The Sympathetic Nervous System in Hypertension
The notion that sympathetic fibers are found on the vascular wall and when stimulated cause vasoconstriction was proposed in 1840. The activity of these fibers is one of the components that control peripheral vascular resistance. Hyperactivity of the sympathetic nervous system is well described not only in hypertensive patients, but also in subjects at risk of progressing to hypertension, namely normotensive individuals with a family history of hypertension and those with white-coat hypertension.
The high adrenergic drive in hypertensive patients is attributed to: (1) enhanced spillover rate from neuroeffective junctions and the resulting augmented norepinephrine secretion from sympathetic nerve terminals ; (2) impaired vagal tone and reduced parasympathetic activity ; and (3) increased central adrenergic drive and peripheral sympathetic nerve traffic to the skeletal muscle circulation.
In patients with sustained hypertension, the high sympathetic drive is demonstrated in all subgroups of the hypertensive population: males, females, diabetics, and those with metabolic syndrome, young and old. Furthermore, the degree of the sympathetic drive has a positive correlation with the severity of hypertension and with hypertensive complications, especially left ventricular hypertrophy.
Alpha Adrenergic Receptors
The alpha adrenergic receptors (α-ARs) are activated by the catecholamines epinephrine and norepinephrine. Alpha and beta ARs are divided into subclasses: α 1 -AR–α 1 A-AR, α 1 B-AR, and α 1 D-AR; α 2 -AR–α 2 A-AR, α 2 B-AR, and α 2 C-AR; and β-AR–β 1 -AR, β 2 -AR, and β 3 -AR. Most of the cells in the human body express at least one of the nine AR subclasses. The α-ARs are composed of α 1 -ARs and α 2 -ARs. The α 1 -ARs are postsynaptic. Their activation results in norepinephrine release and vasoconstriction. The α 2 -ARs are located in the presynaptic and postsynaptic areas. When located presynaptically, they inhibit norepinephrine release, whereas when located postsynaptically, they increase norepinephrine release and mediate vasoconstriction and venoconstriction.
Alpha 1 -Adrenergic Receptors: Organ Distribution and Activity
α 1 -ARs are expressed in various organs, including the brain, heart, liver, kidney, prostate, spleen, and blood vessels. Activation of the α 1 -AR mediates modulation of neurotransmission as well as regulation of the cardiovascular system and metabolism.
Systemic Blood Vessels
All α 1 -ARs play a role in the regulation of vascular tone. However, the most major contribution to vascular tone is made by the α 1 A-AR and α 1 D-AR subclasses; α 1 A-ARs are located in distributing arteries (the mesenteric and renal arteries) and α 1 D-ARs are located in large conducting arteries (the aorta, the carotid), as well in the coronary arteries. The expression of the α 1 B-AR subclass is minor in the vascular structure, but is increased in older individuals (>65 years).
Cerebral Circulation
The cerebral arteries are richly innervated with sympathetic nerve fibers. The adrenergic modulation of cerebral blood flow is delicate and complex. The complexity of sympathetic cerebral vascular autoregulation is further demonstrated by studies using an α-AR vasopressor/agonist. An infusion of phenylephrine (a selective α1-adrenergic vasopressor) resulted in an increase in systemic blood pressure and blood flow velocity in the middle cerebral artery, but a decrease in frontal lobe oxygenation. Using norepinephrine resulted in an even more prominent effect on cerebral vascular autoregulation, secondary to increases in systemic blood pressure; there is a decrease in both middle cerebral artery mean flow velocity and cerebral oxygenation. The blockade of α 1 -AR, on the other hand, also disrupts cerebral autoregulation, mainly during hypotension and exercise.
Alpha 1 -Adrenergic Receptors and the Heart
Various in-vitro and animal studies demonstrate the role of α 1 -ARs as being cardioprotective. α 1 -ARs are involved in the inhibition of myocyte apoptosis, the enhancement of protein synthesis, the improvement of glucose metabolism, and cardiac contractility. The heart contains all three subclasses of α 1 -ARs: α 1 A-AR and α 1 B-AR are found mainly in the myocytes, whereas α 1 D-ARs are located in the coronaries. Myocardial α 1 -ARs have an important role in normal postnatal growth of the heart, and possess protective effects during chronic stress, including heart failure. In the heart failure setting, the abundance of α 1 -ARs and their function is intact or increased, in contrast to β-ARs, which decline in abundance and function. These experimental findings might shed light on the observation that in large-scale human clinical trials, the use of α 1 -AR antagonists was associated with an increased incidence of heart failure. Although the blockade of β-AR is beneficial in left ventricular dysfunction, the blockade of α 1 -ARs probably abolishes their compensatory effect in heart failure.
Alpha 1 -Adrenergic Receptor Blockers: Metabolic Effects
α 1 -AR blocker therapy has been associated with significantly favorable effects on serum lipid profile. Decreases in total cholesterol (about 5%), low-density lipoprotein (LDL) cholesterol (about 5%), and triglycerides (about 5%), and increases in high-density lipoprotein (HDL) cholesterol (about 4%) are typical. These changes occur soon after patients begin therapy and are sustained as long as the drug is continued. They are expressed in multiple mechanisms, including: (1) an increase in the number of LDL cholesterol receptors and lipoprotein lipase activity; (2) a decrease in the synthesis of both LDL cholesterol and very-low-density lipoprotein cholesterol; and (3) a reduction in the absorption of dietary cholesterol. In addition, oxidation of LDL-cholesterol can be inhibited by two different hydroxylated metabolites of doxazosin. Similarly, treatment with an α 1 -AR blocker is found to have favorable effects on insulin sensitivity in hypertensive patients.
In the Antihypertensive and Lipid-Lowering [to prevent] Heart Attack Trial (ALLHAT) trial, as found in previous studies, a significant reduction ( p < 0.001) in mean fasting glucose was noted in patients who received doxazosin (from 122 mg/dL initially to 117 mg/dL at 4 years), whereas patients treated with chlorthalidone experienced an increase from 123 mg/dL at baseline to 125 mg/dL at 4 years. A Japanese study from 2009 found a significant beneficial effect on insulin resistance (evaluated by homeostatic model assessment-insulin resistance [HOMA-IR]) when an α 1 -AR blocker was added to patients’ antihypertensive regimen (compared with patients in whom no change was made in their existing treatment). In multivariate analysis, change in HOMA-IR was found to be independently and significantly associated with morning BP (beta = 0.15, p = 0.016) ( Table 23.1 ). The metabolic effects of α 1 -AR blocker therapy may be most relevant in hypertensive patients with diabetes mellitus and/or metabolic syndrome. For this population, treatment with an α 1 -AR blocker is associated with lower serum lipids and improved glycemic control and endothelial function. A recently published study found that the use of α 1 -AR blockers for the treatment of hypertension resulted in a significantly lower incidence of new-onset diabetes mellitus in women with coronary heart disease.
| Drug Name | Dose Administration | HALF-Life | Other Clinical Indications | Special Considerations | |
|---|---|---|---|---|---|
| α 1 -AR blockers | Prazosin | 2-20 mg/day Every 8-12 hours | 3 hours | PTSD nightmares and sleep disruption. BPH, Raynaud phenomenon | |
| Terazosin | 1-5 mg/day Every 24 hours | 12 hours | BPH | Increased risk for hypotension with PDE-5-inhibitors | |
| Doxazosin | 1-16 mg/day Every 24 hours | 20 hours | BPH, ureteral calculi expulsion | Increased risk for hypotension with PDE-5-inhibitors | |
| α 2 -AR agonists | Clonidine | Oral: 0.1-0.2 mg Every 12 hours Patch 0.1-0.3/24 hours Applied every 7 days | 16 hours | Nicotine withdrawal, Tourette syndrome, pain management (epidural infusion), ADHD | |
| Methyldopa | Oral: 250 mg-3gr Every 8-12 hours IV: 250-1000 mg 6-8 hours | 24-48 hours | |||
| Non selective-AR blockers | Phenoxybenzamine | 20-40 mg every 8-12 hours | 24 hours | Preoperative pheochromocytoma | |
| Phentolamine (used only IV) | 5 mg | 20 min | Pheochromocytoma Before and during surgery. |
Alpha 1 -Adrenergic Receptors Blockers and Cancer
Quinazoline, a compound made up of two fused six-member simple aromatic rings, displays hypotensive and anticancer activities. The α 1 -AR blockers prazosin, doxazosin, and terazosin are quinazoline-based drugs.
α 1 -AR blockers were found to have antitumor efficacy through the induction of apoptosis in benign and malignant prostate cells, to reduce tumor growth and suppressed tumor vascularization in a xenograft model of human ovarian cancer, and to suppress the migration of prostate cancer, breast cancer, and glioma cells, as well as to inhibit both benign and malignant prostate cell growth by down regulating the expression of androgen receptors. These data support the use of quinazoline-based α 1 -AR blockers as safe antihypertensive medications in patients with malignancies.
Clinical Indications and Adverse Effects
The α 1 -AR blockers available as antihypertensive medications include: prazosin, terazosin, and doxazosin. Alfuzosin, silodosin, and tamsulosin are uroselective, and thus reserved for benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS) ( Table 23.2 ).
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Hypertension
From the second half of the 20th century and until the beginning of the current century (2000), α 1 -AR blockers were widely used and considered safe and effective antihypertensive medications. Their blood-pressure-lowering effect was supported by numerous clinical trials published from the mid-1970s that demonstrated a dose-dependent lowering of BP much greater in comparison to placebo, and found that their antihypertensive properties were not affected by patients’ age, race, or plasma renin activity. α 1 -AR blockers were used either as monotherapy or in combination with other antihypertensive drugs. The ALLHAT was the first double-blind, randomized, multicenter, federally funded long-term clinical trial to evaluate doxazosin, an α 1 -AR blocker, as an initial antihypertensive therapy to prevent cardiovascular (CV) events. The ALLHAT assessed four different classes of first-line antihypertensive medications (angiotensin-converting enzyme inhibitors [ACE-I], calcium antagonists, α 1 -AR blockers, and thiazide-like diuretics), comparing the incidence of CV events in high-risk hypertensive subjects aged 55 years or older. In 2000, the National Heart, Lung, and Blood Institute ordered the prompt discontinuation of the α 1 -AR blocker doxazosin arm of ALLHAT because not only did doxazosin show inferiority in lowering BP compared with chlorthalidone, but, more importantly, it was associated with a 25% greater incidence of combined cardiovascular disease (CVD) outcomes. A major component of this treatment difference regarding CVD outcomes was a two-fold increase in risk of heart failure (HF) with doxazosin, which remains highly significant, with a 66% increase in risk even after considering only hospitalized or fatal incidents of HF. The differential effect of treatment on HF was consistently observed in each of the prespecified subgroups (age, gender, race/ethnicity, and diabetic status) ( Table 23.2 ).
Significant adverse trends were also observed for other secondary endpoints, including stroke and combined coronary heart disease. Additional analyses confirm the findings of excess HF with doxazosin treatment. Following publication of the ALLHAT, much debate was generated regarding its study design (withdrawal of diuretics, which might have unmasked the symptoms of HF, in participants who were on antihypertensive therapy before randomization) and the validity of HF diagnosis in the study. Nevertheless, this study was the major driving force for the change in hypertension guidelines. Following its publication, clinical recommendations against the use of α 1 -AR blockers as first-line agents for hypertension treatment were released, and the use of α 1 -AR blockers as antihypertensive drugs declined dramatically worldwide.
During the post-ALLHAT era, although α 1 -AR blockers were not positioned in the first line of antihypertensive treatment, a number of studies (The African American Study of Kidney Disease and Hypertension [AASK] and the Reduction of Endpoints in Non-Insulin-Dependent Diabetes with the Angiotensin II Antagonist Losartan [RENAAL] study) demonstrated the benefit of α 1 -AR blockers in lowering BP in uncontrolled hypertensive patients. α 1 -AR blockers were useful as “add-on” antihypertensive drugs.
Observational analysis of data from the multicenter, international, randomized Anglo-Scandinavian Cardiac Outcomes Trail (ASCOT), conducted on individuals with hypertension and an additional CV risk factor (but no history of coronary heart disease), showed that third-line α 1 -AR blocker gastrointestinal therapeutic system (GITS) therapy is both safe and effective in lowering BP, with a mean BP reduction of almost 12/7 mm Hg achieved in all patients. Exposure to doxazosin did not appear to be associated with excess risk of HF or other adverse CV outcomes. Although favorable results with α 1 -AR blocker treatment, including BP control and beneficial metabolic effects, were shown in the ASCOT study and similar studies, they failed to convince medical panels to change the previously determined guidelines. The eight joint national committees of prevention, detection, evaluation, and treatment of high blood pressure (JNC-8) carried on the same strict approach adopted by the JNC-7, according to which α 1 -AR blockers have no place in recommended treatment.
The European guidelines, published in 2013 by the European Society of Hypertension and European Society of Cardiology (ESH/ESC), stated that α 1 -AR blockers are effective antihypertensive agents and can be employed for combination treatment with diuretics, β-blockers, calcium channel blockers, ACE inhibitors, and/or angiotensin receptor blockers, primarily as part of a multiple-drug combination or for the treatment of resistant hypertension. The Canadian Hypertension Education Program Recommendations (CHEP), published in 2015, took the same approach as the ESH/ESC guidelines, recommending the use of α 1 -AR blockers as an optional third-line treatment in multidrug regimens, whereas, in the latest British guidelines, published in 2011 by the National Institute for Health and Clinical Excellence (NICE), α 1 -AR blockers are located lower on the treatment tree, as a fourth-line therapeutic option ( Table 23.3 ).
| Guideline | Year | Summary of Recommendations |
|---|---|---|
| The American Eight Joint National Committee of Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC-8) | 2014 |
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| The European Society of Hypertension and European Society of Cardiology (ESH/ESC) | 2013 |
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| The British National Institute for Health and Clinical Excellence (NICE) | 2011 |
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| The Canadian Hypertension Education Program Recommendations (CHEP) | 2015 |
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According to the aforementioned guidelines, the main use of α 1 -AR blockers is as an “add-on” agent in hypertension treatment regimens. When treating patients with resistant hypertension, clinicians are faced with the question of which add-on treatment, an aldosterone antagonist or an α 1 -AR blocker, is best. In 2012, a retrospective study aimed to answer this question was performed. The investigators assessed the efficacy of a mechanism-based algorithm for the treatment of resistant HTN. The study included 27 patients with resistant HTN, who, based on clinical judgment, using the clues of volume excess and neurogenic hypertension, received one of three therapeutic interventions: (1) strengthening of the diuretic regimen, usually by means of a potassium-sparing agent; (2) combination therapy that included both an α-blocker and a β-blocker; or (3) both of these two interventions. Study findings indicate that BP control in resistant hypertension can be achieved by two very different treatment options, and that the key to success is logical drug selection, achieved by identifying the patients most or least likely to respond to each treatment.
The PATHWAY-2 trial examined the same issue but prospectively. This randomized, double-blind, controlled, crossover study, with 285 participants, compared different active drug treatments: spironolactone, doxazosin, bisoprolol, and a placebo, as “add-on” fourth-line treatments for resistant hypertension. The intention-to-treat analyses demonstrate that spironolactone was significantly more effective in achieving blood pressure control relative to placebo, bisoprolol, and doxazosin (all p < 0.0001). The superiority of spironolactone was seen particularly in patients with lower plasma renin levels ( Table 23.2 ).
These two studies highlight the significance of personalized medicine in hypertensive patients. Usually when a hypertensive patient needs a fourth drug for blood pressure control, clinical judgment is needed to evaluate whether he will enjoy volume reduction (aldosterone blockade will be effective) or whether sympathetic blockade with α 1 -AR blockers will be more useful. Another trial that examined the cardiac safety of α 1 -AR blockers in hypertensive patients demonstrated the importance of the personalized medicine approach. This study included more than 19,000 hypertensive patients, and evaluated the effect of α 1 -AR blockers on cardiac outcome in patients who had previously undergone single-photon emission computed tomography myocardial perfusion imaging (SPECT MPI) testing, which accurately evaluates the reversibility of cardiac perfusion defects (ischemia). Study results showed that α 1 -AR blockers are safe as antihypertensive therapy in patients with a mild degree or any extent of fixed cardiac ischemia. However, in patients with more substantial (moderate to severe) ischemia, treatment with doxazosin for HTN was associated with increased risk of adverse cardiac outcomes (cardiac death and MI) (hazard ratio [HR] 1.5; 95% confidence incidence [CI], 1.14 to 1.98). This study supports results of previous studies that demonstrate the efficacy and safety of α 1 -AR blocker treatment in combination regimens, even in the presence of mild to moderate heart failure.
Recently, the Randomized Trial of Intensive versus Standard Blood-Pressure Control (the “SPRINT” trial) demonstrated that in nondiabetic patients at high risk for cardiovascular events, targeting a systolic blood pressure of less than 120 mm Hg, as compared with less than 140 mm Hg, resulted in lower rates of fatal and nonfatal major cardiovascular events and death from any cause. To achieve the desired blood pressure target, α 1 -AR blockers were included in the medical regimen in both arms of the study: 10.3% of patients in the intensive group and 5.5% of patients in the standard group. There were fewer cardiovascular events in the intensive care group and the incidence of heart failure was 38% lower. This recent landmark trial confirms the safety of α 1 -AR blockers as add-on medications in high-risk cardiovascular patients. According to the above data, α 1 -AR blockers are not in the first line to treat hypertension, but they can be used as add-on medications in hypertensive patients with resistant hypertension who did not achieve their blood pressure target under treatment with ACE-I/angiotensin-receptor blockers, calcium channel blockers, and diuretics. They are mainly effective in patients with evidence of high sympathetic drive.
α 2 -AR agonists: The α 2 -AR agonists are central sympatholytic drugs and are covered in detail in Chapter 26 . These drugs reduce blood pressure by activating the presynaptic α 2 -AR in the rostral ventrolateral medulla, causing a decrease in central and peripheral sympathetic nerve activity, resulting in a reduction in heart rate, myocardial contractility, and peripheral resistance. The α 2 -AR agonists used as antihypertensive medications are clonidine, methyldopa, guanfacine, and guanabenz. Clonidine, an α 2 -AR agonist medication used to treat hypertension, produces its pharmacologic effect in the central nervous system not only by interacting with the α 2 -AR receptors, but also by activating the central imidazoline receptors. Imidazoline receptor-1(I-1) is found upstream from the α 2 -AR. The I-1 receptors suppress sympathetic outflow at postganglionic sympathetic neurons.
Cardiac Safety
During the 1970s Prazosin (a frequently used α 1 -AR blocker) was found to relieve heart failure and pulmonary congestion as a result of reduced preload and afterload. It also reduced left ventricular filling pressure and systemic vascular resistance, improved cardiac index, cardiac efficiency of stroke work, and myocardial oxygen consumption index. However, a decade later, in the Veterans Administration Cooperative Study (V-HEFT I), conducted on 642 heart failure patients, Prazosin failed to improve survival compared with a placebo, whereas a combination treatment of isosorbide dinitrate with hydralazine reduced mortality. Later, in the ALLHAT study, the α 1 -AR blocker doxazosin was excluded primarily because of an increase in heart failure events in this study arm. However, when an α 1 -AR blocker is used as an add-on medication, it can have beneficial cardiac effects. Ikeda et al. showed that the α 1 -AR blocker doxazosin as an “add-on” therapy not only improved BP control, but was also associated with decreases in left ventricular mass index (LVMI) ( p < 0.001), relative wall thickness ( p < 0.001), and insulin resistance (evaluated by the HOMA-IR) ( p < 0.001).
The prospective, randomized, open-label, blinded-evaluation CARDHIAC (CARduran en pacientes Diabéticos con HIpertensi’on Arterial no Controlada) study found that in type II diabetes mellitus patients, a significant reduction in LVMI ( p = 0.001) was associated with doxazosin treatment, but not with atenolol treatment. Reduced LVMI may contribute to a more favorable pattern of ventricular geometry, which may provide further CV benefits in hypertensive individuals. New evidence from recent studies further demonstrates that α 1 -AR blockers might have a favorable cardiac influence. In a multicenter, randomized study published in 2015, urapidil (an α 1 -AR blocker and 5-HT1A receptor agonist) was compared with nitroglycerin (NG) for treatment of heart failure complicated by hypertension and DM in elderly patients. The study results demonstrated the superiority of urapidil in controlling systolic BP compared with NG ( p < 0.05). Moreover, treatment with urapidil was associated with higher ejection fraction (t = 2.206, p < 0.05), cardiac index (t = 2.206, p < 0.05 and t= 3.13, p < 0.05), and left end-diastolic volume (t = −3.014, p < 0.05), but lower N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels (t = 2.206, p < 0.05) in comparison with NG treatment.
Taken together, the results of the landmark ALLHAT trial and the later studies might lead to the conclusion that α 1 -AR blocker are not recommended as the initial drug of choice to treat hypertension. However, at the same time it should be remembered that they have beneficial effects on cardiac outcome, including heart failure, when taken as part of a multidrug antihypertensive regimen. This favorable effect is probably attributed to improved blood pressure control, the leading factor that prevents diastolic dysfunction.
Benign Prostatic Hyperplasia/Lower Urinary Tract Symptoms and Hypertension
The use of α 1 -AR blockers for the treatment of symptomatic BPH and LUTS has been adequately studied and found to be effective for this indication.
Pharmacologically, α 1 -AR blockers bind to the highly concentrated α 1 -AR present in the prostate, bladder and neck, leading to relaxation of the smooth muscle and thereby reducing resistance to urine flow. Because of their frequent use in the elderly population, which also suffers from hypertension, their efficacy and safety profile in hypertensive patients with BPH/LUTS is important.
Findings from a multicenter, prospective, comparative cohort study showed that treatment of BPH/LUTS with the uroselective α 1 -AR blocker alfuzosin alone in combination with antihypertensive therapy is effective and has only a marginal effect on blood pressure in normotensive patients and in patients with controlled hypertension. In patients with untreated or uncontrolled hypertension, a significant decrease in systolic and diastolic BP was documented, with a mean 12-week reduction of −11.3 mm Hg in systolic BP and −5.1 mm Hg in diastolic BP in the untreated hypertension subgroup and mean decreases in systolic and diastolic BP of −9.9 mm Hg and −2.9 mm Hg, respectively, in the uncontrolled hypertension subgroup (both p < 0.001). The author concluded that although it is safe and effective to start treatment with uroselective α 1 -AR blockers in normotensive and controlled hypertensive patients without further evaluation, patients with untreated or uncontrolled hypertension should undergo careful evaluation before the initiation of treatment with uroselective α 1 -AR blockers for BPH/LUTS ( Table 23.2 ).
Pheochromocytoma
Pheochromocytoma treatment is extensively covered in Chapter 15 . Before surgery, adequate blood pressure control is needed to avoid a hypertensive crisis during surgery and improve morbidity and mortality outcomes. Although there is no consensus regarding the preferred drugs for preoperative blood pressure control, initial treatment with α-AR blockers is widely accepted, with a preference for the nonselective α-blocker phenoxybenzamine. Other selective α 1 -AR blockers, such as prazosin, terazosin, and doxazosin, can also be used although high-dose doxazosin is preferred over the shorter acting agents to reduce the risk of breakthrough during catecholamine surges. Despite preoperative alpha blockade, hemodynamic liability can still occur intraoperatively, especially during tumor manipulation. This fact was confirmed in a recently published retrospective study, in which 48 patients with pheochromocytoma were treated with doxazosin in the perioperative setting. Results from this study showed that adrenergic blockage by selective α 1 -AR blockers did not fully prevent intraoperative hypertensive crisis, but was associated with short episodes without major cardiovascular complication.
Adverse Effects
Large placebo-controlled studies showed very slight decreases in hemoglobin, hematocrit, leukocyte count, serum total protein, and albumin levels, which were generally attributed to mild fluid retention and resultant hemodilution. Prolonged treatment (e.g., as in either ALLHAT or ASCOT ) has not led to any long-term concerns about these parameters. Changes in serum potassium levels were minor and inconclusive in several studies. Elevation in plasma creatinine level was apparent, but had no clinical significance.
During trials against placebo, the following symptoms occurred in more than 5% of the α 1 -AR blocker-treated hypertensive population: dizziness, headache, fatigue/malaise, and palpitations ( Table 23.4 ). α 1 -AR blockers should be used in the evening, preferably before bedtime, increasing the likelihood that patients will remain recumbent for several hours, and thus reducing the risk of syncope. This practice should be recommended especially for the first dose, when vascular dilatation and reduced venous return are the most significant. This “first-dose phenomenon” often attenuates with time, but may reappear with rapid increases in dosage or reinitiation of treatment after therapy interruption. Doxazosin GITS appears to have a lower risk of this problem, probably because doxazosin is released slowly from the tablet. This enables the administration of a therapeutic dose at the initiation of therapy, and eliminates the need for multiple dose titrations.
