Anti-asthma drugs + Beta blockers - Drug Interactions

Non-cardioselective beta blockers (e.g. propranolol,timolol)should not be used in asthmatic subjects because they may causeserious bronchoconstriction, even if given as eye drops. Non-cardioselective beta blockers oppose bronchodilator effects ofbeta-agonist bronchodilators, and higher doses may be requiredto reverse bronchospasm. Even cardioselective blockers (e.g. atenolol) can sometimes cause acute bronchospasm in asthmatics.However,cardioselective beta blockers do not generally inhibitthe bronchodilator effect of beta-agonist bronchodilators.

A review of 29 studies (including 19 single-dose studies) on use of cardioselective beta blockers in patients with reversible airway disease indicated that in patients with mild to moderate disease, short-term use of cardioselective beta blockers does not cause significant adverse respiratory effects. Information on effects in patients with more severe or less reversible disease, or on frequency or severity of acute exacerbations was not available (See reference number 1). Another review indicated that when low doses of cardioselective beta blockers are given to patients with mild, intermittent or persistent asthma, or moderate persistent asthma, and heart failure or myocardial infarction, benefits of treatment outweigh risks. However,it was considered that further study is required to establish long-term safety, and also that beta blockers should be avoided in severe persistent asthma (See reference number 2).

The cardioselective beta blockers would not be expected to affect beta receptors in bronchi, but bronchospasm can sometimes occur following their use by asthmatics and others with obstructive airways diseases, particularly if high doses are used. Deterioration of asthma was reported in a patient taking oral betaxolol with theophylline and pranlukast,although betaxolol is considered to be highly cardioselective and less likely to cause pulmonary adverse effects than other cardioselective beta blockers (See reference number 3).

Celiprolol in asthmatic patients with isoprenaline (isoproterenol),or salbutamol,(See reference number 4,6,7) or terbutaline infusion or inhalation(See reference number 8)

• Metoprolol in asthmatic patients at rest with isoprenaline infusion(See reference number 9,10)In contrast, another study found that increase in forced expiratory volume (FEV) with a terbutaline inhalation and infusion was reduced by about 300 mL by atenolol and metoprolol. The authors considered that this would be clinically relevant in severe asthma (See reference number 11). Another study in 12 patients with mild asthma found that single doses of celiprolol 200mg or nebivolol 5mg reduced FEV1 by 272 mL and 193 mL, respectively, when compared with placebo. Increasing inhalation of salbutamol to a total dose of 800 micrograms reversed these reductions but did not restore FEV1 back to its initial value. None of these changes was considered to be clinically significant by authors (See reference number 12). Fifteen patients with mild to moderate COPD and airways hyperrespon

siveness were given celiprolol 200mg daily,metoprolol 100mg daily or propranolol 80mg daily for 4 days. Propranolol significantly reduced FEV1 and increased airways hyper-responsiveness compared with placebo whereas metoprolol only increased airways hyper-responsiveness. Celiprolol had no significant effects on pulmonary function. The bronchodilating effects of a single 12-microgram dose of formoterol were significantly reduced by propranolol,but not by metoprolol or celiprolol (See reference number 7).

Non-selective beta blockers (e.g. propranolol) are contraindicated in asthmatic subjects because they can cause bronchospasm,reduce lung ventilation and may possibly precipitate a severe asthmatic attack in some subjects. An example of danger is illustrated by an asthmatic patient who developed fatal status asthmaticus after taking just one dose of propranolol (See reference number 13). Another case report describes a patient with bronchial asthma receiving salbutamol who collapsed and died after taking three 20mg propranolol tablets,which had been supplied in error instead of 20mg prednisone tablets (See reference number 14). The manufacturers of propranolol note that from 1965 to 1996, CSM in UK had received 51 reports of bronchospasm due to propranolol, 13 of them fatal, and 5 of them in patients who had a history of asthma, bronchospasm or wheeze (See reference number 15). The non-cardioselective beta blockers oxprenolol(See reference number 5) and propranolol(See reference number 4,5,8-10) oppose effects of bronchodilators such as isoprenaline (isoproterenol),(See reference number 4,9,10)salbutamol (albuterol),(See reference number 4,5) and terbutaline (See reference number 8). Even eye drops containing non-selective beta blockers timolol(See reference number 16,17) and metipranolol(See reference number 18) have been reported to precipitate acute bronchospasm. In patients with heart failure treated with carvedilol,3 of 12 with concurrent asthma had wheezing requiring carvedilol withdrawal. In contrast,only 1 of 31 patients with COPD had wheezing (See reference number 19).

Non-selective beta blockers such as propranolol also block beta2 receptors in bronchi so that normal bronchodilation, which is under control of sympathetic nervous system, is reduced or abolished. As a result bronchoconstriction of asthma can be made worse. Cardioselective beta blockers on other hand, preferentially block beta1 receptors in heart, with less effect on beta2 receptors, so that beta2 stimulating bronchodilators, such as isoprenaline, salbutamol and terbutaline, continue to have bronchodilator effects.

A well established drug-disease interaction. In 1996, CSM in UK(See reference number 20)re-issued following advice: “Beta blockers, including those considered to be cardioselective, should not be given to patients with a history of asthma/bronchospasm.” Non-cardioselective beta blockers (indicated in table 1 below,) should certainly be avoided in asthmatics and those with chronic obstructive pulmonary disease,whether given systemically or in eye drops, because serious and life-threatening bronchospasm may occur. The cardioselective beta blockers are generally safer but not entirely free from risk in some patients,particularly in high dosage. In contrast to 1996 recommendations of CSM on cardioselective beta blockers, one recent review from 2002/3(See reference number 1,21) recommends that “cardioselective beta blockers should not be withheld from patients with mild to moderate reversible airway disease”. However, some concern has been expressed that this conclusion was based on results from short-term studies and state that question of safety in asthmatics over long term has not been answered (See reference number 22). Further, there are no studies to suggest safety of cardioselective beta blockers in patients with exacerbations of asthma,(See reference number 23) and even a highly cardioselective drug such as betaxolol may cause bronchospasm (See reference number 3). In 2004, American College of Cardiology and American Heart Association guidelines for management of ST-elevation myocardial infarction stated that benefits of using beta blockers strongly outweigh risk of adverse events in patients with COPD or mild asthma (non-active), and noted that most patients with asthma are able to tolerate cardioselective beta blockers. Therefore if a beta blocker is required a cardioselective beta blocker should be used, and patient’s pulmonary function monitored (See reference number 24). A recent Cochrane review concluded that cardioselective beta blockers did not produce any significant adverse respiratory effects or reduction in response to beta2 agonists, and it recommended that cardioselective beta blockers should not be withheld from patients with COPD (See reference number 25).

Celiprolol (a cardioselective beta blocker) appears to be exceptional in causing mild bronchodilatation in asthmatics and not bronchoconstriction, although it may still produce a reduction in expiratory volume, as seen in study above,(See reference number 12) but some caution is still necessary as this requires confirmation (See reference number 6).

The bronchoconstrictive effects of beta blockers can be opposed by beta2 agonist bronchodilators such a salbutamol, but as manufacturers point out, large doses may be needed and they suggest that ipratropium and intravenous aminophylline may also be needed (See reference number 15).

Salpeter S,Ormiston T, Salpeter EE. Cardioselective :5.5pt; font-weight:normal; color:#000000″>β-blockers in patients with reversible airway disease: a meta-analysis. Ann Intern Med (2002) 137, 715–25.

Self T,Soberman JE, Bubla JM, Chafin CC. Cardioselective beta-blockers in patients withasthma and concomitant heart failure or history of myocardial infarction: when do benefitsoutweigh risks? J Asthma (2003) 40, 839–45.

Miki A,Tanaka Y, Ohtani H, Sawada Y. Betaxolol-induced deterioration of asthma and a pharmacodynamic analysis based on :5.5pt; font-weight:normal; color:#000000″>β-receptor occupancy. Int J Clin Pharmacol Ther (2003)41, 358–64.

Doshan HD,Rosenthal RR, Brown R, Slutsky A, Applin WJ, Caruso FS. Celiprolol, atenololand propranolol: a comparison of pulmonary effects in asthmatic patients. J Cardiovasc Pharmacol (1986) 8 (Suppl 4), S105–S108.

Fogari R,Zoppi A, Tettamanti F, Poletti L, Rizzardi G, Fiocchi G. Comparative effects ofceliprolol, propranolol, oxprenolol, and atenolol on respiratory function in hypertensive patients with chronic obstructive lung disease. Cardiovasc Drugs Ther (1990) 4, 1145–50.

Pujet JC,Dubreuil C, Fleury B, Provendier O, Abella ML. Effects of celiprolol, a cardioselective beta-blocker, on respiratory function in asthmatic patients. Eur Respir J (1992) 5, 196–200.

Van der Woude HJ,Zaagsma J, Postma DS, Winter TH, Van Hulst M, Aalbers R. Detrimentaleffects of :5.5pt; font-weight:normal; color:#000000″>β-blockers in COPD: A concern for nonselective :5.5pt; font-weight:normal; color:#000000″>β-blockers. Chest (2005) 127, 818–24.

Matthys H,Doshan HD, Rühle K-H, Applin WJ, Braig H, Pohl M. Bronchosparing propertiesof celiprolol, a new :5.5pt; font-weight:normal; color:#000000″>β1, :5.5pt; font-weight:normal; color:#000000″>α2 blocker, in propranolol-sensitive asthmatic patients. J Cardiovasc Pharmacol (1986) 8 (Suppl 4), S40–S42.

Thiringer G,Svedmyr N. Interaction of orally administered metoprolol, practolol and propranolol with isoprenaline in asthmatics. Eur J Clin Pharmacol (1976) 10, 163–70.

Johnsson G,Svedmyr N, Thiringer G. Effects of intravenous propranolol and metoprolol andtheir interaction with isoprenaline on pulmonary function, heart rate and blood pressure inasthmatics. Eur J Clin Pharmacol (1975) 8, 175–80.

Löfdahl C-G,Svedmyr N. Cardioselectivity of atenolol and metoprolol. A study in asthmaticpatients. Eur J Respir Dis (1981) 62, 396–404.

Cazzola M,Noschese P, D’Amato M, D’Amato G. Comparison of the effects of single oraldoses of nebivolol and celiprolol on airways in patients with mild asthma. Chest (2000) 118, 1322–6.

Anon. Beta-blocker caused death of asthmatic. Pharm J (1991) 247,185.

Spitz DJ. An unusual death in an asthmatic patient. Am J Forensic Med Pathol (2003) 24,271–2.

Fallowfield JM,Marlow HF. Propranolol is contraindicated in asthma. BMJ (1996) 313, 1486.

Charan NB,Lakshminarayan S. Pulmonary effects of topical timolol. Arch Intern Med (1980)140, 843–4.

Jones FL,Ekberg NL. Exacerbation of obstructive airway disease by timolol. JAMA (1980)244, 2730.

Vinti H,Chichmanian RM, Fournier JP, Pesce A, Taillan B, Fuzibet JG, Cassuto JP, Dujardin

P. Accidents systémiques des bêta-bloquants en collyres. A propos de six observations. Rev Med Interne (1989) 10,41–4.

Kotlyar E,Keogh AM, Macdonald PS, Arnold RH, McCaffrey DJ, Glanville AR. Tolerabilityof carvedilol in patients with heart failure and concomitant chronic obstructive pulmonarydisease or asthma. J Heart Lung Transplant (2002), 21, 1290–5.

Committee on Safety of Medicines/Medicines Control Agency. Reminder: Beta-blockerscontraindicated in asthma. Current Problems (1996) 22,2.

Salpeter SR,Ormiston TM. Use of :5.5pt; font-weight:normal; color:#000000″>β-blockers in patients with reactive airway disease. Ann Intern Med (2003) 139, 304.

Shulan DJ,Katlan M, Lavsky-Shulan M. Use of :5.5pt; font-weight:normal; color:#000000″>β-blockers in patients with reactive airway disease. Ann Intern Med (2003) 139, 304.

Epstein PE. Fresh air and :5.5pt; font-weight:normal; color:#000000″>β-blockade. Ann Intern Med (2002) 137,766–7.

Antman EM,Anbe DT, Armstrong PW, Bates ER, Green LA, Hand M, Hochman JS, Krumholz HM, Kushner FG, Lamas GA, Mullany CJ, Ornato JP, Pearle DL, Sloan MA, Smith SC,Alpert JS, Anderson JL, Faxon DP, Fuster V, Gibbons RJ, Gregoratos G, Halperin JL, Hiratzka LF, Hunt SA, Jacobs AK.. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction. A report of the American College of Cardiology/AmericanHeart Association Task Force on Practice Guidelines (Committee to revise the 1999 guidelines for the management of patients with acute myocardial infarction). J Am Coll Cardiol (2004) 44, E1–E212. Available at: (accessed 22/08/2007).

Salpeter S,Ormiston T, Salpeter E. Cardioselective beta-blockers for chronic obstructive pulmonary disease (review). Available in The Cochrane Database of Systematic Reviews; Issue

4. Chichester: John Wiley; 2005 (accessed 22/08/2007).