Cough and inhibition of the renin-angiotensin system

To review clinical and experimental data and epidemiological observations on the incidence and mechanism of dry cough that has been seen with the use of angiotensin converting enzyme (ACE) inhibitors in patients with hypertension.

With the increasing clinical use of ACE inhibitors in the treatment of both hypertension and heart failure, an annoying dry cough has been observed. Cough has been reported in postmarketing surveillance studies with an incidence of 1-4%, but clinical reports have shown even higher figures, ranging from 1 to 33%. The mean incidence seems to vary between 6 and 14%, depending on the reporting technique used.

The specific mechanism of this adverse effect is not fully understood. It may be related to effects on the kininogen-kinin (bradykinin) system since the breakdown of bradykinin is prevented by ACE inhibitors. A local accumulation of bradykinin may lead to activation of pro-inflammatory peptides (e.g. substance P, neuropeptide Y) and a local release of histamine. This may also cause cough reflex hypersensitivity. Another more serious adverse effect that has been associated with the use of ACE inhibitors, angioneurotic oedema, may be related to the same mechanisms.

The dry cough almost always disappears upon withdrawal of the specific drug. In some instances a dose reduction may lead to improvement. Recent reports have suggested that treatment with calcium antagonists (nifedipine) or non-steroidal anti-inflammatory drugs (indomethacin and sulindac) may eliminate the cough. Antitussive drugs are usually ineffective, as are antihistamines. In some cases the dry cough may disappear spontaneously. The use of provocative tests has not been clinically satisfactory in exploring possible mechanisms or clinical severity.

Dry cough is the most common and annoying, although harmless, side effect associated with the use of ACE inhibitors. Its incidence has probably been underestimated in earlier studies, but it usually disappears on withdrawal of the specific ACE inhibitor.