Dyspnoea, asthma, and bronchospasm in relation to treatment with angiotensin converting enzyme inhibitorsBMJ 1994; 308 doi: https://doi.org/10.1136/bmj.308.6920.18 (Published 01 January 1994) Cite this as: BMJ 1994;308:18
- H Lunde,
- T Hedner,
- O Samuelsson,
- J Lotvall,
- L Andren,
- L Lindhom,
- B E Wilholm
- Department of Clinical Pharmacology, Sahlgrenska University Hospital, S-413 45, Gothenburg, Sweden.
- Department of Nephrology, Sahlgrenska University Hospital, Gothenburg. Swedish Medical Products Agency, Uppsala, Sweden. Health Science Centre, University of Lund, Dalby, Sweden.
- Correspondence to: Dr Lunde.
- Accepted 15 October 1993
Objective: To evaluate the occurrence of asthma and dyspnoea precipitated or worsened byangiotensin converting enzyme inhibitors.
Design: Summary of reports of adverse respiratory reaction in relation to treatment with angiotensin converting enzyme inhibitors that were submitted to Swedish Adverse Drug Reactions Advisory Committee and to World Health Organisation's international drug information system until 1992. Sales of angiotensin converting enzyme inhibitors in Sweden were also summarised.
Subjects: Patients receiving angiotensin converting enzyme inhibitors who reported adverse respiratory reactions.
Main outcome measures: Clinical characteristics of adverse reactions of asthma, bronchospasm, and dyspnoea.
Results: In Sweden 424 adverse respiratory reactions were reported, of which most (374) were coughing. However, 36 patients had averse drug reactions diagnosed as asthma, bronchospasm, or dyspnoea. In 33 of these cases the indication for treatment with angiotensin converting enzyme inhibitors was hypertension, in only three heart failure. The respiratory symptoms occurred in about half of the patients within the first two weeks of treatment, and about one third needed hospitalisation or drug treatment. Dyspnoea symptoms occurred in conjunction with other symptoms from the airways or skin in 23 out of the 36 cases. In the WHO database there were 318 reports of asthma or bronchospasm, 516 reports of dysponea, and 7260 reports of cough in relation to 11 different angiotensin converting enzyme inhibitors.
Conclusion: Symptoms of airway obstruction in relation to treatment with angiotensin converting enzyme inhibitors seem to be a rare but potentially serious reaction generally occurring within the first few weeks of treatment.
Coughing is a common and well recognised adverse reaction to angiotensin converting enzyme inhibitors whereas reports of asthma and bronchial hyperreactivity are conflicting
This study examined the relation of spontaneously reported adverse respiratory reactions in Sweden to treatment with angiotensin converting enzyme inhibitors
Coughing was reported 8-10 times more often than wheeze and dyspnoea, and in most cases asthmatic symptoms occurred together with coughing, rhinitis, angio-oedema, or other skin reactions
In more than half of the cases wheeze or dyspnoea developed during the first two weeks of treatment.
Doctors should recognise asthma as a possible adverse reaction to angiotensin converting enzyme inhibitors
The angiotensin converting enzyme inhibitors were early suggested to represent a favourable drug in hypertensive patients with obstructive lung disease,1 but coughing and possibly unspecific airway hyperreactivity are common in patients treated with these drugs.*RF 2-5* Furthermore, single case reports indicate that asthma or bronchospasm may be caused by treatment with structurally different drugs such as captopril,6 enalapril,7 and lisinopril.8 In order to evaluate the occurrence of dyspnoea, asthma, and bronchospasm in relation to angiotensin converting enzyme inhibitors, we summarised the results in available registers of adverse drug reactions.
Patients and methods
We obtained data from the Medical Products Agency and the Swedish Drug Information System as described previously.9 On 4 February 1992 we looked for adverse respiratory reactions to angiotensin converting enzyme inhibitors reported during 1981-91 to the Swedish Adverse Drug Reactions Advisory Committee. We included only those reactions judged by the committee to be probably or possibly related to treatment with the drugs, and we obtained clinical reports on cases with aggravated asthma, bronchospasm, and dyspnoea for detailed scrutiny. We also determined the number of defined daily doses of angiotensin converting enzyme inhibitors sold in Sweden during 1981-91.
In addition, we summarised the reported adverse respiratory reactions related to treatment with angiotensin converting enzyme inhibitors that were submitted to the World Health Organisation Collaborating Centre for International Drug Monitoring up to 6 August 1992. We looked for the terms asthma, bronchospasm, aggravated bronchospasm, dyspnoea, and coughing as these are the preferred terms in the WHO's terminology of adverse drug reactions.10 The information in the international drug information system at the WHO Collaborating Centre for International Drug Monitoring (Uppsala, Sweden) is not homogeneous, at least with respect to origin or likelihood that the pharmaceutical product caused the adverse reaction. The information in this paper expresses the judgment of the authors and does not represent the opinion of the WHO.
A total of 1215 adverse drug reactions were judged to have been probably or possibly related to treatment with angiotensin converting enzyme inhibitors in Sweden, of which 424 were adverse respiratory reactions. Coughing was the most common reaction (374/424, 88%) while the remaining 50 reactions were dyspnoea (19), aggravated asthma (11), bronchospasm (6), rhinitis (5), larynx oedema (4), nasal congestion (3), interstitial pneumonitis (1), and pleuritis (1).
Table I gives details of the 36 patients whose adverse drug reactions were dyspnoea, aggravated asthma, or bronchospasm. The patients (20 women and 16 men) had a mean age 58.9 (range 29-82 years), and they had received angiotensin enzyme inhibitors either to treat hypertension (33 patients) or heart failure (three patients). Information about the time when the symptoms first occurred was available in 27 cases: 15 patients (42%) first experienced symptoms during the first week of treatment, and four (11%) first experienced symptoms during the second week. Three patients developed similar symptoms when rechallenged with a chemically different angiotensin converting enzyme inhibitor. Twelve patients also had cough, one had cough and angio-oedema, one reported cough,exanthema, and headache, two had suspected angio-oedema, and three had other skin reactions such as rash, urticaria, and flush. Two of the patients with aggravated asthma also had rhinitis.
One patient died, but the cause of the death was not judged to be related to the drug treatment. In all other cases the symptoms rapidly improved on discontinuation of the angiotensin converting enzyme inhibitor. Five patients needed hospitalisation with bronchodilator treatment or ventilatory support, or both, and six patients were treated with antiasthmatic drugs in outpatient units. In 12 cases obstructive airway disease had been diagnosed, and eight of these patients were taking corticosteroids or β(sub2) agonists. Five patients had been taking β receptor antagonists for some time without any respiratory side effects before they started treatment with angiotensin converting enzyme inhibitors. In four of these cases both drugs were discontinued when the adverse reaction appeared, but in one case metoprolol treatment continued without any adverse respiratory reaction after enalapril was discontinued Four patients had been taking non-steroidal anti-inflammatory drugs for some time before they started treatment with angiotensin converting enzyme inhibitors, and three developed wheeze within one week of taking the enzyme inhibitor. One patient continued taking the anti-inflammatory agent without problems after the angiotensin converting enzyme inhibitor and the Beta receptor antagonist were discontinued.
The figure shows that the annual number of adverse respiratory reactions declined in Sweden after 1988 despite a continuous increase in the sales of angiotensin converting enzyme inhibitors. A similar pattern is shown by the yearly reports of adverse respiratory reactions to the WHO's international drug information system (table II). The reports concerned 11 different angiotensin converting enzyme inhibitors, and reports of cough were about nine times more common than those of asthma, bronchospasm, and dyspnoea (table III).
Angiotensin converting enzyme is an unspecific dipeptide hydrolase with high capacity to degrade bradykinin and substance P to inactive metabolites. Inhibition of this enzyme will inhibit the degradation of these proinflammatory peptides.11 In animal experiments it has been shown that inhibition of angiotensin converting enzyme will potentiate airway obstruction and increase airway plasma leakage in response to bradykinin and substance P.*RF 12-13* Bradykinin can induce bronchoconstriction in asthmatic subjects.14
Only a few published case reports describe the development or exacerbation of asthmatic symptoms during treatment with angiotensin converting enzyme inhibitors.*RF 6-8* A survey of coughing associated with captopril and enalapril treatment did not show any definite association of the cough reaction with asthma even though two of the 59 patients complained of wheeze and another showed exacerbation of asthma.15 In a one year prescription event study of enalapril 2.9% of patients coughed, but there were no reports on asthma or dyspnoea.16 There are few prospective controlled studies on the effects of angiotensin converting enzyme inhibitors on pulmomary function in asthmatic patients. In small, short term studies no overt changes in asthmatic symptoms or spirometric values emerged.*RF 17-19*
In our study, however, we found several cases of angiotensin converting enzyme inhibitors apparently causing or worsening asthmatic symptoms and dyspnoea. Three of the patients developed adverse respiratory reactions with two different angiotensin converting enzyme inhibitors, suggesting that the reactions represented a class phenomenon rather than an allergic reaction to a specific substance. Interestingly, many of the patients had other symptoms such as cough, rhinitis, or angio-oedema as well as dyspnoea and wheeze, which may be explained by a local increase in proinflammatory peptides.
Spontaneous reporting of adverse experiences represents an important means of detecting infrequent adverse drug reactions but it does not provide information about the true incidence. A rough estimate of the risk, however, may be obtained by relating the 19 Swedish cases reported in 1987-8 to the calculated number of new prescriptions of angiotensin converting enzyme inhibitors in Sweden during this period. By extrapolating data from the Jamtland study and the prescription survey,20 the number of new prescriptions can be roughly estimated as 117200. Thus, a risk of one report for every 6200 new prescriptions can be calculated. This estimate is very rough, however, since both the numerator (actual reporting rate unknown) and the denominator (extrapolation from random samples) are associated with a considerable uncertainty.
Symptoms of airway obstruction caused by angiotensin converting enzyme inhibitors seem to be rare, but doctors should be aware of these reactions. Asthmatic patients may be more susceptible than others. Any suspicion of bronchospasm or aggravated asthma, even with patients who cough, should be carefully monitored and documented. Such adverse reactions usually require discontinuation of the angiotensin converting enzyme inhibitor.
The conclusions reached in this paper reflect the judgment of the authors and do not represent the opinion of the WHO.