PHARMACOTHER

EYOB ALEMAYEHU
(BPHARM, MSC)
Y OF
April 2018
BENIGN PROSTET
HYPERPLASIA
 LEARNING
medication for an individual patient.
BPH
g drug treatment forOBJECTIVES
nd contrast different treatment options in
iate
tify counseling
factors
hanism of
Upon that information
guide
action, treatment
completion of for
selection of a particular
outcomes,
this topic, students will be a
.ts,
Listand desired treatment
theinteractions outcomes for a patient wit
PH
1. the symptoms
Explain the andwhen
signs used
of BPH
pathophysiologic forin individual
mechanisms patients
and recog
t of BPH.
• chestnut-sized organ
encircles the portion
Theofprostate:
the proximal urethra
• heart-shaped
that is located at the
base of the urinary
bladder. INTRODUCTI
• produces secretions,
which are part of the
ejaculate
 at least 40 years of age.

Benign Prostatic Hyperplasia (BPH)

INTRODUCTION
CONT…
wer urinary tract voiding symptoms
•enign overgrowth
Enlargement of chiefly
of the prostateglandular
gland caused
tissueby
ommon
ent with benign neoplasm
impaired emptying in males
of who are
storage of urine in the bladder
 age.
elderly males.

mptoms consistent with BPH

male• BPH EPIDEMIOLOGY

is present
patients who as microscopic
live to the age AN
disease
e prevalence increases with advancing patient
in
les 40
uire a prostatectomy more
years of age orfor have voiding
severe
of BPH
ETIOLOGY
 40 years of age

• Two etiologic factors for BPH include:

• advanced patient age
• the stimulatory effect of androgens
EPIDEMIOLOGY AN
• Prostate size in the adult male:
wth spurt after 40 years of age and
ETIOLOGY
e same size (approximately 15 to 20 g) prior to
vances in age clinically symptomatic
CONT…
 • Androgens:

PATHOPHYSIO
the urethra when stimulated.
Y
lar tissue
a) glandular
growth or epithelial tissue, which produces
ffect• onprostatic
The stromal secretions,
tissue
prostate is composed prostate-specific
includingof two types of
d indirectly
scle orantigen
stromal (PSA),
with
tissue,and
stromal hyperplasia
which can contract around
nverted to estrogen in peripheral
PATHOPHYSIOLO
CONT…
 irritative.

when the bladder is full

orce of the urinary stream
esitation, dribbling
to empty the
struction PATHOPHYSIOLO
ofbladder
the bladder neck or a narrowed
hral lumen result
• Symptoms in obstructive
of BPH
CONT… voiding
are classified as obstruc
ptoms:
failure of the urinary bladder to empty urine
 receptors
• Urinary voiding
urgency symptoms:
• Urinary frequency
urine until the bladder is full

PATHOPHYSIOLO
nergic antagonists may be
• Detrusor muscle instability results in irrit
embedded with α1D-
scle fibers areCONT…
ontrolling
Result from these symptoms
the failure of the urinary bladder to store
 ration is 1:5.

of 5α-reductase in prostate size

reduction inhibitors
symptoms of BPH.
em are of the α1A-subtype
PATHOPHYSIOLO
•is
•Androgen
In antagonism
CONT…
theanprimary locus
enlarged does
gland, the induce a complete
of α1-adrenergic
notepithelial : stromal
plains
energicone the limitations
antagonists
prostate of(98%) of the clinical effect
are effective
 Disease progression
cant portion of patients with mild
s will likely experience disease
ion.
s with moderate to severe symptoms:
PATHOPHYSIOLO
rience a decreased quality of life
CONT…
elop complications of BPH
ors of disease progression include:
ed prostate of at least 30 g or
least 1.5 ng/mL
 General

obstructive voiding symptoms.

late stages of disease the patient may
tative voiding symptoms
• Patients acute
may or mayornot be in acute distress.
n, which is painful due to maximal
Clinical Presentation and
urinary
early bladder.
stages of disease, the patient may complain o
nt may be symptomatic of disease
of BPH
including urosepsis, pyelonephritis,
ow urinary incontinence.
 e.g.:
Symptoms
• dysuria
• urgency
• urinary frequency
• nocturia
ry incontinence • Severity of symptoms
should
standardized
American
voiding
• irritative•Association assessed by the
beinstrument.
Urological
symptoms,
patient symptom
(AUA)using a
score

Clinical Presentation and

• of BPH Cont…
• dribbling
emptying e.g.:
•symptoms,
Obstructive voiding
termittency
• straining
urinary
• tostream
urinary
• decreasedvoidforce
• incomplete bladder hesitancy of
 Signs

larged prostate on digital rectal exam (DRE)

tended urinary bladder
sphincter tone
eck analClinical Presentation
as an indirect and
ssment of peripheral innervation to the
of BPH Cont…
usor muscle of the bladder
 • Urinary incontinence
• Refractory urinary retention
urrent gross hematuria
• Chronic renal failure
Complications of Untreated BPH
• Bladder diverticula
• Upper
• Bladder stonesand lower urinary tract infection
• Urosepsis
Clinical Presentation and
of BPH Cont…
 • Urinalysis:
Laboratory Tests
long-standing BOO.

(normal PSA value is <4ng/mL).

3
tient
tion has
as a a prostate volume
Clinical Presentation and
cause of the patient’s greater
voiding than 30
symptoms mm (30 g).
• PSA is a surrogate marker for an enlarged prostate
ng a PSA greater than 1.5 ng/mL (1.5 mcg/L) suggests that due ta
hematuria,
creatinine
ination which
cancer,ofwhichmay
PSA typically
andbeDRE accompanies
increased
could also
of cause
the as an BPH
a result
enlarged
prostate isof
usedprostate
to screen
of BPH Cont…
 g)
biopsy 50 mL)
g cystometry
Other Diagnostic Tests

if the patient has BOO.

15 mL/s) on uroflowmetry (not specific for BPH)

al cystoscopy reveals an enlarged prostate
Clinical Presentation and
show
leck
ound
asedfor
ofretention
an
the of radiocontrast
enlarged
prostate
postvoid prostate
and
residual (more
prostate
urine than
inneedle
volume (PVR) to
15(more than
Decreased peak and mean urinary flow rate (less
20 than
of BPH Cont…
 to:

intervention.

TREATMEN

imizing adverse treatment effects.

50% (or
improving a minimum
quality of life.decrease of 3 or more points)

Desired Outcomes
complications
When
and compared
mean urinary
and
flow
reducing
with
rate by 1
the
pretreatment
to 3
need
mL/s
for surgical
baseline values, drug treatm
h an α-adrenergic antagonist or 5α-reductase
• Reducing or eliminating obstructive and irritative is expecte
inhibitorvoiding
e the American Urological Association (AUA) Symptom Score by 30% to
sy
to normal (less than 50 mL total)
ilize, or decrease serum BUN and creatinine to the normal range
 to 6 months
• Treatment should focus on:
reducing
• slowing•disease BPH symptom
progression
• decrease complications of BPH
irritative voiding symptoms

m (DRE) is repeated annually.

echful
compared
waitingwith reasonable
is a baseline approach
General Approach to Tr
during each to treatment
visit
atients with mild symptoms that the patient does not
er to be bothersome
ent’s symptoms AUA Scoring Index,
out avoiding
atient factors
to schedule that Symptom
thereturn worsen
visits toobstructive
the clinician every 3
 months)

rved for patients with:

• usually offer drug treatment
5α-reductase inhibitors
General Approachbecause:
state gland, of at least 30 g
vere symptoms.
α-reductase
• Patients inhibitors should be
with moderate to severe sympt
symptoms independent of prostate size
rst, α-adrenergic antagonists are preferred ove
r onset of action (days to a few weeks vs up to 6
 • Surgery:

retrograde ejaculation
urinary tract infection
urinary incontinence
Bleeding
• Prostatectomy is the gold standard
General Approach
• for patients with complications
• is potentially curative
• can result in significant morbidity, including:
erectile dysfunction
 diseases
patient responds.
• refuses surgery or

General Approach
• Drug treatment is used in patients with s
not adisease
ment surgical
must be when
candidate patient:
thebecause
continued of concomitant
as long as the
 bed
oilet mapping
eight lose
during the day time
• Voiding before going to sleep.

bstructive voiding symptoms

Nonpharmacologic T
ding excessive caffeine and alcohol intake
nonprescription fluids several
• Stop drinkingmedications hours
that can before go
armacologic Therapy
 α-adrenergic Antag
vely antagonize α-adrenergic
Monotherapy receptors,
sing relaxation of
• are recommended as first-line treatmen
neck
moderate to severe voiding symptoms of BP
duce
ge of an
ethra dynamic
theenlarged factor causing BPH symptom
prostate
ooth remains to be elucidated
f this muscle
e prostatic apoptosis
 despite treatment.
in relieving symptoms.
• 6 years with tamsulosin
hepatic dysfunction

able responses have been demonstrated for up to:

α-adrenergic Antagonis
nists
rs
n of
west
are hepatically
continuous
adequate
possible use of
clinical
dose in
metabolized.
terazosin
trial
patients considered to be at least 1 t
iswith
atients
eks
ars of
with will develop
continuous
doxazosin disease
treatment progression
a full maintenance dos
• All α-adrenergic
th any of these agents. antagonists at are considered equally
 • First-generation agents:
ed for treatment of BPH
desirable for• BPH management
include (e.g., phenoxybenzamine)

• block presynaptic and postsynaptic α-adrenergic

receptors
α-adrenergic Antagonis
(undesirable, as it results in release
de of postsynaptic α-adrenergic receptors is of
catecholamines
ration α-adrenergic
andantagonists
tachycardia)are not
 effects
concentrations:

subtypes of α-adrenergic receptors

ase formulation of doxazin
• include terazosin, doxazosin, and alfuzosin
se
sionformulation
1A-receptors
risk dueinof
to alfuzosin
the genitourinary
• Second-generation
lower tract
peak serum
α-adrenergic Antagonis α-adrenergic antago
1D- receptors
•have
are in the coronary
dose-related arteries
hypotensive
pharmacologically not and bladder
adverse
selective in blocking the
1B-receptors in the peripheral vasculature
 • Uroselectivity

e effects in humans
• less hypotensive adverse effects
be pharmacological or functional
ar to be• clinically
Third-generation
uroselectiveα-adrenergic antagoni
• include tamsulosin and silodosin
α-adrenergic Antagonis
• selectively
logically block postsynaptic
and functionally α1A-receptors, which
uroselective
predominate
toms in the
without causing prostate
cardiovascular
 muscle
antagonists:

• Pharmacologic uroselectivity
• Include tamsulosin and silodosin
ors in the peripheral vasculature
macologically less hypotension
ntial to produceuroselective α1A-adrenergic
α-adrenergic Antagonis
propensity to antagonize α1B-adrenergic
• refers to preferential inhibition of α1A-receptors, whic
oses,
D-receptors,
predominate effective
producewhichin predominate
the prostatic in
ofthe bladder
relaxationstroma, prostaticdetrusor
urethra, a
minimal
ithbladder vascular
neck, and vasodilation
 related phenomena.
• Functional uroselectivity

alfuzosin (extended-release tablets) is the only one

tamsulosin, silodosin, or alfuzosin
α-adrenergic Antagonis
the mechanism of functional uroselectivity is unclear
ic and functional
selectivity, with uroselectivity
resultant are dose-
may be related to the drug formulation, which produces a
igher in some patients.
ness concentration in target tissues than in non-target
ssues.
 silodosin doxazosin
and tamsulosin.

• Need for up-titration of daily dose:

is required
red
α-adrenergic Antagonis
for immediate-release
for extended-release
patient can experiencealfuzosin terazosin
maximalor and
clinical benefit
ally required
• delays for extended-release
its peak doxazosin
onset of action and the time when t
 to take
doses
Best time At Daily oral 5–20
dose (mg)
Generation Second

bedtime Terazosin

Extended-
however, it is Immediate-
4–8, extended-
release: anytime
typically given at release Second
2–8, immediate-Doxazosin
10
during the day
bedtime. release;

release: anytime meals forAfter

for best oral
during the day; best oral absorption; Second
Alfuzosin

absorption if taken 30
of absorption is minutes
reduced,
nsive thereby
adverse consistently
after a meal, as produced
. further reducing the clinical0.4–0.8; (0.8 mg/day
improvement 8
Third
Tamsulosin
potential for over 0.4dose has not
mg/day)
recommended by the would help
manufacturer, extent decrease
On an empty stomach Ta ke with a meal,

hypotensive which decreases

adverse effects. extent of
Theoretically, this Silodosin
Third
absorption.
 alfuzosin
and doxazosin

Dose-limiting adverse effects:

α1A-adrenergic•antagonists
• include hypotension and syncope

α-adrenergic Antagonis
quent
sare more
withcommon
frequent with with immediate-release
pharmacologically uroselective
extended-release doxazosin terazosin
and
 should be allowed

doxazosin immediate-release:
an α-adrenergic antagonist
first dose
• themg/day to ashould be given
therapeutic at bedtime
dose is essential
α-adrenergic Antagonis
•-day up-titration
interval
a• slow
To between
minimize from a subtherapeutic
each dosage
first-dose increase
syncope dose
from of 1
terazo
ld be maintained on the lowest effective
 in patients:
• prostatectomy
hypotension poorly
a 5-reductase inhibitor or

disease
α-adrenergic Antagonis
• At greatest risk for hypotension or who tolerate
orthostatic hypotension
• Tamsulosin
include
or severe0.4
those with mg
poorlyappears
controlled be the safest
tocoronary
ho cannot tolerate tamsulosin, consider:
 • can lead to additive PB-lowering effects
m with tamsulosin and silodosin
ng phosphodiesterase
α-adrenergic inhibitors, to
Antagonis
Combined
ikelihood of use with antihypertensives,
hypotensive effects: diureti
ted on the lowest effective dose
rehosphodiesterase
taking α–adrenergicinhibitors:
antagonists should be
a fixed dose of the α–adrenergic
atment ejaculation
sexual intercourse
re with tamsulosin
not harmful to the mg daily
0.8patient
Ejaculation disorders:
• occur with all adrenergic antagonists
•cessitate delayed, anterograde
includingdiscontinuation of
α-adrenergic Antagonis and retrograde
ence appears
patient to be dose-related
’s satisfaction and highest
with the quality
 ADRs develop)
• Rhinitis and malaise:
bstructed bladder
voiding symptoms
neck (avoid)
esidual urine volumes

urinary
se with
α-adrenergic
retention in patients
anticholinergic with an
adverse
Antagonis
effects:
• occur due to blockade of α-adrenergic receptors in the
r oral
ely decongestants
require
ended in patients
vasculature may
discontinuation
with
of the exacerbate
of treatment
severe
nasal mucosa
BPHandobstructive
in(Tolerance
the centralto
nervou
system, respectively
 5α-Reductase Inhi
ate taking up therapeutically
to 6 months interchangeable)
Monotherapy
g intrprostatic
larged prostate conversion
by of testosterone
approximately 20% to to
25%.
BPH-related
• Include
stesterone, complications
finasteride
the active andand
dutasteride
androgen that (are consi
tike action, with peak
of α–adrenergic shrinkage of the
antagonists)
uce the static factor, which
s prostate tissue growth results in shrinkage of
 adverse effects:

hepatically
ferred metabolized.
for men with moderate to severe
• Finasteride:
at risk of 5 mg QD; Dutasteride
developing complications of BPH 0.5 mg
5α-Reductase Inhibitor
nt has an enlarged prostate of at least 30
5α-reductase
PSA of greaterInhibitors do not produce cardiovasc
than 1.5 ng/mL)
onses have been demonstrated in
tients treated up to 6 years with
d 4 years with dutasteride
 cancer
suggests that:
• Adverse effects include:
• decreased libido
ctase •inhibitor dysfunction
erectile regimen or
• ejaculation disorders
• gynecomastia and breast tenderness
5α-Reductase
cantly elevated Inhibitor
PSA in treated patients
not compliant with his prescribed 5α-
ther diagnostic workup for prostate
 complications

• will relieve voiding symptoms

Combination Ther

uce •associated
the
endneedA for of developing
riskprostatectomy
combination
with theofarray
an of
BPH-related
67%
byα-adrenergic antagon
ciated with each drug
y be considered in the
in symptomatic patients at high risk
5α-reductase inhibitor:
PH complications, which are defined as those with
nlarged prostate of at least 30 g and a PSA of at least
g/mL
 acetylcholine receptors
adrenergic antagonist; Rationale:
Combination Therapy
• Addition of an anticholinergic agent to a
irritative symptoms (e.g., urinary urgency and
requency) are thought to be due to hyper-reactive
symptoms
ladder detrusor ameliorated
can bemuscle by blockade of
contraction
 Diuretics

Pharmacologic Class
α-Adrenergic
Anticholinergic agents agonists
Androgen

Phenylephrine,Example Drugs
Antihistamines,pseudoephedrine
Thiazides diuretics, loop
antiparkinsonian agents
phenothiazines, tricyclic
Drugs That Can Cause Ir Testosterone
diuretics
antidepressants,
Obstructive Voiding Sy

Produce
Blockpolyuria
bladderStimulate Stimulate prostate
detrusorcontraction of
muscle contraction, enlargement
prostatic and bladder
Mechanism of Effect
thereby impairing
neck smooth
bladdermuscle
emptying
 Relaxes prostatic smooth muscle
uces
Reduces
the frequency
the frequency
of BPH-related
of BPH-related
Reduces size
Efficacy in relieving of enlarged
voiding symptomsprostate
and No Yes
gerycomplications Characteristic
flow rate
improving Useful in patients with enlarged prostates

No
Yes
++
No No

No (works independent of the

α-Adrenergic Antagonists
size of the prostate)

Yes No
+ Yes
Yes Yes
Inhibitors
5α-Reductase
 Decreases PSA
Peak onset of action
Characteristic
rdiovascular adverse effects
ug-induced sexual dysfunction Frequency of
Requirement for up-titration of dose
daily dosing

Yes No

Ejaculation disorders
Days–6Yesweeks,
(for terazosinOnce
dependingand or twice daily,
ondoxazosin No depending
need for dose titration
immediate on the
release); and the dosage
agentα-Adrenergic
no (for Antagonists
formulation
alfuzosin or silodosin; possibly
for doxazosin extended-release
and tamsulosin)

Yes
Decreased
libido, ED, No 6 months Once daily
ejaculation Inhibitors
5α-Reductase
Disorders
 Malaise
jaculation
Adverse
isorders Rhinitis
Reaction
α-Adrenergic antagonist

Summary of Adverse Effects of α

Antagonists and Management Su
Hypotension Start with lowest effective dose, give doses at bedtime,
up-
titrate at 0.5- to 1-week intervals to a full therapeutic dose, if using
common adverse
in, silodosin, extended-release not
effect and it isdoxazosin, or alfuzosin, as
immediate-release terazosin or doxazosin
Management
at common
is athis is a adverse
common adverse tolerance
effect;effect; tolerance
may may Suggestion
o immediate-release products, particularly in patients taking
oes
uallynot require
does discontinuation
not require of treatment
discontinuation of treatment
ertensives
 Ejaculation
ErectileDecreased
libido Adverse
disorders
dysfunction
Reaction
5α-Reductase inhibitor

mastia Educate the patient that this may be bothersome, but not harmf
Summary of Adverse Effects of 5α-Red
t that this may Management
andoccur Suggestions
but it is not harmful. May be
atient is sexually
of active, Management
sexual counseling
the 5α-reductase inhibitor Suggestion
be helpful.
fcontinued
sildenafil or
useanother erectogenic drug maymaybe helpful. MayMay be
ble despite
espite continued
continued use
use of the 5α-reductase
theof5α-reductase inhibitor
inhibitor
 • Ensure that:

OUTCOME
nces adverse
sponse to treatment,
drug effects the dose of α–
EVALUATION
onist can be increased (except for
• Monitor the patient for the drug ’s effectiveness
improves
alfuzosin(by
relieving a minimum
and silodosin)
symptoms bydecrease
using
until:the points)
of 3AUA Symptom Sc
nt subjectively
toms
Index.improve feels
or that symptoms have improved
 inhibitors:
disorders this dose
doxazosin, or
• a dosage reduction or

• dizziness or syncope (α-adrenergic antagonists)

OUTCOME EVALUA
the up-titration
gslower up-titration
of of α-adrenergic antagonist
theimmediate-release terazosin or
require:
me
ectileadverse effects
dysfunction, for 5α-reductase
and ejaculatory
e drug if the Cont…
patient develops adverse effects at
 helpful
drug therapy
indicated
of symptoms
cause of symptoms

• adding a 5α-reductase inhibitor may be helpful

ication
al failure
OUTCOME EVALUA
of progressive
to respond BPHtodisease
5α-reductase inhibitors:
• initial failure to respond to α-adrenergic anta
to
ely
ilures adding
orthat afterananα-adrenergic
the dynamic factor
initial good antagonist
may may
predominate
response tobeas the
en or surgical intervention may be
• it is likely that the static factor may predominate as the c
Cont…
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