Figure 2 compares the onset and duration of bron-chodilation and the relative doses required when the same drug, terbutaline, is administered by mouth, by injections, and by inhalation.
The catecholamines, epinephrine, isoproterenol and isoetharine, are too rapidly degraded by COMT to be effective by mouth. Even noncatecholamine adrenergic bronchodilators undergo significant conjugation and inactivation in the gut wall and liver, so the oral dose is quite large. When specific betas agonists, such as albuterol or terbutaline, are given by mouth, the peak effect is usually achieved in two to four hours, and bronchodilation persists for four to six hours. In a study by Wilson et al in which the bronchodilator response to terbutaline was monitored during a year of therapy, the mean response to a 5 mg oral dose was an increase in FEVj of 23 percent, while 25 mg of ephedrine, in the same study, produced a mean increase in FEVj of only 12 percent.
While on theoretical grounds terbutaline should be superior to epinephrine for parenteral use, comparative studies employing conventional doses have not clearly shown an advantage in the incidence of side eifects or in the magnitude or duration of bronchodilation. The report by Pang and colleagues suggests that terbutaline may be employed in considerably larger doses than would be considered with epinephrine. They administered up to 0.04 mg/kg at ten to 15-minute intervals in children with status asthmaticus. One ten-year-old patient received a total of 10.2 mg over a period of three and three-quarter hours. Nine of the ten children, all refractory to aminophylline and conventional doses of epinephrine, responded to this regimen. This study suggests that the dosage schedule recommended for terbutaline may not fully exploit its betas selectivity.
The advantage of administration of beta adrenergic bronchodilators by inhalation is evident in Figure 2. The onset is rapid, the bronchodilation produced is prolonged, and the therapeutic ratio of bronchodilation to side effects is greatly increased over the other routes of administration.
By inhalation, the catecholamines isoproterenol and isoetharine, produce maximal bronchodilation by five to 15 minutes, following which the effect progressively declines and is usually undetectable between one and two hours following administration. The noncatecholamine beta adrenergic agonists are only slightly less rapid in onset, with 75 percent of maximum effect attained by five minutes, peak bronchodilation is attained between 30 and 90 minutes, and there is little loss of effect until after four hours.
An unresolved question is the proper aerosol dose for the selective betas adrenergic agonists. When these drugs are given orally, the occurrence of side effects generally limits the dose to one producing considerably less than maximal bronchodilation. This constraint does not exist when these agents are inhaled, since side effects are rarely experienced with normally recommended doses. Some investigators have reported that maximal bronchodilator effect is achieved with doses of the selective betas agonists which are even less than those ordinarily employed. It is likely that these reports can be credited to a failure to appreciate that bronchodilation is related to the log of the dose (Fig 3), and if the dose is plotted arithmetically, there will be an apparent asymptote. Tbree observations may be made from Figure 3, which shows the dose response to aerosolized terbutaline delivered by metered dose inhaler, IPPB, and compressor powered nebulizer. First, there is no advantage to IPPB over the pressure nebulizer; second, six to eight times as large a stated dose must be employed with either nebulizer compared to the freon-propelled inhaler for the same degree of bronchodilation (and, therefore, for the same amount of deposition in the lungs); and finally, the bronchodilator response continued up to the maximum doses which were tested. Ibese curves were generated by administering doses at 20-minute intervals and constructing a cumulative dose response curve. Hie same results have been obtained in a large group of patients given individual doses of albuterol of increasing size on separate days. In that study there was a linear bronchodilator response to the maximum dose of eight inhalations from a metered dose inhaler or 15 mg by IPPB. Side effects were not encountered with the metered dose inhalei; but were seen with increasing frequency at the higher doses by IPPB. Read all articles on the theme – “Bronchial Asthma“.
Despite obvious advantages in the ratio of bronchodilation to side effects with administration of beta agonists by inhalation, there are other factors which should be considered before embracing aerosols as the exclusive route of administration. When the drug is given by mouth or injected, only the most unusual circumstances will prevent the drug from reaching the adrenergic receptors in the lung. By inhalation, however, especially with the freon-propelled device, careful coordination between actuation and breathing, slow inhalation, and breathholding are required for optimal or even predictable results. A number of recent surveys have documented the frequency of patient error in using these devices. In one survey of 30 regular users of metered-dose inhalers, 14 made major errors, most commonly inhaling completely prior to actuating the device, and second most commonly actuating the device and holding the breath without inhaling. Difficulty with use of inhalers is encountered most commonly, but not exclusively in the young and old. Another reason for caution in relying solely on aerosol therapy is the potential for abuse of this form of treatment especially by teenagers.
Another consideration in reliance on aerosol administration for bronchodilator therapy is the uncertainty of the penetration of aerosols into the peripheral airways. There is no doubt that in stable asthmatic patients, properly inhaled beta-adrenergic agonists can penetrate small airways, since they have been demonstrated to decrease frequency dependence of compliance. Also in a study in patients with acute severe asthma aerosolized albuterol administered by tight-fitting mask relieved paradoxic pulse more effectively than did intravenous albuterol, while causing far less cardiac stimulation. On the other hand, it would not be surprising if inhaled medication failed to penetrate uniformly the distal airways in this disease which is characterized by mucus plugging and uneven distribution of inspired air even in relatively asymptomatic patients. There are studies which lend support to this concern. They show that for the same degree of dilation of large airways, parenterally-admin-istered drug produced greater dilation of small airways than did the same drug by inhalation.
Because of evidence suggesting more effect on peripheral airways with oral medication, Thiringer and Svedmyr have suggested that a proper approach to the chronic use of adrenergic bronchodilators in patients requiring continuous therapy would be to employ oral therapy with aminophylline, a beta agonist, or both in doses which do not cause troublesome side effects and, if significant symptoms persist, to employ the inhaled beta adrenergic agonists on a regular basis.
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Figure 2. Changes in forced expiratory volume in one second (FEY^ following three different routes of administration of terbutaline. (Dulfano MJ, Glass P. Ann Allergy 1976; 37:357, by permission)
Figure 3. Comparison of changes in FEVtwith repeated doses of isoproterenol 0.1 mg, terbutaline 0.125 mg, and terbutaline 0.25 mg via pressurized canister aerosol, and terbutaline 1.5 mg aerosolized via COMP and IPPB. (Weber KW, Petty WE, Nelson HS. J Allergy Clin Immunol 1979; 63:116, by permission.)