A comparison of beta adrenergic function in asthma and chronic bronchitis

A beta adrenergic defect has been postulated in asthma. We compared beta function in asthma to that in chronic bronchitis. Using 5.0 mg terbutaline orally, we measured the drop in diastolic blood pressure and eosinophils, rise in pulse, plasma lactate, blood sugar, plasma cyclic adenosine monophosphate (AMP) and free fatty acids, rise in urine cyclic AMP/creatinine ratio, and airway responses in a large number of obstructed bronchitics and stable “extrinsic” and “intrinsic” asthmatics, all middle-aged males. The diagnosis of asthma required eosinophilia and airway variability and “extrinsic” asthma skin test reactivity. To avoid residual beta tolerance, oral sympathomimetic agents were avoided 1 to 2 wk prior to testing. Fasting metabolic measurments were made at 0 and 180 min and changes in vascular and airway responses summated over 0, 60, 120, and 180 min. Although there was wide variation and group overlap, the “extrinsic” asthmatics had a very significant reduction of 75% in mean urine cyclic AMP/creatinine ratio compared to chronic bronchitics. The bronchitics were marginally more responsive than a “control” group later judged to be defective. Other responses reflected this pattern to a lesser degree, but vascular responses were normal. “Intrinsic” asthmatics had intermediate but still significant beta impairment. Asthmatics with excessive inhaler use (over 40 puffs/day or intermittent positive pressure breathing [IPPB] bronchodilator) had greater beta impairment but also worse bronchoconstriction. Beta function of “extrinsic” asthmatics with minimal inhaler use was still impaired. We conclude that, when compared to chronic bronchitics, asthmatics have impairment of selected responses not including vascular smooth muscle relaxation. The beta responses of chronic bronchitics are probably normal. The atopic state appears to be an independent trait but is superimposed on the beta defect in “extrinsic” asthma.     

Effects of oral terbutaline in children with bronchial asthma

The cardiopulmonary effects of single oral doses of terbutaline were evaluated in children with chronic bronchial asthma. Fifteen children, 6 to 13 yr of age and weighing 22.3 to 51.8 kg, were treated with 1.25, 2.5, 3.75 and 5.0 mg of terbutaline using a double-blind crossover vs placebo design. Before treatment and at intervals up to 420 min following treatment, measurements were made of lung volumes, vital capacity, FEV 1, maximum expiratory flow volume curves, airway resistance (R_aw), and specific airway conductance (G_aw/V_L). Heart rate, systolic and diastolic blood pressures, and electrocardiograms were also obtained. The most consistent and sensitive indicators of pulmonary function were G_aw/V_L and FEV₁, both of which showed significant improvement after all doses, The peak improvement of these parameters was proportional to the dose of terbutaline. Cardiovascular effects of terbutaline consisted of small increases in systolic blood pressure or transient EKG changes and were clinically unimportant. Other side effects such as headache, tremor, dizziness, and nausea, although proportional to the dose of terbutaline, were mild and transient. The dose of 2.5 mg terbutaline produced the most improvement in pulmonary function in relation to the number of side effects.     

Clinical implications of drug-induced desensitization of the beta receptor after continuous oral use of terbutaline

Normal (n = 6) and asthmatic (n = 8) subjects received oral therapy with 5 mg of terbutaline three times a day for 2 wk, followed by 1 wk of placebo administration. The asthmatics were deprived of all bronchodilator therapy for at least 10 days prior to the investigation. At day 0, 7, 14, and 21 of this scheme, directly before (0900 hr) and 3 hr after oral administration of 5 mg of terbutaline, blood was sampled for (1) in vitro stimulation experiments of leukocytes, (2) determining the beta-adrenoceptor binding capacity of lymphocytes, (3) determination of plasma cyclic AMP levels, and (4) measurement of terbutaline serum concentrations. In addition to these variables, spirometry and finger tremor measurements were performed. Compared with baseline values, it appeared that most of these variables (plasma cyclic AMP, serum terbutaline, spirometry, and finger tremor) showed elevated levels at 0900 hr after 7 and 14 days of therapy with terbutaline. Three hours after an oral dose of 5 mg of terbutaline on days 7 and 14 of therapy with terbutaline, these variables were not significantly different from the 3-hr level of day 0, with the exception of terbutaline serum concentration, which was significantly higher on days 7 and 14 (p < 0.04). Furthermore, the in vitro stimulation and binding experiments showed a reduced beta-adrenergic response and a decrease in the number of beta-adrenergic receptors. Also a reduced response for the in vivo measurements was registered. This suggests that desensitization occurred. Since the basal lung function of the asthmatic subjects remained clinically improved during the oral terbutaline therapy (2.1 ± 0.4 and 1.9 ± 0.4, FEV₁ in liters, mean ± SEM) as compared with the values before therapy (1.6 ± 0.3), the beta-adrenergic therapy still remained beneficial. Therefore desensitization should be interpreted as cellular protection against over stimulation to prevent cellular exhaustion via the beta-adrenergic receptor. Since our study suggests a basal beta-adrenergic subsensitivity in asthmatics, as seen from the lower basal cyclic AMP levels of the mixed leukocytes, there could be some risk from reinforcement of the beta-adrenergic subsensitivity by beta-2-adrenergic agents. This process may lead to a domination of constrictive mechanisms in the asthmatics. For this reason, maximal beta-adrenergic monotherapy should be avoided. From this point of view it would be advisable to consider as a better alternative combination therapy of beta-adrenergic drugs with theophylline and/or anticholinergic drugs in lower dosages than would be used in monotherapy. Such a combination therapy should be utilized when prophylactic drugs like cromoglycate or corticosteroids administered systemically or by inhaler have only little effect.     

Comparison of subcutaneous terbutaline with epinephrine in the treatment of asthma in children.

Comparison of the bronchodilator and cardiovascular effects of subcutaneous terbutaline and epinephrine in the treatment of acute asthmatic attacks in children disclosed that bronchodilation occurred with 5 min after subcutaneous injection of either drug (0.01 mg/kg, maximum 0.25 mg). Bronchodilation was maintained for 4 hr after administration of either drug. Small increases in pulse rate followed administration of terbutaline but not epinephrine. No clinically significant side effects were noted with either drug.     

A comparison of a theophylline-ephedrine combination with terbutaline.

In a single-blind, crossover study 10 adult asthmatic patients received a theophylline-ephedrine combination tablet (theophylline 90 mg, ephedrine 16 mg and phenobarbital 25 mg in an immediate release layer and theophylline 90 mg and ephedrine 32 mg in a sustained release layer) twice daily or terbutaline 5 mg three times daily for two weeks. There was no significant difference in bronchodilator response to a single dose of the study drugs on either the initial day of treatment or after two weeks of continuous therapy. Mean increases in serum cyclic-AMP levels produced by both drugs were not significantly different. Mean peak plasma theophylline levels were 2.9 +/- 1.3 microgram/ml following the initial dose and 7.3 +/- 3.4 microgram/ml after two weeks of continuous dosing with the combination drug. No adverse effects on blood pressure or pulse rate were observed to either drug. Overall, the incidence and severity of reported side effects (tremor, nausea and nervousness) were less with the theophylline-ephedrine combination.     

Adrenoceptor desensitization after immobilization stress or repeated injection of isoproterenol

Immobilization stress (2.5 h daily) or repeated injection of isoproterenol (1 mg/kg, 3 times daily) for 1 wk caused a subsensitivity to the chronotropic and pressor effect of epinephrine in pithed rats. Propranolol (1 mg/kg) inhibited, to a greater extent in control than in immobilized rats, the chronotropic effect of epinephrine. The residual heart rates did not differ significantly among control, immobilized, and isoproterenol-treated rats. Practolol (1 mg/kg) but not butoxamine (5 mg/kg) mimicked the effect of propranolol. The subsensitivity in the blood pressure responses was not abolished by injection of either of the beta-adrenoceptor blockers. Butoxamine or propranolol shifted the epinephrine dose-blood pressure response curves to the left. The degree of shift was similar in control and immobilized or isoproterenol-treated rats. Daily injection of quinacrine (16 mg/kg), an antimalarial agent that inhibits phospholipase A2, blocked the subsensitivity to the chronotropic effect of epinephrine, but not that to the pressor effect of epinephrine. These observations suggest that immobilization stress causes desensitization of alpha- and beta 1-receptors but not beta 2-receptors. The mechanism of desensitization of beta 1-receptors by immobilization appears to be similar to that after isoproterenol treatment, possibly due to increased turnover of phospholipids.     

Subsensitivity to epinephrine following the administration of epinephrine and ephedrine to normal individuals.

Cardiovascular and metabolic responses to exercise and consecutive epinephrine infusions 24 hours apart were measured in 7 normal individuals before and following a week's administration of ephedrine sulfate. There was evidence of less beta adrenergic response to the second control epinephrine infusion compared to the first control infusion, and the depression of the rise in blood lactate was significantly different. A week of ephedrine produced more profound depression of the beta adrenergic responses to epinephrine with significant differences in the rise in blood glucose and lactate, and the pulse and blood pressure responses. Furthermore, these same responses remained significantly altered when a second epinephrine infusion was performed 36 hours following the last dose of ephedrine. The alterations in the response to epinephrine induced by ephedrine are consistent with the concept of effector cell "subsensitivity," an adaptive response to prolonged excessive stimulation.     

Effect of prednisone on spontaneous canine asthma

This study was designed to investigate the effect of corticosteroids in spontaneous ragweed-sensitive asthmatic dogs. Two animals were treated with prednisone, 40 mg. daily for 3 weeks, and with gradually tapered doses for 6 weeks. The animals were challenged with an aerosol or ragweed extract (RW) before and at intervals during and after drug therapy, and their skin reactivity to the antigen was determined at the same time. The Prausnitz-Küstner (PK) titer and the amount of serum necessary to passively transfer ragweed anaphylaxis to nonatopic dogs were also determined at the same intervals. Treatment of the atopic dogs with corticosteroids completely prevented the ragweed-induced asthma during and for up to 3 months after cessation of therapy. Although the skin reactivity of the atopic dogs was depressed, the PK titer of the sera did not change appreciably during therapy. Increased amounts of serum, however, were necessary to passively sensitize nonatopic dogs for ragweed anaphylaxis for up to 7 months after cessation of drug therapy. The results of the study indicate that corticosteroids can abolish active and passive allergic responses in dogs for as long as 7 months after cessation of the drug, but the mechanism of action is not clear.     

Double-blind evaluation of nebulized cromolyn, terbutaline, and the combination for childhood asthma

To evaluate whether the potency of a long-acting selective beta 2-agonist negates the need for cromolyn, 27 children, aged 6 to 12 years, with mild to moderate asthma requiring long-term medication, were assessed for the therapeutic effects of cromolyn and/or terbutaline by jet nebulizer. Patients received either cromolyn, 20 mg, terbutaline, 0.1 mg/kg up to 4 mg, or the combination, three times daily. The study design was double-blind, crossover with each patient receiving the three treatment regimens in randomized order for a period of 8 weeks each. Daily diary mean scores generally demonstrated best symptom control with cromolyn or the combination than with terbutaline alone. Cough was significantly less with cromolyn than with terbutaline (p less than 0.05). Morning peak flow measures were higher with combination therapy than with terbutaline (p less than 0.05). Evening peak flow measures were higher with the combination and cromolyn alone than with terbutaline alone (p less than 0.01). Methacholine challenge demonstrated less bronchial hyperreactivity with the combination or cromolyn alone than with terbutaline alone (p less than 0.02). The effectiveness of the nebulizer regimen for children with chronic asthma is better when cromolyn is used alone or in combination with terbutaline than when the beta-agonist is used alone.     

Aerosolized terbutaline in asthmatics. Comparison of dosage strength, schedule, and method of administration.

Sixteen patients with bronchial asthma participated in three studies of inhaled terbutaline. Onset of action, duration, and peak effects were compared for a dose of 0.5 mg given in one, two, or four inhalations at 1 min intervals from a freon-propelled, metered-dose aerosol. There was no significant difference in the response between the schedules. Dose-response curves were compared for terbutaline from a metered-dose aerosol, and pressure nebulized with and without intermittent positive pressure breathing (IPPB). There was no difference between the response with IPPB and simple nebulization. Improvement continued to the total dose administered of 9.0 mg. For a given bronchial response, six to eight times as much terbutaline was required by pressure nebulization as from the metered-dose aerosol.     

A comparative study of the aerosolized bronchodilators, isoproterenol, metaproterenol and terbutaline in asthma.

Twenty-one patients with asthma were studied in a double-blind manner for the effects of three aerosolized bronchodilators (isoproterenol, metaproterenol and terbutaline) on small, large and mixed airways, blood pressure, heart rate and various blood chemistries. Favorable responses were measured within 30 seconds for each drug. However, only the newer, selective beta-2 agonists, metaproterenol and terbutaline, produced significantly prolonged action upon small as well as large airways and lung volumes. Of the two, terbutaline tended to have an earlier and higher peak activity and longer duration of action, especially on large airways. Such prolonged activity by the newer agents suggests a safer and more effective alternative to isoproterenol inhalation.     

Nifedipine – a Calcium Channel Blocker – in Asthmatic Patients Interaction with Terbutaline

Seven asthmatic patients were studied in a single-blind randomized, crossover study after oral administration of 20 mg nifedipine or placebo Four increasing doses of i.v. terbutaline were then given with 30 min interval. The study was concluded with inhalation of five terbutaline puffs. FFAV₁ measurements 30 min after intake of nifedipine did not show any difference compared to placebo. During the terbutaline treatment, however, there was a more pronounced bronchodilation after nifedipine than after placebo (P < 0.051. Terbualine-induced skeletal muscle tremor was similar after nifedipine and placebo pretreatments. After nifedipine intake there was a decrease of diastolic blood pressure and a reflexogenic tachycardia. Thus, this study showed a small potentiation of the beta₂-adrenoceptor mediated bronchodilation. which is of importance when treating patients with simultaneous asthma and hypertension or angina pectoris.     

Acute effects of terbutaline and epinephrine on asthma: Double-blind crossover placebo study

In order to assess the efficacy and safety of subcutaneous terbutaline 0.25 mg and 0.5 mg as compared to subcutaneous epinephrine, 28 stable asthmatics were studied. After control of environmental exposures in the clinical research facility at the University Hospitals of Case Western Reserve Medical School, the patients were entered into a double-blind crossover placebo-controlled 4-day study. All of the patients showed significant responses to both doses of terbutaline and after epinephrine as compared to placebo (greater than 15% increase in FEV₁). In general, the side effects experienced were similar for 0.25 mg epinephrine and 0.25 mg terbutaline. They were slightly more pronounced with 0.5 mg of terbutaline. In terms of duration of action, there was a substantial difference between the duration of effect of subcutaneous epinephrine and subcutaneous terbutaline at both dosages. No cardiovascular side effects of any significance were noted in this study with either agent. We conclude that subcutaneous terbutaline is at least as effective as epinephrine in the management of reversible bronchospasm and may be considered a drug of choice in stable asthmatics.     

Blood pressure variation in healthy humans: a possible interaction with beta-2 adrenergic receptor genotype and renal epithelial sodium channels

Renal control of Na(+) regulation is a critical component to blood pressure regulation. It has recently been suggested that the beta-2 adrenergic receptor plays a role in blood pressure regulation possibly via renal epithelial sodium channels (ENaC). In the kidneys, gain of function mutations of the ENaC leads to increased salt-sensitivity and hypertension (Liddle's syndrome). In contrast, loss of function mutations of the ENaC leads to pseudohypoaldosteronism and is characterized by hypotension. Polymorphic variation of the beta-2 adrenergic receptor (beta2AR, the Arg16Gly polymorphism) leads to differences in physiologic function, in vivo. Specifically, subjects homozygous for Glycine at amino acid 16 have been shown to have enhanced forearm blood flow in response to isoproterenol and better airway function at baseline and during exercise when compared to subjects homozygous for Arginine at amino acid 16. We hypothesize, therefore, that subjects that are homozygous for Gly at amino acid 16 of the beta2AR have higher baseline blood pressure than Arg16 homozygotes due to beta2AR-mediated increases in ENaC activity in the kidney, caused, at least in part, by greater beta2AR density or enhanced beta2AR function of the Gly16 group.     

Chronic chlorpheniramine therapy: subsensitivity, drug metabolism, and compliance

To investigate whether patients develop true subsensitivity to antihistamines during chronic therapy, we studied 14 adult subjects who received chlorpheniramine for 3-day and 3-week trials of therapy. Titrated skin tests to histamine and compound 48/80, chlorpheniramine blood levels (by HPLC), compliance, and side effects were monitored and compared during the two courses of therapy and their respective 72-hour washout periods. We found a significant correlation between chlorpheniramine blood levels and skin test suppression during both the 3-day and 3-week therapies. The 3-day chlorpheniramine therapy was more clinically effective (measured by skin test suppression corrected for serum chlorpheniramine concentration) than the 3-week therapy (P less than .01). Chlorpheniramine serum half-lives and 2-hour chlorpheniramine blood levels were not significantly different after the 3-day and 3-week trials. Compliance was significantly worse (P less than .01) during 3-week therapy. Medication side effects (particularly drowsiness) were frequently reported during both courses of therapy. We conclude that subsensitivity to chlorpheniramine does develop in adult patients receiving 3 weeks of therapy. This subsensitivity is not explained by changes in drug metabolism. In addition to subsensitivity, poor compliance may contribute to sub-therapeutic results during chronic antihistamine therapy. Side effects from antihistamines may also require individualization of therapy for certain patients.     

The efficacy and tolerability of amlodipine and hydrochlorothiazide in Nigerians with essential hypertension.

The efficacy and safety of the novel calcium antagonist Amlodipine (Pfizer Laboratories, New York, New York) and hydrochlorothiazide were evaluated and compared in a randomized, single-blind, parallel group study in black Africans with essential hypertension. Twenty Nigerians with newly diagnosed mild to moderate essential hypertension were randomized to receive ascending doses of Amlodipine (5 mg and 10 mg) or hydrochlorothiazide (25 mg or 50 mg), and blood pressure and heart rate were measured at baseline and at 2, 4, and 6 weeks of therapy. Both Amlodipine and hydrochlorothiazide significantly reduced supine and erect blood pressure. Supine blood pressure on Amlodipine fell from a mean of 190/104 mm Hg to 150/79 mm Hg, and on thiazide from 180/103 mm Hg to 141/84 mm Hg. There was, however, no significant difference between both drugs in antihypertensive efficacy. Neither drug induced a reflex increase in heart rate. The fall in blood pressure on both agents was associated with an increase in plasma urea. Amlodipine induced no change in plasma potassium, but hydrochlorothiazide caused hypokalemia. Both agents were well tolerated, and Amlodipine should undergo further study in the treatment of hypertension in blacks.     

Impaired tracheal mucus transport in allergic bronchoconstriction: Effect of terbutaline pretreatment

The transport velocity of mucus within the trachea, pulmonary resistance, and arterial blood gas composition were measured in intubated conscious sheep with Ascaris suum sensitivity before and during allergic bronchoconstriction. Inhalation of A. suum extract for 15 min increased mean pulmonary resistance significantly from 1.9 cm H₂O · L^?1 sec^?1 to 5.1 cm H₂O · L^?1 sec^?1 after 60 min and to 4.5 cm H₂O · L^?1 sec^?1 after 120 min, while it decreased mean arterial P_O2 from 85 to 59 and 53 mm Hg, respectively, without altering arterial P_CO2 or pH. This was associated with a decrease in mean mucus velocity from 11.2 to 6.0 and 5.7 mm min^?1, respectively. The decrease in mucus velocity was accompanied by endoscopically visible increases in the quantity of tracheal mucus. No alterations in mucus velocity or pulmonary resistance were observed in animals who inhaled a control antigen (ragweed) or breathed a mixture of 10% oxygen 90% nitrogen, which produced a mean arterial P_O2 of 51 mm Hg. The administration of 0.25 mg terbutaline sulfate by subcutaneous injection prior to A. suum challenge prevented the changes in mucus velocity, pulmonary resistance, and arterial P_O2. We conclude that the decreased mucus velocity in the trachea during antigen-induced bronchoconstriction in conscious sheep is related to the allergic response, and can be prevented by the subcutaneous administration of terbutaline sulfate, a beta adrenergic agonist. This suggests that the protective effect of terbutaline sulfate in antigen-induced bronchoconstriction includes the effect on the associated impairment of mucociliary function.     

Antihypertensive efficacy and tolerability of once-daily sustained-release diltiazem alone and in combination with ramipril in hypertension

This study assessed once-daily (OD), sustained-release (SR) diltiazem alone and in combination with ramipril in essential hypertension. Fifty patients with supine diastolic blood pressure (DBP) > or = 95-< or = 114 mm Hg were entered into the active treatment phase of the study after 2 weeks of placebo run-in. Sustained-release diltiazem 180 mg OD was administered for 2 weeks, then optimally titrated, at 2 week intervals, to SR diltiazem 240 mg OD and then SR diltiazem 180 mg + ramipril 2.5 mg OD to achieve supine DBP < or = 90 mm Hg. After 4 weeks of diltiazem monotherapy (SR diltiazem 180 mg or 240 mg OD) mean supine DBP was reduced from 102.84 +/- 3.81 mm Hg to 90.15 +/- 5.02 mm Hg (P < 0.01) and mean supine heart rate was reduced from 85.15 +/- 11.02 bpm to 77.62 +/- 11.45 bpm (p < 0.01). Diltiazem monotherapy reduced supine DBP to < or = 90 mm Hg in 35/45 (77.77%) patients. Combination therapy (SR diltiazem 180 mg + ramipril 2.5 mg OD), received by non-responders to diltiazem monotherapy, reduced supine DBP to < or = 90 mm Hg in 3/10 (30%) patients. Sinus bradycardia was observed in one patient. Sustained-release diltiazem alone and in combination with ramipril reduce blood pressure in a dose related manner and is well tolerated.     

Cumulative dose-response curves for early evaluation of bronchodilator drugs.

SM 220, a new beta-receptor agonist, was compared with terbutaline by construction of dose response curves for FEV1, heart rate and blood pressure. The pharmacological profile of SM 220 after preclinical studies was that of a potent and highly selective bronchodilator. In this study the beta2 selectivity of SM 220 was poorer than that of terbutaline. The importance of commencing clinical evaluation of bronchodilators with a dose-response test is stressed.     

Occupational asthma caused by low molecular weight chemical agents.

The increasing mortality in acute asthma noted during the sixties has been ascribed to resistance of the beta₂ receptors of the bronchi due to treatment with beta-stimulating drugs. This study questions that theory. Eight patients with reversible airways obstruction were studied. Treatment with oral terbutaline 5 mg 3 times a day was given for 1 yr. Thereafter, terbutaline as metered aerosol was added in the dose of 2 puffs (0.5 mg) 4 times a day for 4 days and 6 puffs (1.5 mg) 4 times a day for further 4 days. The responsiveness of the receptors of bronchi, heart, skeletal muscles, and peripheral vessels was tested before and after 1, 2, 3, 6, 9, and 12 mo of treatment with oral terbutaline and after the two 4-day periods with inhaled terbutaline. The receptors were tested by infusion of increasing doses of isoprenaline, so that dose-response curves for isoprenaline were recorded. No signs of resistance of the beta₂ receptors of the bronchi developed during the terbutaline treatment period. Thus not even spray in moderate overdose caused resistance. Within 1 mo of treatment with oral terbutaline, resistance developed to the tremorogenic effect of terbutaline. Six of the 8 patients showed no signs of development of resistance to the chronotropic effect of isoprenaline. No signs were found of resistance of the beta₂ receptors of peripheral blood vessels.