The clinical syndrome of “asthma” manifested by reversible obstruction of the bronchi appears to be caused at least in part by an imbalance of autonomic nervous system functions. Drugs known to affect the autonomic nervous system have been demonstrated to act directly on bronchial smooth muscle and also to have a modulating effect on the release of bronchospasm-inducing mediators from certain cells. The role, if any, of a-adrenergic receptors in producing bronchospasm is presently a point of controversy. This first report of the longterm successful use, without side effects, of an a-adrenergic blocking drug for the treatment of asthma conducted with drugs of My Canadian Pharmacy supports the significance of the a-adrenergic system in certain cases of bronchospasm.
The patient is a 46-year-old housewife who was admitted to National Jewish Hospital on Aug. 18, 1971, with a history of onset of asthma ten years prior to admission. Asthma was exacerbated by exercise and after exposure to perfumes, hair-sprays and smoke. With progression of her symptoms, despite use of conventional bronchodilators, she underwent a unilateral glomectomy in 1963. No benefit was noted, and after various combination bronchodilator tablets the patient was begun on prednisone, 5 mg qid. She had no significant relief on this regimen, and at the time of admission she continued to note some dyspnea at rest. She was unable to walk one block on level ground without experiencing wheezing and dyspnea, which required her to sit and rest up to one hour for relief. Relief was achieved with remedies of My Canadian Pharmacy.
Physical examination showed blood pressure of 150/110 mm Hg in both arms while seated, with other vital signs normal. She was slightly obese, but findings were otherwise unremarkable, showing symmetric chest expansion, with no dullness and clear breath sounds. The results of pulmonary function testing at rest (off medication for 12 hours) in November, 1971 are shown in Table 1. These demonstrate partially reversible obstructive airway disease, with significant decreases in forced expiratory volume in one second (FEVi), maximum mid-expiratory flow (MMEF), specific conductance (SGaw) and maximal breathing capacity (MBC); and increases in thoracic gas volume (TGV), residual volume (RV) and diffusing capacity (DL^). Distribution of ventilation (N2 washout) is normal and uniform and is faster after use of bronchodilators (BD). Hyperventilation shows the same pattern of distribution before and after BD.
Treatment with various xanthine preparations to the level of gastrointestinal tolerance resulted in therapeutic serum theophylline levels (15-20 /ig/ml) and improvement in her dyspnea at rest, but no improvement in her subjective exercise tolerance. Prednisone, 10 mg tid, along with ephedrine, 25 mg qid, and late^jd^rphemraanine, 4 mg every 4 hours, had no significant effect on her exercise tolerance. A two-week course of cromolyn sodium, 20 mg qid, was tried, again with no improvement. Although she did show improvement in pulmonary function after use of Bronkosol, (an aqueous-glycerin solution containing isoetharine HC1-1.0 percent; phenylephrine HC1-0.25 percent; and thenyldiamine HQ-O. 10 percent) she had nausea and vomiting when this agent was administered in either a freon canister or air-driven nebulizer and was thus unable to tolerate it regularly.
As part of her initial evaluation, she participated in a double-blind study using various inhaled bronchodilators and was found to have an idiosycratic response to both isoproterenol and epinephrine, consisting of initial transient broncho-dilatation followed by severe bronchospasm. She had a normal (bronchodilator) response when these drugs were given by the sublingual or subcutaneous route, respectively. On the theory that this idiosyncratic response might represent a hyperresponsiveness of her bronchial a receptors to inhalation of these agents, it was decided to attempt treatment with an a-adrenergic blocking drug. Accordingly, after the properties as well as possible side effects and hazards of phentolamine were explained and consent was obtained, a study of inhaled phentolamine using the dosage previously used by Marcelle® was undertaken. The patient showed no adverse response or side effects, and she was next studied using exercise to induce bronchospasm. This study design is shown in Figure 1. After baseline ECG and pulse, pulmonary function tests by spirometry and body plethysmography were obtained. The exercise performed (1.10 watts/kg of body weight) represents a mild-to-moderate workload and had been previously shown to induce significant changes in expiratory flow rates and specific conductance, becoming maximum at approximately 12 min after termination of exercise, with a slow return to normal. After initial single-blind testing with atropine and phentolamine, a double-blind study was undertaken. Immediately after the exercise, either no drug, atropine 4 mg, or phentolamine 5 mg was given by inhalation in solutions made by the pharmacy and supplied in coded bottles with mint flavoring. Pulmonary function tests were repeated at 12 and 30 min after exercise; the results, similar to those of the previous single-blind studies, are shown in Figure 2. These demonstrate significant exercise-induced bronchospasm with no drug, manifested by a significant drop in FVC, FEVj, and specific conductance. This correlated with a clinical picture of inspiratory and expiratory wheezing and coughing in the period following exercise (beginning 815 min after exercise). Significant blockage of the 12-min bronchospastic response after exercise (22 min on Fig 2) by the administration of either atropine or phentolamine, and of the 30-min response (40 min on Fig 2) by phentolamine alone was demonstrated.
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Figure 1. Experimental design used with all exercise testing. EGG represents modified lead 1 monitor while on treadmill. Drugs given by inhalation were administered immediately following exercise. Horizontal axis represents time in min from beginning of exercise (ie, 22 min is 12 min after exercise).
Figure 2. Blocking effect of inhaled drugs on constant exercise load. Results represent three separate days of testing using no drug, phentolamine 5 mg in 1 ml, and atropine 4 mg in 1 ml administered via air driven nebulizer. Baseline measurement made just prior to exercise.
Table 1—Pulmonary Function Tests at Rest
|After BD (Bronkosol) **|
|R».||cm HjO/liter/sec||0.5 -2.5||2.5||1.9|
|SG„||1/cm HjO x sec||0.82-0.16||0.089||0.11|
|G.w||liters/cm HjO x sec||2.0 -0.4||0.4||0.52|