Alpha 1 Adrenoreceptor Antagonists


  • Richard H. Grimm, Jr MD, PhD,

    1. From Cardiolgy and Epidemiology, University of Minnesota, Minneapolis, MN;
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  • John M. Flack MD, MPH, PhD

    1. Director, Berman Center for Outcomes and Clinical Research; Division Head, Clinical Research, Hennepin County Medical Center, MMRF; Professor of Medicine and Epidemiology, University of Minnesota Medical School and School of Public Health, Minneapolis, MN
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Richard H. Grimm, Jr, MD, PhD, Cardiolgy and Epidemiology, University of Minnesota, 825 South Eight Street, Suite 440, Minneapolis, MN 55404


J Clin Hypertens (Greenwich). 2011;13:654–657. ©2011 Wiley Periodicals, Inc.

Key Points and Practical Recommendations

  •  α Antagonists lower blood pressure by selectively blocking post-synaptic α1-adrenoreceptors, which antagonizes catecholamine-induced constriction of the arterial and venous vascular beds.
  •  α1-Adrenoreceptor antagonists are not indicated for initial, first-line antihypertensive therapy; however, they can be added to most other antihypertensive drug classes in—preferably diuretic-containing—drug regimens.
  •  When used over time, these agents cause expansion of the extracellular fluid and plasma volumes that typically manifests as weight gain and an attenuation of the blood pressure–lowering efficacy in persons who are consuming usual amounts of dietary sodium.
  •  Utilization of α1-adrenoreceptor antagonists with diuretics such as chlorthalidone or hydrochlorothiazide is beneficial because these agents minimize the α antagonist–induced expansion of the extracellular and plasma volumes while providing significant incremental reductions in blood pressure.
  •  α1-Adrenoreceptor antagonists are especially useful in men with benign prostatic hypertrophy because they increase mean and peak urinary flow rates as well as reduce lower urinary tract symptoms.
  •  α1-Adrenoreceptor antagonists are contraindicated in persons with heart failure because of their aforementioned ability to expand extracellular and plasma volumes.

Post-synaptic α1-adrenoreceptor antagonists are predominately used to lower blood pressure (BP) in hypertensive patients already taking other antihypertensive drug classes. Ideally, the antihypertensive drug regimens to which α1-adrenoreceptor antagonists are added should include a diuretic that is appropriately matched to the level of kidney function. α1-Adrenoreceptor antagonists are not indicated for initial, first-line antihypertensive therapy. These agents will, however, be particularly useful in older hypertensive men with benign prostatic hyperplasia (BPH) who are experiencing symptoms of bladder outlet obstruction.


The first generation of α receptor antagonists, phentolamine and phenoxybenzamine, used in the treatment of hypertension were of the nonselective variety. These agents caused a biochemical sympathectomy by blocking pre- and post-synaptic α1-adrenoreceptor subtypes. This resulted in reduced epinephrine and norepinephrine levels as well as peripheral vasodilatation of both the arterial and venous capacitance systems. These agents were not well tolerated because they caused numerous therapy-limiting side effects such as orthostatic hypotension, tachycardia, dizziness, drowsiness, syncope, nausea, and nasal congestion. Thus, non-selective α1-adrenoreceptor antagonists are uncommonly used today unless being used to pre-treat patients with known pheochromocytoma for surgery.

In 1976, the first quinazoline-selective α1-adrenoreceptor blocker, prazosin, was first approved for use in the United States. Prazosin had the advantage of not interfering with the compensatory beneficial effects of the α2 adrenoreceptors, thus preventing tachycardia. At the time, prazosin was a valuable addition to the armamentarium of oral antihypertensive agents because, quite frankly, there were few other available therapeutic options. Prazosin therapy was not successfully undertaken, however, without consideration of several important caveats. First-dose syncope was an important prazosin-related side effect necessitating that its therapy be preferentially initiated at a low dose around bedtime when, hopefully, the patient would remain supine in bed without rising until the following morning. Secondly, utilization of this agent over the long-term was associated with waning antihypertensive effectiveness because of the expansion of extracellular and plasma volumes in many hypertensives who were consuming typical levels of dietary sodium. Finally, the relatively short duration of action of this drug required multiple—2 or 3—daily doses to provide sustained BP-lowering.

Terazosin, a later-generation selective post-synaptic α1-adrenoreceptor antagonist, had one main advantage over prazosin. That is, terazosin had a much longer half-life, which allowed for once-daily dosing instead of the multiple-daily doses required by prazosin. Doxazosin, another long-acting selective post-synaptic α1-adrenoreceptor antagonist, subsequently became available.

Clinical Uses of αα1-Adrenoreceptor Receptor Antagonists

All of the quinazoline-selective post-synaptic α1-adrenoreceptor antagonists (prazosin, terazosin, doxazosin) are indicated for the treatment of hypertension. These agents differ mainly in their pharmacokinetic effects. α1-Adrenoreceptor antagonists are, however, not recommended for initial monotherapy of hypertension. These agents are typically added to an existing antihypertensive drug regimen with the aim of incrementally lowering BP to below goal levels. Ideally, α1-adrenoreceptor antagonists should be added to diuretic-containing regimens because of their tendency to expand the extracellular fluid and plasma volumes, which attenuates the magnitude of BP reduction and, in predisposed patients, may precipitate clinically manifest heart failure. The Table gives the dose range and dosing frequency for the quinazoline α1-adrenoreceptor antagonists.

Table I.   Dosing of Alpha-1 Adrenoreceptor Drugs
 Dose RangeDosing Frequency
  1. TID, three times daily; QD, once daily; BID = twice daily.

Prazosin1–20 mgBID – TID
Terazosin1–20 mgQD – BID
Doxazosin1–16 mgQD

There have only been a few longer-term placebo-controlled comparative trials conducted comparing α1-adrenoreceptor antagonists with other commonly used antihypertensive drug therapies. The largest such trial was the Treatment of Mild Hypertension Study (TOMHS, the pilot study for Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial [ALLHAT]). In TOMHS, the multi-year BP change with doxazosin was compared with placebo (multifactorial lifestyle modification only) as well as with a diuretic (chlorthalidone), angiotensin-converting enzyme inhibitor (lisinopril), dihydropyridine calcium blocker (amlodipine), and a β-blocker with intrinsic sympathomimetic activity (acebutolol).1 All TOMHS participants received multifactorial lifestyle advice (weight loss, dietary sodium reduction, alcohol restriction, and increased physical activity.1,2 Doxazosin lowered systolic BP by 15.8 mm Hg in non-black and 9 mm Hg in black patients, which was similar to that seen with lisinopril but not as much as with chlorthalidone, amlodipine, and acebutolol. A similar racial pattern of BP response was subsequently observed in the ALLHAT trial.3 The most prominent doxazosin-related side effects were swollen feet and weight gain, which were, in all likelihood, related to the expansion of the extracellular fluid volume that is known to occur with post-synaptic α1-adrenereceptor antagonists such as doxazosin.

Lipid Effects of α1-Adrenoreceptor Antagonists

Not long after the introduction of prazosin, reports emerged indicating favorable lipid changes with prazosin.4 In TOMHS, doxazosin reduced total cholesterol by −6%, low-density lipoprotein cholesterol by −7% and increased triglycerides by 19% and high-density lipoprotein cholesterol by 5% (results averaged during 4 years of follow-up). Similar lipid changes were also noted in ALLHAT. Doxazosin was the only TOMHS drug that lowered fasting blood glucose as well as fasting insulin levels. The favorable changes in the lipoprotein profile are attributable to antagonism of the α1-adrenoreceptor that results in an increase in low-density lipoprotein receptor number, downregulation of 3-hydroxy-3-methyl-glutaryl-CoA reductase (the rate-limiting enzyme in the synthesis of cholesterol), reduced synthesis of very low-density lipoprotein, and up-regulation of lipoprotein lipase activity.5,6

Hemodynamic Effects of α1-Adrenoreceptor Antagonists

Selective post-synaptic α1-adrenerecptor antagonists are mixed arterial and venous dilators as they dilate both the resistance and capacitance sides of the vasculature. The dilation of the venous capacitance system, which decentralizes blood volume, is a likely contributor to the enhanced renal sodium absorption that leads to expansion of the extracellular fluid volume. This drug class also reduces ventricular preload without changing heart rate or cardiac output.

Doxazosin in the ALLHAT Study

There were multiple reasons to believe that doxazosin would result in favorable cardiovascular outcomes during the conceptualization and planning of the ALLHAT study. Not only did doxazosin favorably affect all lipoprotein fractions, including lower apoprotein B particle number, this agent also reduced platelet aggregation, inhibited fibrinolysis, reduced insulin resistance, and improved glucose metabolism. Nevertheless, in February 2002, the doxazosin arm of the ALLHAT study was terminated early by the data safety and monitoring board and National Heart Lung and Blood Institute only 3.3 years into the trial.7 One reason for the decision of early termination of the doxazosin study was “futility” in the primary end point event rates (fatal coronary heart disease + nonfatal myocardial infarction) between the chlorthalidone and doxazosin arms. That is, there was virtually no chance of finding any difference in the end point between these two study arms if both arms continued until the end of the study. The other important reason was that ALLHAT participants in the doxazosin arm experienced more combined cardiovascular disease and stroke (secondary end points) and heart failure (a component of a secondary end point) than participants in the chlorthalidone study arm.7–9 Throughout follow-up at each annual study visit, systolic BP was 2- to 3-mm Hg higher in the doxazosin compared with the chlorthalidone treatment arm, while diastolic BP at these same annual visits was identical in both groups. In ALLHAT, most new-onset heart failure was characterized by reduced ejection fraction (<50%) rather than preserved ejection fraction (≥50%) (55.6% vs 44%).10 In addition, chlorthalidone was more effective than doxazosin in preventing both reduced and preserved ejection heart failure. Furthermore, there was no evidence that the type of antihypertensive treatment prior to entry into ALLHAT influenced heart failure event rates during the trial itself.11 In ALLHAT patients with glucose disorders, doxazosin was equally as effective as chlorthalidone in preventing the occurrence of the primary study end point (fatal coronary heart disease + nonfatal myocardial infarction); however, there were higher rates of combined cardiovascular disease and heart failure despite lower glucose levels in the doxazosin group.12

There are, however, several caveats regarding the interpretation of the aforementioned ALLHAT heart failure data. First, these data do support relegation of doxazosin and, by implication, other selective post-synaptic α1-adrenoreceptor antagonists, to non–first-line status in the treatment of hypertension. Second, in-study use of diuretics was not allowed as either second- or third-line therapy in any of the ALLHAT randomized treatment groups as would optimally be done in contemporary medical practice. Nevertheless, it is plausible to recommend that the combined use of α1-adrenereceptor antagonists with a diuretic(s) is a reasonable antihypertensive drug combination—especially when the α1-adrenoreceptor antagonist is needed for improvement in urine flow and relief of symptoms in older men with symptomatic benign prostatic hypertrophy.


Selective post-synaptic α1-adrenoreceptor antagonists are effective antihypertensive agents but post-ALLHAT, these agents have been relegated to use as adjunctive therapy. The use in ALLHAT of doxazosin, a prototypical agent of this drug class, without the benefit of a diuretic is not ideal given the well-known propensity of this drug class to expand extracellular fluid and plasma volumes. This drug class will be most useful in men with symptomatic benign prostatic hypertrophy who also have drug-, preferably diuretic-treated, hypertension. Also, it is imperative to use enough antihypertensive agents, in addition to the α1-adrenoreceptor antagonist, to consistently maintain BP below target levels. Thus, practitioners might find it necessary, on occasion, to use two diuretics—a thiazide plus an aldosterone antagonist or other potassium-sparing diuretic—to combat the plasma volume expansion that undermines BP control and likely precipitates heart failure symptoms in hypertensive patients taking an α1-adrenoreceptor antagonist. It is, however, unnecessary to shun the inclusion of these agents in complex drug regimens as long as enough other antihypertensive drugs are given to keep BP persistently below goals and enough diuretic(s) is used to prevent expansion of the extracellular and plasma volumes. This drug class should not be used in patients with a history of preserved or reduced ejection fraction heart failure.

Practitioners should, however, take special caution when using these agents based on their well-established side effect profile. In older patients, especially those taking diuretics or sympatholytic drugs (eg, clonidine), orthostatic hypotension is a very realistic concern. Thus, older patients should always have their BP measured in both the seated and standing position if at all possible. This is also more likely to occur in persons with diabetes who may have varying degrees of autonomic neuropathy as well as those concurrently treated with diuretics. Also, in patients (likely men) with nocturia who awaken and rise from bed at various times throughout the night, orthostatic BP changes are of particular concern. It is not uncommon in clinical practice to see α1-adrenoreceptor antagonists used with other antihypertensive agents that also primarily work via their effects on the sympathetic nervous system (eg, clonidine). Simultaneous use of α1-adrenoreceptor antagonists and other sympatholytic agents (eg, clonidine) should be avoided because of only modest incremental BP-lowering as well as an unacceptably high likelihood of orthostatic hypotension.

Disclosure:  The authors received no honoraria for their contribution to this issue.