John W. Jenne

Subsensitivity of beta responses during therapy with a long-acting beta-2 preparation☆

The question whether some tolerance or subsensitivity of various beta receptors develops during therapy with long-acting oral beta-2 agents has practical and theoretical importance. We applied a strong beta-2 stimulus (terbutaline, 5.0 mg orally) at weekly intervals for up to three weeks in 19 stable asthmatics and bronchitics while commencing 5.0 mg terbutaline three times daily. The evening dose was omitted before each morning challenge. Challenges were continued at one and two weeks off terbutaline in some patients to test return of beta function. Patients received no ephedrine for two weeks before the study but were allowed aminophylline or isoproterenol inhalations up to 18 and 4 hr before challenges, respectively. Pulmonary function, pulse, and blood pressure were monitored at 0, 60, 120, and 180 min, and metabolic parameters measured at 0 and 180 min. There was significant drug tolerance in the drop and minimum diastolic pressure reached, rise in lactate, cyclic AMP, and blood glucose, and drop in eosinophils. Peak FEV1 and V50 dropped slightly, but vital capacity and minimal airway resistance did not change significantly. During continuous therapy this slight bronchial subsensitivity is probably obscured by elevated baseline function. It might assume importance during periods of excessive inhaler use or abrupt drug withdrawal.

Decreased theophylline half-life in cigarette smokers.

Abstract In a group of 19 hospitalized patients, most of whom smoked, the half-life of theophylline following an I.V. aminophylline bolus was 3.6 ± 1.5 hours. When the young male control group was broken down by smoking history, 10 smokers had a theophylline half-life of 4.1 ± 1.2 hours, and 14 non-smokers a theophylline half-life of 7.2 ± 1.8 hours. The prolongation of half-life in the non-smokers was very significant (p

Whither beta-adrenergic tachyphylaxis?

at the outset, or no longer has any regard for his professional reputation. The writer fears that he is guilty of all three, and hence is easily trapped into this assignment. The question of tachyphylaxis arose as a result of a rise in asthma deaths in the United Kingdom in the 6Os, which paralleled the appearance on the market of a metered dose inhaler delivering large doses of isoproterenol.’ Coincident with the manufacturer’s reduction in dose/puff and warnings against overuse was a subsidence in this excess of deaths, leading many to conclude that the two may have been related through the phenomenon of tachyphylaxis. Myocardial toxicity from the combination of isoproterenol, freon propellents, and hypoxemia was also considered. Delay in treatment after initial effectiveness of the new inhaler was perhaps the principal cause. The subsidence in mortality also coincided with the introduction of better management of asthma and particularly the introduction of corticosteroids and cromolyn sodium, so that the descending limb of this epidemic of deaths cannot necessarily be invoked in support of the isoproterenol association. In spite of steadily increasing sales of specific beta,-aerosol inhalers since 1969, death rates remained stable .2 There also seemed to be good evidence that isoproterenol used excessively can be responsible for insensitivity of the bronchial beta receptors in certain individuals, leading to worsening of their asthma,3 while a few individuals had adverse reactions to usual doses.* With the introduction of oral beta, agonists, the issue of tachyphylaxis rose again, with evidence

MULTICENTRE EVALUATION OF DISPOSABLE VISUAL MEASURING DEVICE TO ASSAY THEOPHYLLINE FROM CAPILLARY BLOOD SAMPLE

A device using enzyme immunochromatography to indicate visually theophylline concentration in a small capillary blood sample was evaluated for precision and accuracy at four hospitals. Preliminary studies indicated sensitivity as low as 2.5 micrograms/ml, and accuracy and precision matched those in test samples ranging from 5 to 30 micrograms/ml. Absence of theophylline was also reliably detected. Paired samples of capillary and venous blood from 214 patients were used to compare this method with four standard laboratory assays. Correlations with the standard assays were 0.93-0.97, slopes 1.00-1.27, and y intercepts -1.91-0.46. The within-run coefficients of variation on twenty replicate patient sample analyses at the four hospitals were 5.1-9.7% and between-run coefficients of variation on a 15.9 microgram/ml control 5.7-9.4%. This disposable device for theophylline monitoring, which can be done within 15 min at the patients side without instruments, is sufficiently accurate to replace laboratory analysis for routine therapeutic drug monitoring.

Effect of disease states on theophylline elimination

Host factors play an important role in the dosing requirements of theophylline. Theophylline metabolism and clearance depend principally on liver cell function rather than on hepatic flow. The effects of acute hypoxemia require more study; however, patients with chronic obstructive pulmonary disease who have chronic hypoxemia appear to have some impairment of clearance. Clearance is variably and sometimes drastically reduced in patients with liver disease and heart failure, and is reduced by some viral infections. It is not impaired by renal failure. Current split-virus vaccine mixtures do not appear to affect clearance. Clearance is increased in patients with cystic fibrosis and hyperthyroidism. The depressed clearance seen in the severely ill patients who require intensive care improves with improvement in the patients condition, but the individual factors involved have not been identified. An area requiring more study is the effect of pH on the apparent distribution volume for theophylline. In the presence of liver disease, heart failure, or serious illness, caution must be applied in theophylline dosing, with frequent monitoring of serum levels. Stable patients also warrant an initially conservative dose until serum levels are obtained to guide further dose adjustments.

Isoniazid uptake and growth inhibition of Mycobacterium tuberculosis in relation to time and concentration of pulsed drug exposures.

We have examined the relationships of drug concentration and exposure time to drug uptake and growth inhibition of tubercle bacilli following single pulsed isoniazid exposures. Isoniazid-sensitive strain H37Ra of Mycobacterium tuberculosis was grown in Sautons medium with aeration at 37C. Cells were suspended in fresh medium at 0·6 mg. dry wt./ml., isoniazid or 14C-isoniazid was added and incubation continued. Pulses were terminated by two methods. Samples were either diluted l:200 in drug-free medium for turbidimetric growth assay or filtered and cell-bound 14C. activity determined. When isoniazid was varied from 0-l to 0·5 ug./ml. and the period of exposure varied accordingly to give a constant time-concentration product (TCP) of exposure equal to 0·5 μg. hr., a transient growth inhibition resulted followed by rapid recovery. At six days pulsed cells were inhibited approximately 25% A more pronounced effect occurred at a TCP of l-0 μg. hr. and at six days inhibition was about 50%. Populations arising from treated cells retained isoniazid sensitivity. At TCPs of 0·5 and 1·0 μg. hr., 14C. activity corresponding to 20–26 and 37–47 nanograms isoniazid/mg. cells was bound respectively. Since drug carry-over became a problem in growth assays with isoniazid pulses in excess of 0·5 μg./ml., filtration was substituted for dilution to terminate exposures. At a TCP of 1·0 μg. hr. over a range of 0·25 to 4·0 μg./ml., growth inhibition was about 50%. Our data indicate that the degree or extent of inhibition following short pulsed isoniazid exposures is rather precisely governed by the time-concentration product of exposure and is closely correlated with the amount of drug bound by the cells.

The Effect of Nitroglycerin in Gas Exchange on Chronic Obstructive Pulmonary Disease1, 2

Nitroglycerin was administered to a group of 11 patients with chronic obstructive pulmonary disease in a dose of 0.4 mg sublingually. Arterial blood gases and blood pressure and pulse were measured at 5-min intervals for 30 min after nitroglycerin. There was a slight decrease in arterial O2 tension for the duration of the study; the maximal change was from a mean pre-nitroglycerin value of 53.5 mm Hg to 50.3 mm Hg at 20 min. In addition, there was a slight reduction in arterial CO2 tension and bicarbonate for 25 min. It is postulated that decreased O2 transport (due to increased hypoxemia and probably decreased cardiac output) plus hypocapnia were a sufficient stimulus to raise blood lactate. It is recommended that in patients receiving nitroglycerin who have obstructive airway disease, attention be directed toward the effect on arterial blood gases.

Beta adrenergic agents—how much is enough?

The article by Weber, Petty, and Nelson appearing in this issue of the JOURNAL is not only a precise and useful comparison of the dose of inhaled isoproterenol and terbutaline by several method of administration, but is also a reminder to us that the log-dose response curve extends far beyond the 20% improvement conventionaliy used for diagnosis when the dose is pushed. This prompts the questions: “Under what circumstances should the dose of beta agonists be pushed?” “How much is too much?” Certainly the issue is being forced upon us by the often successful use in some quarters of isoproterenol intravenously in children as a last-ditch pharmacologic effort in status asthmaticus before resorting to assisted ventilation with its own set of hazards. Moreover, the optimum use of inhaled and oral beta agents is far from settled. What information do we have at this date bearing on these questions? If we limit the questions to the effects on bronchospasm, I believe that we are indeed narrowing the areas of uncertainty. Evidence comes from both in vitro and in vivo studies. We should recall the study of Paterson, Courtenay Evans, and Prime2 in their comparison of doubling doses of, first, intravenous isoproterenol and, then, salbutamol, on the FEVi and pulse rate in stable but severe asthmatics. The abrupt cessation of the salbutamol drip was followed by “rebound bronchoconstriction” (more severe than that originally present) in 4 of the 15 subjects. Two of these failed to respond to recommencement of salbutamol at high doses, but dramatically responded to intravenous aminophylline. This is precisely the type of study needed to clarify this issue, and we are fortunate that it is in the literature. First, the unexpected result of “rebound bronchoconstriction” strongly indicts beta receptor fatigue or tachyphylaxis during intense beta stimulation. Perhaps endogenous catecholamines, responding to such a crisis, contributed to this stimulation as well. Second, aminophylline is demonstrated to be literally indispensable in such circumstances. The behavior of bronchial smooth muscle beta re

Workshop 2: Special pharmacologic considerations

Abstract Because NBAAD are designed to either prevent release or antagonize the effects of cellular mediators, special pharmacologic problems during their development and clinical evaluation phases are bound to arise. Many of these drugs exert optimal effects in local tissue sites, where the adverse effects of delayed onset asthmatic response are most apparent. Thus controlled bioavailability studies often have to be extended for longer periods of time. For similar reasons, evaluation of tachyphylaxis and interactions with other active drugs may be more difficult to interpret in this category of drugs. Whenever possible, detailed pharmacokinetic investigations of these drugs should include determination of both single- and multiple-dose absorption assays, protein binding, distribution, rate of elimination, and extent of absorption. The steadystate equilibrium status of these drugs is particularly relevant to evaluate their durations of actions. Thus dose response effects of longer acting drugs may only become apparent after multiple, chronic dosing studies. For these reasons, new agents in the NBAAD category must often be evaluated in the context of unique drug effects combined with generally accepted pharmacodynamic techniques. In addition, the development of an NBAAD will almost always require consultation with clinical pharmacologists.