Beta Adrenergic Agonists: Subsensitivity

Subsensitivity or tolerance is a diminished responsiveness which develops in many physiologic systems when receptors are repeatedly exposed to increased levels of their agonist either natural or administered. With chronic administration, subsensitivity develops to the beta adrenergic agonists and results in a reduced bronchodilator response. Ibis occurs over a period of one to two weeks and requires a similar period of time to reverse after the beta adrenergic drug has been discontinued. In vitro studies of tissue from patients in whom adrenergic subsensitivity has developed show markedly decreased numbers of available beta-adrenergic receptors and a similarly diminished generation of cAMP from ATP on stimulation of adenylate cyclase.

Since adrenergic subsensitivity is caused by decreased receptor density, it is not specific for any particular beta adrenergic agonist. Failure to completely exclude all adrenergic medication, oral and inhaled, for two weeks prior to initiating drug studies has resulted in failure to detect the development of subsensitivity during many drug trials.

What is the magnitude of the loss of the adrenergic bronchodilator response, and does it significantly reduce the clinical effectiveness of these medications? Table 1 summarizes some of the studies in which the development of adrenergic subsensitivity has been reported. It is evident that adrenergic subsensitivity occurs with both oral and aerosol therapy. In these studies, the peak FEVj response declined by 14 to 58 percent, and the duration during which the FEV, remained more than 15 percent above the baseline was reduced even more, usually about 50 percent for long-acting bronchodilator s. Once subsensitivity develops to a particular dose, usually after one or two weeks, there is no further loss of bronchodilator effect with continuing observation for up to 12 months. In most patients, the beta agonists continue to be effective bronchodilators even after subsensitivity has developed. Perhaps the importance of recognizing the phenomenon of subsensitivity is to serve as a note of caution in assessing the findings of single-dose studies, particularly if there is no information on preceding adrenergic therapy. Since the duration of bronchodilation is reduced more than the peak, one should not expect patients to obtain the same prolonged bronchodilator effect during chronic administration that is often reported in the literature.

AerosolCorticosteroids have been reported to restore beta adrenergic responsiveness. Ellul-Micallef and Fench identified ten stable asthmatic patients who foiled to respond to inhaled isoproterenol. Following intravenous infusion of 40 mg prednisolone, eight of the ten became responsive to isoproterenol. There was some effect evident after one hour and it was even more marked in eight hours. Holgate et al induced adrenergic subsensitivity in normal individuals with aerosolized albuterol (Table 1). Six hours following intravenous administration of 200 mg hydrocortisone, their response to inhaled albuterol was restored to the original level. From the study by Weber et al (Table 1) it appears that low-dose alternate day and inhaled steroids, such as are ordinarily employed in the chronic treatment of patients with bronchial asthma, are not sufficient to prevent the development of adrenergic subsensitivity.

Since patients with status asthmaticus have many reasons for poor response to beta adrenergic bronchodilators, including mucosal edema and mucus plugging, they would not be expected to respond as dramatically to corticosteroids as did the patients of Ellul-Micallef and Holgate. Nevertheless, there is often a history of recent overuse of adrenergic bronchodilators, particularly by aerosol, in patients seen in emergency rooms, so an element of induced adrenergic subsensitivity may exist as well. Awareness that corticosteriods can restore adrenergic responsiveness in as little as one hour provides an additional reason for their prompt use in moderate doses in patients with exacerbations of asthma not responding to normal adrenergic therapy.

Previously published articles on the topic:

Beta Adrenergic Agonists
Beta Adrenergic Agonists: Specific Beta Adrenergic Bronchodilators
Beta Adrenergic Agonists: The Role of Beta Adrenergic Bronchodilators in the Treatment of Asthma

Table 1—Development of Subsensitivity with Long-term Administration of Beta-Adrenergic Bronchodilators

Author B-AdrenWashout RouteAdmin Drug Duration Change in Peak Bronchodilator Response Change in Duration of Bronchodilator Response
Nelson yes oral albuterol 1 week FE ^120% >6 hr to 5 hr
        12 weeks FEVj439%
Jenne inhaled oral terbutaline 2 weeks FEV1U4%
Holgate yes aerosol albuterol 4 weeks SGawi54%
Plummer inhaled oral fenoterol 3 months FEV1I31% but not signif tFEV1>15% 5 hr to 3V4 hr
  allowed oral ephedrine и tFEVi>15% 2 hr to Vi hr
Chervinsky® aerosol metaproterenol 2 months SigniftFEV1 4 hr-* 2 hr
      isoproterenol SigniftFEV| 3 hr-*5 min
Trautlein aerosol terbutaline 6 weeks FEV1I60%
Brandon aerosol fenoterol 3 months tFEVl 15% 4 hr-*2 hr
    aerosol isoproterenol tFEVt 15% 1 hr “*20 min
Miller yes oral fenoterol 6 weeks Reduced FEVi signify at 2 3 hr
      terbutaline ** FEVj signif! 1 at 2,3 4 hr
Branscomb yes aerosol fenoterol 3 months FEVjJ31% FEVt above baseline 6 hr-*3 hr
Van Arsdel yes oral fenoterol 3 months significant reduction
Weber* yes aerosol terbutaline 3 months FEVl*37% FEVj>15% 4 hr-*2 hr