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supplement to Journal of the association of physicians of india Published on 1st of every month 1st september, 2014 VOL. 62

Role of Alpha Blockers in Hypertension with

Benign Prostatic Hyperplasia
RP Mathur*, Sumanlata Nayak**, R Sivaramakrishnan***, Vikas Jain
Abstract
Hypertension and benign prostatic hyperplasia (BPH) are common disorders of aging men. As the world
population is aging these two diseases are becoming a significant public health problem worldwide.
Approximately 30% of men treated for BPH have coexisting hypertension.
The -Adrenergic Blockers: Prazosin, Terazosin and Doxazosin are established agents in the therapy of
hypertension, and are also effective drugs in the treatment of BPH.
It is reasonable to use -Adrenergic Blockers as the treatment of choice for men with hypertension and BPH.

Introduction

ypertension and benign prostatic hyperplasia are common, age related disorders in
men leading to a substantial burden on health care resources worldwide.
Although hypertension and BPH are two diverse disease entities, still they have some
features in common in the form of aetiological involvement of sympathetic nervous
system. These two diseases occur concomitantly in about 25% of men over 60 years of
age, hence the use of alpha receptor blockers (ABs) to treat both diseases simultaneously
is preferable and convenient for patient compliance, cost and safety. 1

Epidemiology of Hypertension
Nearly one billion adults i.e. more than a quarter of the worlds population
had hypertension in the year 2000 and is predicted to rise to 1.56 billion by 2025.
Hypertension is the fourth contributor to premature death in developed countries and
seventh in developing countries. 2
The direct and indirect costs of hypertension are enormous. In 2008, the total
estimated direct and indirect cost of hypertension was estimated at $69.9 billion. 3
In India, prevalence of hypertension has been reported by various studies ranging
between 2-15% in urban India and 2-8% in rural India. 4,5
Hypertension is an established and modifiable risk factor for cardiovascular disease
and the prevalence of hypertension increases with age. 6 The probability that a middleaged or elderly individual will develop hypertension in his or her lifetime is 90%.
The population of India with persons aged 65 and above has been projected to increase
from 51 million in 2005 to 65 million in 2015 and 76 million in 2020. 7

Epidemiology of BPH

*
Senior Consultant, **Associate
Professor, ***Assistant Professor,
Nephrology, Assistant
professor, Renal transplant and
Urology, Institute of Liver &
Biliary Sciences, New Delhi

BPH is a common and progressive disease of aging men and the prevalence of BPH
increases with age. 8 Around 50% of men above 65 years of age (more than 80% among
men 70-79 years of age) suffer some symptoms of BPH. 9 Over the coming years,
however, an increasing number of patients may report prostatic problems as the worlds
population is aging. With increasing public awareness about prostate gland, more men
are likely to present to their physician. Also, the men in their 50s and 60s no longer
consider themselves old and are not prepared to accept the negative impact of BPH on
their quality of life. 1 By the year 2020 around 200% increase in the number of persons
over 60 years of age is expected. 10
The cost of managing BPH has a considerable impact on healthcare budgets worldwide.

supplement to Journal of the association of physicians of india Published on 1st of every month 1st se ptember, 2014 VOL. 62

admitted for non genitourinary surgery. Relative risk

of hypertension was around 10 in BPH patients with
age 45-64 years and 5 in patients 65 years and above.
They postulated that hypertension was a risk factor
for BPH. 16

Urinary Bladder

-Adrenergic
Receptors
Selective Non Selective
1A
1B / 1D

Prostate Gland

41

Bladder Outlet Obstruction (Dynamic)

Fig. 1 : Distribution of 1-adrenergic receptors in the lower

urinary tract and site of action of 1-adrenergic
receptor blockers. Selective agents target receptors
predominantly localised to the bladder and prostate.
Non selective agents may have more systemic effects

Six of the main industrialised nations spent almost

3 billion USD in 1990 on prostate surgery alone. 11
Indirect costs are difficult to quantify, however, data
from Swedan and UK suggest that it ranges between
4-20% of the total cost of prostatic surgery. 12,13
BPH is a histological diagnosis involving
proliferation of smooth muscle and epithelial cells of
the prostate gland. The enlarged gland causes clinical
manifestations due to static component i.e. direct
bladder outlet obstruction from enlarged prostatic
tissue or due to dynamic component from increased
smooth muscle tone and resistance within the enlarged
gland. The common symptoms due to enlarged
prostate are described as lower urinary tract symptoms
(LUTS) including voiding symptoms (hesitancy, poor
stream, intermittent urinary stream, terminal dribbling
and sense of incomplete evacuation of bladder ) and
storage symptoms (frequency, urgency, nocturia). The
therapy for BPH targets one or both of the disease
components (static or dynamic) for relief of LUTS. 14

Concomitant Hypertension and BPH

Prevalence of hypertension and BPH increases
with age, hence both are common diseases in elderly
males. Around 25% of the men above 60 years of age
have concomitant hypertension and BPH. 1 Although
hypertension and BPH are two different disease
processes, it has been postulated that age related
increase in sympathetic tone may be a common factor
in their pathophysiology. 1,15 The sympathetic nervous
system plays an important role in both hypertension
and BPH via alpha adrenergic fibres and receptors.
In a study by Bourke and Griffin, it was found
that men admitted for elective prostatectomy had
higher blood pressure (BP) than age matched patients

In view of larger number of persons with concomitant

Hypertension and BPH, it would be worthwhile to
monitor BP by Urologists in all cases of BPH and
to assess urinary functions in all elderly males with
hypertension by the physicians. In this context, use of
a single pharmacological agent (ABs) to treat both the
diseases have the potential cost effectivity, compliance
and convenience. 1

Role of Autonomic Nervous System in

maintenance of arterial pressure
The autonomic nervous system maintains
cardiovascular homoeostasis via pressure, volume, and
chemoreceptor signals. Adrenergic reflexes maintain
blood pressure over the short term, and adrenergic
function, along with hormonal and volume-related
factors, modulate the long-term regulation of arterial
pressure through the endogenous catecholamines:
norepinephrine, epinephrine, and dopamine. 17
The kidneys receive extensive sympathetic nerve
supply, which upon activation reduces sodium
excretion by increasing tubular reabsorption or
decreasing the filtered load of sodium via alpha
adrenergic receptor activation. Increased renal
sympathetic nerve activity also activates renin
angiotensin system leading to enhanced tubular
sodium reabsorption. 18 The most convincing evidence
to establish the role of renal nerves in human
hypertension is the recent observation that renal
sympathetic nerve ablation by a radio frequency
emitting catheter leads to significant reduction in
blood pressure in cases of resistant hypertension. 19

Role of Autonomic Nervous System in

Benign Prostatic Hyperplasia
Autonomic nervous system overactivity has a
positive correlation with symptom score and other
BPH measures and may contribute to LUTS in men
with BPH. 20
Prostatic smooth muscle cells contribute to a
significant volume of the prostate gland and their
contractile properties are similar to that seen in other
smooth muscles in the body. Active smooth muscle
tone in the gland is regulated by the adrenergic
nervous system. 21

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Medical Treatment of BPH with Adrenergic Blockers

Rationale

The rationale for -adrenergic blockers in the

treatment of clinical BPH is based on the hypothesis
that BPH is in part caused by bladder outlet obstruction
(BOO) mediated by 1adrenergic receptors associated
with prostatic smooth muscle. 22 The smooth muscle
is one of the major cellular constituent of BPH. The
human prostate contracts in the presence of 1
adrenergic agonist norepinephrine. 23 The observation
of high levels of smooth muscle 1 adrenergic
receptors and norepinephrine in the human prostate
suggests an important role of adrenergic innervations
in prostatic function (Figure 1).
Activation of 1 adrenergic receptors leading
to increase in prostatic smooth muscle tone with
urethral constriction and impaired flow of urine is a
major factor in the pathophysiology of symptomatic
BPH. Also, the 1adrenergic receptors mediate the
symptoms of BPH via their activation within CNS and
urinary bladder.

Classification of - Adrenergic Blockers

The two basic subtypes of -receptors: 1and 2 are
distributed ubiquitously throughout the human body.
2-receptors are typically located presynaptically and
down-regulate norepinephrine release via a negative
feedback mechanism leading to smooth muscle
relaxation on stimulation.
1-receptors are post synaptic receptors that affect
the response to neurotransmitter release. Several
subtypes of 1 -receptors have been identified and
classified into three groups: 1A, 1B and 1D.

The 1A receptors are predominantly expressed

by prostatic stromal smooth muscle cells. The 1B
receptors are mainly located in the smooth muscles
of arteries and veins including the microvasculature
within the prostate gland.

The 1D.receptors are mainly located in the bladder

body and dome, and also in the spinal cord where
they play a role in the sympathetic modulation of
para-sympathetic activity. The 1D receptors mediate
the irritative components of LUTS. 14
The knowledge of 1- receptor subtype location
and function is the key to effective therapy for BPH.
The blockade of 1A adrenoceptor receptors reduces
prostatic tone and improve the dynamic aspects of
LUTS. The blockade of 1B receptors leads to arterial
and venous dilatation due to relaxation of smooth
muscles in the vessel walls. In some patients, this may
lead to giddiness and hypotension due to reduced total
peripheral vascular resistance.
A s t h e s t i m u l a t i o n o f 1D r e c e p t o r s l e a d s t o

detrussor overactivity, the blockade of this receptor

can reduce irritative voiding symptoms. Thus,
combined blockade of 1A and 1D receptors is a good
option in the management of BPH as it combines
the benefit of reduction in prostatic smooth muscle
tone and decreased detrussor instability without the
cardiovascular side effects of 1B receptor blockade.

Clinical Experience with - Adrenergic

Blockade
First Generation Alpha Blockers

Phenoxybenzamine was the first generation of

- blocking agents found to be useful for relief
of BPH symptoms. It is a nonselective 1 and 2
receptor blocker. Its use has been discontinued due
to significant side effects of syncope, orthostatic
hypotension, reflex tachycardia, cardiac arrhythmia
and retrograde ejaculation, mostly due to 2- receptor
blockade. 14
Second Generation Alpha Blockers

Postsynaptic, selective -adrenoreceptor antagonists

lower blood pressure by decreasing peripheral vascular
resistance. They are effective antihypertensive agents
used either as monotherapy or in combination with
other agents.
The second generation - blocking agents: Prazosin,
terazosin, doxazosin and alfuzosin were developed in
an effort to reduce the side effects. These are specific
to 1 receptor and have reduced 2 receptor activity
hence, they improve LUTS symptoms with lesser
vasodilatation related side effects.
Prazosin was the first AB developed as second
generation drug in this series. It exerts its
antihypertensive effect by relaxation of peripheral
arterioles due to post-synaptic receptor blockade. It
does not block presynaptic receptors which modulate
the release of neurotransmitter, thereby avoiding
adverse effects due to reflex activation of sympathetic
nervous system. 24 The antihypertensive properties of
Prazosin make it an obvious choice for the treatment
of hypertension, at the same time it can be used for the
treatment of LUTS associated with BPH, thus it is the
drug of choice for the patients who suffer from both
the problems concomitantly. 25
Doxazosin is 1 receptor blocker with high
bioavailabilty and a long plasma half life resulting
in prolong pharmacologic activity following a single
oral dose. Doxazosin is effective in relieving BOO via
reduction in prostatic tone. 26
Doxazosin and other -adrenergic blockers may
influence smooth muscle growth in the prostate. In
patients with BPH, treated with 1 receptor blocker
there is a decreased expression of myosin heavy chain
messenger RNA, which is a functional marker for the
smooth muscle phenotype. 27

supplement to Journal of the association of physicians of india Published on 1st of every month 1st se ptember, 2014 VOL. 62

Table 1 : 1-Adrenergic Receptor Blockers

Drug
Non Selective
Prazosin
Doxazosin
Terazosin
Alfuzosin
Selective
Tamsulosin
Silodosin

Dose

Receptor Selectivity

2-20 mg
1-8 mg
1-20 mg
10 mg

1A = 1B = 1D
1A = 1B = 1D
1B = 1D > 1A
1A = 1B = 1D

0.4-0.8 mg

1A = 1D > 1B

8 mg

1A > 1D >> 1B

Significant changes in systolic BP were observed in

various clinical trials using doxazosin and lowering of
BP was a desirable outcome in these patients. 28
Terazosin is selective 1 receptor antagonist with
a relatively long plasma half life so that once a day
dosing is possible. Kirby 29has examined the mean
changes in BP in subjects who were normotensive or
hypertensive at baseline. In normotensive patients,
small, clinically insignificant decrease in BP was
recorded. Untreated hypertensive men had larger
and clinically significant decrease in BP. In men with
medically controlled hypertension, terazosin had no
clinically significant effect on BP, on the other hand,
in men with poorly controlled medically treated
hypertension, terazosin significantly lowered BP. The
ability to treat two common coexisting conditions
(BPH and hypertension) is a potentially desirable
feature of this drug.
Alfuzosin is another second generation 1 receptor
antagonist, which has a short plasma half life and
has been found to be a safe and effective agent in the
treatment of BPH. The efficacy of Alfuzosin is similar
to other second generation 1 receptor antagonists
whereas, the cardiovascular side effects and BP
changes are reported to be lower as compared to other
agents of this group, hence it has been labelled as a
uroselective drug. 30
Alfuzosin needs to be given in 2-3 daily doses, while
the extended/ sustained release formulations require
only once a day dosing.
Third Generation Alpha Blockers

The third generation - blocking agents: Tamsulosin

and Silodosin are more specific - blocking agents
acting on prostatic 1 receptors, selectively targeting
the smooth muscle cells in the prostate gland with
lesser side effects related to other receptors.
Tamsulosin is the most widely used - blocking
agents in the management of BPH and exhibits some
degree of specificity for 1A adrenergic receptors. 31
Clinical t rials have suggested that it provides
relatively rapid improvement in symptoms as well as
peak urinary flow rate and the beneficial effects are
sustained over time. 32 A large multicentre trial has
demonstrated that the mean changes in systolic and
diastolic blood pressure in the placebo and tamsulosin
groups were not significantly different for both

43

hypertensive and normotensive subjects. Tamsulosin

does not lower the BP in hypertensive men but can be
safely given with other antihypertensive medications.33
Silodosin is a newer agent with high selectivity
for 1A receptors (which predominate in male bladder
outflow tract) relative to 1B receptors. Clinical studies
suggest that Silodosin has rapid onst of action and
sustained relief of LUTS with a positive cardiovascular
safety profile and no significant BP lowering effect. 34
Naftopidil is a selective 1D adrenergic receptor
antagonist. It has been shown to improve storage
symptoms in the patients with BPH with better
preserved sexual function as compared to selective
1A receptor blockers. 35 Its long term clinical efficacy
remains to be established (Table 1).

Adverse Side Effects of - blocking

Agents
All - blocking agents may be associated with
adverse reactions depending upon dosage and
selectivity. Dizziness is the most common side effect
which is thought to result from the effect on CNS or
other unconventional mechanism unrelated to the
effects on blood vessels as dizziness may even be
associated with highly selective 1 receptor blocker like
Tamsulosin. Hypotension is less common with longer
acting drugs and occurs least with 1A selective agents.
Dizziness and hypotension are more common in
patients over 65 years of age. Ejaculatory dysfunction
is also a side effect of this group of drugs.
Intraoperative floppy iris syndrome (IFIS) occurs
in around 2% cases of cataract surgery leading to
poor preoperative pupil dilatation, iris billowing,
prolapse and progressive intraoperative miosis. The
association of IFIS is well established with Tamsulosin,
but has also been reported less commonly with other
1 receptor blockers like Terazosin, Doxazosin and
Alfuzosin. The 1A is the predominant receptor subtype
in the iris dilator muscle as well. The persistence of
IFIS long after the discontinuation of Tamsulosin
suggests a semipermanent muscular atrophy and loss
of tone of iris muscles. 36

- Adrenergic Blocker Therapy and

Coexisting Hypertension
The - Adrenergic Blockers: Prazosin, Terazosin and
Doxazosin are established agents for the treatment of
hypertension. Approximately 30% of men treated for
BPH also have hypertension and it is convenient to
use - adrenergic blockers as the treatment of choice
for men with hypertension and BPH. 36
The ALLHAT study (anti hypertensive and lipid
lowering treatment to prevent heart attack trial) 37
questioned the use of doxazosin in men at risk of
developing congestive heart failure. This study did not

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assess the relative risks and benefits of doxazosin in

men with BPH and hypertension nor did it have any
bearing on the use of doxazosin in combination with
other antihypertensive drugs. Hence doxazosin and
other - adrenergic blockers remain acceptable agents
to treat BPH with coexisting hypertension. 36

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