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REVIEW ARTICLE |
From Christ Hospital in Jersey City (Dr Fine) and the Division of Urology at the Albert Einstein Medical Center in Philadelphia (Dr Ginsberg).
Address correspondence to Shari R. Fine, DO, University of Medicine and Dentistry of the New Jersey School of Osteopathic Medicine, Department of Family Medicine, 324 Palisade Avenue, Jersey City, NJ 07307.E-mail: sfine324{at}verizon.net
Benign prostatic hyperplasia (BPH) is highly prevalent in men older than 50
years and is associated with a range of lower urinary tract symptoms that may
have a negative impact on patient quality of life.
Alpha1-adrenergic receptor antagonists are the first-line of
pharmacologic management for lower urinary tract symptoms associated with BPH.
However, many patients take multiple medications that may exacerbate
age-related orthostatic hypotension. Thus, clinicians should evaluate the
treatment of these patients within the context of comorbidities. The present
article discusses the role of non–subtype-selective and
subtype-selective
1-adrenergic receptor antagonists in the
clinical management of BPH. Safety and tolerability for both
non–subtype-selective and subtype-selective
1-adrenergic receptor antagonists for patients with BPH are
also reviewed.
Although the etiology of BPH has not been clearly defined, the disorder
most likely involves age-related proliferation of stromal and glandular cells
in the periurethral and transition zones of the prostate gland as well as
long-term exposure of prostatic tissue to
androgens.5 The
microscopic proliferative process that occurs in prostatic tissue may
eventually result in an enlarged prostate, which may constrict the urethra and
lead to bladder outlet obstruction. In addition, this process increases the
smooth muscle tone of the prostate, which is also associated with urethral
constriction and is mediated by
1-adrenergic
receptors.2
For patients with BPH, the main medical options for relieving LUTS are (1)
1-adrenergic receptor antagonists (eg, alfuzosin, doxazosin,
tamsulosin, terazosin) to reduce smooth muscle tone in the prostate and the
bladder neck or (2) antiandrogen therapy with 5
-reductase inhibitors
(finasteride and dutasteride) to reduce prostate
size.2
Because men in this age group are likely to have comorbidities (Figure 1),1,6-8 clinicians should consider BPH within the context of coexisting medical conditions that may complicate clinical management. In fact, according to Harris et al,8 20.2% of men aged 60 to 74 years have diabetes, which is nearly twice the diabetes prevalence rate among men aged 50 to 59 years (12.9%). Similarly, the prevalence of cardiovascular disease (CVD) among men between the ages of 65 and 74 (65.2%) is almost twice that of men between the ages of 45 and 54 (34.2%).7
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| Benign Prostatic Hyperplasia in Context: The Aging Circulatory System |
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Several age-related changes may predispose elderly patients to orthostatic hypotension and consequent risk of falls and related injuries. These changes include decreased cardiac output, vagal response, and maximum heart rate. In addition, vascular stiffening results in reduced vascular compliance and increased systolic pressure, while increased aortic impedance leads to decreased diastolic pressure. Diminished baroreflex activity results in abnormal regulation of blood pressure, which may also contribute to orthostatic hypotension. Hypertension and coronary artery disease may also contribute to orthostatic hypotension and are more likely to be present in older patients.13-17
The risk of hypotension and dizziness in elderly patients increases with
the development of certain disease states and ameliorative
pharmacotherapies.18
For example, diuretics, commonly used to manage hypertension, are associated
with hypovolemia and orthostatic
hypotension.19
Concomitant use of antihypertensives and sedatives, antipsychotics,
hypoglycemics, or
1-adrenergic receptor antagonists in
elderly patients may further decrease blood pressure and increase the risk of
falls.20 Therefore,
physicians are encouraged to consider each patient's potential for
treatment-related adverse events, such as dizziness or hypotension.
| Pharmacologic Treatment of Benign Prostatic Hyperplasia |
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1-adrenergic receptor subtypes.
The
1A subtype generally regulates smooth muscle tone in the
prostate and bladder neck, whereas the
1B subtype regulates
BP via vascular smooth muscle contraction. The
1D subtype is
believed to be associated with bladder muscle contraction and sacral spinal
cord innervation. It has been hypothesized that age-related changes in the
distribution of vascular
1-adrenergic receptors may occur,
with the greatest increase observed for the
1B-receptor
subtype.21,22
Terazosin, doxazosin, and alfuzosin are
1-adrenergic
receptor antagonists that show equal affinity for all
1-receptor subtypes. Tamsulosin is selective for the
1A- and
1D-adrenergic receptors, while it
shows less affinity for the
1B
subtype.20,23
The efficacy of these agents is comparable. However, some
1-adrenergic receptor antagonists (ie, terazosin, doxazosin)
need to be titrated, and their full therapeutic doses are only achieved 2 to 4
weeks
postinitiation.24,25
Unlike other
1-adrenergic receptor antagonists, alfuzosin
and tamsulosin do not require
titration.26,27
An 8-week, randomized, open-label comparative
study28 (N=1993) of
tamsulosin (0.4 mg per day) and terazosin (titrated to 5 mg per day)
demonstrated that subjects treated with tamsulosin had a statistically
significant (P<.001) reduction of symptoms after 4 days of
treatment when compared with subjects treated with terazosin. On day 4,
terazosin had not yet reached maintenance dosing, as it was administered at 1
mg per day for the first 8 days of the
trial.28
Non–Subtype-Selective
1-Adrenergic Receptor Antagonists
Treatment-related adverse events are more likely to occur with some
-adrenergic receptor antagonists than others, especially in elderly
patients.30
Terazosin, doxazosin, and alfuzosin are long-acting,
non–subtype-selective
1-adrenergic receptor
antagonists. Originally marketed as antihypertensives, these medications may
cause increased risk of hypotension or dizziness when administered at
therapeutic
levels.4,25,29,30
In a safety analysis of six placebo-controlled trials, researchers found
that terazosin-treated patients with BPH had a statistically significant
(P<.05) increase in the incidence of dizziness and orthostatic
hypotension than did patients treated with placebo. Adverse events were more
common in terazosin-treated patients older than 65
years.31 In another
study, terazosin was associated with statistically significant (P<.001)
decreases in systolic and diastolic BP in both normotensive and untreated
hypertensive
patients.32 Similar
observations have been reported for studies of
doxazosin.33
Alfuzosin (2.5 mg twice daily) has also been associated with vasodilatory
adverse events, particularly for patients who are older than 75 years, have
concomitant CVD, or receive treatment with antihypertensives or vasodilatory
agents.34 A
oncedaily formulation of alfuzosin (10 mg per day) was released in the United
States in 2003. A clinical
study35 comparing
the 2.5 mg thrice-daily formulation and the 10 mg once-daily formulation to
placebo demonstrated that vasodilatory adverse events were more common for
patients taking either of the alfuzosin formulations than those in the placebo
arm. However, the incidence of vasodilatory adverse events was lower for
patients receiving 10 mg of alfuzosin once per day than those receiving 2.5 mg
of alfuzosin three times per day. Thus, while non–subtype-selective
1-adrenergic receptor antagonists are effective in the
management of BPH, their use may be associated with dizziness and hypotension,
which is likely related to their vasodilatory
properties.26,36,37
Subtype-Selective
1-Adrenergic Receptor Antagonists
Tamsulosin, which selectively antagonizes
1A- and
1D-adrenergic receptors while demonstrating little affinity
for the
1B subtype, was developed specifically for the
treatment of LUTS associated with
BPH.23 Studies
comparing tamsulosin with terazosin and doxazosin indicate that tamsulosin has
greater affinity for prostatic rather than vascular
1-adrenergic
receptors.20,38
Tamsulosin may, therefore, be expected to produce few BP-related adverse
effects.19 In
addition, clinical trials investigating the efficacy and safety of tamsulosin
(0.4 mg per day) in the treatment of patients with BPH have reported symptom
reduction, including significant improvements in urine flow, without
clinically significant effects on BP or heart rate. A comparison of clinical
trial results for available BPH drugs indicates that tamsulosin may not
increase the incidence of orthostatic hypotension. In one
study,39 patients
received either tamsulosin (0.4 mg per day) or placebo once daily. The
incidence of treatment-emergent orthostatic hypotension and syncope was
greater in the placebo group than in the tamsulosin group. These observations
were independent of patient positioning (supine vs standing).
Similarly, Chapple et al40 compared tamsulosin's safety and tolerability in patients younger than 65 years and those aged 65 years or older when treated with 0.4 mg of tamsulosin per day vs placebo. For the tamsulosin-treated group, the incidence of adverse events possibly associated with vasodilation was 8.4% for the younger group and 4.2% for the older cohort. A similar incidence rate was noted in the placebo-treated groups—7.5% for those younger than 65 years and 6% for older patients.40 There were no statistically significant differences between placebo- and drug-treated groups for either age category, and changes in BP or pulse rate were minimal for both study groups.40
In an open-label extension study of the above trials evaluating the safety of tamsulosin for up to 3 years, 2.5% of patients cumulatively had treatment-emergent orthostatic hypotension, while 2.0% of patients had drug-related orthostatic hypotension.41 In another open-label study that was extended up to 6 years, 1.3% of tamsulosin-treated subjects had orthostatic hypotension.42
To confirm the hypothesis that receptor selectivity allows fewer vasodilatory adverse events, a direct comparative study of terazosin (titrated to 5 mg once daily) and tamsulosin (0.4 mg once daily) was conducted on ambulatory BP using nocturnal orthostatic stress testing in 50 elderly normotensive patients with LUTS. Symptomatic hypotensive orthostatic stress occurred more frequently in the terazosin-treated group than in those who received tamsulosin.37
Data from tamsulosin trials demonstrate that coadministration of tamsulosin
with nifedipine, enalapril, or atenolol—cardiovascular drugs frequently
prescribed for hypertension or heart failure—produced no clinically
significant differences in BP and pulse rate and did not increase adverse
effects.27,43
Therefore, for patients with cardiovascular comorbidities, the use of
tamsulosin for the clinical management of BPH may be a safer choice than the
non–subtype-selective
1-adrenergic receptor
antagonists.
Adverse events observed in studies of tamsulosin efficacy and safety include dizziness, which occurred in 10% of patients enrolled in six US and European trials, as well as cephaligia and rhinitis.27
Concomitant Medications and Conditions
Medical comorbidities are common among older patients. Approximately 25% to
30% of all men older than 60 years have concomitant hypertension and
BPH.1 It is possible
that elderly patients with CVD may have unfavorable reactions to medications
used in the management of BPH. For example, commonly prescribed medications
for patients diagnosed with CVD (eg, diltiazem) may increase plasma levels of
a given
1-adrenergic receptor antagonist by inhibiting
cytochrome enzymes, resulting in an increased risk of
hypotension.26 In
addition, medications used to manage BPH may cause adverse effects in comorbid
patients. For example, blood levels of certain
1-adrenergic
receptor antagonists may increase with moderate hepatic insufficiency or renal
insufficiency.26
Thus, it is important to consider the potential for interactions when
prescribing a pharmacologic agent for the management of BPH in a patient who
either has a comorbid condition, is taking concomitant medications, or
both.
Erectile dysfunction (ED) is increasingly prevalent with advancing age and
is often associated with a perception of reduced quality of
life.44
Epidemiologic studies indicate that older men with ED are likely to have
concomitant diabetes and CVD, including
hypertension.45
Vascular disease is thought to be the most common organic etiology of
ED.45 Pharmacologic
therapies for ED (eg, sildenafil, vardenafil, and tadalafil) are selective
inhibitors of cyclic guanosine monophosphate-specific phosphodiesterase type
5.46-48
Currently, there are precautions in the prescribing information for
phosphodiesterase type 5 inhibitors about concomitant use with
1-adrenergic receptor
antagonists.46-48
In a clinical pharmacology
study,48 the
simultaneous administration of tadalafil 20 mg and tamsulosin 0.4 mg produced
no statistically significant decrease in BP.
In some patients treated with
1-adrenergic receptor
antagonists, a surgical condition known as intraoperative floppy iris syndrome
has been observed during phacoemulsification cataract
surgery.49 This
syndrome is characterized by a flaccid iris that billows in response to
ordinary irrigation currents, progressive pupil constriction despite
preoperative dilation with standard dilatory drugs, and potential prolapse of
the iris toward the phacoemulsification
incisions.49 The
cause of this syndrome is
unknown,49 and,
until it is better understood, surgeons should ask patients undergoing
cataract surgery if they have taken
1-adrenergic receptor
antagonists.50 If
necessary, the surgeon should be prepared to modify his or her surgical
technique. The benefit of stopping
1-adrenergic receptor
antagonist therapy before cataract surgery has not been
established.50
| Conclusion |
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1-adrenergic receptor antagonists used in the management of
BPH may block
1-adrenergic receptors in the vasculature,
which may in turn precipitate hypotension, dizziness, syncope, falls, and
subsequent morbidity and
mortality.51 As
many elderly patients with BPH may take multiple medications that, in
combination, may also exacerbate age-related hypotension, appropriate drug
selection is particularly important. | Footnotes |
|---|
Submitted August 20, 2007; accepted November 19, 2007.
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