A 46-year-old man is diagnosed with resistant hypertension. He had a comprehensive workup for secondary hypertension, which was unrevealing. The patient has tried multiple antihypertensive medications without significant effect. Past medical history is otherwise unremarkable. He agrees to enroll in a trial of a new long-acting medication that causes selective direct relaxation of the smooth muscle of arterioles but does not affect the veins. Which of the following adverse effects is most likely to be caused by the drug during the clinical trial?
Selective arteriolar vasodilators (eg, hydralazine, minoxidil) lower blood pressure by reducing systemic vascular resistance. However, this effect is limited by subsequent stimulation of baroreceptors with resulting reflex sympathetic activation. This leads to increased heart rate, contractility, and cardiac output (Choices B and D). In addition, sympathetic stimulation of the renin-angiotensin-aldosterone axis results in sodium and fluid retention with peripheral edema. These effects offset much of the blood pressure lowering effect of these drugs and limit their long-term efficacy.
These agents are rarely used as monotherapy for chronic management of hypertension. However, they are useful acutely for patients with severely elevated blood pressure. They can also be given in combination with sympatholytics and diuretics to mitigate the side effects and provide synergistic blood pressure lowering in patients with resistant hypertension.
(Choices A and E) Persistent cough and angioedema are well recognized side effects of ACE inhibitors. Angioedema refers to acute, localized subcutaneous or submucosal edema caused by increased vascular permeability. It differs from the chronic peripheral edema due to sodium retention seen with arteriolar dilators.
(Choice C) Beta blockers decrease cardiac output, leading to peripheral vasoconstriction and resulting in cold hands and feet. However, direct arteriolar vasodilators enhance blood flow to peripheral tissues, including skin and muscle, and they can be used to relieve symptoms in patients with Raynaud phenomenon.
(Choice G) Although selective arteriolar vasodilators trigger reflex sympathetic activation, this does not raise blood pressure above baseline unless they are discontinued abruptly.
Educational objective:
Direct arteriolar vasodilators lower blood pressure but trigger reflex sympathetic activation and stimulate the renin-angiotensin-aldosterone axis. This results in tachycardia and edema. To counteract such compensatory effects, these agents are often given in combination with sympatholytics and diuretics.