Mechanisms of Cough From Angiotensin-Converting Enzyme Inhibitors

The inhibition of ACE (also known as kininase II and bradykinin dehydrogenase) prevents the conversion of angiotension I to
angiotensin II, with consequent salutary benefits via the renin-angiotensin system in pathological states. ACE inhibitor cough is thought to be
linked to the suppression of ACE, which is proposed to result in an accumulation of substances normally metabolized by ACE: bradykinin or
tachykinins (with the consequent stimulation of vagal afferent nerve fibers) and substance P. However, the development of cough may result from
a more complex cascade of events than originally believed. Bradykinin has been shown to induce the production of arachidonic acid metabolites
and nitric oxide (NO), and there is some evidence that these products, which are subject to regulation by other pathways, may promote cough
through proinflammatory mechanisms.

In a study to determine how cough could be promoted by increased prostaglandin synthesis that might follow stimulation of the
arachidonic acid cascade by ACE inhibition. The authors concluded that an imbalance between thromboxane and prostacyclin may represent a
marker of patients susceptible to ACE inhibitor cough. Although the study has some limitations, and its findings would need to be confirmed in a
larger number of patients, the results do serve as an example of how an interplay of several different pathways may ultimately determine whether
an ACE inhibitor causes cough in a patient.

Can Angiotensin II Receptor Blockers be Used in Patients With a History of Angiotensin-Converting Enzyme Inhibitor Cough?

Angiotensin II receptor blockers (ARBs) confer many of the same hemodynamic benefits as ACE inhibitors, but they do not directly
inhibit ACE activity or inhibit the breakdown of bradykinin. Theoretically, ARBs would be predicted to be acceptable substitutes for ACE inhibitors
in patients who have adverse events such as kinin-mediated cough. [5]

However, almost as soon as ARBs became available, there were reports of patients with a history of ACE inhibitor cough who also
developed cough in association with ARBs, calling into question both the proposed mechanism of ACE inhibitor cough, and the validity of
recommending ARBs as alternative agents for patients with a history of ACE inhibitor cough. Mechanistically, it has been suggested that the
pharmacological actions of ARBs may involve not only the blockade of the angiotensin 1 receptor, but also activation of the angiotensin 2 receptor
by increased levels of angiotensin II. [6] Some studies have suggested that the angiotensin 2 receptor may be involved in the activation of the
bradykinin-prostaglandin-NO cascade.[7,8] This raises the question as to whether some patients intolerant of ACE inhibitors could be at risk of the
same reaction to ARBs.

Controlled studies have provided reassuring data that ARBs are in fact generally well tolerated in patients with a history of ACE
inhibitor cough. In a double blind, randomized, parallel-group comparison of the ARB losartan, the ACE inhibitor lisinopril, and hydrochlorothiazide
diuretic for 8 weeks in a total of 135 patients, [9] the frequency of cough with losartan was lower than with lisinopril (29 versus 72%, P<0.01), and
similar to hydrochlorothiazide (34%).

Similarly, a multicenter study by Paster et al.[10] reported that the incidence, severity, and frequency of dry cough in 100 patients with a history of
ACE inhibitor dry cough was significantly lower in those treated with losartan than in those treated with the ACE inhibitor lisinopril, and was similar
to the incidence, severity, and frequency of dry cough in those receiving placebo.

Another randomized, double blind, parallel group study of 129 patients with a history of ACE inhibitor-induced cough [11] also found that the
occurrence of cough after 3 and 6 weeks of therapy was significantly less with the ARB valsartan (19.5%) and hydrochlorothiazide (19%) than
with lisinopril (68.9%).

Treatment of Angiotensin-Converting Enzyme Inhibitor Cough

In cases in which the continuation of an ACE inhibitor is necessary despite cough, cromolyn, baclofen, theophylline, and local
anesthetics have been reported to be of benefit, although none has been subjected to large-scale trials. [12-14] Although no large, controlled studies
have demonstrated the inhibition of ACE inhibitor cough with cyclooxygenase inhibitors, sulindac has been reported to be of benefit, and two
studies suggested that intermediate doses of aspirin (500 mg/day) but not low doses (100 mg/day) can suppress ACE inhibitor cough. [15-17] In a
small series, Lee et al.[18] tested the hypothesis that because NO has proinflammatory effects on bronchial epithelial cells, supplemental iron, an
inhibitor of NO synthase, may reduce the cough associated with the use of ACE inhibitors. Patients treated with iron, but not placebo, had
significant reductions in cough scores.