Direct Vasodilators and Sympatholytic Agents

Abstract

Direct vasodilators and sympatholytic agents were some of the first antihypertensive medications discovered and utilized in the past century. However, side effect profiles and the advent of newer antihypertensive drug classes have reduced the use of these agents in recent decades. Outcome data and large randomized trials supporting the efficacy of these medications are limited; however, in general the blood pressure-lowering effect of these agents has repeatedly been shown to be comparable to other more contemporary drug classes. Nevertheless, a landmark hypertension trial found a negative outcome with a doxazosin-based regimen compared to a chlorthalidone-based regimen, leading to the removal of α-1 adrenergic receptor blockers as first-line monotherapy from the hypertension guidelines. In contemporary practice, direct vasodilators and sympatholytic agents, particularly hydralazine and clonidine, are often utilized in refractory hypertension. Hydralazine and minoxidil may also be useful alternatives for patients with renal dysfunction, and both hydralazine and methyldopa are considered first line for the treatment of hypertension in pregnancy. Hydralazine has also found widespread use for the treatment of systolic heart failure in combination with isosorbide dinitrate (ISDN). The data to support use of this combination in African Americans with heart failure are particularly robust. Hydralazine with ISDN may also serve as an alternative for patients with an intolerance to angiotensin antagonists. Given these niche indications, vasodilators and sympatholytics are still useful in clinical practice; therefore, it is prudent to understand the existing data regarding efficacy and the safe use of these medications.

Minoxidil for Treatment of Resistant Hypertension in Chronic Kidney Disease––A Retrospective Cohort Analysis

“…These studies included only a small number of patients or were case series, but BP control could be achieved in nearly all patients, particularly in those with resistant hypertension. There are only a few studies that directly compare minoxidil with other antihypertensive agents . While minoxidil showed results similar to nifedipine and felodipine, minoxidil was shown to be more effective than captopril, labetalol, methyldopa, hydralazin, and prazosin; however, it had a higher incidence of side effects limiting its use .…”

“…Nevertheless, with the initiation of minoxidil, antihypertensive drug classes increased by only 0.6 on average (4.5 to 5.1), including minoxidil. Hence, the BP‐lowering effect could be mainly attributed to minoxidil, since minoxidil is known to achieve rapid and prompt BP control with the maximal effect achieved within 2 to 3 hours . Recent studies highlight the major role of sodium retention, and the Optimum Treatment for Drug‐Resistant Hypertension (PATHWAY‐2) study showed spironolactone to be the most effective add‐on drug for the treatment of resistant hypertension, which further underlines this approach.…”

“…Despite the availability of many antihypertensive drugs, resistant hypertension remains a challenge because increasing dosage and adding drug after drug often has a limited effect and induces unnecessary cost and side effects. Hence, better use of the available drugs is desirable . Minoxidil, a direct vasodilator, was first discovered in 1965 as a potent antihypertensive agent.…”

“…Minoxidil acts on adenosine triphosphate–modulated potassium channels, which results in relaxation of smooth muscles. This lowers peripheral resistance and results in a decrease in both systolic and diastolic BP . Minoxidil not only triggers the activation of the peripheral sympathetic nervous system with resultant increases in heart rate and cardiac output but also increases plasma renin activity with resultant sodium and water retention .…”

“…More serious adverse events include thrombocytopenia, pericarditis, pericardial effusion, and tamponade. The incidence of pericardial effusion has been reported to be approximately 3%, so that monitoring for signs of this complication is advisable . Because of these notable side effects, the use of minoxidil was restricted mainly to men with refractory or resistant hypertension.…”