Captopril in severe treatment-resistant hypertension.

Abstract The blood pressure of the majority of hypertensive patients can be controlled by sodium restriction and by one or at most two antihypertensive drugs. When the blood pressure does not respond, a widely recommended three-drug regimen is an oral diuretic, propranolol and hydralazine. 10 Our 16 patients had essential and renovascular hypertension and were refractory to all previous therapy. The majority had end-organ manifestations of severe hypertension such as left ventricular hypertrophy, renal impairment, retinopathy and neurologic sequelae. When they were placed on STT, their blood pressure remained uncontrolled (SDBP > 100 mm. Hg). Because of the resistance of their blood pressure to STT, all our patients were ultimately switched to captopril in an effort to achieve better control. According to the protocol, patients were hospitalized after stopping STT the night before. Captopril was started in a dose of 25 mg. and increased according to the response. After the first dose, no patient had a symptomatic hypotensive response though one patient's SDBP did fall 6030 mm. Hg. The maximum response to the initial dose usually occurred by 30 minutes, rapid for an oral medication. This initial response was often greater than the response to subsequent doses, most likely due to the residual effects of STT. It is controversial as to whether the pretreatment PRA is a predictor of the response to captopril. 7, 12 In our study, it was not possible to determine PRA unifluenced by drugs on a controlled sodium intake because of the severity of the hypertension. PRA increased after captopril, a response consistent with interruption of negative feedback inhibition of renin release. 13 As a group, the patients' blood pressure on captopril alone approximated that on STT, but no one was adequately controlled. The addition of a diuretic enhanced the effectiveness of captopril and in six of the 16 patients it resulted in satisfactory blood pressure control. Several of these patients who had hypertension in association with renal artery stenosis, howeve, manifested an upright tachycardia. Worsening of angina pectoris occurred in one man and he and another woman developed subendocardial myocardial infarctions; the role of the tachycardia in the precipitation of these events is unclear. Nonetheless, diuretic-induced volume depletion with blockade of the renin-angiotensin system by captopril may cause standing tachycardia, which may constitute a problem in patients with compromised coronary or cerebral circulation. In this regard, two of the eight patients in Group 2, though well controlled on captopril and diuretic, had propranolol added in small doses (40 mg./day) to control symptomatic standing tachycardia. In the other six patients in this group, blood pressure was normalized by this new three-drug regimen and the regimen was well tolerated. Two patients (Group 3) could not be controlled even with this regimen, and were considered treatment failures. It is of interest that propranolol produced additional blood pressure lowering in the presence of captopril, which supports a hypotensive action of propranolol not due wholly to blockade of renin release. 14 In general, captopril was well tolerated; a number of patients remarked how much better they felt on captopril as compared to their previous regimens, especially with regard to central side effects. Five patients manifested a maculopapular and pruritic rash, but in only one did discontinuation of captopril prove necessary. In three patients, the rash disappeared in 7 to 10 days with only a temporary reduction of captopril dosage. Two men developed a loss of taste which similarly resolved despite continuation of captopril. No other adverse effects have been noted in our patients. Renal function was maintained, as serum creatinine did not change during the study. Captopril-induced proteinuria has been reported since the start of our study, 15 but could not be documented retrospectively in our patients. However, continued surveillance of captopril's side effects, especially proteinuria, is necessary. In summary, in our three month trial, captopril appears to provide a useful and important alternative for the management of severe, refractory hypertension. Its mechanism of action seems to be ideal for such patients in whom the renin-angiotensin system appears to play an important role. Although alone it was insufficient to adequately control the blood pressure in our severely hypertensive patients, its combination with a diuretic or a diuretic and a beta-blocker often provided an effective and well-tolerated combination. Nevertheless, even with the latter three-drug combination, there were two treatment failures. Adverse effects such as skin rash, which occurred in 30% of our patients, and loss of taste, do not seem to seriously limit the use of the drug. The development of a sustained standing tachycardia when a diuretic is added to captopril may be harmful in some patients with a compromised cardiovascular system and requires careful consideration before treatment. Addition of low doses of beta-adrenergic blocking agents, if not contraindicated, will control these heart rate increases. The benefits and hazards of long-term captopril therapy in severe hypertension requires further assessment.