1

Benign Prostatic Hyperplasia

(BPH)

Benign Prostatic Hyperplasia

 Most common benign tumor in men where benign nodules enlarge the prostate gland
 Common problem among men aged over 50 years and its prevalence increases with age
(90% by age of 80)
 BPH is an irregular benign hyperplasia of smooth muscle cells and stromal cells in
transitional area of prostate gland that compresses the urethra a series of lower
urinary tract symptoms (LUTS)

Lower urinary tract symptoms (LUTS)

 In 25% of men over 60 years, incidence rises with age
 LUTS may include problems with either storage or ability to void urine, or both
 Storage symptoms result from functional changes in detrusor muscles
overactive bladder
 Voiding symptoms - usually due to bladder outflow obstruction

 SYMPTOMS:
 sensation of incomplete bladder emptying, straining to void, urinary hesitancy, and a
weak urinary stream
 Nocturia

 Complications:
 Sexual dysfunction,
 urinary incontinence,
 renal insufficiency,
 UTI,
 acute urinary retention (AUR)
 Symptoms are often measured with a tool developed by the American Urological
Association (AUA), known as the International Prostate Symptoms Score (IPSS).
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BPH symptoms by IPSS

 Sensation of not emptying bladder
 Frequency of urination
 Interruption of urine stream
 Difficulty postponing urination
 Weakness of urine stream
 Need to strain to begin urination
 Frequency of urination overnight (nocturia)
 Symptoms assessed by patients from 0-5 points:
 Total score of 0-7 points = mild symptoms
 8-19 points = moderate symptoms
 20-25 points = severe symptoms

Mechanisms of bladder obstruction

 Static - enlarging prostatic adenoma results in a narrowing of urethral lumen causing

mechanical obstruction
 Dynamic - tone of prostatic smooth muscle and bladder neck mediated by alpha-
adrenergic receptors
 This smooth muscle encapsulates prostate, urethra, and prostate stoma.
 Overstimulation of alpha-adrenergic receptors can increase muscle tone, worsening
symptoms of obstruction → ↓ urinary flow rate and retention of urine
 Compensatory – hypertrophy and irritability of the bladder muscle (detrusor)

Treatment
 Conservative - lifestyle changes
 Men with mild to moderate symptoms may choose watchful waiting and frequent
monitoring
 Medications
 Surgery
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Treatment
 The primary goals of treatment are to ameliorate LUTS, improve QOL, inhibit disease
progression, and reduce complications
 Medical therapy for BPH largely works by reducing dynamic and static components of BPH
 The treatment of BPH involves three different stages:
 1. Watchful waiting - for mild to moderate symptoms
 recommended by AUA for patients in whom QOL has not been influenced by mild
LUTS
 Life-style changes - dietary changes, exercise, education, and regular review

 2. Medications
 for patients with severe LUTS
 Alpha adrenoceptor antagonists
 5-alpha-reductase inhibitors

 3. Surgical treatment

Medications
 1. Selective α1-adrenoceptor antagonists - first line when treating BPH-LUTS in men
with small prostates

 2. 5-alpha-reductase inhibitor - recommended in men with large symptomatic prostates

 3. Phosphodiesterase 5 (PDE-5) inhibitors

 4. Combination of drugs - to provide short term symptom relief with long term disease
management
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α1-adrenoceptor antagonists

α1-adrenoceptor antagonists
 Alpha-blockers used in the treatment of BPH include:
 Terazosin (Hytrin)
 Doxazosin (Cardura, Cardura XL) block α1A & α1B
 Alfuzosin (Uroxatral) receptors

 Tamsulosin (Flomax)
 Silodosin (Rapaflo) block α1A receptors

 All five agents are indicated for the treatment of BPH

 selective competitive blockers of the α1 receptor - end with “-osin”
 selective α1A antagonists: tamsulosin, silodosin
 non-selective antagonists: terazosin, doxazosin, alfuzosin - these drugs can block all α1-
adrenoceptor subtypes equally (1A, 1B, 1D)
 Alfuzosin –
 nonselective α1-blocker
 clinically it is uroselective and has no significant effect on vascular α-adrenoceptors

 The most effective agents used to treat the moderate-to-severe symptoms associated
with bladder outlet obstruction (BOO) secondary to BPH
 These drugs treat the dynamic component of BPH by relaxing smooth muscle in
prostate and bladder neck, this causes urethral lumen to widen and improving urinary
flow
 Decrease the symptoms related to urinary storage including frequency, nocturia,
urgency, and incontinence which have the largest impact on QOL

 Alpha blockers can improve symptoms and increase the maximal urinary flow rate
 Some alpha-blockers are available in short- and long-acting formulations:
 Short-acting drugs work quickly, but their effects only last a few hours.
 Long-acting versions may take longer to work, but their effects last longer
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Mechanism of action
 -adrenoceptors (1A, 1B, and 1D) are highly expressed in smooth muscle cells of
prostate gland, bladder neck, and urethra
 α1A receptors are found in the prostate (70%)
 α1B receptors are found in the prostate and peripheral vasculature - vital to blood
pressure regulation, with very little effect on BPH
 α1D receptors in the vasculature.
 When stimulated by α-adrenergic nerve fibers, they cause strong contractions,
resulting in increased levels of urethral resistance (constriction)

 -adrenergic antagonists bind to α1A and α1B-adrenoceptors on smooth muscle cells of

bladder neck, prostate and urethra smooth muscle relaxation reducing
urethral resistance and relieving LUTS and improve urine flow
 Blocking α1A and α1B receptors in prostate
 inhibit contraction of hypertrophied smooth muscle and internal urethral sphincter
without affecting the detrusor
 Relaxation of these muscles improves urine flow rate and symptoms of BPH
 Most alpha-antagonists must be titrated slowly to the effective doses with exception of
alfuzosin and silodosin, which can be started at their recommended dose

Pharmacokinetics
 Well absorbed following oral administration.
 Food increase absorption of tamsulosin, alfuzosin, silodosin
 For best efficacy, these agents should be taken with meals (typically supper)
 Doxazosin, alfuzosin, tamsulosin, and silodosin are metabolized through CYP450
system in liver
 Terazosin is metabolized in the liver, but not through the CYP450 system
 Half-life of α-blockers is 8 to 22 hours, with peak effects in 1 to 4 hours after
administration.
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Adverse effects

1. Cardiovascular events –
 Postural hypotension, asthenia, and dizziness or fainting especially at initiation of
treatment
 Almost all α1-blockers, particularly terazosin, doxazosin can cause these side effects
 They block α1B receptors relaxation of both arterial and venous smooth muscle
↓ peripheral vascular resistance ↓ arterial blood pressure
 Terazosin and doxazosin - taken at bedtime. The dose can be increased over time if
needed.
 Tamsulosin and silodosin- selectively block α1A receptors on smooth muscle of prostate
minimal effects on blood pressure

2. Ejaculatory dysfunction (EjD)

 α1-blockers cause inhibition of ejaculation and retrograde ejaculation, but do not affect
libido
 By blocking α receptors located in spermatic ducts and seminal vesicles
 insufficient contraction of seminal vesicles,
 insufficient rhythmic contraction of muscles of pelvic floor
 loss of seminal emission, inhibition of ejaculation and retrograde ejaculation (semen
enters bladder)
 In general, silodosin had the strongest effects followed by tamsulosin and
nonselective α1-blockers
 Alfuzosin could improve ejaculatory function

3. Intraoperative floppy iris syndrome (IFIS, eye complication during cataract surgery)
 “floppy iris syndrome,” a condition in which the iris billows in response to
intraoperative eye surgery
 This side effect often occurs in patients taking α-blockers who undergo cataract surgery;
but the risk of IFIS, is relatively low
 The highest level of risk is associated with tamsulosin.
tamsulosin IFIS also occurs in patients
that have discontinued α-blockers
 Blockade of α-adrenoceptors could lead to:
 contraction of iris dilator muscle
 interaction between α-blockers and melanin induces atrophy in the dilator muscle

Other adverse effects

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 fatigue or weakness, dizziness

 water retention → swelling in hands, ankles or feet
 headache and nasal congestion, paranasal sinus congestion, rhinitis, rhinorrhea
 nausea, upset stomach
 allergic reactions

Contraindications
 Terazosin and doxazosin should not be taken with drugs to
treat impotence or pulmonary arterial hypertension - sildenafil, tadalafil, or vardenafil
 Alfuzosin - used in younger LUTS-BPH patients as it has been proven to improve
ejaculatory function
 Silodosin and tamsulosin are contraindicated.
 Drugs to treat high blood pressure
 Should not be used for patients with postural hypotension, asthenia, dizziness, and other
risk factors associated with cardiovascular events
 Patients scheduled to undergo cataract surgery should not be administered α-blockers,
particularly tamsulosin
 Hypersensitivity reactions to drug
 Liver or kidney disease

Drug interactions
 Drugs that inhibit CYP3A4 and CYP2D6 (verapamil, diltiazem) may increase the plasma
concentrations of doxazosin, alfuzosin, tamsulosin, and silodosin.
 Drugs that induce the CYP450 system (carbamazepine, phenytoin) may decrease
plasma concentrations.
 Alfuzosin may prolong the QT interval, so it should be used with caution with other
drugs that cause QT prolongation (class III antiarrhythmics).
 Silodosin is a substrate for P-glycoprotein, drugs that inhibit P-gp, such as cyclosporine,
may increase silodosin concentrations.

Tamsulosin
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(Flomax)

 The most frequently used drug

 Selective blocker for a1A receptor subtype in smooth muscle of the prostate
 Available in slow-release formulation - reduces adverse effects such as postural
hypotension and need for dose titration
 Tamsulosin capsules (0.4 mg) - used in men to treat the symptoms of an enlarged
prostate
 Dosage: 0.4 mg orally once a day; the dose may be increased to 0.8 mg orally once a day
in patients who fail to respond to 0.4 mg once a day within 2 to 4 weeks

Adverse effects
 Allergic reaction to tamsulosin -
 hives, difficult breathing, swelling in face or throat
 severe skin reaction - fever, sore throat, burning eyes, skin pain, red or purple skin
rash with blistering and peeling
 should not be used in patients allergic to drug or sulfa drugs
 Postural hyotension –
 may cause dizziness or fainting, especially when first starting taking it or at dose
changes

Silodosin

 has a high selectivity for the -1A subtype of the receptor

 Silodosin - more effective and less likely to cause side effects such as low blood pressure
or eye problems
 Clinically, silodosin
 improved maximum urinary flow rate
 voiding symptoms
 Silodosin was found to be non-inferior to tamsulosin

Pharmacokinetics
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 Orally, absorbed, with bioavailability of 32%, with peak concentration in about 2 hours. It
is mostly bound to proteins (97%) and distributed throughout the body
 Metabolized in liver to an active glucuronide metabolite, that is less active than
silodosin and has a longer half-life of about 13 hours
 Silodosin is also metabolized by CYP3A4
 Silodosin and its glucuronide are eliminated from the body through kidneys (33%) and
feces (55%)

Clinical uses
 treat moderate to severe symptoms of an enlarged prostate in men to:
 Improve urination, and reduce risk of acute urinary retention
 Improve the QOL and sexual function
 In pts with small prostate and large prostate
 Significant improvements in IPSS
 Improvement of storage and voiding function parameters, in small prostate group
(PV < 40 ml)
 Relieve symptoms, but does not shrink prostate - difficulty in starting flow of urine,
weak stream, and need to urinate frequently or urgently

 Although voiding function declined over time, the benefits in storage function were
maintained for 2 years in large prostate group
 Increase in bladder flow caused by α1-adrenoceptor antagonists direct
improvement in storage function
 The greater structural changes taking place in prostate stroma in BPH
improvement in bladder outlet obstruction index (BOOI)
 α1-blockers worked better in men with a PV ≤ 35 ml compared with those with larger PV

Efficacy of α1-Blockers in the Treatment of BPH

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 work well in men with small prostates and mild to moderate symptoms
 About 50% of men show an improvement in symptoms within first 48 hours to one week
after therapy initiation
 α1-blockers can significantly improve LUTS of BPH
 reduce IPSS by 50%
 increase maximum urinary flow rate (Q-max) by 40%
 Urinary symptoms improve in two or three days in 70% of men, and the benefit can
last several years.

 Several clinical trials have reported that α1-blockers can be efficacious over both short
and long terms, and in some cases, can exert effect in a rapid manner
 These drugs target only α-adrenoceptors and do not induce changes in size of the prostate
 In the absence of contraindications, they are the first-line therapy for all men.men
 In men with larger prostate volumes, combination therapy of an alpha blocker and
5-alpha-reductase inhibitor has been shown to have increased efficacy

 The main difference between various alpha-antagonists appears to be their side

effect profiles
 Second-generation alpha-antagonists (doxazosin, terazosin) can cause many
vasodilatory adverse effects → dizziness, hypotension and other syncopal events and
have increased risk of falling → negatively impact their QOL and increase health
utilization cost.
 Alfuzosin and tamsulosin - improvement in QOL due to amelioration of LUTS
without significant adverse effects (less hypotension)
 These adverse effects are dose related, so lowest effective dose should be used

 Tamsulosin and silodosin, are more likely to cause abnormal ejaculations,

ejaculations with
silodosin causing more retrograde ejaculation than tamsulosin
 Dizziness has been associated with all agents
 All agents should be started at the lowest dose if patient is concurrently taking a PDE-5
inhibitor and vice versa because of possibility of a systemic hypotensive reaction with
concurrent use
 Alfuzosin and silodosin are contraindicated in use with concurrent potent CYP3A4
inhibitors,
inhibitors and silodosin is not recommended for use with potent P-glycoprotein
inhibitors

5-alpha reductase inhibitors (5ARI)

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Dutasteride, Finasteride
(ending with “-teride”)

alpha reductase inhibitors (5ARI)-5

 Inhibition of 5α-reductase blocks enzymatic conversion of testosterone to 5-alpha
dihydrotestosterone (DHT) in prostatic cells, but does not affect circulating
testosterone levels

Dihydrotestosterone (DHT)
 A potent androgen, and normal prostate development and BPH progression occurs under
influence of DHT
 DHT binds androgen receptor with higher affinity leading to formation of a stronger
ligand-receptor complex with a longer half-life (> 3 times) than androgen-receptor
testosterone complex
 DHT has been implicated in BPH, prostate cancer and androgenic alopecia in men
 DHT is considered to be the primary androgen playing a role in the development
and enlargement of prostate gland

 It serves as the hormonal mediator for hyperplasia in prostate gland

 DHT displays a higher affinity towards androgen receptors in the prostate gland
compared to testosterone
 By acting on androgen receptors, DHT modulates genes that are responsible for
cell proliferation and stimulates prostate growth
 ↓ in DHT shrinks the enlarged prostate, improves urine flow and prevents the progression
of disease into BPH

5α-reductase enzymes
 Can be divided into two subtypes, with very different patterns of biodistribution: type I
and type II. The two isoenzymes are found in prostate
 Type I 5α-reductases - widely expressed in skin, sebaceous glands, liver, and prostate
epithelial cells.
 Type II 5α-reductases - mainly expressed in stromal cells of prostate, seminal vesicles,
epididymides, and hair follicles as well as liver
 Type I 5α-reductase and type II 5α-reductase are responsible for production of one-
third and two-thirds of circulating DHT, respectively
Mechanism of Action
 inhibit 5-alpha reductase enzymes that responsible for conversion of testosterone to the more
active DHT in prostatic cells
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 By inhibiting the formation of DHT, 5-alpha-reducatase inhibitors are able to reduce the effects of
androgens on the prostate.
 Androgenic effects include
 proliferation of prostate cells
 decrease in prostate cell apoptosis
 elevation of rate of angiogenesis within prostate
 DHT is an androgen that stimulates prostate growth and ↓ DHT→ the prostate shrinks and urine
flow improves

Medications
 There are two inhibitors of 5α-reductase:
 1. Finasteride (Proscar) - works on the 5-alpha-reductase type II enzyme by inhibiting
about 70% of the conversion of testosterone to DHT within the body
 2. Dutasteride (Avodart) - inhibit both 5-alpha-reductase type I and type II, II
preventing 95% conversion of testosterone to DHT
 Dutasteride is more potent and causes a greater decrease in DHT
 Inhibition of type II 5α-reductase
 blocks peripheral conversion of testosterone to DHT
 significant ↓ in serum and tissue DHT concentrations
 minimal to moderate increase in serum testosterone concentrations
 substantial increases in prostatic testosterone concentrations
 Although finasteride is 100-fold more selective for type II 5α-reductase than for the type I
isoenzyme, chronic treatment with this drug may have some effect on type I 5α-reductase.
 In order for the 5-α reductase inhibitors to be effective, the prostate must be enlarged

Pharmacokinetics
 Both finasteride and dutasteride are well absorbed after oral administration. Food does not affect
absorption of either agent.
 They are highly protein bound (99%)
 Eliminated by hepatic metabolism, by CYP450 system and mainly excreted in feces
 The mean plasma elimination half-life of
 finasteride is 6 to 16 hours
 dutasteride is 4 weeks once steady-state concentrations are achieved (after 6 months of
therapy)
 Compared to the α-blockers,
α-blockers which provide patients with relief from BPH symptoms within 7 to
10 days, these agents may take up to 12 months to relieve symptoms
Clinical uses
 Treatment produced an improved IPSS and peak urinary flow rate in patients who have
prostate volumes >30 ml
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 Individuals with lower prostate volumes have not shown statistically significant
improvement in their symptom scores or peak urinary flow rates
 Prostate specific antigen (PSA) levels are monitored for the detection of prostate cancer -
5-alpha-reductase inhibitors typically decrease a patient’s PSA by about 50%

Adverse effects
 Sexual side effects - decreased volume of ejaculate, reduced libido, erectile dysfunction
(ED), gynecomastia, and oligospermia
 These adverse effects can be irreversible and debilitating
 All adverse effects have been shown to diminish after first year of treatment
 They have teratogenic potential
 Pregnant women should not handle the drug because of possibility of percutaneous
absorption and teratogenicity to a male fetus (inhibit normal development of
external genitalia)
 Although both agents are metabolized by the CYP450 system, drug interactions are rare
 Reduction of the plasma concentration of prostate-specific antigen (PSA) by an average of
50%, when screening for prostate cancer
 Cuations:
 Hepatic impairment
 Men cannot donate blood until at least 6 months after last dose

Finasteride (Propecia and Proscar)

 Finasteride works selectively, where it preferentially displays a 100-fold selectivity for the
human type II 5α-reductase over type I enzyme
 ↓ prostatic volume by about 20-30% after 6-24 months of continued therapy
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 Finasteride may work to reduce bleeding of prostatic origin by inhibiting vascular

endothelial growth factor (VEGF) in prostate, leading to atrophy and programmed cell
death
 Useful in patients with idiopathic prostatic bleeding, or bleeding after
instrumentation

pharmacokinetics
 Well absorbed following oral administration, bioavailability is about 65%
 Peak plasma levels are reached in 1-2 hours and are higher in elderly male patients aged 70
years or older
 Undergoes extensive hepatic metabolism predominantly mediated by CYP3A4 enzyme
 Route of elimination - about 30-45% was excreted in urine as metabolites while about
50-65% of the dose was excreted in feces
 In renal impairment, the extent of urinary excretion is decreased while the fecal excretion
is increased
 The mean elimination half-life was 6 - 8 hours

Clinical uses
1. Benign Prostatic Hyperplasia (BPH)
 Treatment of symptomatic BPH, with an enlarged prostate (>40 ml):
 reduce risk of acute urinary retention
 reduce the risk of the need for surgery including transurethral resection of the
prostate (TURP) and prostatectomy
 Finasteride, 5 mg for 4 years, produced
 reduction in serum DHT concentrations by approximately 70% and intraprostatic
DHT level by 91%
 testosterone circulating level increased by 10-20% within the physiologic range.
 DHT levels return to normal within 14 days upon discontinuation of the drug

 It is poorly effective in patients with prostatic obstruction and small prostate

glands

 Compared to alpha-blockers that provide rapid relief of symptoms, 5α-reductase

inhibitors aim to target the underlying disease by blocking the effects of the primary
androgen involved in benign prostate hyperplasia and androgenic alopecia, thus reducing
the risk for secondary complications while providing symptom control
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2. Androgenetic Alopecia (AGA)

 As finasteride blocks conversion of testosterone to DHT, it is also indicated for treatment
of male pattern hair loss (androgenetic alopecia, hereditary alopecia, or common male
baldness)

3. Idiopathic Hirsutism
 hirsutism related to hyperandrogenism (e.g., in polycystic ovary syndrome) in women due
to its ability to block the conversion of testosterone to dihydrotestosterone

4. Prostate cancer
 used in the prevention and treatment of prostate cancer

Special populations
 Finasteride can be safely used in elderly patients or those with renal impairment with no
specific dosing adjustment recommendations

Dutasteride
Avodart, Jalyn
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 It is a dual 5α-reductase inhibitor that works by blocking both isoforms of 5α-reductase

enzymes in a potent, selective, and irreversible manner
 approved by the FDA in 2001 for the treatment of symptomatic BPH in men as
monotherapy or in combination with the α-adrenergic antagonist tamsulosin
 Its clinical efficacy against BPH is comparable to that of finasteride. However, unlike
finasteride, dutasteride is not yet indicated for the treatment of androgenic alopecia

Pharmacodynamics
 The effect of the reduction of DHT is dose-dependent, with the maximum effect
observed within 1-2 weeks following initial administration
 After 1- 2 weeks of daily dosing with 0.5 mg, mean serum DHT concentrations were
reduced by 85- 90% and maintained reduced after 1 year of oral administration
 It reduces the size of the prostate gland, improves urinary flow, and symptoms of BPH
alone or in combination with tamsulosin
 Dutasteride may also cause decreases in serum PSA in the presence of prostate cancer
 Due to its dual inhibition of both isoenzymes of 5α-reductase, dutasteride causes a near-
complete suppression of DHT.
 Compared to a 70% reduction of serum DHT levels caused by finasteride, a near-complete
suppression of serum DHT-more than 90% is seen with dutasteride

Pharmacokinetics
 Following oral administration of a single dose of 0.5 mg, peak serum concentrations were
reached within 2 to 3 hours and steady-state is achieved after 6 months.
 The bioavailability 60% , not affected by food intake
 It has a large volume of distribution (300 - 500 l) and is about 96-99% bound to plasma
proteins; albumin and α-1 acid glycoprotein

 Extensive hepatic metabolism, by CYP3A4 and CYP3A5 → active metabolites that

inhibit both isoforms of 5α-reductase but with lower potency when compared to the
parent drug
 The activity of 6 β-hydroxydutasteride is comparable to that of dutasteride
 Elimination - dutasteride (1-15%) and its metabolites mainly undergo fecal excretion
 The terminal elimination half-life of dutasteride is approximately 5 weeks at steady state.
This long half-life accounts for the serum concentrations remaining detectable for up to 4
to 6 months after discontinuation of treatment
Clinical uses
 Dutasteride is used alone or with another medication to treat BPH
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 Monotherapy - for treatment of symptomatic BPH in men with an enlarged prostate

 Combination with -adrenergic antagonist – tamsulosin
Dosage
 One capsule (0.5 mg) taken orally once daily
 With -adrenergic antagonist - 1 capsule (0.5 mg) taken once daily and tamsulosin 0.4
mg taken once daily

Adverse effects
 The incidence of erectile dysfunction, ejaculatory dysfunction and decreased
libido resulting in discontinuation from therapy was significantly higher
in dutasteride compared with finasteride group (p < 0.01)
 The incidence of self-reported breast tenderness and/or enlargement was significantly
greater in dutasteride (3.5%) compared with that in finasteride (1.2%) group (p < 0.01)
 Hypersensitivity reactions – swelling of the face, tongue, or throat, difficulty breathing or
swallowing

 Prostate cancer risk - may increase the risk to develop high-grade prostate cancer. Not
approved for the prevention of prostate cancer
 The most common adverse reactions reported in subjects receiving combination
therapy (dutasteride + tamsulosin) were
 impotence, decreased libido, breast disorders (breast enlargement and tenderness),
ejaculation disorders, and dizziness
 Ejaculation disorders occurred significantly more in subjects receiving
combination therapy (11%) compared with those receiving dutastride (2%) or
tamsulosin (4%) as monotherapy.

Contraindications and precautions

 Pregnancy
 Blood donation - contraindicated for those taking dutasteride for at least 6 months after
the last dose of medication, to prevent blood donation to a pregnant female
 In elderly patients, the half-life of dutasteride may increase.
 The use of dutasteride in patients renal insufficiency is reported to be safe

Drug interactions
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 Dutasteride is metabolized by CYP3A4 and chronic use of CYP3A4 inhibitors → ↑ blood

concentrations of dutasteride
 CYP3A4 inhibitors such as ritonavir, ketoconazole, verapamil, diltiazem, cimetidine and
ciprofloxacin may increase plasma levels of dutasteride

Combination therapy
 combination of
 doxazosin and finasteride
 dutasteride and tamsulosin,
 A fixed dose combination of tamsulosin and dutasteride

5-Alpha-reductase inhibitor; alpha-1 blocker

 Dutasteride inhibits 5-alpha reductase, and reducing DHT in prostate gland and
serum DHT level.
 Tamsulosin is an α1 antagonist that targets receptors around the bladder neck and
prostate capsule, which relaxes smooth muscle and improves urinary flow and symptoms
of prostatic hypertrophy
 The combination reduces size of prostate gland and symptoms of BPH

Indications and Dosages

 Benign Prostatic Hyperplasia (BPH)
 Orally, 1 capsule (0.5 mg dutasteride/0.4 mg tamsulosin) once daily.
 Taken 30 min after the same meal each day.
 Oropharyngeal contact with capsule contents may result in irritation of the mucosa

Adverse effects
 Frequent
 Dizziness, somnolence, gynecomastia, sexual dysfunction (decreased libido,
impotence, and decreased volume of ejaculate)
 Occasional
 Headache, anxiety, insomnia, orthostatic hypotension, nasal congestion, pharynitis,
rhinitis, nausea, vertigo
Precautions and Contraindications
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 Hypersensitivity to dutasteride, tamsulosin, other 5α-reductase inhibitors

(finasteride), or any component of the formulation
 Potential syncope risk caused by hypotension, vertigo, dizziness, carcinoma of prostate.
Avoid use with other adrenoreceptor antagonists
 Avoid in patients with previous severe allergic reaction to sulfonamides

Drug Interaction
 CYP3A4 inhibitors (e.g., macrolide antibiotics): increased risk of adverse effects of
dutasteride.
 dutasteride dosage reductions may be warranted in patients concurrently taking CYP3A4
and CYP3A5 inhibitors
 Opioids and anticholinergics may increase urinary retention

:Combination therapy
advantages, disadvantages
 The AUA guidelines - in enlarged prostate, the use of a combination -antagonist and
5-reductase inhibitor is effective and appropriate
 alpha-antagonists were equally efficacious and safe compared with combination
therapy but were better than 5-alpha-reductase inhibitor therapy alone
 In long-term studies in men with enlarged prostates, combination therapy with both
alpha-antagonist and 5-alpha-reductase inhibitor has demonstrated clear benefit
when compared to either agent alone in:

 preventing disease progression and improving symptoms

 reducing risk of urinary retention and BPH-related surgery
 providing a greater improvement in lower urinary tract symptoms compared to
monotherapy

 Combination therapy also has an increased risk of adverse effects such as sexual
dysfunction, and this needs to be balanced against potential benefits for
urinary symptoms

Alpha blocker with anticholinergic

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 Used for select men with bladder outlet obstruction secondary to BPH and concomitant
storage symptoms such as urgency & frequency
 Tolterodine is the only anticholinergic drug to be used in combination with alpha-
antagonists in patients with BPH who have a post-void residual volume of less than
250 to 300 ml because of risk of urinary retention with anticholinergic medications
 The most common adverse effect that has been reported with tolterodine is dry mouth,
with a reported incidence of up to 24%

Comparison of 1-adrenergic antagonists and 5-reductase

inhibitors

Phosphodiesterase-5 inhibitors
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 Epidemiological data link erectile dysfunction (ED) and BPH-associated lower urinary
tract symptoms (LUTS), two highly prevalent conditions in aging men, assuming common
pathophysiological pathways
 Phosphodiesterase-5 inhibitors are more commonly used to treat erectile dysfunction
 They can be effective in treatment of LUTS due to BPH, however they are less effective
than  adrenoceptor blockade therapy
 Tadalafil: the only PDE-5 inhibitor approved for the treatment of BPH

Mechanism of action
 PDE-5 enzyme is present in
 prostate (prostatic stromal smooth muscle cell layers)
 bladder (detrusor and vascular smooth muscles).
 Inhibition of PDE-5 by tadalafil vasodilation and relaxation of prostate and bladder
smooth muscles improvement of BPH symptoms
 The mechanisms by which tadalafil may reduce BPH:
 Upregulation of nitric oxide (NO)/cGMP activity - NO activates guanylyl cyclase
→ forms cyclic guanosine monophosphate (cGMP) from guanosine triphosphate.
cGMP → produces smooth muscle relaxation through a reduction in intracellular
Ca2+ concentration

 modulation of autonomic nervous system over-activity and afferent nerve

activity
 increased prostatic blood perfusion
 attenuates the expression of various inflammatory markers;
markers tumor necrosis
factor [TNF]-α, interleukin [IL]-1β and IL-8, and therefore may reduce
atherosclerotic damage and overall inflammation by reducing leukocyte
recruitment

 Clinical studies reported

 partial reversal of noradrenaline-and endothelin-1-reduced prostatic tissue
contraction
 an antiproliferative effect on prostate and bladder smooth muscle cells
 These mechanisms may decrease smooth muscle tension in the prostatic stroma and
capsule and attenuate cellular proliferation associated with prostate/bladder
hypertrophy
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Pharmacokinetics
 Tadalafil has a slower onset of action than sildenafil and vardenafil, but a significantly
longer half-life of 18 hours - approved for once-daily dosing (as-needed dosing)
 Combination of PDE-5 inhibitors with an  blocker → greater reductions in IPSS,
post-void residual volumes, QOL scores, and greater increases in maximum urinary
flow rate than both drugs used as monotherapy

Clinical uses
 1. BPH
 For prevention and treatment symptoms of BPH and erectile dysfunction such as
urinary urgency, hesitancy, weak stream, dribbling, and incontinence. It significantly
improved total IPSS, with significant improvements in QOL and International Index of
Erectile Function (IIEF)
 2. Erectile dysfunction (ED)
 3. Pulmonary arterial hypertension

Side effects
 Headache is a common adverse effect of phosphodiesterase-5 inhibitors.
 They should be avoided in patients receiving nitrates for ischaemic heart disease or those
with poor cardiac function
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Medication Recommendations

 BPH is mainly featured by histological prostatic hyperplasia and glandular components,

anatomical enlarged prostate (BPE), urodynamic bladder outlet obstruction (BOO), and
low urinary tract symptoms (LUTS)
 pharmacological therapy could sufficiently relieve symptoms for many patients, causing
fewer adverse events
 Studies have shown that about 85% of patients receiving conservative treatment enjoy
stable statuses during a follow-up of 1 year, and about 65% show no clinical progress within
5 years

 α1-Blockers, 5α-reductase inhibitors, and muscarinic receptor antagonists were

recommended by most guidelines.
 Drugs such as phosphodiesterase 5 inhibitor, arginine vasopressin, and beta-3 agonist
medications were also recommended by some guidelines
 Almost all of the guidelines recommended α1-blockers and 5α-reductase inhibitors,
and most of the guidelines recommended muscarinic receptor antagonists. Meanwhile,
eight guidelines recommended the use of phosphodiesterase 5 inhibitor

 Guidelines for combined medication

 had a high degree of uniformity in recommending “α1-blockers and 5α-reductase
inhibitors”
 11 guidelines recommended “α1-blockers and muscarinic receptor antagonists”
 A total of three guidelines from Japan, Germany, and China, respectively,
recommended a combination of “α1-blockers and phosphodiesterase 5
inhibitors”