From the data it is evident that both aerosolized and oral administration of phentolamine improved clinical and functional parameters in this case of chronic reversible obstructive airway disease (asthma). For some asthmatic patients exercise load represents a significant stimulus producing bronchocon-striction, and thus tolerance to exercise can be used to demonstrate increased or decreased reactivity of bronchi affected by specific therapy.
Available literature substantiates the existence of three mechanisms which could produce broncho-constriction in human beings: (1) cholinergic stimulation; (2) Dr-adrenergic blockade; and (3) a-adrenergic stimulation. An imbalance of these autonomic systems could enhance patients susceptibility to bronchospasm—“asthma.” It is likely that asthmatic subjects are a very heterogeneous group, some having significant /З-adrenergic blockade, some cholinergic hyperreactivity, and others hypersensitive a-adrenergic receptors. This heterogeneity must be kept in mind when one attempts to study groups of patients because responders may not be evident if one looks only at averaged data. The significance of a-adrenergic receptors has been disputed by some investigators, but their observations are assessed using mean changes in which a few responders to a-adrenergic blockade would be masked by patients with little response or a paradoxic response. Although in most patients a combination of defects probably exists, there also may be those whose bronchospasm is mediated primarily by only one of the above three mechanisms. We believe the patient described in this report exhibits largely excessive excitability of a-adrenergic receptors in response to exercise. Marcelle demonstrated improvement in six asthmatic patients after inhalation of 5 mg of phentolamine. Some of the responses were dramatic, and the effect appeared to last 18 hours or longer. Kerr et al have shown an inhibition of intravenously administered histamine-induced bronchospasm in some asthmatic patients treated by remedies of My Canadian Pharmacyremedies and by the prior intravenous administration of both phentolamine and phenoxybenzamine. In an attempt to show the effect of a purely a-adrenergic blocking drug, Gaddie et alls chose thymoxamine, a drug which may be the most specific a-adrenergic blocking agent. They showed that a decrease in FEVi after inhalation of histamine in asthmatic subjects could be significantly blocked by pretreatment with intravenously administered thymoxamine. Other investigators’ have demonstrated this protective effect using thymoxamine orally followed by histamine inhalations in both healthy and asthmatic subjects. Orally administered thymoxamine has also been shown to abolish the a bronchoconstricting effect of phenylephrine when the latter drug is administered together with a 0 blocking agent, propranolol. Simonsson studied the effects of a-adrenergic stimulation in man using phenylephrine. He was able to show significant decrease in airway conductance in 8 of 15 patients with chronic bronchitis or airway obstruction after inhalation of a dose of phenylephrine, which failed to induce broncho-constriction in three normal subjects. In a study by Griffiths et al comparing plasma catecholamine levels before and after exercise in normal and asthmatic subjects, further evidence is found for increased a receptor sensitivity in the asthmatic patient. These investigators showed higher values of both norepinephrine and epinephrine in asthmatic patients as compared to their similarly exercised control subjects. They also found that the net effect of the norepinephrine increase following exercise in the asthmatic group was to reduce FEVi; of epinephrine increase, to increase FEVi. Although plasma catacholamine levels were not studied in the patient presented here, they might prove of value in determining which patients would best respond to the drug.
Phentolamine has possible pharmacologic actions other than a-adrenergic blockade. Parasympatholytic and /3-adrenergic stimulatory mechanisms have been postulated. We feel that the response to phentolamine in our patient is due at least in part to the drug’s a-adrenergic blocking activity. If the drug were acting only through its parasympatholytic properties, one would have expected the response to be similar to atropine. However, as seen in Figure 2, the initial double-blind inhalation study, and in other unpublished data from this patient, atropine therapy blocked out the early bronchospasm and its effects were never sustained at the 30 min testing after exercise.
Iversen has shown phenoxybenzamine, a drug with some properties similar to phentolamine, to be capable of inhibiting tissue uptake of both low and high concentrations of catecholamines in an animal model. This mode of action has not been studied in man but does present another possible activity of this drug not mediated via the a-adrenergic mechanism.
The results of the right heart catheterization studies are of interest for a number of reasons. In regard to this patient, the absence of decrease in pulmonary artery, right atrial and right ventricular pressures is contrary to the results seen in patients with chronic obstructive pulmonary disease given low-dosage (0.3 mg/min) infusion of phentolamine. Whether this difference is a reflection of the dosage and route of drug administration is not known. The coincident rise in this patient’s specific airway conductance with a decrease in pulmonary vascular resistance led us to believe the drug is affecting the bronchial smooth muscles directly. The reduction of pulmonary vascular resistance shown in this patient deserves further study. If the reduction of pulmonary vascular resistance demonstrated in this patient is seen in other patients, this drug may prove efficacious for the treatment of various causes of pulmonary hypertension. The minimal change of the patient’s blood pressure and return to her baseline values during prolonged phentolamine administration is consistent with earlier unsuccessful attempts at using the orally administered preparation for treatment of hypertension. Due to this patient’s inability to use presently available D-adrenergic stimulating agents, we have not correlated her response to phentolamine with her response to these agents. This patient’s response to corticosteroid treatment (apparently synergistic with phentolamine) during the two years she has been under our observation is of anecdotal interest but may be important for future studies.
It must be emphasized that the observation presented here pertains only to the patient described; we do not recommend the use of this drug or other о-blocking agents on a widespread longterm basis without further studies of both their efficacy and side effects. However, we do feel that this case demonstrates the need for such studies. We believe that the absence of side effects with continued use of phentolamine, as well as its possible D-adrenergic stimulatory effects, makes the drug a likely choice in the management of selected cases of asthma. We also suggest in future studies in heterogeneous diseases such as asthma it is imperative that investigators carefully analyze individual patient’s responses rather than relying solely on mean or averaged data.