PHARMACODYNAMICS OF CALCIUM BLOCKERS IN ASTHMA

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Altered regulation of intracellular calcium is probably the final common pathway for the pathogenesis of asthma. However, the role of calcium channel blockers in this disease has not been defined. This study proposes to investigate, in a logical and systematic manner, the potential efficacy and safety of this group of drugs in controlling the symptoms of chronic asthma, and to evaluate the usefulness of methacholine-induced bronchoconstriction for selecting a clinically effective member of this class, route, dose and frequency of administration. In the first phase, three groups of ten patients with chronic asthma will receive, on seven separate days, placebo and graded doses of either inhaled verapamil, inhaled diltiazem or oral diltiazem;one drug per group. A bronchial provocation test with methacholine will be performed before and after each dose. ECG, blood pressure and the presence of subjective complaints of side effects will be monitored at intervals to determine the safety of each dose. Blood samples will be obtained at intervals to measure verapamil, diltiazem and metabolite serum concentrations. The dose of each drug that produces maximum blocking effect without toxicity will be used for Phase II. In this phase, the effect of inhaled verapamil, oral and inhaled diltiazem and placebo in blocking the bronchoconstrictor response to methacholine will be determined in a double-blind randomized cross-over manner in 40 patients with chronic asthma. On four separate days serial methacholine challenges will be performed, serum concentrations measured, and toxicity assessed at 2 hour intervals for a 12 hour period after the dose. The area under the response-time curve will be used to determine the relative intensity and durationof each regimen. In the third phase, 40 patients will be treated for three one month periods with placebo and the two active drug regimens in Phase II that were judged least effective and most effective, in a randomized double-blind cross-over manner. The dose and frequency of administration will be the same as those used in Phase II. The frequency of asthmatic symptoms, adverse effects, peak expiratory flow rate, and the need for inhaled beta agonists and additional medicatons for acute symptoms will be recorded by the patinets in a diary twice daily. In addition, patients will be seen at two week intervals for evaluation, spirometry, a standardized exercise stress test, serum level measurements, and compliance check.