Alpha¹‐Adrenergic Blockers: Current Usage Considerations

Abstract

Alpha₁‐adrenergic‐blocking drugs are effective in reducing blood pressure and do so in a fashion comparable to most other antihypertensive drug classes. These compounds are most effective in patients in the upright position, reducing systolic and diastolic pressures by 8%–10%. Alpha₁‐adrenergic‐blocking drugs incrementally reduce blood pressure when combined with most drug classes and are the only antihypertensive drug class to improve plasma lipid profiles. Alpha₁‐adrenergic‐blocking drugs are also accepted as important elements of the treatment plan for symptomatic benign prostatic hypertrophy. Dose escalation of an α₁‐adrenergic‐blocking drug can trigger renal Na⁺ retention, and the ensuing volume expansion can attenuate its blood pressure‐lowering effect. Orthostatic hypotension can occur with these compounds, particularly when a patient is volume‐contracted. Dizziness, headache, and drowsiness are common side effects with α₂‐adrenergic blockers. A modest decline in the use of doxazosin and other α₁‐adrenergic‐blocking drugs has occurred coincident to the early termination of the doxazosin treatment arm in the Antihypertensive and Lipid‐Lowering Treatment to Prevent Heart Attack Trial.

Selective α₁‐adrenergic blockers retain a small market share among all antihypertensive medications in the United States. ¹ , ² Prazosin, released in 1976, was the first marketed drug in this class. Since then two additional α₁‐adrenergic blockers, doxazosin and terazosin, have become available, and their potential for once‐daily dosing has provided additional treatment flexibility. ³ More recently, sustained‐release formulations for prazosin and doxazosin have been released. Tamsulosin and alfuzosin are so‐called uroselective agents with a higher affinity for prostatic α₁ adrenoceptors and are commonly used in the management of patients with benign prostatic hypertrophy (BPH). ⁴

RECEPTOR SUBTYPES

Alpha adrenoceptors have been divided into α₁ and α₂ receptors. Multiple α₁ and α₂ adrenoceptor subtypes exist. Relevant to this discussion, three α₁ adrenoceptor subtypes have been cloned and are designated α_1a, α_1b, and α_1d. Alpha₁ adrenoceptors are localized postsynaptically in smooth muscle adjacent to nerve terminals. When these α₁ receptors are stimulated by endogenously released norepinephrine, vasoconstriction occurs in both arteries and veins.

After extensive characterization of cloned and native receptors in diverse tissues, it remains difficult to ascribe a definite clinical purpose to each α₁ adrenoceptor subtype beyond the role of α₁ adrenoceptor stimulation in the symptom profile of BPH. There is evidence that tamsulosin and alfuzosin have a higher affinity for α_1a and α_1d adrenoceptor subtypes. Binding studies have shown that tamsulosin is as much as 12 times more selective for α₁ adrenoceptors in human prostate tissue than for α₁ adrenoceptors in the aorta. ⁵ Tamsulosin and alfuzosin are approved as uroselective agents for the treatment of symptomatic BPH. ⁶

MECHANISM OF ACTION

Alpha₁‐adrenergic‐specific antagonists inhibit the vasoconstrictor effect of norepinephrine. They do so by selectively inhibiting the activation of post‐synaptic α₁ receptors by circulating and/or neurally released catecholamines. The drop in peripheral vascular resistance that follows is the basis for the ensuing blood pressure (BP) fall. Alpha₁‐adrenergic antagonists have little‐to‐no effect on cardiac output or renin release, in part because of a balanced effect on venous and arteriolar tone. ⁷ The presynaptic α₂‐adrenergic receptor goes unblocked with these selective compounds; therefore, inhibition of additional norepinephrine release by a feedback mechanism of α₂‐adrenergic receptor stimulation is preserved.

This inhibition of norepinephrine release explains the absence of tachycardia, increased cardiac output, and rise in renin levels that characterize drugs that block both the presynaptic α₂ receptor and the postsynaptic α₁ receptors (e.g., phentolamine). ⁸ Because these agents do not interfere with the renin‐angiotensin‐aldosterone system, they may be a practical choice for the control of hypertension in patients undergoing dynamic testing of this axis. ⁹ These drugs may also have beneficial effects on hemorheology, ¹⁰ including blood viscosity, red blood cell deformability, and endothelial function. ¹¹ Doxazosin also inhibits the proliferation and migration of human vascular smooth muscle cells, independent of α₁‐adrenoceptor blockade. ¹²

Baroreceptor reflexes as well as supine and upright heart rate do not ordinarily change with α₁‐adrenergic antagonist therapy. Orthostatic hypotension can occur in α₁‐adrenergic antagonist‐treated patients who are either volume‐depleted or hemodynamically sensitive to the loss of α₁‐adrenergic‐mediated vasoconstriction that might otherwise occur with assumption of an upright posture. The effectiveness of α₁‐adrenergic antagonists is proportional to the level of sympathetic activation in the treated patient. This is why these drugs will not reduce BP in normotensive persons at a normal level of sympathetic nervous system activity.

AVAILABLE AGENTS

Both selective and nonselective α₁‐adrenergic antagonists are clinically available. Phenoxybenzamine is a noncompetitive, nonselective a blocker that is now reserved for the preoperative management of pheochromocytoma‐related hypertension. Nonselective α blockade means that presynaptic α₂ receptors, which reduce the release of norepinephrine, are inhibited because the negative feedback mechanism is blocked. Phentolamine is a short‐acting, competitive, nonselective α blocker parenterally administered and used almost exclusively for urgent, severe forms of hypertension prompted by excessive catecholamine release.

Prazosin was the first selective α blocker. This compound has a high affinity for the α₁ receptor, and when given as an immediate‐release formulation it has a rapid onset of action. This feature probably accounts for its relatively higher rate of syncope and orthostatic hypotension compared with doxazosin and terazosin. Syncopal episodes can be minimized by limiting the initial dose to 1 mg, administering the first dose at bedtime, and increasing the dosage slowly. ¹³ Both terazosin and doxazosin are less lipid‐soluble than prazosin and have a lower affinity for α₁ receptors.

The individual members of the α₁‐adrenergic antagonist class are pharmacologically distinct (Table I). ¹⁴ , ¹⁵ , ¹⁶ Prazosin has a relatively short duration of action and should be given at least twice daily. ¹⁴ Terazosin and doxazosin have longer half‐lives and can be administered once daily. ¹⁵ , ¹⁶ Doxazosin can be administered at bedtime, with its pattern of slow absorption allowing for a maximal effect on the early morning surge in BP. ¹⁷ In general, α₁‐adrenergic antagonists should be used cautiously in children or in pregnancy, since the efficacy and/or safety of these compounds have not been evaluated in these patient types (Table II).

Table I.

Pharmacokinetics of Selective α₁‐Adrenergic Antagonists

Drug	Daily Dose (mg)	Doses per Day	Bioavailability (%)	Half‐Life (h)	Urinary Excretion (%)
Prazosin	2–20	2–3	44–69	2.5–4	10
Terazosin	1–20	1	90	12	10
Doxazosin	1–16	1	65	19–22	5

Table II.

Pharmacokinetics of Selective α₁‐Adrenergic Antagonists in Special Populations

Drug	Pregnancy Category	Breast Milk Transmission	Pediatric Studies
Prazosin	C	Yes	No
Terazosin	C	Not known	No
Doxazosin	C	Yes	No
C=risk cannot be ruled out; adequate studies lacking

BP‐LOWERING EFFICACY

The degree to which BP is reduced with α₁‐adrenergic antagonists is comparable to that observed with other major classes of antihypertensive medications including diuretics, β blockers, angiotensin‐converting enzyme (ACE) inhibitors, and calcium channel blockers (CCBs). ¹⁸ , ¹⁹ , ²⁰ , ²¹ , ²² , ²³ , ²⁴ , ²⁵ Alpha₁‐adrenergic antagonists reduce systolic and diastolic BP by approximately 10% and are more effective in reducing upright than supine BP. Most BP lowering occurs at low‐ to mid‐range doses, such as 4–8 mg/d of doxazosin and 5–10 mg/d of terazosin. ²⁶ Higher doses bring about Na⁺ retention, perhaps because plasma renin activity and plasma aldosterone do not suppress as completely with α₁‐adrenergic antagonists as they do with other adrenergic‐inhibiting drugs. ²⁷

Alpha₁‐adrenergic antagonists are most effective in low and medium plasma renin activity states. ²⁸ Studies have been inconsistent as to the effect of age and race on the BP‐lowering response to these drugs. ¹⁸ , ¹⁹ , ²⁹ Alpha₁‐adrenergic antagonists may find their greatest use as add‐on therapy to other antihypertensives. These compounds reduce BP significantly when added to multiple antihypertensive medication classes, oftentimes controlling BP in patients resistant to two or more therapies. ³⁰ , ³¹

ALPHA₁‐ADRENERGIC ANTAGONISTS AND TREATMENT GUIDELINES

For many years α₁‐adrenergic antagonists had been considered suitable initial drugs for uncomplicated early‐stage hypertension. More recently, guideline‐generating groups including the European Society of Hypertension/European Society of Cardiology and the authors of the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) no longer include α₁‐adrenergic antagonists as initial agents. ³² , ³³ This removal of α₁‐adrenergic antagonists from initial therapy status related to findings from the Antihypertensive and Lipid‐Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). ³⁴ , ³⁵

ALLHAT was a large, simple trial that studied high‐risk hypertensive patients aged 55 years or older. Its goals were to determine whether the incidence of the primary outcome—a composite of fatal coronary heart disease and nonfatal myocardial infarction—differed between treatment with a diuretic (chlorthalidone, 12.5–25.0 mg/d) and treatment with each of three other types of anti‐hypertensive drugs: a CCB (amlodipine), an ACE inhibitor (lisinopril), and an α‐adrenergic blocker (doxazosin, 2–8 mg/d). In this study, doxazosin titration occurred on a monthly basis. Secondary outcomes included all‐cause mortality, stroke, and all major cardiovascular (CV) disease events. If patients did not meet the BP goal with the maximum tolerated dose of the initial medication, an open‐label step 2 agent (atenolol, 25–100 mg/d; reserpine, 0.05–0.2 mg/d; or clonidine, 0.1–0.3 mg b.i.d.) or an open‐label step 3 agent (hydralazine, 25–100 mg b.i.d.) could be added. ³⁴

In ALLHAT there was no difference in the primary outcome of fatal/nonfatal myocardial infarction or all‐cause mortality when the doxazosin‐based regimen was compared with one utilizing chlorthalidone. The doxazosin treatment arm of this study was terminated early, however, because increased CV end points were seen when compared with chlorthalidone. There was a 19% excess stroke incidence with doxazosin and a highly significant increase (25%) in combined CV disease. There was also a 66% increase in fatal or hospitalized heart failure in the doxazosin group, which was a major contributor to the increase in combined CV disease. ³⁴ , ³⁵ The basis for the increased incidence of doxazosin‐related heart failure in ALLHAT remains uncertain despite a number of explanations having been proffered. Etiologic considerations in this process include plasma volume expansion, sympathetic nervous system activation, inadequate BP control, and suboptimal regression of left ventricular mass. ³⁶ , ³⁷ What remains to be more carefully elucidated is the exact interplay of these variables in the final outcome of ALLHAT.

ALPHA₁‐ADRENERGIC ANTAGONISTS AND PRESCRIPTION TRENDS

As a consequence of the ALLHAT findings, the number of prescriptions for α₁‐adrenergic antagonists has fallen off significantly (Figure). ¹ , ² Between 1999 and 2002, new annual α‐blocker prescription orders declined by 26%, from 5.15 to 3.79 million, dispensed prescriptions dropped by 22% from 17.2 to 13.4 million, and physician‐reported drug use fell by 54%, going from 2.26 to 1.03 million. This downward trend in α₁‐adrenergic antagonist use is further supported by a recent audit of a large computer‐stored prescription information base from the Kaiser Permanente of Southern California health maintenance organization. ²

Figure.

Trends in new α blocker and doxazosin prescriptions received by retail pharmacies. Data are from the National Prescription Audit Plus from IMS Health (Plymouth Meeting, PA) and are based on new prescriptions from January 1996 through December 2002. “ALLHAT Results” indicates the release date of findings from the Antihypertensive and Lipid‐Lowering Treatment to Prevent Heart Attach Trial. Reproduced with permission from JAMA. 2004;291:54–62. ¹

SIDE EFFECTS

In long‐term, well controlled studies, the side‐effect rates with α₁‐adrenergic antagonists compare favorably with those observed with other major drug classes. ³⁸ , ³⁹ For most patients, the side effects of α₁‐adrenergic antagonists are highly dose‐dependent but tend to diminish with continued therapy. The most distressing side effect with α₁‐adrenergic antagonists has been first‐dose hypotension or syncope, which is seen most frequently with shorter‐acting agents, in volume‐depleted states, and with higher doses of these compounds. ³⁹ For example, in the Treatment of Mild Hypertension Study (TOMHS), ²⁰ the reported incidence of syncope was no different than that observed with placebo; however, only a 2‐mg dose of doxazosin was given. Alternatively, giving more than 4 mg of doxazosin significantly increases the likelihood of postural dizziness/vertigo, hypotension, and syncope. Alpha₁‐adrenergic antagonists do not routinely cause impotence. In TOMHS, the incidence of erectile dysfunction with doxazosin was similar to that with placebo. ³⁸ In women, urinary incontinence may be triggered by α₁‐adrenergic antagonists, a side effect that is reversible on withdrawal of the offending drug. ⁴⁰

METABOLIC AND ANCILLARY EFFECTS OF α ₁‐ADRENERGIC ANTAGONISTS

Alpha₁‐adrenergic antagonists are the only class of antihypertensive agents that have consistently been shown to favorably affect plasma lipids ²³ , ⁴¹ , ⁴² , ⁴³ and insulin sensitivity. ²³ , ⁴³ , ⁴⁴ , ⁴⁵ Total cholesterol and low‐density lipoprotein cholesterol are both lowered by approximately 5%, triglycerides by 10%, and in some studies high‐density lipoprotein cholesterol increases with drugs in this class. ⁴¹ , ⁴² , ⁴³ An example of this beneficial metabolic effect can be found in the study by Andersson and Lithell ²³ of 43 hypertensive and hypertriglyceridemic patients treated with either doxazosin or enalapril. Over a 6‐month period, both agents provided similar BP reduction as determined by 24‐hour ambulatory BP monitoring. Doxazosin, more so than enalapril, however, significantly reduced serum lipids, and increased lipoprotein lipase activity and the elimination rate of an IV‐administered fat load, while improving insulin sensitivity. Doxazosin has also been shown to improve fibrinolysis. Its administration is accompanied by a lowering of plasminogen activator inhibitor‐1 activity and higher tissue plasminogen activator activity after venous occlusion. ⁴⁶

Alpha₁‐adrenergic antagonists do not adversely affect renal function ²⁵ and, like a number of other agents, they regress left ventricular hypertrophy, ²⁴ , ⁴⁷ , ⁴⁸ , ⁴⁹ although regression of left ventricular hypertrophy with α₁‐adrenergic antagonists may be less than that seen with hydrochlorothiazide, captopril, or atenolol. ⁵⁰ During isotonic exercise, these drugs will not reduce the exercise‐associated rise in systolic BP as well as β blockers ⁵¹ ; alternatively, α₁‐adrenergic antagonists will suppress the pressor response better during isometric exercise than will a β blocker. ⁵²

Alpha₁‐adrenergic antagonists have emerged as an effective form of therapy for symptomatic BPH. ⁴ , ⁵ , ⁶ Alpha‐adrenergic receptors have been identified in the bladder neck and prostatic capsule, and their stimulation is responsible for the dynamic pressure component of BPH symptoms. In clinical studies, use of α₁‐adrenergic blockers in patients with BPH increases urinary flow rate and reduces residual volume and obstructive symptoms. ⁴ , ⁶ In those BPH patients who are hypertensive, BP will fall in a dose‐dependent fashion with α₁‐adrenergic antagonists; however, single‐drug therapy with an α₁‐adrenergic antagonist—for BP control and BPH symptom relief—may require doses larger than those used for the treatment of patients with BPH alone. The most recent American Urologic Association guidelines on the management of BPH advocate the use of an α₁ blocker to manage a patient's lower urinary tract symptoms; however, such therapy should not be presumed per se to represent a best‐care strategy for management of a patient's hypertension, if also present. ⁵³

FUTURE TRENDS WITH β ₁‐ADRENERGIC ANTAGONISTS

Alpha‐adrenergic blocking drugs have been used with considerable success in the treatment of hypertension over the past two decades. Much of their past success has occurred when they have been used in resistant hypertensives as add‐on therapy to drug classes such as ACE inhibitors or CCBs. The future for this drug class will not change in that regard, particularly since overactivity of the sympathetic nervous system, either on a primary or secondary basis, is commonplace in resistant forms of hypertension.

Another area of use for α₁‐adrenergic blocking drugs will be in the treatment of the male hypertensive with BPH symptoms. These compounds typically improve both symptom score and urinary flow in men with BPH. Uroselective α‐adrenergic‐blocking drugs have been developed to treat individuals with BPH and, for the most part, they do not adversely affect BP. Uroselective α‐adrenergic‐blocking drugs are important treatment tools for the hypertensive patient with BPH, since such patients are best treated by the separate management of each condition—as has been suggested by the American Urologic Association and JNC 7. ⁵³ This highly selective form of BPH therapy typically sidesteps the vasodepressor risk of α₁‐adrenergic‐blocking drugs in normotensive patients.