Skip to main content
SpringerLink
Log in

ACE Inhibitor-Induced Cough and Bronchospasm

Incidence, Mechanisms and Management

Drug Safety Aims and scope Submit manuscript

Cite this article

Summary

A dry, tickly and often bothersome cough is the most common adverse effect of ACE inhibitors. Recent studies indicate that cough may develop in around 10% of the patients treated with ACE inhibitors. In half of these patients, the ACE inhibitor has to be discontinued. Cough has emerged as a class effect occurring with all ACE inhibitors with no clear difference between the single substances. While ACE inhibition is safe in the vast majority of patients with obstructive airways disease, asthmatic symptoms or exacerbation of asthma as well as a rise in bronchial reactivity have been occasionally reported.

ACE inhibition increases the cough reflex. The mechanisms underlying ACE inhibitor-induced cough are probably linked to suppression of kininase II activity, which may be followed by an accumulation of kinins, substance P and prosta-glandins.

Physicians should be aware that a dry cough is the most common adverse effect of ACE inhibitors and that this symptom may occur not necessarily shortly after institution of therapy but months or even a year later. Replacement by another ACE inhibitor should not be tried, since the cough will almost always recur on rechallenge with the same or another ACE inhibitor. After withdrawal of the ACE inhibitor, which is the treatment of choice, cough will resolve usually within a few days.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Jayarajan A, Prakash O. Cough syncope induced by enalapril. Chest 1993; 103: 327–8

    Article  PubMed  CAS  Google Scholar 

  2. Israili ZH, Hall D. Cough and angioneurotic edema associated with angiotensin-converting enzyme inhibitor therapy. Ann Intern Med 1992; 117: 234–42

    PubMed  CAS  Google Scholar 

  3. Todd PA, Heel RC. Enalapril: a review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in hypertension and congestive heart failure. Drugs 1986; 31:198–248

    Article  PubMed  CAS  Google Scholar 

  4. Coulter DM, Edwards IR. Cough associated with captopril and enalapril. BMJ 1987; 294: 1521–3

    Article  PubMed  CAS  Google Scholar 

  5. Inman WHW, Rawson NSB, Wilton LV, et al. Postmarketing surveillance of enalapril. I: Results of prescription-event monitoring. BMJ 1988; 297: 826–9

    Article  PubMed  CAS  Google Scholar 

  6. Chalmers D, Whitehead A, Lawson DH. Postmarketing surveillance of captopril for hypertension. Br J Clin Pharmacol 1992; 34: 215–23

    Article  PubMed  CAS  Google Scholar 

  7. Fletcher AE, Palmer AJ, Bulpitt CJ. Cough with angiotensin converting enzyme inhibitors: how much of a problem? J Hypertens 1994; 12 Suppl. 2: S43–7

    CAS  Google Scholar 

  8. Ravid D, Lishner M, Lang R, et al. Angiotensin-converting enzyme inhibitors and cough: a prospective evaluation in hypertension and in congestive heart failure. J Clin Pharmacol 1994; 34: 1116–20

    PubMed  CAS  Google Scholar 

  9. Simon SR, Black HR, Moser M, et al. Cough and ACE inhibitors. Arch Intern Med 1992; 152: 1698–1700

    Article  PubMed  CAS  Google Scholar 

  10. Sebastian JL, McKinney WP, Kaufman J, et al. Angiotensin-converting enzyme inhibitors and cough. Prevalence in an outpatient medical clinic population. Chest 1991; 99: 36–9

    Article  PubMed  CAS  Google Scholar 

  11. Fletcher AE, Bulpitt CJ, Chase DM, et al. Quality of life with three antihypertensive treatments: cilazapril, atenolol, nifedipine. Hypertension 1992; 19: 499–507

    Article  PubMed  CAS  Google Scholar 

  12. Yeo WW, Maclean D, Richardson PJ, et al. Cough and enalapril: assessment by spontaneous reporting and visual scale under double-blind conditions. Br J Clin Pharmacol 1991; 31:356–9

    Article  PubMed  CAS  Google Scholar 

  13. Lacourciere Y, Brunner H, Irwin R, et al. Effects of modulators of the renin-angiotensin-aldosterone system on cough. J Hypertens 1994; 12: 1387–93

    PubMed  CAS  Google Scholar 

  14. Reisin L, Schneeweiss A. Complete spontaneous remission of cough induced by ACE inhibitors during chronic therapy in hypertensive patients. J Hum Hypertens 1992; 6: 333–5

    PubMed  CAS  Google Scholar 

  15. Yeo WW, Foster G, Ramsay LE. Prevalence of persistent cough during long-term enalapril treatment: controlled study versus nifedipine. Q J Med 1991; 293: 763–70

    Google Scholar 

  16. Os I, Bratland B, Dahlöf B, et al. Female preponderance for lisinopril-induced cough in hypertension. Am J Hypertens 1994; 7: 1012–5

    PubMed  CAS  Google Scholar 

  17. Wood R. Bronchospasm and cough as adverse reactions to the ACE inhibitors captopril, enalapril and lisinopril: a controlled retrospective cohort study. Br J Clin Pharmacol 1995; 39:265–70

    Article  PubMed  CAS  Google Scholar 

  18. Berkin KE, Ball SG. Cough and angiotensin converting enzyme inhibition. BMJ 1988; 296: 1279–80

    Article  PubMed  CAS  Google Scholar 

  19. Sorooshian M, Eynon CA, Webb DJ, et al. Cough associated with ACE inhibitors: increased frequency in renal failure. Eur J Int Med 1991; 2: 15–7

    Google Scholar 

  20. Goldszer RC, Lilly LS, Solomon HS. Prevalence of cough during angiotensin-converting enzyme inhibitor therapy. Am J Med Sci 1988; 85: 887

    CAS  Google Scholar 

  21. Strocchi E, Valtancoli G, Ambrosioni E. The incidence of cough during treatment with angiotensin converting enzyme inhibitors. J Hypertens 1989; 7 Suppl. 6: S308–9

    CAS  Google Scholar 

  22. Puolijoki H, Nieminen M, Moilanen E, et al. Cough induced by enalapril but not by captopril. Eur Respir J 1989; 2: 289–91

    PubMed  CAS  Google Scholar 

  23. Saruta T, Nishikawa K. Characteristics of a new angiotensin converting enzyme inhibitor: delapril. Am J Hypertens 1991; 4: S23–8

    Google Scholar 

  24. Sharif MN, Evans BL, Pylypchuk GB. Cough induced by quinapril with resolution after changing to fosinopril. Ann Pharmacother 1994; 28: 720–2

    PubMed  CAS  Google Scholar 

  25. Overlack A, Müller B, Schmidt L, et al. Airway responsiveness and cough induced by angiotensin converting enzyme inhibition. J Hum Hypertens 1992; 6: 387–92

    PubMed  CAS  Google Scholar 

  26. Sala H, Abad J, Juanmiquel LI, et al. Captopril and bronchial reactivity. Postgrad Med J 1986; 62 Suppl. 1: 76–7

    PubMed  Google Scholar 

  27. Bertoli L, Fusco M, LoCicero S, et al. Influence of ACE inhibition on pulmonary haemodynamics and function in patients in whom beta-blockers are contraindicated. Postgrad Med J 1986; 62 Suppl. 1:47–51

    PubMed  Google Scholar 

  28. Peacock AJ, Matthews AW. The effect of captopril on pulmonary haemodynamics and lung function in patients with chronic airflow obstruction [letter]. Thorax 1986; 41: 225

    Google Scholar 

  29. Riska H, Stenius-Aarniala B. Sovijarvi ARA. Comparison of the efficacy of an ACE-inhibitor and a calcium channel blocker in hypertensive patients: a preliminary report. Postgrad Med J 1986; 62 Suppl. 1:52–3

    PubMed  Google Scholar 

  30. Kaufman J, Casanova JE, Riendl P, et al. Bronchial hyperreactivity and cough due to angiotensin-converting enzyme inhibitors. Chest 1989; 95: 544–8

    Article  PubMed  CAS  Google Scholar 

  31. Mue S, Tamura G, Yamauchi K, et al. Bronchial response to enalapril in asthmatic, hypertensive patients. Clin Ther 1990; 12: 335–43

    PubMed  CAS  Google Scholar 

  32. Popa V. Captopril-related (and induced?) asthma. Am Rev Respir Dis 1987; 136:999–1000

    Article  PubMed  CAS  Google Scholar 

  33. Semple PF, Herd GW. Cough and wheeze caused by inhibitors of angiotensin converting enzyme. N Engl J Med 1986; 314: 61

    PubMed  CAS  Google Scholar 

  34. Goh TC, Ong YY. Bronchial hyperreactivity induced by angiotensin converting enzyme inhibitor. Singapore Med J 1991; 32: 183–4

    PubMed  CAS  Google Scholar 

  35. Lunde H, Hedner T, Samuelsson O, et al. Dyspnoea, asthma, and bronchospasm in relation to treatment with angiotensin converting enzyme inhibitors. BMJ 1994; 308: 18–21

    Article  PubMed  CAS  Google Scholar 

  36. Bucknall CE, Neilly JB, Carter R, et al. Bronchial hyperreactivity in patients who cough after receiving angiotensin converting enzyme inhibitors. BMJ 1988; 296: 86–8

    Article  PubMed  CAS  Google Scholar 

  37. Andersson RGG, Persson K. ACE inhibitors and their influence on inflammation, bronchial reactivity and cough. Eur Heart J 1994; 15 Suppl. C: 52–6

    PubMed  Google Scholar 

  38. Hinojosa M, Quirce S, Puyana J, et al. Bronchial hyperreactivity and cough induced by angiotensin converting enzyme-inhibitor therapy. J Allergy Clin Immunol 1990; 85: 818–9

    Article  PubMed  CAS  Google Scholar 

  39. Boulet LP, Milot J, Lampron N, et al. Pulmonary function and airway responsiveness during long-term therapy with captopril. JAMA 1989; 261: 413–6

    Article  PubMed  CAS  Google Scholar 

  40. Dixon CMS, Fuller RW, Barnes PJ. The effect of an angiotensin converting enzyme inhibitor, ramipril, on bronchial responses to inhaled histamine and bradykinin in asthmatic subjects. Br J Clin Pharmacol 1987; 23: 91–3

    Article  PubMed  CAS  Google Scholar 

  41. Fuller RW, Choudry NB. Increased cough reflex associated with angiotensin converting enzyme inhibitor cough. BMJ 1987; 295: 1025–6

    Article  PubMed  CAS  Google Scholar 

  42. Morice AH, Lowry R, Brown MJ, et al. Angiotensin-converting enzyme and the cough reflex: Lancet 1987; II: 1116–8

    Article  Google Scholar 

  43. McEwan JR, Choudry N, Street R, et al. Change in cough reflex after treatment with enalapril and ramipril. BMJ 1989; 299:13–6

    Article  PubMed  CAS  Google Scholar 

  44. Buck SH, Burks TF. The neuropharmacology of capsaicin: review of some recent observations. Pharmacol Rev 1986; 38: 179–226

    PubMed  CAS  Google Scholar 

  45. Sant’Ambrogio G. Afferent pathways for the cough reflex. Bull Eur Physiopathol Respir 1987; 23 Suppl. 10: 19S–23S

    PubMed  Google Scholar 

  46. Kellstein DE, Price DD, Hayes RL, et al. Evidence that substance P selectively modulates C-fiber-evoked discharges of dorsal horn nociceptive neurons. Brain Res 1990; 526: 291–8

    Article  PubMed  CAS  Google Scholar 

  47. Barnes PJ. Neuropeptides in human airways: functional and clinical implications. Am Rev Respir Dis 1987; 136: 77–83

    Article  Google Scholar 

  48. Casceiri MA, Bull Hg, Mumford RA, et al. Carboxyl-terminal tripeptidyl hydrolysis of substance P by purified rabbit lung angiotensin-converting enzyme and the potentiation of substance P activity in vivo by captopril and MK-422. Mol Pharmacol 1984; 25: 287–93

    Google Scholar 

  49. Thysell H, Andersson KE, Andersson SI, et al. Angiotensin-converting enzyme inhibition, cough and the serum concentration of substance P. Eur J Clin Pharmacol 1988; 34: 649–50

    Article  PubMed  CAS  Google Scholar 

  50. Erdös EG. The angiotensin I converting enzyme. Fed Proc 1977; 36: 1760–5

    PubMed  Google Scholar 

  51. Fuller RW, Warren JB, McCusker M, et al. Effect of enalapril on the skin response to bradykinin in man. Br J Clin Pharmacol 1987; 23: 88–90

    Article  PubMed  CAS  Google Scholar 

  52. Fuller RW, Dixon CMS, Cuss FMC, et al. Bradykinin-induced bronchoconstriction in humans: mode of action. Am Rev Respir Dis 1987; 135: 176–80

    PubMed  CAS  Google Scholar 

  53. Ujiie Y, Sekizawa K, Katsumata U, et al. Bradykinin-induced cough reflex markedly increases in patients with cough associated with captopril or enalapril [abstract]. Am Rev Respir Dis 1990; 141:A923

    Google Scholar 

  54. Puolijoki H, Nieminen MM, Moilanen E, et al. Bradykinin and eicosanoids in enalapril-induced cough [abstract]. Am Rev Respir Dis 1990; 141: A918

    Google Scholar 

  55. Gradman A, Arcuri KE, Goldberg AI, et al. A randomized, placebo-controlled, double-blind, parallel study of various doses of losartan potassium compared with enalapril maleate in patients with essential hypertension. Hypertension 1995; 25: 1345–50

    Article  PubMed  CAS  Google Scholar 

  56. Hartung HP, Heininger K, Schäfer B, et al. Substance P and astrocytes: stimulation of the cyclooxygenase pathway of arachidonic acid metabolism. FASEB J 1988; 2: 48–51

    PubMed  CAS  Google Scholar 

  57. Coleridge HM, Coleridge JC, Ginzel KH, et al. Stimulation of ‘irritant’ receptors and afferent C-fibres in the lungs by prostaglandins. Nature 1976; 264: 451–3

    Article  PubMed  CAS  Google Scholar 

  58. Greenberg R, Osman Jr GH, O’Keefe EH, et al. The effects of captopril (SQ 14.225) on bradykinin-induced bronchoconstriction in the anaesthetised guinea pig. Eur J Pharmacol 1979; 57: 287–94

    Article  PubMed  CAS  Google Scholar 

  59. Rossoni G, Omini C, Vigano T, et al. Bronchoconstriction by histamine and bradykinin in guinea pigs: relationship to thromboxane A2 generation and the effect of aspirin. Prostaglandins 1980; 20: 547–57

    Article  PubMed  CAS  Google Scholar 

  60. Nicholls MG, Gilchrist NL. Sulindac and cough induced by converting enzyme inhibitors [letter]. Lancet 1987; I: 872

    Google Scholar 

  61. Gilchrist NL, Richards AM, March M, et al. Effect of sulindac on angiotensin converting enzyme inhibitor-induced cough: randomised placebo-controlled double-blind cross-over study. J Hum Hypertens 1989; 3: 451–5

    PubMed  CAS  Google Scholar 

  62. Yeo WW, Ramsey LE, Morice AH. Ace inhibitor cough: a genetic link [letter]? Lancet 1991; 337: 187

    Article  PubMed  CAS  Google Scholar 

  63. Rigat B, Hubert C, Alhenc-Gelas F, et al. An insertion deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half of the variance of serum enzyme levels. J Clin Invest 1990; 86: 1343–6

    Article  PubMed  CAS  Google Scholar 

  64. Furuya K, Yamaguchi E, Hirabayashi T, et al. Angiotensin-I-converting enzyme gene polymorphism and susceptibility to cough [letter]. Lancet 1994; 343: 354

    Article  PubMed  CAS  Google Scholar 

  65. Kreft-Jais C, Laforest L, Bonnardeaux A, et al. ACE inhibitors, cough, and genetics [letter]. Lancet 1994; 343: 740

    Article  PubMed  CAS  Google Scholar 

  66. Chadwick AG, Yeo WW, Higgins KS, et al. ACE inhibitors, cough, and genetics. Lancet 1994; 343: 740–1

    Article  PubMed  CAS  Google Scholar 

  67. Fogari R, Zoppi A, Tettamanti F, et al. Effects of nifedipine and indomethacin on cough induced by angiotensin-converting enzyme inhibitors: a double-blind, randomized, cross-over study. J Cardiovasc Pharmacol 1992; 19: 670–3

    PubMed  CAS  Google Scholar 

  68. Fujita T, Yamashita N, Yamashita K. Effect of indomethacin on antihypertensive action of captopril in hypertensive patients. Clin Exp Hypertens 1981; 3: 939–52

    Article  PubMed  CAS  Google Scholar 

  69. Cazzola M, Matera MG, Liccardi G, et al. Theophylline in the inhibition of angiotensin-converting enzyme inhibitor-induced cough. Respiration 1993; 60: 212–5

    Article  PubMed  CAS  Google Scholar 

  70. Kamei J, Kasuya Y. The effect of hydrochlorothiazide on the enhanced coughing associated with treatment with enalapril. Eur J Pharmacol 1992; 213: 137–9

    Article  PubMed  CAS  Google Scholar 

  71. Hargreaves MR, Benson MK. Inhaled sodium cromoglycate in angiotensin-converting enzyme inhibitor cough. Lancet 1995; 345: 13–6

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Am Burg-weiher 54, 53123, Bonn, Germany

    Axel Overlack

Authors
  1. Axel Overlack
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Overlack, A. ACE Inhibitor-Induced Cough and Bronchospasm. Drug-Safety 15, 72–78 (1996). https://doi.org/10.2165/00002018-199615010-00006

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00002018-199615010-00006

Keywords

search

Navigation