Cough and Angioneurotic Edema Associated with Angiotensin-Converting Enzyme Inhibitor Therapy

Abstract

Cough occurs in 5% to 20% of patients treated with ACE inhibitors, recurring with reintroduction of the same or another ACE inhibitor. It is more common in women. The mechanism may involve accumulation of prostaglandins, kinins (such as bradykinin), or substance P (neurotransmitter present in respiratory tract C-fibers); both bradykinin and substance P are degraded by ACE. A 4-day trial of withdrawal of the ACE inhibitor or temporary substitution of another class of antihypertensive agent inexpensively and easily ascertains if the ACE inhibitor caused the cough. Change to another ACE inhibitor or additive therapy with nonsteroidal anti-inflammatory drugs is not recommended. Prompt recognition of ACE inhibitor-related cough can prevent unnecessary diagnostic testing and treatment. Angioedema occurs in 0.1% to 0.2% of patients receiving ACE inhibitors. The onset usually occurs within hours or, at most, 1 week after starting therapy. The mechanism may involve autoantibodies, bradykinin, or complement-system components. Treatment involves first protecting the airway, followed by epinephrine, antihistamines, and corticosteroids if needed. Therapy is then resumed with an alternate class of antihypertensive agent.

A randomised, double-blind comparison of the angiotensin II receptor antagonist, irbesartan, with the full dose range of enalapril for the treatment of mild-to-moderate hypertension

“…This study was not designed to specifically compare the incidence of cough. Results of other studies have shown that treatment with ACE inhibitors is associated with increased incidence of cough [11][12][13] whereas treatment with AII receptor antagonists is not. 18,19 The overall database incidence of cough is 2.7% for placebo and 2.8% for irbesartan (Data on file, Bristol-Myers Squibb).…”

“…Moreover, because ACE is also involved in the breakdown of bradykinin, inhibition of ACE tends to increase circulating levels of this peptide, [8][9][10] which may account for the increased incidence of cough reported in up to 20% of patients treated with ACE inhibitors. [11][12][13] All receptor antagonists, however, inhibit the potent pressor effect of AII by blocking its binding to the receptor. Therefore, it is expected that they will effectively lower systemic blood pressure without inducing adverse effects, such as cough, that are associated with ACE inhibitors.…”

Clinical pharmacokinetics of angiotensin II (AT1) receptor blockers in hypertension

“…[2][3][4][5][6][7][8][9][10][11][12][13][14][15] First dose hypotension is uncommon (except in salt-and/or volume-depleted patients). Cough, the main adverse effect of ACE inhibitors, 111 occurs much less frequently with ARB therapy, and angioneurotic oedema is relatively rare. [112][113][114][115][116] Pharmacokinetics and metabolism of angiotensin receptor blockers Candesartan cilexetil: Candesartan cilexetil, an inactive racemic prodrug, is rapidly and completely metabolised (by ester hydrolysis) in the gastrointestinal tract to the active achiral candesartan.…”

Dose-response efficacy of valsartan, a new angiotensin II receptor blocker

“…1,2 However, inhibition of the converting enzyme has effects beyond the RAS and results in well recognised sideeffects associated with this class of agents including cough and angioneurotic oedema. These side-effects are thought to be due to the accumulation of other substrates of the converting enzyme such as bradykinin and substance P. 3,4 Selective inhibition of the RAS at a more distal level would be anticipated to result in effective antihypertensive agents devoid of these unwanted effects. Angiotensin II antagonists, also known as angiotensin II receptor blockers, have a novel mechanism of action and have been reported to effectively lower blood pressure without cough as a side effect.…”