Interaction between Corticosteroid and β-Agonist Drugs: Biochemical and Cardiovascular Effects in Normal Subjects

doi:10.1378/chest.102.2.519

Chest

Volume 102, Issue 2, August 1992, Pages 519-524

https://doi.org/10.1378/chest.102.2.519 Get rights and content

The aim of this study was to investigate whether the administration of prednisone potentiates any of the acute biochemical and cardiovascular effects of high-dose inhaled β-agonist drugs. These agents are known to cause dose-related changes in plasma potassium and glucose, as well as ECG changes in heart rate, corrected QT interval (QT_c), T wave, and U wave. On theoretical grounds, the concomitant use of systemic corticosteroids might enhance these actions. Twenty-four healthy subjects were randomized to receive one of three treatments: salbutamol 5 mg or fenoterol 5 mg or normal saline solution. Each drug was administered twice, 30 min apart by nebulizer, and the procedure was repeated after each subject had received prednisone 30 mg daily for one week. Plasma potassium and glucose levels were measured, and ECGs were obtained after each treatment, together with 12-h Holter monitoring for arrhythmias. Changes in plasma potassium and glucose following nebulized β-agonist were significantly greater after treatment with prednisone. Baseline potassium level fell from 3.75 mmol/L (95 percent CI 3.61, 3.89) to 3.50 mmol/L (95 percent CI 3.36, 3.64), and thereafter all values were significantly lower at each time point (p = 0.003). The lowest mean plasma potassium was obtained 90 min after fenoterol administration with prednisone pretreatment: 2.78 mmol/L (95 percent CI 2.44, 3.13). Increases in heart rate and QT_c interval following both β-agonist drugs were significant, but T-wave amplitude reductions did not reach significance. Prednisone treatment did not significantly alter the cardiovascular responses. Supraventricular and ventricular ectopic activity was related to β-agonist use, but no potentiating effect was noted following steroid treatment. We conclude that the acute biochemical effects of β-agonist administration are augmented by prior treatment with prednisone, but this is not the case for ECG effects. However, the degree of hypokalemia noted as a result of this drug interaction may be of clinical significance in the hypoxic conditions of acute airways obstruction.

Section snippets

Subjects

Twenty-four healthy male volunteers (age range, 18 to 33 years) were studied. Each underwent a full physical examination and ECG assessment prior to participation. Any volunteer with a history of cardiovascular disease, hyperthyroidism, or previous β-agonist use was excluded. Written informed consent was obtained from each subject, and the study protocol was approved by the ethical committee of the Otago Area Health Board.

Study Design

Subjects were randomly assigned to receive one of three drug treatments

Biochemical Data

The administration of salbutamol and fenoterol resulted in immediate significant falls in the plasma potassium concentration compared with placebo (p<0.001; Fig 1a). Mean values for the maximum fall in plasma potassium were 0.51 mmol/L (95 percent CI 0.35, 0.67) for salbutamol and 1.13 mmol/L (95 percent CI 0.82, 1.43) for fenoterol (p<0.0005). Even after 4 h, the fenoterol-treated subjects had not recovered their baseline potassium levels. The lowest individual value for plasma potassium was

DISCUSSION

The results of the present study confirm previously identified biochemical and cardiovascular changes that follow the short-term administration of inhaled β-agonist drugs.10, 11, 12 Hypokalemia, hyperglycemia, increases in heart rate and QT_c interval, reductions in the magnitude of the T-wave, and increased frequency of supraventricular premature beats were all observed. In most instances, these effects were greater following fenoterol administration than following salbutamol, except for

ACKNOWLEDGMENT

We wish to acknowledge and thank the Auckland Asthma Society (Mackie Research Fund) and Glaxo Group Research for their financial assistance towards this investigation.

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Asthma is a chronic inflammatory disease which has increased during the last 20 years, putting a strain on medical resources, particularly severe forms of the disease. Treatment in such cases is inhaled corticosteroids and beta agonist drugs that can produce a range of side effects. The aim of this study is to identify echocardiograph abnormalities and correlate them with severity of disease.
Eight-seven outpatients were selected at the asthma unit of the Gaffree Guinle University Hospital (HUGG). Each patient underwent spirometry, electrocardiogram (ECG) and echocardiogram (ECO) during the trial within a month maximum. Echocardiograph abnormalities found related to degree of asthma. Statistical analysis was made by nonparametric tests.
We found significant differences (p ≤ 0.05) for age, disease duration and haemoglobin saturation (SaO₂) between the moderate and severe groups. In the sample a high prevalence of tricuspid insufficiency (41.4%) was identified.
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A asma é uma doença inflamatória crónica cuja prevalência vem aumentando nos últimos 20 anos. Demanda grande utilização de recursos, principalmente no grupo grave. Neste, há consumo crónico de corticóides inalatórios e de β2-agonistas, que podem produzir uma série de problemas. O objectivo deste trabalho é o de rastrear as alterações electro e ecocardiográficas e relacioná-las ao grau da asma.
Selecionámos 87 doentes do ambulatório de asma do HUGG, que, por rotina, possuem uma espirografia, um eletrocardiograma (ECG) e um ecocardiograma (ECO) feitos com um intervalo máximo de um mês. As alterações ecocardiográficas encontradas foram relacionadas com o grau da asma. Foram usadas estatísticas não paramétricas para essas comparações.
Encontrámos diferenças significativas (p ≤ 0,05) quanto à idade, tempo de asma e saturação da hemoglobina (SaO₂) entre os grupos leve e grave. Na amostra, foi identificada alta prevalência de insuficiência tricúspide (41,4%).
O ECO identificou uma série de anormalidades, dependentes ou não da gravidade da asma. O ECO pode identificar a hipertensão arterial pulmonar, pelo cálculo da pressão média da artéria pulmonar.
Life-Threatening Hypokalemia in an Asthmatic Patient Treated with High-Dose Hydrocortisone
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Citation Excerpt :
In this case, profound hypokalemia and severe metabolic alkalosis were accompanied by excessive renal K+ wasting after admission. Although bronchodilators and aminophylline were administered and could have caused hypokalemia as a result of a shift of K+ into cells, their K+-lowering effects are usually modest in degree and do not induce an acid-base disorder.4–6 These 2 points and the longer time course did not suggest bronchodilators as the most important cause of the profound hypokalemia.
Although modest hypokalemia is frequently observed in asthmatic patients being treated with bronchodilators, profound hypokalemia and metabolic alkalosis are rarely reported in patients receiving high-dose hydrocortisone (HC). We describe a 66-year-old man who complained of generalized muscle weakness, shallow respiration, and palpitations after receiving highdose intravenous HC (total dose, 2400 mg over 4 days) to treat a severe asthma attack. During this therapy, there was a weight gain of 1.0 kg. An electrocardiogram revealed ventricular arrhythmia with frequent premature ventricular contractions. Hypokalemia was profound, with plasma potassium (K⁺) concentration of 1.7 mEq/L, and associated with renal potassium wasting, as evidenced by a transtubular potassium concentration gradient of 12; metabolic alkalosis (plasma HCO₃^–, 37 mEq/L) was also present. When treated with spironolactone, KCl supplementation, and substitution of HC with prednisolone, his plasma K⁺ concentration rapidly normalized, metabolic alkalosis was corrected, and arrhythmia disappeared within 3 days. Because of unwanted mineralocorticoid side-effects, high-dose HC may cause life-threatening hypokalemia in asthmatic patients. Because of these potential risks, plasma acid-base and electrolyte concentrations should be monitored frequently in any patient treated with high-dose HC.
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2003, American Journal of Cardiology
Citation Excerpt :
The association between the use of QTc-prolonging drugs and hospitalization for cardiac arrhythmias in this population-based study may be confounded by secondary factors that were associated with both the exposure and the outcome, such as confounding by indication.21 We therefore adjusted the calculated associations for concomitant use of drugs that can lower blood potassium levels (non–potassium-sparing diuretics,22 laxatives,23,24 corticosteroids for systemic use,25 and systemic β2 agonists25,26). We also adjusted calculated associations for current treatment for arrhythmias, number of hospitalizations in the year before the index date, and history of cardiac disease, asthma,27 and diabetes mellitus.28
Cardiac arrhythmia as an adverse effect of noncardiac drugs has been an issue of growing importance during the past few years. In this population-based study, we evaluated the risk for serious cardiac arrhythmias during the use of several noncardiac QTc-prolonging drugs in day-to-day practice, and subsequently focused on several specific groups of patients who could be extremely vulnerable for drug-induced arrhythmias. We performed a case-control study in which patients (cases), hospitalized for nonatrial cardiac arrhythmias from 1987 to 1998, were compared with their matched controls regarding current use of QTc-prolonging drugs. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using multivariate conditional logistic regression, adjusting for potential confounding factors. Data were obtained from the PHARMO record linkage system. We identified 501 cases, 39 of whom used QTc-prolonging drugs. A statistically nonsignificant increased risk for arrhythmias (OR 1.2, 95% CI 0.8 to 1.9) was observed in patients who received QTc-prolonging drugs. A clearly increased risk of arrhythmias was, however, found in patients with a history of asthma (OR 9.9, 95% CI 1.0 to 100) and in patients using potassium-lowering drugs (OR 5.3, 95% CI 1.1 to. 25.9). Our data do not suggest that there is a strong overall association between the use of QTc-prolonging drugs and hospitalization for cardiac arrhythmias in the population at large. However, there appears to be clinically relevant associations of patients with a history of asthma and patients taking potassium-lowering drugs. The use of QTc-prolonging drugs should therefore be either avoided or monitored closely in these specific patients.
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Asthma mortality has been increasing over the past 15 years. Since the incidence of fatal asthma is rare, death is perceived as an unexpected outcome. This paper reviews the nature of asthma, and the circumstances and characteristics of patients with fatal asthma attacks. In light of these features, the emergency care of acute asthma is discussed. Recommendations for improvement of prehospital and hospital care are made. Despite optimum therapy and management, death is sometimes unavoidable.
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There are few experimental data evaluating the effect of inhaled bronchodilator treatment in the critically ill patient in the intensive care unit. Extrapolating from the data that are available in chronic and acute asthma and chronic obstructive pulmonary disease (COPD) studies, it appears that both agents may be beneficial. Beta-adrenergic receptor agonists are first-line agents in asthma. However, anticholinergics may be valuable as additive agents or as single agents if the patient is intolerant of β-adrenergic side effects. This may be especially important in the critically ill patient with multiple organ failure in whom excessive tachycardia may reduce oxygen delivery. Anticholinergics and β₂-adrenergic agonists both appear to be beneficial in smoking-related chronic bronchitis. Finally, because of the severity of illness in the critical care setting, both drugs should be titrated to maximal effect when possible, monitoring closely for adverse effects of the larger than normal doses that are used.

View all citing articles on Scopus

: Manuscript received August 5; revision accepted November 18.

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Chest

Clinical InvestigationsInteraction between Corticosteroid and β-Agonist Drugs: Biochemical and Cardiovascular Effects in Normal Subjects

Section snippets

Subjects

Study Design

Biochemical Data

DISCUSSION

ACKNOWLEDGMENT

Lancet

Lancet

Am J Med

Lancet

Chest

Lancet

Chest

Seventy-five deaths in asthmatics prescribed home nebulisers

BMJ

Asthma in New Zealand

BMJ

Case control study of prescribed fenoterol and death from asthma in New Zealand, 1977-1981

Thorax

Prescribed fenoterol and death from asthma in New Zealand, 1981-7: a further case control study

Thorax

A controlled trial of methylprednisolone in the emergency treatment of acute asthma

N Engl J Med

A self management plan in the treatment of adult asthma

Thorax

An analysis of the time relations of electrocardiograms

Heart

Metabolic and cardiovascular side effects of the ß2-adrenoceptor agonists salbutamol and rimiterol

Br J Clin Pharmacol

Clinical Investigations
Interaction between Corticosteroid and β-Agonist Drugs: Biochemical and Cardiovascular Effects in Normal Subjects

Metabolic and cardiovascular side effects of the ß₂-adrenoceptor agonists salbutamol and rimiterol