the use of ß-agonists on asthma control are often ascribed to the entire class of drugs without consideration of pharmacologic differences among them. In this regard, it is remarkable that both of the New Zealand asthma mortality epidemics were associated with the use of high-dose formulations of ß-agonists of high intrinsic efficacy (first isoproterenol, then fenoterol) (5). However, despite this negative association, an agonist of high intrinsic efficacy might offer advantages in clinical effectiveness over a weak partial agonist. For example, epinephrine and isoproterenol have much higher intrinsic efficacy than albuterol and could be expected to be more clinically effective in severely decompensated asthma in an emergency setting. Because of the potential significance of ß-agonist intrinsic efficacy, both for current treatment of asthma and chronic obstructive pulmonary disease and for ongoing clinical research, we review its pharmacologic determination and clinical implications.

MEASUREMENT OF ß-AGONIST INTRINSIC EFFICACY

Several parameters have been used traditionally to characterize the interaction of a drug with its target receptor. These include affinity, potency, and efficacy (Figure 1) (2, 6, 7). Affinity refers to the attraction between a drug and its receptor, and it can be measured either kinetically as the ratio of the drug–receptor association and dissociation rates or at equilibrium as the dependency of receptor occupancy on drug concentration. Both forms of measurement yield the same value, and this is most commonly expressed as the dissociation constant (KD). Potency refers to the dependency of receptor activation on drug concentration, and this is most commonly expressed as the concentration of a drug that achieves half the maximal receptor activation of which that drug is capable (EC50). A drug's potency depends both on its affinity for its receptor and on its efficacy (see EFFICACY, following paragraph). Although potency is an important parameter in preclinical drug development, because it indicates that a compound both interacts with a target with high affinity and interacts functionally, it is relatively unimportant clinically because it makes little difference to a patient whether he or she takes 100 or 1 mg of a drug if the therapeutic ratio of desired effect to undesirable side effects is the same.



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  		Figure 1. Dose-response relationships illustrating the difference between potency and efficacy. Receptor activation, measured as a downstream effect such as cAMP level, is indicated on the vertical axis; drug concentration, expressed logarithmically, is indicated on the horizontal axis. Drug A is more potent than drug B; drug C is more efficacious than drug D; drug E is more potent, but drug F is more efficacious.

 
Efficacy refers to the ability of a drug to activate its receptor, without regard for drug concentration. In other words, even though it may require a higher concentration of one drug than another to saturate a receptor, if the drug of lower affinity ultimately causes greater receptor activation, it is more efficacious (Figure 1). The drug that most completely activates a receptor is referred to as a full agonist (epinephrine for the ß2-adrenoceptor), and drugs that only partially activate a receptor are referred to as partial agonists. Colloquially, partial agonists of low efficacy are referred to as "weak partial agonists," and partial agonists of high efficacy as "strong agonists." Receptor activation may be measured as a conformational change by physical techniques (e.g., change in intrinsic fluorescence of the receptor due to changes in the local environment of tryptophan residues), as a biochemical response to activation of the signal transduction pathway downstream of the receptor (e.g., change in the level of cAMP) (8), or as a physiologic response (e.g., change in smooth muscle relaxation in vitro or change in airway resistance in vivo) (9). If receptor activation is directly measured by a physical technique (e.g., receptor fluorescence), then measured efficacy accurately reflects the capability of the drug to activate the receptor. However, efficacy is most commonly measured by a downstream biochemical response (e.g., level of cAMP) or physiologic response (e.g., smooth muscle relaxation). In that case, measured efficacy very much depends on variable factors in the target cell, such as receptor number or the presence of functional antagonism (i.e., activation of an opposing signal transduction pathway). In a cell with high receptor numbers (i.e., a cell with numerous "spare receptors," also described as high "receptor reserve"), activation of only a small fraction of receptors suffices to generate a full response (Figure 2) . Conversely, in a cell with low receptor number and functional antagonism (e.g., a desensitized smooth muscle cell with acetylcholine-induced elevation of intracellular calcium), activation of even a high fraction of receptors may not yield a full relaxation response. Thus, measurement of drug efficacy can be highly variable depending on tissue conditions (10). Receptor number is particularly important in this regard, but the relative abundance of other components of the signal transduction pathway and the level of activation of antagonistic pathways also play substantial roles. It may seem surprising that, despite long being aware of tissue dependency in analyzing drug efficacy by biochemical or physiologic measurement (11, 12), pharmacologists have not made widespread use of a formulation to express the capability of a drug to activate a receptor independent of particular tissue conditions—that is, a formulation of "intrinsic efficacy" (also termed "intrinsic efficiency" or "intrinsic activity"). For the most part, this was due to the difficulty of verifying experimentally the validity of theoretic models. In 1966, Furchgott used the alkylating agent dibenamine-HCl to inactivate receptors in a variety of adrenergic and cholinergic tissue preparations, including contractile responses of aortic strips to epinephrine, contractile responses of gastric smooth muscle strips to carbamylcholine, and negative inotropic responses of electrically driven reserpinized guinea pig left atrium to carbamylcholine (11). He then followed the rightward and downward shifts in the tissue effect curves (see Figures 1 and 3) and developed a semiempirical equation to describe the data. The possibility of unintended effects of dibenamine-HCl and the other agents used in these studies on tissue components other than the targeted receptors limited confidence in the results. Nonetheless, this equation was subsequently used successfully to analyze the magnitudes of changes in cellular responsiveness after ß2-adrenoceptor desensitization (13, 14). More recently, the advent of techniques of molecular biology provided the means to rigorously test theoretic models, reigniting interest in formulating intrinsic efficacy in terms of readily measured pharmacologic parameters. For example, to test the independence of measurements of intrinsic efficacy from variation in receptor number, DNA encoding the ß2-adrenoceptor could be transfected into cells, and determinations of intrinsic efficacy based on measurements in several cell lines with varying receptor number could be compared.



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  		Figure 2. Schematic representation of the effects of receptor density and functional antagonism on drug efficacy. On the left is illustrated a cell with relatively high receptor density (e.g., naive airway smooth muscle), and on the right is illustrated a cell with relatively low receptor density (e.g., skeletal muscle, inflammatory cell, or desensitized airway smooth muscle). The full agonist in the top row succeeds in activating most receptors to which it binds, whereas the partial agonist in the bottom row activates only a fraction. The full agonist (top row) causes a strong intracellular signal in cells with high receptor density and in cells with low receptor density. However, the partial agonist generates a strong intracellular signal only in cells with high receptor density (bottom row, left). For each scenario, the final tissue response can be reduced by the presence of functional antagonism (i.e., activation of a signal transduction pathway that antagonizes the effect of the ß2-adrenoceptor pathway downstream of the receptor itself). In the airway wall, this is commonly due to acetylcholine, histamine, and cytokines. During an asthma exacerbation, in which there is a reduction in receptor number due to desensitization from the use of rescue medication and functional antagonism from the presence of inflammatory mediators, a full ß-agonist may yield only a partial tissue response, and a partial ß-agonist may yield little or no tissue response.

 


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  		Figure 3. Graphic illustration of drug intrinsic efficacy in terms of receptor occupancy and tissue effect. (A) A drug of low intrinsic efficacy, with relatively little distance between the curves. Thus, drug occupancy of a relatively large fraction of receptors is required to achieve a large effect. (B) A drug of high intrinsic efficacy, with greater distance between the "effect" and "binding" curves. Thus, drug occupancy of only a small fraction of receptors results in a large tissue effect.

 
The derivation of one such formulation of intrinsic efficacy (8), which has been empirically verified by DNA transfection technology (10), is provided in the APPENDIX in the online data supplement. In brief, the difference between affinity (KD) and potency (EC50) is compared for each drug, with more efficacious drugs having greater differences (Figure 3). In other words, highly efficacious drugs (i.e., strong agonists) need to occupy only a small fraction of receptors to achieve the same effect that weak partial agonists achieve by occupying many more receptors. The following formula expresses the ratio of the intrinsic efficacies of any two ß-agonists as a fraction between 0 and 1:

If the full agonist epinephrine is included in the analysis and designated as "drug 2," then the resulting ratio, generally expressed as a percentage, is a convenient measure of the intrinsic efficacy of "drug 1." An alternative formula, useful in conditions of low receptor number or low effector response, is given in the APPENDIX in the online data supplement (Equation E9), as is a simplified version of the above formula that can be used in the common situation wherein KD exceeds EC50 for both drugs by more than 10-fold (Equation E10).

Desensitization refers to the reduced responsiveness of a tissue to an agonist on continued or repeated exposure to an agonist (synonyms include tachyphylaxis and subsensitivity). This occurs by a variety of molecular mechanisms including ß2-adrenoceptor uncoupling from the downstream G protein by a combination of receptor phosphorylation, ubiquitination, and binding of the adaptor protein ß-arrestin; receptor internalization via clathrin-mediated endocytosis; and downregulation of total cell receptor number due to a combination of accelerated receptor degradation and reduced synthesis (9, 15, 16). The rate at which a ß-agonist drives receptor desensitization parallels the agonist's intrinsic efficacy (15), indicating that the active conformation of the receptor, which couples with the downstream signal transduction pathway, is also recognized by the cellular desensitization machinery. Similar to the situation with efficacy, the rate and extent of apparent desensitization induced by a ß-agonist vary with tissue conditions. In tissues with numerous "spare receptors," loss of activity of a substantial fraction of receptors by one or more molecular mechanisms of desensitization (such as phosphorylation or internalization) may not cause loss of tissue responsiveness if sufficient coupled receptors remain. Thus, desensitization to different endpoints can develop at different apparent rates, reflecting different levels of receptor reserve in different tissues, such as mast cell stabilization (mast cells have low receptor reserve) versus bronchodilation (airway smooth muscle cells have high receptor reserve). In addition to high receptor reserve, airway smooth muscle is relatively resistant to desensitization because of limited expression of critical components of the desensitization machinery (16, 17) and expression of relatively high levels of ß2-adrenoceptor mRNA (9).

CLINICAL SIGNIFICANCE OF ß-AGONIST INTRINSIC EFFICACY

The intrinsic efficacies of commonly used ß-agonists are listed in Table 1, and these can be seen to vary greatly. For example, the intrinsic efficacy of albuterol is only 5% that of epinephrine (18). Stated otherwise, epinephrine will activate 20 times more ß2-adrenoceptors than albuterol when both drugs occupy the same number of receptors. In view of these striking differences in intrinsic efficacy, it is worth considering the clinical implications. As with any class of drugs, the therapeutic goal with ß-agonist use is achievement of maximal therapeutic effect with minimal undesirable side effects. There are several areas in which ß-agonist intrinsic efficacy should inform the clinical choice of a particular agent.


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  		TABLE 1. Intrinsic efficacies of some commonly used ß-agonists*

 
Target Effect
The principal therapeutic effect of ß-agonists is relaxation of airway smooth muscle. Because of the high density of ß2-adrenoceptors on airway smooth muscle cells (see Figure 2), ß-agonists of low intrinsic efficacy give an excellent clinical response in most patients with asthma most of the time (see, for example, the large trials of salmeterol) (19, 20). However, there is evidence that agonists of higher intrinsic efficacy elicit a greater response in some settings. In dose–response studies, there occurs a plateau in the effect of the weak partial agonist, albuterol, at a lower level of bronchodilation compared with the strong agonist, fenoterol (21–23). Differences in the responses to partial and full agonists become particularly apparent in situations of functional antagonism. This phenomenon can be likened to revealing a subtle degree of muscular weakness by having a patient lift a weight when the weakness is not apparent with a simple arm raise. In the presence of a bronchoconstrictive stimulus, such as methacholine, there is considerably greater bronchoprotective effect of the strong agonist formoterol than of the weak partial agonist salmeterol with repetitive dosing (24) (even though these drugs show similar bronchodilating and bronchoprotective effect with routine dosing [25–27]).

It is thus possible that patients with more severe asthma, or those expressing ß2-adrenoceptor alleles that are less readily activated by ß-agonists (28–30), will show a greater response to a stronger agonist. In the maintenance setting, a well-controlled head-on comparison of long-acting ß-agonists with different intrinsic efficacies (i.e., salmeterol and formoterol) in patients with asthma stratified according to disease severity and genotype might show a difference in therapeutic effect in some groups. Three multicenter prospective studies demonstrated a trend toward superiority of formoterol over salmeterol, but patients in these studies were not stratified according to genotype or disease severity, and the studies were open label (31–33). Intriguingly, several case reports describe bronchodilator responses to formoterol in patients with severe, persistent asthma who failed to respond to salmeterol (34). In patients with moderate to severe chronic obstructive pulmonary disease, treatment with the combination of formoterol and ipratropium was more effective than the combination of albuterol and ipratropium (35).

In the emergency setting, most individuals with asthma will respond to a partial agonist, such as albuterol or terbutaline. However, those patients that fail to respond to a partial agonist might respond to stronger agonists such as epinephrine, isoproterenol, fenoterol, or formoterol, reducing the need for intubation and mechanical ventilation (23, 36). Thus, prospective trials designed to clarify the utility of ß-agonists of different intrinsic efficacies in the maintenance and emergency settings are needed.

Desensitization
Extensive data from in vitro experiments indicate that full ß-agonists drive more rapid receptor desensitization than partial agonists (9, 10, 15–17). However, the maximal extent of desensitization in airway smooth muscle cells is markedly limited by a variety of molecular mechanisms, as mentioned above. Despite the nonprogressive nature of airway smooth muscle desensitization that tends to blur differences among agents of different intrinsic efficacy, examination of the clinical literature reveals examples suggesting the clinical relevance of the in vitro observations. Two large, prospective trials examining maintenance use of salmeterol in asthma showed sustained bronchodilation effect from the first through the last day of the trial (19, 20). In contrast, a prospective trial of the strong agonist formoterol showed dramatic improvement in expiratory airflow on the first study day, followed by a progressive loss over the next 1 to 2 weeks such that approximately 50% of the initial improvement was lost (37). The level of desensitization then reached a plateau, and the formoterol-induced improvement in airway function remained stable for the rest of the study. It is also important to note that desensitization occurs even with ß-agonists of low intrinsic efficacy; under conditions of functional antagonism, such as exercise (38, 39), antigen (40), or methacholine challenge (41), some loss of the bronchoprotective response of the weak partial agonist salmeterol is consistently observed.

The clinical significance of the desensitization induced by ß-agonists is not well understood. It is possible that some of the loss of asthma control observed with the regular use of ß-agonists in some studies is due to receptor desensitization, and that this effect is worse with a strong agonist. Of interest is the observation that both of the asthma mortality epidemics in New Zealand were associated with the use of strong agonists (5). There is also evidence that the effects of receptor desensitization on airway function and symptom control vary with allelic variants of the ß2-adrenoceptor that have different susceptibility to desensitization (28, 42). Thus, it is possible that patients with highly desensitizing ß2-adrenoceptor alleles will experience better asthma control with an agonist of low intrinsic efficacy that induces a lower rate of desensitization. On the other hand, the greater therapeutic effect of a strong agonist may outweigh its effect on desensitization even in patients with highly desensitizing alleles. This provides an additional rationale for a head-on comparison study of asthma control using maintenance ß-agonists of differing intrinsic efficacies in patients stratified according to ß2-adrenoceptor genotype.

A distinct issue is whether chronic treatment with a long-acting ß-agonist of low intrinsic efficacy, such as salmeterol, may antagonize the response to a short-acting rescue ß-agonist of higher intrinsic efficacy, such as albuterol. Considerable debate has swirled around a study that showed a lower fractional response to rescue ß-agonist in this setting (43), but this may have been due to higher baseline lung function from the maintenance ß-agonist. Other short-term studies failed to demonstrate this phenomenon (44, 45). Clearly, antagonism of agonists of high intrinsic efficacy by agonists of lower intrinsic efficacy can be demonstrated in vitro, but this phenomenon depends on a high level of receptor occupancy that may not occur in vivo, and a real-life study demonstrated that chronic use of salmeterol does not interfere with the effects of standard doses of albuterol for the treatment of acute asthma (46).

Nontarget Effects
Extrapulmonary side effects.
Nontarget tissues, such as skeletal muscle and the heart, have a lower ß2-adrenoceptor density than airway smooth muscle (9, 16). This accounts, in part, for the excellent side-effect profile of partial agonists such as albuterol, because there are sufficient spare receptors in the target tissue for full cell activation by a partial agonist but not in nontarget tissues (Figure 2). Furthermore, the desensitization that occurs during the first few days of regular use of a ß-agonist results in further reduction in the responsiveness of nontarget tissues, accounting for the commonly observed resolution of side effects, such as tachycardia and tremor, after the first few doses. In view of the low receptor density of nontarget tissues, it might be expected that full ß-agonists would elicit a greater response than partial agonists, and this is indeed the case. In dose-response studies, strong agonists have been demonstrated to be capable of causing more severe side effects, such as greater tachycardia and reduction in serum potassium, than weak partial agonists (23, 24).

Although some degree of side effects from ß-agonist use is tolerable in an acute situation to achieve a critical therapeutic effect, the acceptable therapeutic ratio shifts in less urgent settings. For maintenance use, the available long-acting ß-agonists, salmeterol and formoterol, both induce very mild side effects at Food and Drug Administration–approved doses, probably because of limited release from the lung because of their lipophilicity. For example, no significant change in heart rate was detected with salmeterol at 50 µg or formoterol at 12 µg, inhaled twice daily, compared with placebo (47, 48). However, a subtle degree of difference may be important for patients with comorbidity, such as heart disease, or for patients with great subjective sensitivity to drug side effects (49). In the emergency setting, the risk of side effects from an agonist of high intrinsic efficacy needs to be weighed against the potential benefit, taking into account that most deaths from asthma appear to be asphyxic rather than cardiac (50).

Effects on immune cells and nontarget effects on lung cells.
Immune cells and lung epithelial, endothelial, and mesenchymal cells all express ß2-adrenoceptors, and activation of these receptors has the potential to modulate the asthma phenotype. In airway epithelium, for example, ß-agonists accelerate ciliary beat frequency, increase epithelial fluid secretion, and promote metaplasia of ciliated airway epithelial cells to mucus-secreting goblet cells (9, 51). Whether the net effect of these activities is to relieve or exacerbate airflow obstruction in vivo is not clear. Similarly, ß-agonists augment the release of some inflammatory mediators from parenchymal and immune cells while suppressing the release of others and have complex effects on endothelial cells (9, 51). Because it is impossible to predict from in vitro activities of ß-agonists toward individual cell types their net effect on the asthma phenotype in vivo, the effects of ß-agonists on inflammation and other phenotypic changes, and on global asthma control, must be directly measured in animals and patients. Differential effects from ß-agonists of different intrinsic efficacies can be anticipated because of the low ß2-adrenoceptor density of immune cells and lung parenchymal cells other than airway smooth muscle cells and their propensity for marked desensitization. Thus, head-on comparisons of ß-agonists with differing intrinsic efficacies in the maintenance treatment of asthma may reveal differences in asthma control associated with differential effects on immune and parenchymal cells, and these may vary according to disease-causing alleles and environmental stimuli.

CONCLUSION

Intrinsic efficacy is a key pharmacologic parameter that differs dramatically among available ß-agonists. In the maintenance setting, salmeterol has low intrinsic efficacy (i.e., is a weak partial agonist, with intrinsic efficacy less than 2% relative to epinephrine), whereas formoterol has relatively high intrinsic efficacy. The clinical implications of this difference will not be known with certainty until the drugs are directly compared in controlled trials. It can be expected, however, that more severely affected patients with asthma and chronic obstructive pulmonary disease will show greater responses to formoterol, whereas patients having problems with side effects might do better with salmeterol. In the emergency setting, epinephrine and isoproterenol are full agonists and fenoterol is nearly a full agonist, whereas albuterol is a partial agonist with only 5% of the intrinsic efficacy of epinephrine or isoproterenol. Again, the clinical importance of this difference needs to be rigorously tested in controlled trials, but in the meantime it is reasonable to use one of the short-acting ß-agonists of high intrinsic efficacy in a final effort to avert intubation. Patients admitted to the hospital with decompensated asthma or chronic obstructive pulmonary disease might derive greater benefit from regular administration of the strong agonist formoterol than the partial agonist albuterol.

The Food and Drug Administration and other drug-licensing agencies should require pharmaceutical companies to measure the intrinsic efficacy of all approved ß-agonists for which it is not already known and require inclusion of this information in package inserts. Widely used pharmacology and formulary texts should also include this information so that it is readily available to clinicians and clinical researchers.

Acknowledgments

The authors thank Dr. Elliott M. Ross for his helpful comments.

FOOTNOTES

This article has an online data supplement, which is accessible from this issue's table of contents online at www.atsjournals.org

Received in original form September 18, 2001; accepted in final form March 1, 2002

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