Merck's antihypertensive losartan -- marketed as a single agent in Cozaar and combined with hydrochlorothiazide in Hyzaar -- was the first (and is so far the only) angiotensin II inhibitor to receive FDA approval. The drug is generally well tolerated and highly effective for treating hypertension, producing a smooth, gradual, 24-hour reduction in blood pressure without significant side effects. Losartan is also under investigation for treating heart failure and for slowing or preventing the progression of kidney disease in diabetic patients. In addition, Merck is conducting a long-term, multicenter trial to compare the efficacy of losartan versus beta-blockers for decreasing cardiovascular deaths and non-fatal heart attacks or strokes in 8,300 hypertensive patients with left ventricular hypertrophy.

Like the angiotensin converting enzyme (ACE) inhibitors, losartan interferes with a vasoconstrictor -- angiotensin II -- but it does so by blocking the angiotensin II receptor, rather than by inhibiting ACE. The enzyme ACE actually has two functions in the body and two names: as ACE, it activates the vasoconstrictor angiotensin II; as kininase, it breaks down the vasodilating kinins. Thus, the ACE inhibitors reduce blood pressure by blocking production of vasoconstricting angiotensin II and by prolonging the activity of vasodilating kinins. Unfortunately, kinins also stimulate chemosensitive nerve endings in the airways, causing cough. This cough -- known as "the ACE inhibitor cough" -- is common to most drugs in this class. Kinins may also be involved in angioneurotic edema, another ACE inhibitor side effect.

Since losartan has no ACE activity, it theoretically should not cause cough or angioedema. In comparative clinical trials, the frequency of cough was less than half that observed with the ACE inhibitor lisinopril, and only one case of angioedema was reported in clinical trials that included more than 4,000 patients. However, Acker et al recently described a 52-year old man with uncontrolled hypertension who developed angioedema shortly after being treated with losartan. The man had been treated with a variety of drugs, including captopril (discontinued because of cough) and bisoprolol/hydrochlorothiazide plus terazosin (current therapy). At presentation his blood pressure was 170/105 mm Hg. He had a history of glomerulosclerosis (serum creatinine concentration was 1.2 mg/dL, with 4+ proteinuria), but other than hypertension and evidence of renal impairment, the physical examination was unremarkable. He was allergic to radiographic contrast material, but had no history of angioedema.

After the discontinuation of bisoprolol/hydrochlorothiazde, the patient was given a single 50-mg dose of losartan. Within 30 minutes, his throat was "scratchy" and felt like something was stuck in it. Facial flushing occurred, with swelling of the lips and the right side of the face. There was no dyspnea, and the pulmonary examination was normal. All symptoms resolved after treatment with diphenhydramine. The mechanism of losartan-induced angioedema is unknown, said the investigators, but the drug should probably be used with caution in patients with a history of allergic sensitivity to ACE inhibitors. (Acker CG et al. N Engl J Med 333;1995:1572.)