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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.

Keywords

vasodilators hypertension heart failure sympatholytics

Introduction

Rarely used as first-line therapy for cardiovascular diseases in contemporary practice other than for specific indications, direct vasodilators and central sympatholytic agents were commonly used in the past century. First recognized and used for their ability to reduce blood pressure, these drugs are limited by adverse effects and a paucity of contemporary literature supporting longitudinal benefit on patient outcomes. The exception is hydralazine that has experienced a reemergence largely due to its application in management of systolic heart failure. Despite their decline in use, these drugs have niche indications, and therefore it is important for practitioners to understand the optimal use of these medications (Table 1).

Table 1.

Clinical Application and Pharmacokinetic Properties.

Class	Generic Name	Trade Names	Dosage Forms	Usual Dosage Range	Major Adverse Drug Reactions	Major Pharmacokinetic Parameters	Major Drug Interactions	Pregnancy Category
Direct Vasodilators	Hydralazine	–	Orally, IM, and IV	10-50 mg orally 4 times daily (max 300 mg/day); 5-20 mg (max 30 mg in pregnancy)	Headache, N/V, palpitations, tachycardia, peripheral neuritis, blood dyscrasias, hepatitis, SLE	Absorption 30%-50%, peak 1-2 h, t_1/2 2-7 h, metabolized and excreted in urine	–	C
Direct Vasodilators	Minoxidil	–	Orally	5-40 mg/day (max 100 mg/day)	Tachycardia, edema, hypertrichosis, thrombocytopenia, pericarditis/pericardial effusion	Absorption 90%, peak 1 h, t_1/2 4.2 h, metabolized and excreted in urine	Guanethidine	C
α-1 Adrenergic Blockers	Prazosin	Minipress	Orally	6-15 mg orally daily	First dose hypotension/syncope, orthostatic hypotension, intraoperative floppy iris syndrome	Absorption 48%-68%, Peak 3 h, t_1/2 2-3 h, metabolized in liver, excreted in feces/urine	Alfuzosin, silodosin, tadalafil, tamsulosin	C
	Terazosin	–	Orally	1-5 mg orally qHS (max 20 mg/day)	SVT, atrial fibrillation, priapism, thrombocytopenia, intraoperative floppy iris syndrome	Absorption 100%, peak 1 h, t_1/2 12 h, metabolized in liver, excreted in feces/urine	Alfuzosin, silodosin, tadalafil, tamsulosin	C
	Doxazosin	Cardura, Cardura XL	Orally	1-4 mg orally daily (max 16 mg/day)	Orthostatic hypotension, syncope, arrhythmias, intraoperative floppy iris syndrome, priapism	Absorption 54%, peak 8 h, t_1/2 22 h, metabolized in liver, excreted in feces/urine	Boceprevir	C
α-2 Adrenergic Agonists	Clonidine	Catapress, Catapress-TTS, Kapvay	Orally, TD	0.1-0.3 mg orally twice daily (max 2.4 mg/day)	Bradycardia, AV block, angioedema, depression, withdrawal symptoms or rebound hypertension if abrupt d/c	Absorption 70%-80%, peak 1-3 h, t_1/2 6-16 h (20 h patch), metabolized in liver, excreted in urine, bile/feces	–	C
	Methyldopa	–	Orally, IV	250-500 mg orally twice daily (max 3 g/day)	Myocarditis, hemolytic anemia, thrombocytopenia, hepatic necrosis, leukopenia, bradycardia, pancreatitis	Absorption 50%, peak 12-24 h, t_1/2 105 min, metabolized in central adrenergic neurons and liver, excreted in urine	Isocarboxazid, phenelzine, procarbazine, rasagiline, selegiline, tranylcypromine	B
	Guanfacine	Tenex, Intuniv	Orally	1-3 mg orally qHS	Exfoliative dermatitis, withdrawal symptoms or rebound hypertension if abrupt d/c	Absorption 80%, peak 1-4 h, t_1/2 17 h, metabolized in liver, excreted in urine	–	B
	Guanabenz	–	Orally	4-8 mg orally twice daily (max 64 mg/day)	AV block, arrhythmias, withdrawal symptoms or rebound hypertension if abrupt d/c	Absorption 75%, peak 2-4 h, t_1/2 6 h, metabolized in liver, excreted in urine, feces	–	C
Central Monoamine-Depleting Agents	Reserpine	–	Orally	0.1-0.25 mg/day	GI distress, nasal congestion, arrhythmias, depression, EPS, vision changes	Absorption 50%, peak 2.5 h, t_1/2 200 h, metabolized with minimal urine excretion of unchanged drug	Digoxin, quinidine, MAO inhibitors, tricyclic antidepressants	C

Abbreviations: IM, intramuscular; IV, intravenous; qHS, daily at bedtime; TD, transdermal; SVT, supraventricular tachycardia; GI = gastrointestinal; MAO = monoamine oxidase; SLE = systemic lupus erythematosus; EPS = extrapyramidal symptoms; AV = atrioventricular; Pregnancy category B = animal studies show no fetal risk, but not studied in humans; Pregnancy category C = animal studies have shown fetal risk, but no studies in humans, or no studies in humans or animals.

Hydralazine

Mechanism of Action

Hydralazine was first recognized for its blood pressure-lowering effects in 1950, and since then it has been utilized in the treatment of hypertension and heart failure over the past 60 years.^1
–3 Hydralazine is a direct vasodilator of arterioles, resulting in reduced peripheral resistance with compensatory arterial baroreceptor-mediated release of norepinephrine and epinephrine.^2,4

–7 As a result, administration of hydralazine is associated with decreased blood pressure and increased venous return, heart rate, and cardiac output.^2,4,6,7 Proposed mechanisms for the direct arterial vasodilatory properties of hydralazine include inhibition of IP3-induced release of calcium from the sarcoplasmic reticulum and inhibition of myosin phosphorylation in arterial smooth muscle cells, although the precise mechanism has not been fully elucidated.^8
–10 The compensatory sympathetic response observed with hydralazine made the combined use of hydralazine with a β-adrenergic antagonist an appealing option for the treatment of essential hypertension in the 1970s.^2,3,11 Combined use with a diuretic has also been a common practice.^2,11

Clinical Indications

Hypertension

Hydralazine was first approved in the United States as an antihypertensive agent by the Food and Drug Administration (FDA) in 1953; however, the compensatory tachycardia and increase in cardiac output limited its use. Studies comparing hydralazine monotherapy with placebo are limited, but oral hydralazine was noted to have significant blood pressure-lowering effects.^12

–15 Combining hydralazine with a β-blocker was found to have an even greater capacity to reduce blood pressure while limiting the rise in pulse rate observed with hydralazine alone.^14

–18 This combination has been compared to various other regimens: β-blocker or verapamil monotherapy, the combination of a thiazide diuretic with either methyldopa or a β-blocker, and the combination of a β-blocker with prazosin.^18

–24 In each case, the combination of hydralazine with a β-blocker was found to be at least as effective as the comparators in lowering blood pressure. In contrast, a randomized trial of 120 patients with essential hypertension found that the combination of felodipine with a β-blocker reduced blood pressure to a greater extent when compared to the combination of hydralazine with a β-blocker (10-19 mm Hg greater reduction in systolic blood pressure); however, it should be noted that there were maximum doses used for each group (10 mg twice daily for felodipine and 50 mg twice daily for hydralazine).²⁵

Hydralazine has also been studied as an add-on therapy to multi-drug treatment with a β-blocker and a thiazide diuretic.^26,27 Addition of hydralazine was found to enhance blood pressure-lowering effects,^26,27 and efficacy was similar to add-on therapy with a dihydropyridine calcium channel blocker (DHP-CCB),^28,29 minoxidil, or an angiotensin-converting enzyme inhibitor (ACEI).^29
–31 However, a few studies did suggest that add-on therapy with a DHP-CCB was more efficacious than add-on therapy with hydralazine.^32
–34

Outcome trials assessing the efficacy of hydralazine are limited. The Veterans Administration Cooperative Study (VACS) Group on Antihypertensives included a hydralazine treatment arm, which demonstrated that treating hypertension significantly decreased morbid events, such as the development of congestive heart failure or stroke.³⁵ Hydralazine was also utilized as a step 3 medication in the Hypertension Detection and Follow-up Program Cooperative Group (HDFP) trial, which showed that a stepped approach to hypertension management decreased 5-year mortality.³⁶ In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), hydralazine was used as a step 3 add-on agent to step 1 (chlorthalidone, amlodipine, or lisinopril), and step 2 (atenolol, clonidine, or reserpine) therapy. This study demonstrated that each of the treatment arms had a similar impact on mortality, fatal coronary heart disease, and nonfatal myocardial infarction.³⁷

Pregnancy

Although hydralazine is classified as pregnancy category C, it has been utilized for hypertension during pregnancy for several decades³⁸ and has been cited as the most commonly used medication for acute hypertension in this population.^39,40 Several small, comparative trials found both intravenous (IV) hydralazine and labetalol to be effective in the acute lowering of maternal blood pressure.^41

–44 Although there were conflicting results regarding which agent provided the greatest degree of blood pressure lowering, each trial concluded that both hydralazine and labetalol were effective treatment options.^41

–44 Reflexive maternal tachycardia has been observed with hydralazine treatment. Fetal heart rate may be unaffected, however, fetal distress has been reported with antenatal hydralazine.^42,45 Hydralazine has also been shown to be as effective as DHP-CCB in achieving blood pressure control; however, nifedipine may achieve blood pressure more quickly, with fewer doses, and for a sustained period of time.^46
–48 While both hydralazine and DHP-CCB decrease systemic vascular resistance and increase heart rate, hydralazine is associated with greater decreases in pulmonary capillary wedge pressure and a trend toward more fetal distress.⁴⁵ A meta-analysis on the use of hydralazine for severe hypertension in pregnancy found that there was a trend toward less persistent severe hypertension with hydralazine when compared to labetalol.⁴⁹ However, when compared to nifedipine or isradipine, there was a trend toward more persistent hypertension with hydralazine.⁴⁹ Hydralazine was also associated with more headaches, palpitations, and maternal tachycardia. However, hydralazine did not have the neonatal bradycardia associated with labetalol, the flushing associated with nifedipine, or the need for treatment discontinuation due to side effects.⁴⁹ Comparison of fetal hemodynamic effects showed that neither hydralazine nor labetalol altered placental blood flow or fetal Doppler readings, but hydralazine did increase blood flow in the umbilical vein and the uterine artery resistance index.^50
–52

Heart failure

Studies in the 1970s began to investigate hydralazine as a potential therapy for heart failure after recognition of the beneficial hemodynamic effects of vasodilators.⁵³ Early studies found that the combination of hydralazine, an arterial vasodilator, with isosorbide dinitrate (ISDN), a venous vasodilator, reduced left ventricular filling pressure while increasing cardiac output⁵⁴ and that these hemodynamic effects were similar to treatment with nitroprusside.⁵⁵ Prior to the widespread use of β-blockers and ACEIs, The VACS (Vasodilators in Heart Failure Trial, V-HeFT I) examined hydralazine in combination with ISDN in patients with chronic heart failure and found a trend toward decreased mortality compared to placebo.² However, when compared to enalapril in V-HeFT II, ISDN did not confer the same reduction in mortality observed with enalapril, but both treatment regimens were associated with improvement in left ventricular ejection fraction.⁵⁶ The greater benefit derived from ACEI was confirmed in comparative trials of captopril versus hydralazine alone or the combination of hydralazine/ISDN.^57,58 Captopril had a greater mortality benefit, impact on the hemodynamic profile, and symptom improvement was sustained for a longer duration.^57,58 However, retrospective analysis of earlier trials suggested that perhaps African American patients had a greater response to hydralazine/ISDN and reduced response to drugs affecting the renin–angiotensin–aldosterone system (RAAS). This led to the African American Heart Failure (A-HeFT) trial,⁵⁹ which evaluated the addition of hydralazine/ISDN compared to placebo in self-identified black patients to background therapy of a β-blocker combined with either an ACEI or an angiotensin receptor blocker (ARB). The study demonstrated a significant reduction in death from any cause and hospitalization for heart failure with hydralazine/ISDN. Hydralazine/ISDN was also associated with improved quality-of-life scores. Secondary analyses suggested that hydralazine/ISDN also enhanced regression of left ventricular remodeling and appeared to have an even greater overall benefit in patients >64 years old.^60,61 Additionally, in the extension trial, compliance with hydralazine/ISDN was found to be 87%, with only 6% of patients discontinuing use due to side effects, such as headache or dizziness.⁶²

Practical Considerations

Hydralazine is available in oral (10 mg, 25 mg, 50 mg, and 100 mg tablets) and IV formulations. The initial dose for IV administration is 5 to 10 mg via slow injection. A repeat dose can be given in 20 to 30 minutes. A typical oral, starting dose is 10 mg 4 times daily with uptitration after 2 to 4 days. Bidil (Arbor Pharmaceuticals, Atlanta, GA) is a combination product approved for use in systolic heart failure and contains ISDN 20 mg/hydralazine 37.5 mg in each tablet. Dosing begins at 1 tablet 3 times daily, with uptitration to 2 tablets 3 times daily as the target dose for heart failure. Hydralazine is absorbed rapidly, and peak plasma levels are seen within 1 to 2 hours after oral administration. Approximately 88% to 90% of the serum concentration represents drug bound to protein. The serum concentration of hydralazine is variable among patients, and concentrations are dependent on the degree of acetylation in a given patient. Slow acetylators may require lower doses of hydralazine due to higher plasma levels. Hydralazine undergoes hepatic metabolism, and it is eliminated in the urine primarily as metabolites (86% to 98%). The half-life of hydralazine is 2 to 7 hours, but it may be much shorter in rapid acetylators that receive the IV formulation (average 45 minutes). There is evidence of increased renal blood flow without changes in the glomerular filtration rate, suggesting that hydralazine may be used in patients with renal dysfunction. However, in patients with an estimated creatinine clearance less than 20 mL/min, the half-life may be prolonged up to 16 hours.

The most common adverse effects associated with hydralazine include headache, nausea/vomiting, diarrhea, palpitations, and tachycardia. Rarely, hydralazine can cause more serious adverse reactions, such as peripheral neuritis, psychotic reactions or disorientation, blood dyscrasias, purpura, and hepatitis. Hydralazine also has a warning regarding a clinical picture similar to systemic lupus erythematosus (SLE), including glomerulonephritis. This lupus-like syndrome typically regresses once the medication is discontinued. Hydralazine is also contraindicated in patients with idiopathic SLE. Additional contraindications include severe tachycardia with heart failure and high cardiac output, myocardial insufficiency due to mechanical obstruction, cor pulmonale, and dissecting aortic aneurysm due to the compensatory myocardial stimulation and potential for increased pulmonary artery pressure caused by hydralazine. Caution should be used in patients suspected of having coronary artery disease in the absence of concomitant β-blocker therapy, as the compensatory tachycardia observed with hydralazine may increase myocardial oxygen demand.

Minoxidil

Mechanism of Action

The hypotensive effect of minoxidil was discovered in 1965, and it was available for restricted study in 1969; however, it did not receive FDA approval as an antihypertensive until 1979.^63,64 Minoxidil is a direct arterial vasodilator which lowers peripheral resistance and results in a decrease in both systolic and diastolic blood pressure.^65,66 Minoxidil effectively opens adenosine triphosphate (ATP)-modulated potassium channels in the vascular smooth muscle cells, allowing potassium efflux and smooth muscle relaxation.^64,67
–69 Similar to hydralazine, minoxidil triggers a baroreceptor-mediated activation of the peripheral sympathetic nervous system with resultant increases in heart rate and cardiac output as well as increases in plasma renin activity with resultant sodium and water retention.^65
–67,70 Combined use with a β-adrenergic antagonist or a central inhibitor of the sympathetic nervous system, such as clonidine or methyldopa, may counteract the reflexive increases in heart rate and cardiac output.⁶⁶ Inhibition of the sodium-retaining properties of minoxidil with a diuretic may also enhance blood pressure lowering.⁶⁶

Clinical Indications

Although minoxidil’s antihypertensive properties have been recognized for decades, it has typically been reserved for patients with severe, refractory hypertension or renal insufficiency.^66,71,72 Minoxidil, in conjunction with a β-blocker and diuretic (loop, thiazide, or aldosterone antagonist), has repeatedly been shown to reduce blood pressure in patients with severe or refractory hypertension without associated orthostatic hypotension, reflex tachycardia, or fluid retention.^{63,73

–84} Alternatively, methyldopa and clonidine have both been utilized in lieu of a β-blocker to control tachycardia with some success.^85

–88 Once-daily regimens of minoxidil appear to have effective 24-hour blood pressure control.^89

–92

Minoxidil has also been used for patients with hypertension having renal dysfunction, demonstrating the ability to prevent progression of renal disease and serving as an alternative to nephrectomy in dialysis patients.^93

–96 However, some longitudinal studies still found evidence of renal disease progression over a period of several years.^97,98

Studies directly comparing minoxidil to other antihypertensive medications are limited. The DHB-CCBs (nifedipine and felodipine) were found to have comparable blood pressure-lowering effects to minoxidil without the need for continued diuretic use.^99,100 Captopril had similar blood pressure-lowering capabilities but was associated with fewer side effects than minoxidil.¹⁰¹ Minoxidil had greater blood pressure-lowering capabilities when compared to hydralazine (in combination with a β-blocker and a diuretic), but adverse effects were more common with minoxidil.^30,102 Minoxidil was also found to decrease blood pressure to a greater extent than labetalol, methyldopa, or prazosin, but it was associated with fluid retention, which limited its use in severe hypertension.¹⁰² Despite the evidence suggesting that minoxidil is an effective antihypertensive, the introduction of new antihypertensive agents and the potential side effects associated with minoxidil, including hypertrichosis, tachycardia, fluid retention, pericardial effusion, and electrocardiogram changes, has limited its use to refractory, male patients.^{72,76,85,92,103

–107}

Practical Considerations

Minoxidil is available as 2.5 and 10 mg tablets. It is indicated for use in severe hypertension that is symptomatic or associated with target organ damage and cannot be adequately treated with maximum doses of a 3-drug regimen (including 1 diuretic). The recommended initial dose is 5 mg once daily, with effective doses typically in the range of 10 to 40 mg daily. Dose titration should occur after a period of at least 3 days, and the maximum recommended daily dose is 100 mg. Although minoxidil can be given once daily, it may also be divided into multiple daily doses, particularly if the supine diastolic blood pressure is decreased more than 30 mm Hg. Minoxidil is well absorbed from the gastrointestinal tract (90%), and plasma levels peak within 1 hour although the effect on blood pressure is faster with decreases noted within 30 minutes and maximal effect achieved within 2 to 3 hours. Minoxidil is primarily metabolized via glucuronidation in the liver with a plasma half-life of approximately 4.2 hours. The parent compound and its metabolites are excreted in the urine and may also be removed with hemodialysis, although dialysis patients may require a smaller dose.

One of the most common adverse effects of minoxidil is tachycardia, and concomitant use of a rate-lowering drug is recommended. Other common side effects include water retention/edema and hypertrichosis. Thickening and enhanced pigmentation of fine body hair develops within 3 to 6 weeks in approximately 80% of patients and can be particularly upsetting for women and children. Hair growth is halted when the medication is discontinued, but it may take up to 6 months to restore the patient’s appearance. More serious adverse effects include thrombocytopenia, pericarditis, pericardial effusion, and tamponade. The incidence of pericardial effusion is approximately 3%, and it may be more common in patients with renal dysfunction. A smaller percentage of patients develop tamponade, and the majority of patients who developed pericardial effusion have risk factors, including connective tissue disease, heart failure, uremic syndrome, or substantial fluid retention. However, pericardial effusion has been observed during treatment with minoxidil without a notable risk factor; therefore, it is pertinent to monitor for signs of this complication.⁷⁰ Minoxidil is contraindicated for use in pheochromocytoma due to the potential for stimulation of catecholamine release. Additionally, minoxidil carries a warning against the combined use with guanethidine due to the potential for profound orthostatic hypotension.

α-1 Adrenergic Receptor Blockers

Mechanism of Action

The α-1 adrenergic receptors mediate the actions of endogenous catecholamines, which include contraction of arterial, venous, and visceral smooth muscle. Blockade of α-1 adrenergic receptors inhibits vasoconstriction induced by catecholamines, resulting in vasodilation in both arteriolar resistance and possibly venous capacitance vessels, which leads to a decrease in peripheral resistance and blood pressure.^108

–112 This decrease is opposed by baroreceptor reflexes that increase heart rate, cardiac output, and fluid retention, an effect that is heightened if the antagonist also blocks α-2 receptors on peripheral sympathetic nerve endings.¹¹³ Since selective α-1 antagonists provide both afterload and preload reduction, resulting in a fall in peripheral vascular resistance and venous return to the heart, increases in cardiac output and heart rate are not usually significant. Prazosin, the prototypical α-1 adrenergic receptor blocker, was also shown to act centrally causing sympathetic outflow suppression and baroreflex function depression in patients with hypertension.¹¹⁴ Catecholamines also mediate lipid metabolism, thus this class of medications can exert favorable effects on serum lipids. Specifically, the α-1 antagonists have been shown to decrease triglyceride and total cholesterol levels while elevating high-density lipoprotein (HDL) levels. This has been demonstrated in patients treated with prazosin,^115,116 doxazosin,^117
–119 and terazosin.^120,121

The primary α-1 adrenergic receptor blockers studied for the treatment of hypertension and heart failure are prazosin, terazosin, and doxazosin. Alfuzosin, silodosin, and tamsulosin have been shown to be efficacious in the treatment of benign prostatic hyperplasia (BPH) with little effect on blood pressure.

Prazosin is a prototypical α-1 selective antagonist, with an affinity for α-1 receptors approximately 1000-fold greater than for α-2 adrenergic receptors. Terazosin is a close structural analog of prazosin. It is less potent but retains a high specificity for α-1 receptors. The pharmacodynamic profile of terazosin is similar to prazosin, but its half-life is 3 to 4 times longer.^122,123 Doxazosin is another structural analog of prazosin and is a highly selective antagonist of α-1 adrenergic receptors.^124,125 The long half-lives of terazosin and doxazosin allow for once-daily dosing.

Clinical Indications

Hypertension

Prazosin was approved by the FDA as Minipress in 1976 for the treatment of hypertension. The earliest investigations of prazosin as monotherapy for the treatment of mild hypertension showed a noninferior blood pressure-lowering effect compared to methyldopa,^126
–128 hydrochlorothiazide, or propranolol.¹²⁹ Others reported positive experiences in the treatment of arterial hypertension^130
–132 and portal hypertension in patients with cirrhosis.¹³³ Data suggest that prazosin is also effective as a second-line agent to control early, severe hypertension in pregnancy not adequately controlled by methyldopa.¹³⁴

Terazosin was approved by the FDA as Hytrin in 1987. The first studies evaluating terazosin for hypertension date back to 1985, when it was first used as an adjunct to various antihypertensive regimens.¹³⁵ Its antihypertensive effect was comparable to prazosin but showed less effect on supine diastolic blood pressure compared to hydrochlorothiazide.¹³⁶ As a monotherapy, it was found to be safe for the long-term treatment of up to 2 years for both supine systolic and diastolic blood pressures.¹³⁷ As a once-daily antihypertensive, it has been shown to produce sustained blood pressure-lowering throughout the day.^138,139 Chronic exposure to terazosin has not been associated with tolerance, reflex volume expansion, or activation of the renin–angiotensin–aldosterone or sympathetic nervous systems.¹⁴⁰

Doxazosin was approved as Cardura by the FDA on November 2, 1990. In 2005, the US FDA approved Cardura XL, a sustained release form of doxazosin. The immediate release (IR) formulation is indicated for the treatment of hypertension, and the extended release (XR) formulation is indicated in the treatment of benign prostatic hyperplasia. The first studies evaluating doxazosin’s efficacy in treating hypertension date back to 1985. These studies demonstrated effectiveness in reducing total peripheral resistance acutely and chronically (over 1 year). The antihypertensive effect was evident both at rest and during exercise.¹⁴¹ Its antihypertensive effects compare favorably to terazosin as a once-daily medication.¹⁴² However, in the ALLHAT, an antihypertensive regimen based on doxazosin was associated with a 25% higher incidence of cardiovascular disease and 2-fold risk of new-onset congestive heart failure compared to a chlorthalidone-based regimen. This led to early termination of the doxazosin treatment arm.¹⁴³ As a consequence, guidelines currently do not recommend α-1 adrenergic receptor blockers as first-line therapy or monotherapy for hypertension.

Heart Failure

Prazosin is the most well-studied α-1 adrenergic receptor blocker in the setting of left ventricular dysfunction and heart failure. Prazosin reduces afterload and preload in congestive heart failure,¹⁴⁴ with resulting relief of pulmonary congestion and improved exercise tolerance.¹⁴⁵ In chronic refractory congestive heart failure, prazosin was found to have comparable beneficial hemodynamic effects to nitroprusside. This included reduction in left ventricular filling pressure and systemic vascular resistance and improvements in cardiac index, cardiac efficiency of stroke work, and myocardial oxygen consumption index.¹⁴⁶ Similarly, in patients with heart failure on chronic digoxin and diuretic therapy, prazosin was associated with improvement in cardiac hemodynamics, clinical symptoms, left ventricular and atrial dimensions, left ventricular ejection fraction, and treadmill exercise duration.¹⁴⁷ These effects were duplicated in patients with ischemic cardiomyopathy and demonstrated no tachyphylaxis over 6 to 18 months.¹⁴⁸ The most important trial evaluating the potential role of α-1 adrenergic receptor blockers in heart failure was the Veterans Affairs V-HEFT I. In this study patients on digoxin and diuretics were randomized to double-blind treatment with placebo, prazosin (20 mg/day), or the combination of hydralazine (300 mg/day) and ISDN (160 mg/day) for an average of 2.3 years. Mortality in the prazosin group was not reduced compared to placebo, whereas there was a significant improvement in the hydralazine/ISDN combination (see Hydralazine Discussion). In addition, there was no improvement in left ventricular ejection fraction at 8 weeks or at 1 year with prazosin.² It was concluded that prazosin did not alter the natural history of patients with chronic congestive heart failure.

Studies evaluating terazosin’s benefit in heart failure are limited. Terazosin has been shown to decrease pulmonary and systemic vascular resistances, and right atrial and pulmonary capillary wedge pressures, with concomitant increase in stroke volume and cardiac output secondary to afterload reduction.^149,150 It induces systemic vasodilation and improves myocardial circulatory parameters without inducing coronary dilation or altering metabolic autoregulation.¹⁵¹ These effects suggest terazosin may confer hemodynamic benefits in heart failure, but prospective, longitudinal outcome studies are lacking.

Practical Considerations

For the treatment of hypertension, prazosin is administered orally at a dose of 1 mg every 8 to 12 hours, with a daily maintenance dose of 2 to 20 mg divided every 8 to 12 hours. It is also indicated for the treatment of postraumatic stress disorder-related nightmares and sleep disruption. Other off-label uses include the treatment of BPH and Raynaud Phenomenon. The bioavailability of prazosin is 50% to 70%, with peak concentrations generally achieved within 1 to 3 hours. The plasma half-life is 3 hours but may be prolonged to 6 to 8 hours in congestive heart failure. The duration of action of the drug is typically 7 to 10 hours in the treatment of hypertension necessitating twice-daily dosing.

Terazosin is initiated at an oral dose of 1 mg nightly, with maintenance dosing of 1 to 5 mg daily. Compared to prazosin, terazosin is more water soluble, has a higher bioavailability (>90%), and a longer half-life of 12 hours. Its duration of action extends beyond 18 hours, making it suitable for once-daily dosing in the treatment of hypertension and BPH.

Doxazosin is initiated at an oral dose of 1 mg to treat hypertension or BPH, with maintenance doses of 1 to 16 mg daily. It has the longest half-life (20 hours) and duration of action (36 hours) of the α-1 receptor antagonists. It can be dosed in either the morning or the evening.

In general, α-1 adrenergic receptor blockers should be dosed in the evening so that patients can remain recumbent for several hours to reduce the risk of syncope. This is particularly prudent for the first dose, where vascular dilatation and reduced venous return have been noted to cause significant hypotension and syncope. This “first-dose phenomenon” often attenuates with time, but it can be observed with rapid increases in dosage or reinitiation of α-1 adrenergic receptor blockers after therapy interruption. All the α-1 adrenergic receptor blockers are extensively metabolized in the liver, and little unchanged drug is excreted in the kidneys. Therefore, they should be avoided in the setting of severe hepatic impairment. The most common side effects of α-1 adrenergic receptor blockers include dizziness, drowsiness, headache, weakness, and palpitations. There are additive interactions with sildenafil, vardenafil, tadalafil, avanafil, tamsulosin, and yohimbine where excessive hypotension may occur. Prazosin, terazosin, and doxazosin are pregnancy category C medications.

α-2 Adrenergic Receptor Agonists

Mechanism of Action

α-2 Adrenergic receptors are located both centrally and peripherally. Activation of presynaptic α-2 adrenergic receptors results in increased reuptake of neurotransmitters from the synaptic cleft and decreased activation of postsynaptic adrenergic receptors. This results in reduced brain stem vasomotor center-mediated central nervous sysytem (CNS) activation; hence, the term central sympatholytic is sometimes used to describe these agents. The resultant physiologic effects include reduction in heart rate, myocardial contractility, and peripheral vasodilation. Medications considered within the class of α-2 adrenergic receptor agonists are clonidine, methyldopa, guanfacine, and guanabenz. Apraclonidine and brimonidine are relatively selective α-2 adrenergic receptor agonists used topically to reduce intraocular pressure. Tizanidine is a muscle relaxant used for the treatment of spasticity associated with cerebral and spinal disorders.

Clonidine has a high specificity toward the presynaptic α-2 adrenergic receptors. The exact mechanism of clonidine’s blood pressure lowering is not completely understood and appears to result in part from activation of α-2 receptors in the lower brain stem region. Clonidine also stimulates parasympathetic outflow due to increased vagal tone and lower sympathetic drive. It has also been proposed that the antihypertensive effect is due to agonism of the imidazoline receptor that mediates the sympathoinhibitory actions of imidazolines to lower blood pressure.¹⁵² Clonidine was initially developed as a nasal decongestant. During clinical trials as a topical nasal decongestant, clonidine was found to cause hypotension, sedation, and bradycardia. The earliest studies into the central action of clonidine suggested that there are central adrenergic neurons that inhibit cardiovascular autonomic reflexes and that the central autonomic effects of clonidine are due to the stimulation of inhibitory adrenoreceptors. Therefore, it was believed the antagonism by clonidine was due to activation of these inhibitory pathways.¹⁵³ Interestingly, IV infusion of clonidine causes an acute rise in blood pressure due to activation of postsynaptic α-2 receptors in vascular smooth muscle. This effect is not seen when the drug is given orally, and this hypertensive response to IV clonidine is followed by a more prolonged hypotensive response from decreased sympathetic outflow from the CNS.¹⁵⁴ Clonidine is mainly used in the treatment of hypertension and has been found to be useful in reducing diarrhea in diabetic patients with autonomic neuropathy and treating withdrawal from narcotics, alcohol, and tobacco. Among the other off-label uses of clonidine are atrial fibrillation, attention-deficit/hyperactivity disorder, Tourette syndrome, mania, and herpetic neuralgia.

Methyldopa has a dual mechanism of action. It is metabolized to α-methylnorepinephrine in the brain, which is then thought to activate central α-2 adrenergic receptors. It is also a competitive inhibitor of DOPA decarboxylase. Conversion of l-DOPA into dopamine via DOPA decarboxylase results in the formation of norepinephrine and subsequently epinephrine. The attenuation of norepinephrine release in the brain stem reduces the output of vasoconstrictor adrenergic signals to the peripheral nervous system.⁶⁴

Guanfacine is an α-2 receptor agonist that is more selective than clonidine, reflected in a higher α-2A–α-2C affinity ratio. Studies demonstrate that its pharmacologic actions are mediated through sympatholysis,^155,156 with a longer duration of action than clonidine.¹⁵⁵ Guanfacine decreases plasma noradrenaline concentration and plasma renin activity both acutely and chronically. There is a noted tolerance to the blood pressure-lowering effect of the drug which appears to develop during the third or fourth month of chronic therapy.¹⁵⁶

Guanabenz is a centrally acting α-2 agonist with similar activity as the other agents in this class.^157

–160 It has been shown to have effects both centrally, through suppression of sympathetic nervous system activity from bulbar vasoconstriction centers, and peripherally, through peripheral adrenergic neuron blockade.^161,162

Clinical Indications

Hypertension

Clonidine is an effective treatment for hypertension. Although it has not been studied as monotherapy in a long-term hypertension outcome trial, clonidine was a step 2 option in ALLHAT where 10.6% of patients were taking clonidine at the end of 5 years. As a monotherapy, clonidine had similar efficacy to captopril¹⁶³ and propranolol¹⁶⁴ in randomized, blinded studies. Transdermal administration of clonidine was also found to be as effective as hydrochlorothiazide.¹⁶⁵ Clonidine also confers additional blood pressure lowering when used in combination with other antihypertensives such as chlorthalidone,^166,167 hydrochlorothiazide,¹⁶⁸ or guanethidine.¹⁶⁸ An exception may be when used in combination with sotalol, where an antagonistic effect resulting in blood pressure elevations was observed in one study,¹⁶⁹ although this paradoxical response is not universal.

An important clinical consideration with clonidine (and other sympatholytic drugs) is rebound hypertension. Rebound hypertension after cessation of clonidine was first reported by Hokfelt et al¹⁷⁰ in 1969 and subsequently by others.^171
–173 It was originally described as pheochromocytoma-like complaints after interruption of clonidine, which had been administered for 6 to 30 days at a dose of 0.3 to 0.9 mg daily.¹⁷⁰ Blood pressures can rise to pretreatment levels within 24 to 48 hours after withdrawal of clonidine and frequently result in blood pressures above pretreatment levels.¹⁷⁴ The degree of rebound blood pressure increase has been described to be related to the dosage of clonidine.^175,176 The rise in blood pressure may stabilize by the third day near pretreatment levels.¹⁷⁶ Overactivity of the sympathetic nervous system is the purported mechanism. This is corroborated by observed elevations in plasma and urinary catecholamine levels in response to clonidine withdrawal¹⁷⁶ and the observation that β-adrenergic receptor blocking drugs may alleviate some of the associated symptoms,¹⁷² such as insomnia, headache, flushing, sweating, and apprehension.^29,170,174

Methyldopa was discovered and recognized for its blood pressure-lowering effect over 50 years ago.¹⁷⁷ Methyldopa was a commonly employed second-line antihypertensive in the 1970s and 1980s.^178

–181 It has largely been replaced by drug classes with fewer side effects but is still used in developing countries due to its low cost.¹⁸² Contemporary studies of methyldopa as monotherapy are lacking, however, it was found to provide similar reductions in systolic and diastolic blood pressure when compared to guanfacine.¹⁸³ Methyldopa has been a part of several small combination studies. In a multicenter, randomized, double-blind trial, captopril plus methyldopa was found to be inferior to captopril plus isradipine in achieving blood pressure goals, with a higher incidence of cardiovascular and gastrointestinal complaints.¹⁸⁴ Methyldopa may be most useful in severe or refractory hypertension. The combination of enalapril, hydrochlorothiazide, and methyldopa was effective in controlling severe hypertension (average starting systolic blood pressure of 210 mmHg) in a Nigerian cohort study.¹⁸⁵ The addition of methyldopa also contributed to improved blood pressure control among patients with resistant hypertension (uncontrolled on 3 antihypertensive drugs including a diuretic).¹⁸⁶

Contemporary studies of guanfacine and guanabenz for hypertension are also limited. Guanfacine has demonstrated efficacy¹⁸⁷ but appears to be inferior to clonidine.¹⁸⁸ Guanabenz has been shown to provide similar blood pressure lowering compared to methyldopa,^189,190 however, in one study, the incidence of dry mouth was greater with guanabenz.¹⁹⁰ In combination studies, guanabenz was found to enhance the antihypertensive efficacy of hydrochlorothiazide without compromising its natriuretic properties.¹⁹¹ Furthermore, the combination of guanabenz and clonidine effectively suppressed morning blood pressure elevations in treated patients with hypertension.¹⁹² Guanfacine and guanabenz are not considered first- or even second-line agents for the treatment of hypertension.

Pregnancy

Methyldopa is considered a first-line medication in the management of pregnancy-induced hypertension.¹⁹³ Treatment of mild to moderate pregnancy-induced hypertension with methyldopa is associated with a lower rate of some maternal and fetal–neonatal nonfatal adverse events compared to no routine therapy.¹⁹⁴ Short-term treatment with methyldopa during the last trimester has been shown to effectively reduce maternal blood pressure and heart rate, without adverse effects on uteroplacental and fetal hemodynamics.^195,196 However, it remains controversial as at least 1 report found methyldopa use was associated with impaired placental perfusion, compromised function of the fetoplacental unit, and a need for more frequent surgical deliveries.¹⁹⁷ Overall, published reports on the use of methyldopa during all trimesters indicate that use in pregnancy is safe, and the risk of fetal harm appears remote. In multiple studies involving several hundred women, treatment with methyldopa was associated with an improved fetal outcome.^{198

–204} The majority of these women were in the third trimester when methyldopa therapy was begun. Methyldopa is pregnancy category B. Although methyldopa is historically regarded as first-line therapy for hypertension in pregnancy, labetalol may represent a superior option.²⁰⁵

Practical Considerations

Clonidine is available in IR and XR oral formulations. The IR tablets are dosed 0.1 mg every 12 hours and can be given up to a total daily dose of 2.4 mg/day. The XR tablet is dosed 0.17 mg at bedtime and may be increased by 0.09 mg/day every week to a maximum of 0.52 mg/d. The XR formulation is available as 0.17 mg and 0.26 mg tablets and a 0.09 mg/mL suspension. To convert from IR to XR, patients on IR 0.1 mg twice daily should be placed on XR 0.17 mg daily, IR 0.2 mg twice daily to XR 0.34 mg daily, and IR 0.3 mg twice daily to XR 0.52 mg daily. Clonidine is well absorbed after oral administration, and its bioavailability is nearly 100%. Its half-life ranges from 6 to 25 hours with a mean of 12 hours. Although dosing adjustments are not defined for changes in renal function, half-life is prolonged (17-41 hours) in renal impairment. A transdermal patch is also available with a starting dose of one 0.1-mg/24-hour patch placed every 7 days. Recommendations are to increase by 0.1 mg after 1 to 2 weeks of use, with a usual dose range of 0.1 to 0.3 mg weekly (maximum 0.6 mg weekly). With the transdermal patch, 3 to 4 days are required to reach steady state plasma concentrations. When the patch is removed, plasma concentrations remain stable for 8 hours and then decline gradually over a period of several days. It is recommended that the patch be removed before defibrillation and magnetic resonance imaging. The most common adverse effects of clonidine are dry mouth and sedation, occurring in approximately 50% of patients. Other major adverse effects include bradycardia, AV nodal block, depression, and sexual dysfunction. Clonidine is pregnancy category C.

Methyldopa is initially dosed at 250 mg 2 or 3 times a day for the first 48 hours. The dose may then be increased or decreased, preferably at intervals of not less than 2 days, until an adequate response is achieved. The usual daily dosage of methyldopa is 500 mg to 2 g given in 2 to 4 divided doses. In the setting of hypertensive crisis, the IV dose is 20 to 40 mg/kg/d divided every 6 hours, not to exceed 65 mg/kg/d or 3 g/d (whichever is less). Although occasional patients have responded to higher doses, the maximum recommended daily dosage is 3 g. The onset of action for oral and IV administration is 3 to 6 hours and 4 to 6 hours, respectively. Methyldopa is variably absorbed from the gastrointestinal tract. It is metabolized in the liver/intestines and excreted in the urine. Methyldopa is dialyzable, with hemodialysis removing approximately 60% while peritoneal dialysis removes less.

Guanfacine is generally dosed as a once-daily regimen due to the observation that such daily dosing is the most tolerable.²⁰⁶ The initial dose is 1 mg orally at bedtime, with 1-mg dose increments every 3 to 4 weeks to a maximum dose of 3 mg. The bioavailability of the IR formulation is 80% to 100%. An XR tablet is available for treatment of attention-deficit–hyperactivity-disorder, but this formulation is not approved for hypertension.

Guanfacine is 70% protein bound and hepatically metabolized via the CYP3A4 pathway. Its elimination half-life is 17 to 18 hours. Despite the long half-life, tapering the dose prior to discontinuation of therapy is still recommended. Guanfacine is pregnancy category B.

Guanabenz is dosed 4 mg orally every 12 hours initially, with the dose increased by 4 to 8 mg/d at 1 to 2 week intervals. Its maintenance dose range is typically 4 to 16 mg orally every 12 hours, not to exceed 32 mg orally every 12 hours. Its bioavailability is 75%. Guanabenz is extensively metabolized by the liver and should be used cautiously or undergo dose adjustment in those with hepatic impairment. Its elimination half-life is 4 to 6 hours. Guanabenz is pregnancy category C.

The most common adverse effects with the α-2 adrenergic receptor antagonists are sedation, fatigue, depression, memory or cognitive impairment, orthostatic hypotension, xerostomia (dry mouth), and sexual dysfunction. Abrupt discontinuation of any of the drugs in this class should be avoided to minimize the risk of rebound hypertension. Methyldopa is associated with additional adverse effects related to the interference of dopamine synthesis, including myalgias, Parkinsonian symptoms, and hyperprolactinemia. It is important to recognize that a positive Coombs test, hemolytic anemia, and liver disorders may occur with methyldopa therapy. Positive Coombs test results occur in up to 20% of patients with long-term use, but hemolytic anemia is rare. However, prior existence or development of a positive direct Coombs test is not in itself a contraindication to use of methyldopa.

Reserpine

Mechanism of Action

Reserpine is a lipid-soluble alkaloid primarily found in the root of Rauvolfia (Rauwolfia) species.^64,207 It was first isolated in India from snake root Rauvolfia serpentina in 1952, and its discovery marked a new era in antihypertensive pharmacotherapy.^64,207 Reserpine blocks postsynaptic activity of norepinephrine and binds to amine storage granules in central and peripheral neurons, inhibiting the ability to concentrate and store monoamines, serotonin, and the catecholamines.^207,208 Catecholamine stores are depleted, and recovery of sympathetic function can take days to weeks, as new storage vesicles must be synthesized.^64,209 These actions make reserpine an effective CNS depressant and antihypertensive agent. Other hemodynamic effects include decreased cardiac output and peripheral vascular resistance. Atrioventricular conduction can be slowed with resultant decreases in ventricular heart rate.^64,210

Clinical Uses

Reserpine has been utilized in the treatment of hypertension for many decades, and it may be particularly useful in developing countries due to its low cost.^211,212 However, there has been a stigma associated with reserpine due to a perceived negative side effect profile. In the 1960s, reserpine was commonly used to treat hypertension at doses much higher (0.75-10 mg/d) than utilized today, resulting in a greater incidence of side effects such as gastric intolerance, peptic ulceration, and depression.²¹² Additionally, there was some concern about an association between reserpine use and breast cancer which has never been fully validated.²¹² However, it has been demonstrated that reserpine has dose-dependent blood pressure-lowering effects at doses as low as 0.05 to 0.25 mg/d; therefore, doses of 0.1 to 0.25 mg/d are recommended today. Reserpine has primarily been studied in combination with a thiazide diuretic (with or without additional antihypertensives).²¹³ ^213,214 Comparison of reserpine and methyldopa as add-on therapy to a thiazide diuretic demonstrated reserpine is at least as effective, if not more effective, than methyldopa in lowering blood pressure with fewer associated side effects and better compliance.^215
–217 The reserpine plus thiazide combination has also been compared to diltiazem, low-dose enalapril, nitrendipine, and a combination of thiazide plus sustained-release nifedipine.^218

–221 Reserpine in conjunction with a thiazide diuretic reduced blood pressure to a similar or greater degree than the other drug therapies,^218

–221 however, diltiazem appeared to have fewer side effects.²¹⁸ Reserpine has also been used to treat hypertension in older adults. The most notable study utilizing reserpine in this context was the Systolic Hypertension in the Elderly Program (SHEP). Adults aged 60 years or older received primary treatment with chlorthalidone and step-up therapy with either atenolol or reserpine.²²² Both treatment strategies appeared beneficial without a notable difference between step-up therapy with atenolol or reserpine.

Practical Considerations

Reserpine is available as 0.1 and 0.25 mg tablets. It is indicated for use in mild essential hypertension or as add-on therapy in more severe hypertension. The maintenance dose for hypertension is 0.1 to 0.25 mg daily, which is lower than the doses utilized for psychiatric disorders. Approximately 50% of reserpine is absorbed from the gastrointestinal tract, and peak levels are achieved 2.5 hours after the dose. Reserpine is almost completely metabolized with minimal excretion of unchanged drug in the urine. Although the initial half-life is 5 hours, the terminal half-life is up to 200 hours, with measurable plasma levels up to 14 days after a single dose. The effect of reserpine on both the cardiovascular and the CNSs is often prolonged.

The most common side effects include gastrointestinal distress and nasal congestion. Potentially serious adverse effects associated with reserpine include arrhythmias (especially with concurrent use of digoxin or quinidine), depression, extrapyramidal symptoms, and vision changes. Use is contraindicated in patients with a history of depression, an active peptic ulcer or ulcerative colitis, and patients receiving electroconvulsive therapy. In addition to potential drug interactions with digoxin/quinidine, reserpine should be avoided or used with caution in patients taking MAO inhibitors, and tricyclic antidepressants. Additionally, the action of direct-acting amines (eg, epinephrine, isoproterenol, etc) may be prolonged when used with reserpine. Alternatively, the action of indirect-acting amines (eg, ephedrine, amphetamines, etc) may be inhibited when used with reserpine.

Guanethidine

Mechanism of Action

Guanethidine is a synthetic drug that has been recognized for its antihypertensive properties since 1959.^223,224 Initially, guanethidine causes rapid release of catecholamines from the nerve terminals resulting in depletion of norepinephrine in the periphery and cardiac tissue.^{223,225
–227} Guanethidine also inhibits uptake of neurotransmitters into the nerve terminals, thereby preventing repletion.²²⁵ However, the long-term antihypertensive effects of guanethidine are due to peripheral inhibition of adrenergic neurotransmitter release from nerve terminals, which is often referred to as “adrenergic neuron blockade.” ^225,226 These actions cause depression of sympathetic activity with resultant decreases in blood pressure, heart rate, and cardiac output.²²⁶

Clinical Uses and Practical Considerations

Guanethidine has been shown to effectively lower blood pressure when used alone²²⁸ or in combination with a diuretic.^228

–232 It was comparable to guanfacine or methyldopa in its blood pressure-lowering effects,^228,229 but orthostatic hypotension may be more common with guanethidine than either guanadrel or methyldopa.^228,232,233 Ferguson and colleagues found that the potential adverse effects associated with guanethidine, including fatigue, dizziness, and diarrhea, were tolerable to patients.²³¹

Guanethidine is eliminated slowly due to tissue binding, which results in 2 elimination phases and a terminal half-life of 4 to 8 days.²³⁴ It is metabolized in the liver into 3 metabolites and excreted in the urine. Guanethidine carries a significant risk of orthostatic hypotension and erectile dysfunction with impaired ejaculation. Furthermore, it is contraindicated with monoamine oxidase inhibitors and in patients with pheochromocytoma or heart failure. Use of guanethidine has declined due to a lack of availability in the United States; however, it is still available in other countries.

Conclusion

Vasodilators and centrally acting sympatholytic drugs continue to have important roles in the management of cardiovascular diseases. Most drugs in these pharmacologic classes lack robust clinical trial data linking their use to improved longitudinal outcomes such as survival. The exception is hydralazine, which, used in combination with oral nitrates, has been shown to improve survival in patients with heart failure with reduced ejection fraction. However, they appear comparable in terms of antihypertensive efficacy when compared to contemporary drug classes. Their efficacy has also been demonstrated in combination with many contemporary drugs such as angiotensin II antagonists, calcium channel blockers, and thiazide diuretics. Many of these agents, such as hydralazine, clonidine, and α-1 adrenergic antagonists, are also useful in the setting of renal impairment which negates the ability to use certain contemporary drugs. These drugs are also commonly avoided for potential adverse drug effects. However, a thorough understanding of their pharmacologic and physiologic effects should allow clinicians to utilize them safely and effectively.

Footnotes

Acknowledgments

The authors would like to thank Himika Patel for her assistance with preparation of the manuscript.

Author Contributions

T. Ng contributed to conception and design, drafted manuscript, critically revised manuscript, gave final approval, and agreed to be accountable for all aspects of work ensuring integrity and accuracy. M. McComb contributed to conception and design, drafted manuscript, critically revised manuscript, gave final approval, and agreed to be accountable for all aspects of work ensuring integrity and accuracy. J. Chao contributed to design, drafted manuscript, critically revised manuscript, gave final approval, and agreed to be accountable for all aspects of work ensuring integrity and accuracy

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

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Direct Vasodilators and Sympatholytic Agents

Abstract

Keywords

Introduction

Hydralazine

Mechanism of Action

Clinical Indications

Hypertension

Pregnancy

Heart failure

Practical Considerations

Minoxidil

Mechanism of Action

Clinical Indications

Practical Considerations

α-1 Adrenergic Receptor Blockers

Mechanism of Action

Clinical Indications

Hypertension

Heart Failure

Practical Considerations

α-2 Adrenergic Receptor Agonists

Mechanism of Action

Clinical Indications

Hypertension

Pregnancy

Practical Considerations

Reserpine

Mechanism of Action

Clinical Uses

Practical Considerations

Guanethidine

Mechanism of Action

Clinical Uses and Practical Considerations

Conclusion

Footnotes

Acknowledgments

Author Contributions

Declaration of Conflicting Interests

Funding

References