Joseph J. Crowley

Impaired Bronchodilator Response to Albuterol in Healthy Elderly Men and Women

BACKGROUND Lymphocytes of normal elderly subjects and young asthmatics display dysfunctional beta-adrenoceptors. If beta-adrenoceptor dysfunction were found in senescent airways, it might help explain the pathogenesis of late onset asthma. METHODS The bronchodilatory effects of albuterol after methacholine-provoked bronchoconstriction were compared in 17 healthy young (age 20 to 36 years) and 17 healthy elderly (age 60 to 76 years) volunteer subjects. Albuterol was inhaled via dosimeter (initially 7.8 micrograms, doubling every 7.5 min) with forced expiratory flow at 50% vital capacity (FEF50) measured prior to each dose. Albuterol sensitivity was expressed as the cumulative logarithm of the area under the FEF50 recovery curve (AUC); a greater AUC meant lower sensitivity. On another study day, spontaneous recovery from methacholine was assessed similarly. RESULTS There was no intergroup difference in spontaneous recovery. Despite lower methacholine doses provoking similar (35%) FEF50 falls in elderly subjects, albuterol AUC was greater in elderly subjects (6,552%.min.microgram) than young subjects (3,922%.min microgram; p = 0.03). Multiple regression showed that AUC and age were related (p = 0.02). CONCLUSION Airway beta 2-adrenoceptor responsiveness is diminished in old age, suggesting that airway beta-adrenoceptor dysfunction may be implicated in late-onset asthma.

Therapeutic concentrations of theophylline and enprofylline potentiate catecholamine effects and inhibit leukocyte activation

Methylxanthines are primary agents used in treatment of hypersensitivity disease. Because polymorphonuclear leukocyte (PMN) activation is associated with generation of potent inflammatory mediators, xanthine effects on the PMN respiratory burst were studied. Enprofylline, a xanthine with important therapeutic potential, does not antagonize adenosine and was contrasted with theophylline. Although enprofylline was more potent at low concentrations, both drugs exhibited dose-dependent inhibition of PMN activation at concentrations greater than 10 mumol/L (1.8 micrograms/ml). Oxygen metabolite generation was decreased by 30% to 40% at therapeutic drug concentrations and by 85% at 1 mmol/L of theophylline. Inhibition by isoproterenol or prostaglandin E2 but not dibutyryl cAMP was potentiated by either xanthine. Isoproterenol effects were also increased when isoproterenol was evaluated in whole blood specimens obtained from subjects after a loading dose of aminophylline. Although these results were most compatible with cAMP phosphodiesterase inhibition, other commonly proposed mechanisms of methylxanthine activity were also studied. Theophylline but not enprofylline blocked adenosine inhibition of PMN activation. Neither xanthine shifted the calcium dose-response when PMNs were activated with calcium ionophore. Because oxygen metabolites generated by the FMN are mediators of inflammation and hypersensitivity, direct inhibition of PMN activation as well as potentiation of catecholamine activity may be important therapeutic effects of theophylline and enprofylline.

Impaired beta-adrenoceptor function, increased leukocyte respiratory burst, and bronchial hyperresponsiveness☆

Inflammatory processes have potential importance in the pathogenesis of bronchial hyperresponsiveness and asthma. Because beta-adrenoceptor function may be impaired in asthma, we studied regulation of the leukocyte respiratory burst using blood samples from subjects with bronchial hyperresponsiveness to methacholine. Leukocytes from hyperresponsive subjects were less responsive to the beta-agonist isoproterenol than were leukocytes from healthy control subjects. The magnitude of the respiratory burst was increased in cells from hyperresponsive subjects and correlated with the degree of methacholine responsiveness. These results demonstrate that peripheral leukocytes reflect a functional impairment in beta-adrenergic responsiveness that parallels airway hyperresponsiveness. Because untreated subjects demonstrated a reduction in beta-adrenergic response, the impairment in beta-adrenoceptor function was not a result of drug therapy and may be associated with the pathogenesis of asthma.

Cigarette smoking and theophylline metabolism: Effects of phenytoin

The induction of theophylline clearance by phenytoin was investigated in 12 young male subjects (six nonsmokers and six cigarette smokers). Each subject received intravenous theophylline to determine baseline pharmacokinetics. This was followed by an intravenous loading dose of phenytoin sodium and oral maintenance dosing for 2 weeks, after which the intravenous theophylline study was repeated. Phenytoin concentrations were similar in nonsmokers (10.8 ± 2.0 μg/ml) and smokers (11.5 ± 0.9 μg/ml). Control theophylline elimination half‐life was 35% less and clearance 88% greater in smokers than in nonsmokers. The proportionate changes in half‐life (26.8% ± 5.6% in smokers and 25.8% ± 3.5% in nonsmokers) and clearance (48.0% ± 10.1% in smokers and 39.7% ± 7.2% in nonsmokers) as the result of phenytoin induction were similar in both groups. These results demonstrate that the induction of theophylline clearance by phenytoin is additive to that caused by cigarette smoking and provide support for the suggestion that theophylline metabolism is influenced by multiple polymorphisms.

Aging and the response to inhibition and induction of theophylline metabolism.

The twofold to threefold higher incidence of adverse drug reactions in elderly as opposed to younger patients is due mainly to more severe disease and the requirement for more complex drug treatment regimens. The incidence of adverse drug reactions increases with the number of prescribed drugs. Because of multiple drug use by the elderly, the potential for drug interactions is greater in this patient group. Surprisingly, the effect of age on the clinical pharmacology of drug interactions has not been thoroughly investigated. Our studies have shown that cimetidine inhibits and phenytoin induces the metabolism of theophylline to a similar extent in healthy male nonsmokers and smokers. Preliminary analysis of the results of a study to investigate the inhibition of theophylline metabolism by cimetidine and ciprofloxacin administered in combination to healthy male and female nonsmokers also does not show an age difference in response. Additional careful studies are needed to evaluate further the pharmacology and clinical importance of pharmacokinetic and pharmacodynamic drug interactions in the elderly.