Effects of budesonide and bambuterol on circadian variation of airway responsiveness and nocturnal symptoms of asthma

doi:10.1016/S0091-6749(05)80014-4

Journal of Allergy and Clinical Immunology

Volume 90, Issue 3, Part 1, September 1992, Pages 349-357

https://doi.org/10.1016/S0091-6749(05)80014-4 Get rights and content

Effects of the inhaled corticosteroid budesonide and the oral β-agonist bambuterol on the nocturnal worsening of asthma were studied in patients with allergic asthma with a circadian peak expiratory flow variation≥15% (group l, n=8) and <15% (group 2, n=9). Airflow limitation and airway responsiveness to histamine were measured during 24 hours after 4 weeks of treatment with (A) 0.4 mg budesonide at 8 am and 8 pm. (B) 20 mg bambuterol at 8 pm, and (C) placebo, in a randomized, crossover design. Patients in group 1 had worse nocturnal symptom scores and a greater airway responsiveness than patients in group 2; in addition. patients in group 1 had a larger increase in responsiveness during the night (1. 1 versus 0.6 doubling concentrations [DC]). Both budesonide and bambuterol improved responsiveness more at night than during daytime, thus decreasing circadian variation: at 4 am, increases in PC₂₀ were 2.0 DC after budesonide and 0.8 DC after bambuterol. compared with placebo. Bambuterol reduced circadian variation in FEV₁, but in contrast to budesonide, did not improve 24-hour mean levels of FEV₁ and PC₂₀. Both drugs beneficially influenced nocturnal symptoms; the effects of budesonide were stronger than those of bambuterol. Our findings demonstrate that budesonide and bambuterol reduce nocturnal airway responsiveness and asthma symptoms and suggest a relationship between the degree of airway responsiveness and the presence of nocturnal symptoms of asthma.

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Nearly all functions of the body, including those influencing pharmacokinetic parameters, such as drug absorption and distribution, drug metabolism, and renal elimination display significant daily variations. Also, the onset and symptoms of diseases such as asthma attacks, coronary infarction, angina pectoris, stroke, and ventricular tachycardia are circadian-phase dependent. Asthma attacks predominatly occur around 4 o'clock at night. Blood pressure and heart rate in normotensives and essential (primary) hypertensive patients display highest values during daytime followed by a nightly drop and an early morning rise. In about 70% of forms of secondary hypertension, however, this rhythmic pattern is abolished or even reversed exhibiting nightly peaks in blood pressure. Similar findings were obtained in children. This form of hypertension is accompanied by increased end organ damages. These observations call for a circadian time-specified drug treatment. In nocturnal asthma unequal dosing of antiasthmatic drugs with a higher/single evening dose is recommended. In secondary hypertension not only the elevated blood pressure must be reduced but the disturbed blood pressure profile should be normalized, too, possibly best achieved by evening dosing. Pharmacokinetics may also not be constant within 24 hours of a day as shown for cardiovascular active drugs, antiasthmatics, anticancer drugs, psychotropics, anlagesics and local anesthetics, antibiotics to mention but a few. Far more drugs were shown to display significant daily variations in their effects even after chronic application or constant infusion. Because circadian rhythms undergo maturation with development, drug therapy in children can/may also be modified by circadian time of drug dosing as shown for anticancer drugs. In conclusion, there is clear evidence that the dose/concentration-response relationship of drugs can be significantly dependent on the time of day. Thus, circadian time has to be taken into account as an important variable influencing a drug's pharmacokinetics and/or its effects or side effects.
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Although nocturnal asthma is a well documented clinical problem, the effect of asthma on sleep itself and morbidity caused thereby have not received adequate attention. It is now recognized that partial sleep deprivation has a considerable effect on human functions.
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At 6 am, both FEV₁ and PC₂₀FEV₁ were significantly higher on theophylline than on placebo (3.52 ± 0.22 versus 3.17 ± 0.25 L; P < .005 and 2.76 divided by 3.61 versus 1.55 divided by 3.73 mg/mL; P < .05, respectively). At 2 pm and 10 pm FEV₁, but not PC₂₀FEV₁, was higher on theophyline than on placebo (3.73 ± 0.21 versus 3.54 ± 0.25 L; P < .05 and 3.40 ± 0.22 versus 3.24 ± 0.24 L; P < .05). Serum theophylline was 12.8 ± 1.1 μg/mL, 8.9 ± 0.77 and 9.5 ± 0.85 at 6 am, 2 pm, and 10 pm, respectively.
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Circadian rhythms in the functions of the body are well established, e.g. in cardiovascular (blood pressure, heart rate, blood flow, etc.), pulmonary, hepatic and renal functions. Also the symptoms and the onset of diseases are not randomly distributed within 24 hours of a day (e.g. coronary infarction, angina pectoris attacks, silent ischaemia, asthmatic attacks). Accordingly, the effects and/or pharmacokinetics of drugs can display significant daily variations. Recent data on the chronopharmacodynamics and chronopharmacokinetics of H₂-blockers, antiasthmatics (theophylline,β-agonists, glucocorticoids), cardiovascular active drugs (β-blockers, organic nitrates, calcium channel blockers, ACE-inhibitors) are described as representative examples. The data demonstrate that biological rhytms can have an impact on drug therapy.
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Effects of budesonide and bambuterol on circadian variation of airway responsiveness and nocturnal symptoms of asthma*

Am J Med

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin immunol

Chest

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

Lancet

Comparison of normal and asthmatic circadian rhythms in peak expiratory flow rate

Thorax

Asthma: analysis of sudden death and ventilatory arrests in hospital

BMJ

Nocturnal asthma: mechanisms and treatment

BMJ

Changes during 24 hours in the lung function and histamine hyperreactivity of the bronchial tree in asthmatic and bronchitic patients

Int Arch Allergy

Circadian change in bronchial responsiveness and airflow obstruction in asthmatic children

Thorax

Nocturnal and morning asthma. Relationship to plasma corticosteroids and response to cortisol infusion

Thorax

Nocturnal asthma and changes in circulating epinephrine, histamine, and cortisol

N Engl J Med

The effect of the circadian rhythm of vagal activity on bronchomotor tone in asthma

Br J Clin Pharmacol

Recurrent nocturnal asthma after bronchoprovocation with western red cedar sawdust: association with acute increase in non-allergic bronchial responsiveness

Clin Allergy

Recurrent nocturnal asthma after exposure to grain dust

Am Rev Respir Dis