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Home , ACE inhibitor

Eur Respir J EDITORIAL 1989, 2, 198-201

Respiratory effects of converting enzyme inhibition

K.E. Berkin*

Angiotensin converting enzyme (ACE) inhibitors have drawals for . In the post-marketing been available for the treatment of and surveillance study, nonsmokers constituted 88% (113 failure for several years. This class of is generally out of 128 patients) of withdrawals, whereas 77% of the well accepted by the patient (1), but an unusual, infre­ 54, 072 patients entered into the study were nonsmokers quent, and troublesome side-effect, cough, has become (E.R. Squibb and Sons Ltd, personal communication). It apparent. This article reviews this side-effect and also is possible that either smokers are less susceptible to this the possibility of other respiratory effects of ACE inhi­ side-effect as a result of prior activation of the cough bition. reflex (1 0) or they do not report change in a pre-existing cough. Cough Airflow obstruction The cough associated with administration of ACE inhibitors (2-4) is non-productive and persistent, with an ACE inhibitors are likely to be used in patients with irritating sensation in the throat. It may become worse on airflow obstruction in whom beta-adrenoceptor antago­ lying down and can cause sleep disturbance. The cough nists are contra-indicated. It is important, therefore, to often takes several weeks to become apparent, although determine whether ACE inhibitors cause or exacerbate it may appear within several hours of the first dose or be airflow obstruction. delayed for many months (5). This may reflect individ­ Sixty four patients with hypertension had no deteriora­ ual reaction to the as well as differential recognition tion in forced expiratory volume in one second ) (fEV1 .._) and reporting of the symptom by patients and doctors. It and forced expiratory fl ow at 25% vital capacity (V 25 resolves within several days of discontinuing treatment after two months treatment with cnalaprH 20 or 40 mg. [2]. On rechallenge with an ACE inhibitor the cough Patients with reversible airflow obstruction were excluded . returns, sometimes within several hours. Although the from this study in view of possible randomization to cough is not a serious side-effect, failure to recognize it [11). A smaller study in hypertensives also may result in the patient undergoing unnecessary inves­ showed no effect on FEV1 (12], and patients with chronic tigations. airflow obstruction had a slight improvement in lung function (13]. Several patients who developed wheezing Incidence and predisposing factors or an exacerbation of pre-existing when given ACE inhibitors have been reported (14-16]. However, Cough has been reported as a side-effect of at least adequate control of the asthma in two patients by inhaled four ACE inhibitors (2-4), and is likely to be a general steroids allowed the ACE inhibitor to be re-introduced class effect of these agents. The size of the problem is without adverse effects (17]. Other patients with asthma not known; reported frequency varies from 0.2% [6] to have not developed worsening wheeze or deterioration in 33% (7). One of the main difficulties in assessing the spirometric measurements. One study (2), which included frequency of cough has been the lack of recognition of four asthmatic patients, noted an increased wheeze in this symptom as a side-effect. Published studies have not one patient, and wheeze was noted in 2 out of 52 non­ therefore sought cough prospectively, but have merely asthmatic patients who reported cough, although one of documented spontaneous reports. However, figures from these patients was also taking atcnolol. There are insuf­ studies including at least 250 patients suggest the inci­ ficient data to assess whether asthmatic patients are any dence of withdrawal of treatment due to cough to be up more prone to develop cough on ACE inhibitors than to 3% for and captopril [2, 5, 6, 8, 9]. non-asthmatic patients. Apart from individual case re­ There does not appear to be any relationship between ports there is no evidence to suggest that airflow obstruc­ the occurrence of cough and age, drug dose or heart tion is caused by ACE inhibitors in either asthmatic or failure (2]. The cough is more frequent in women [2, non-asthmatic subjects. RAwsoN and lNMAN, personal communication] who ac­ count for two thirds of reported cases. Nonsmokers also Pathogenesis of cough account for a disproportionately high number of with- Cough as a side-effect of ACE inhibition may be • Respiratory Medicine, Killingbcck Hospital, Leeds, LS14 6UQ. UK. explained by the known of these drugs, RESPIRATORY EFFECTS OF ACE INHIDITION 199

but why only a small percentage of patients treated duction independent of its effects through [29], develop this symptom is not clear. There does not appear and may increase lung concentrati ons of PGE and be to any "cross-sensitivity" for side-effects, for example prostaglandin F2u(PGF2«). However, this direct erlect of between cough and angio-ocdema. Cough does not appear captopril on prostaglandin production is probably not to be due to the hypotensive or vasodilating effects of important in the pathogenesis of cough, as the incidence ACE inhibitors [12). of cough does not appear to be any greater with captopril than with enalapril and sulindac was as effective in Angiotensin converting enzyme inhibition and bradyki­ inhibiting cough in patients on captopril as it was in nin those on enalapril [27].

Angiotensin converting enzyme has effects other than Neural pathways - the type J receptor the conversion of angiotensin I to angiotensin II. It is the same enzyme as kininase ll which is responsible, par­ Whereas the exact roles of and prostaglandins ticularly in the lung, for the breakdown of bradykinin in the production of cough are not established, the neural [18] and other tachykinins such as substance P [19]. Thus, pathway predominantly involved is probably the type J inhibition of ACE would allow accumulation of these receptor (one of three types of receptor involved in the substances, providing this was a rate-limiting step in the cough reflex) and the unmyelinated c-fibres forming a metabolic pathways. It has been difficult to demonstrate local axon reflex. It has been demonstrated that ACE accumulation of such substances in the plasma since their inhibition causes increased sensitivity to inhaled capsa­ assay is difficult, changes may be small, and plasma icin, the specific c-fibre , in patients who cough concentrations may not be relevant to tissue effects. In [24, 25], but whether this also occurs in subjects not support of accumulation of these substances at tissue level, affected by cough is not clear [25, 30]. Further evidence it has been shown that ACE inhibitors augment skin for c-fibre afferent involvement with ACE inhibition responses to intradennal bradykinin [20] and potentiate comes from the observation that the wheal and flare substance P-induced salivation [19]. reactions in the skin are potentiated by enalapril [20]. Bradykinin and other tachykinins are relevant to the pathogenesis of cough. Bradykinin stimulates the unmye­ Rapidly adapting "irritant" receptors and bronchial linated afferent sensory c-fibres via type J receptors [21] reactivity which through a local axon reflex result in the release of tachykinins [22] and consequent influx of inflammatory Whilst the above mechanisms explain the possible cells. Excitation of type J receptors by bradykinin [23], pharmacological basis for cough, they do not explain or the specific c-fibre stimulant, capsaicin [24, 25], causes why a minority of patients arc affected. There is evi­ a non-productive cough. Cough can be induced by intra­ dently some individual susceptibility. The increased dermal bradykinin in normal subjects taking ACE inhib­ incidence of this side-effect in nonsmokers and women itors [20]. In addition to cough, bradykinin inhalation does not offer any obvious unifying explanation. also causes bronchoconstriction in asthmatic patients [23], Another group ofreccptors involved in the cough reflex but neither captopril (in vitro) [23] or [26] arc the rap idly adapting rcceptors. Although PGE* does enhanced bradykinin-induced bronchoconstriction. How­ not stimulate these receptors, PGF a can do so [2~] and ever, the bronchoconstrictor effects of bradykinin may 2 may be involved in addition to PG E • Captopril did not be dissociated from, and therefore not relevant to, the 2 alter the cough response to inhaled citric acid, a potent cough reflex. "irritant" receptor stimulant, in normal subjects [25], but There is evidence to suggest that ACE inhibitor­ ACE inhibitors increased the cough index in patients induced cough is not quite the same as bradykinin­ affected by ACE inhibitor-induced cough [17]. induced cough, as the former is inhibited by prostaglandin In addition to cough the rapidly adapting receptors synthetase inhibitors [27], in contrast to the latter which mediate bronchoconstriction, and therefore the role of is inhibited by sodium cromoglycate and anticholiner­ bronchial reactivity has been investigated. BucKNALL et gics [23]. Prostaglandins are probably involved. al. [17] found that six patients who coughed had in­ creased bronchial reactivity compared to normal subjects. Angiotensin converting enzyme inhibition and Bronchial reactivity remained high a year after stopping prostaglandins ACE inhibition suggesting that bronchial hyperreactivity was a predisposing factor. LINDGREN [12] found that bron­ ACE inhibitors may cause increased prostaglandin chial reactivity was within the nonnal range in patients ) production via bradykinin [18]. Prostaglandin E2 (PGE2 with this side-effect, but that ACE inhibition caused a can stimulate the unmyelinated afferent c-fibres and may modest increase in bronchial reactivity. No change in therefore cause cough [28]. That prostaglandins are bronchial reactivity on ACE inhibitors was seen in the important in the mechanism of cough production by ACE patient reported in this issue of the Journal [31] and an inhibitors is suggested by the observation that sulindac, earlier study found no ACE inhibitor-induced changes in a prostaglandin synthetase inhibitor, inhibited the cough bronchial reactivity in patients who coughed, even in in six patients in whom it was tried [27]. Captopril, unlike the presence of pre-existing airflow obstruction [7]. other ACE inhibitors, has effects on prostaglandin pro- Carefully controlled assessments of bronchial reactivity 200 K.E. BERKIN

have not been done in sufficiently large numbers of 8. Berkin KE, Ball SO. - Cough and angiotensin converting patients to exclude a small effect or an effect present in enzyme inhibition. Br Med J, 1988, 296, 1279-1280. only a small percentage of the population. Bronchocon­ 9. Dreslinski OR. - Incidence of cough associated with striction itself can lead to cough, but several studies have captopril therapy. Western J Med, 1987, 146, 622. shown no adverse effect of ACE inhibition on airflow, 10. Lundberg JM, Harlling CR, Saria A. - Cigarette smoke­ induced airway oedema due to activation of capsaicin-sensitive even in patients who cough [7, 11, 31]. vagal afferents and substance P release. Neuroscience, 1983, 10, 1361-1368. Management of cough 11. Berkin KE, Murray GD. - Effect of enalapril and atenolol on lung function in hypertensive patients. Thorax, 1988, 43, p It is important to recognize cough as a possible side­ 832. effect of ACE inhibition. If other causes of cough have 12. Lindgren BR. -New aspects of inflammatory reactions and cough following inhibition of angiotensin converting been excluded, the relationship of cough to the ACE enzyme. Acta Physiol Scand, 1988, 133 (Suppl. 573), 1-60. inhibitor should be documented if possible. In some 13. Howard P, Proctor AR, Sugget AJ. - Enalapril in the circumstances, it may be desirable to continue treatment. treatment of hypertensive patients with chronic obsuuctive The cough may become less troublesome particularly if airways . International Society of Hypertension, the dose of ACE inhibitor is reduced, which may not Heidelberg, 1986, 306 (Abst). necessarily lead to loss of therapeutic effect [32]. Some 14. Hood S, Nicholls MO, Gilchrist NL. - Cough with angio­ patients may cough less on an alternative ACE inhibitor tensin converting-enzyme inhibitors. N Z Med J, 1987, 100, [31], but whether this is due to a true difference in 6-7. sensitivity or merely dosage differences is hard to say. 15. Oavras H. Brunner H, Turini G, et al. - Antihypertensive effect of the oral angiotensin converting SQ The cough is not responsive to usual cough remedies. 14225 in man. N Engl J Med, 1978, 298, 991-995. The inhaled anticholinergic drug, ipratropium bromide, 16. Papa V. - Captopril-related (and -induced) astluna. Am has been shown to inhibit bradykinin-induced bronchocon­ Rev Respir Dis, 1987, 136, 999-1000. striclion [23], but it may not be effective for ACE 17. Bucknall CE, Neilly JB, Carter R, Stevenson RD, Semple inhibitor-induced cough [33), and as might be expected PF. - Bronchial hyperreactivity in patienL~ who cough after [28], beta-agonists have not been helpful [32]. Intal does receiving angiotensin converting enzyme inhibitors. Br Med J, not block capsaicin-induced cough [34] and is unlikely 1988, 296, 86-88. to be helpful. Although sulindac prevented ACE 18. Regoli D. Barabe J. - Pharmacology of bradykinin and inhibitor-induced cough [27], prostaglandin synthetase in­ related . Pharmacal Rev, 1980, 32, 1-46. hibitors can exacerbate hypertension and 19. Casceiri MA, Bull HO, Murnford RA, et al. - Carboxyl­ terminal tripeptidyl hydrolysis of substance P by purified rabbit [29]. There is some evidence to suggest that clonidine lung angiotensin converting enzyme and the potentiation of (through its alph~-agonist effects) counteracts the "pro­ substance P activity in vivo by captopril and MK 422. Mol inflammatory" effects of ACE inhibition in the skin [12). Pharmacol, 1984, 25, 287-293. but its effects on cough have not been reported. Interest­ 20. Fcmer RE, Simpson JM, Rawtins MD. - Effects of intrad­ ingly, inhaled bupivicaine was effective in preventing ermal bradykinin after inhibition of angiotensin convening cough in one patient [33], presumably by blocking the J enzyme. Br Med J, 1987, 294, 1119-1120. rcceptors. The effect of one dose lasted several weeks. 21. Kaufman MP, Coleridge HM, Coleridge JCO, Baker DO. Inhaled local anaesthetics can occasionally cause bron­ - Bradykinin stimulates afferent vagal C fibres in intrapulmon­ choconstriction, but they may prove useful in selected ary airways of dogs. J 1\ppl Physiol, 1980, 48, 511-517. patients. 22. Rossoni 0, Omini C, Vigano T, Mandelli V, Folco GC, Berti F. - Bronchoconstriction by histamine and bradykinin in

guinea-pigs: relationship to thromboxane A2 generation and References the effect of aspirin. Prostaglandins, 1980, 20, 547-557. 23. Fuller RW, Dixon CMS. Cuss FMC, Bames PJ. - 1. Johnston cr. - Angiotensin converting enzyme inhibition Bradykinin-induced bronchoconstriction in humans. Am Rev - the balance sheet. Med J Aust, 1988, 148, 488-489. Respir Dis, 1987, 135, 176-180. 2. Coulter DM, Edwards IR. - Cough associated with cap­ 24. Fuller RW, Choudry NB. -Increased cough reflex asso­ topril and cnalapril. Br Med J, 1987, 294, 1521-1523. ciated with angiotensin converting enzyme inhibitor cough. Br 3. Doering W, Maass L, Irmisch R, Konig E.- Pharmacoki­ Med J, 1987, 295, 1025-1026. netic interaction study with ramipril and in heallhy 25. Morice AH, Brown MJ, Lowry R, Higenbottam T. - volunteers. Am J Cardiol, 1987, 59, 600- 640. Angiotensin-converting enzyme and the cough reflex. Lancet, 4. Bolzano K, Arriaga J, Bemal R, et al. -The antihyperten­ 1987, 2, 1116-1118. sive effect of compared to atenolol in patients with 26. Dixon CMS, Fuller RW, Bamcs PJ. - TI1e effect of an mild to moderate . J Cardiovasc Phar­ angiotensin converting enzyme inhibitor ramipril on bronchial macol, 1987, 9 (Suppl. 3), 543- 547. response to inhaled histamine and bradykinin in astlunatic 5. Inman WHW, Rawson NSB, Willon LV, Pearce GL, Speirs CJ. - Post marketing surveillance of enalapril. I: Results of subjects. Br J Clin Pharmacol, I 987, 23, 91-93. prescription event monitoring. Br Med J, 1988, 297, 826-829. 27. Nicholls MG, Oilchrist ML. - Sulindae and cough in­ 6. Chalmers D, Dombey SL. Lawson OH. - Post marketing duced by converting enzyme inhibitors. Lancet, 1987, J, 872. surveillance of captopril (for hypertension): a preliminary report. 28. Coleridge HM, Coleridge JCG, Ginzcl KH, et al.- Stimu­ Br J Clin Pharmacol, 1987, 24, 343-349. lation of "irritant" receptors and afferent C fibres in the lungs 7. Town GI, Hallwright GP, Maling TJB, O'Donnell TV.­ by prostaglandins. Nature, 1976, 264, 451-453. Angiotensin converting enzyme inhibitors and cough. NZ Med 29. Fozzard HA, et al. -In: The Heart and Cardiovascular J, 1987, 100, 161-163. System, chapter 68. Raven Press, 1986, pp. 1613-1629. RESPIRATORY EFFECTS OF ACE INHIBITION 201

30. McEwan JR, Choudry N, Fuller RW. - Change in the 32. Webb D, Benjamin N, Collier J, Robinson B. - Enalapril­ cough reflex during angiotensin converting enzyme inhibition. induced cough. Lancet, 1986, 2, 1094. 12th Scientific Meeting of the International Society of Hyper­ 33. Brown RC, Turton CWG. - Cough and angiotensin con­ tension. Kyoto, 1988, 1346 (Abst). verting enzyme inhibition. Br Med J, 1988, 296, 1741. 31. Puolijoki H. Nicm.inen M, Moilanen E, et al. - Cough 34. Collier JG, Fuller RW.- Capsaicin inhalation in man and induced by enalapril bul not by captopril. Eur Respir J, 1989, the effects of sodium cromoglycate. Br J Pharmaol, 1984, 81, 2, 289-290. . 113-117.