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Farmakoterapi inkontinensia urin,

enuresis, BPH, disfungsi ereksi

Nerves and Micturition

Alpha Adrenergic Drugs


Phenylpropanolamine

Once a first line drug

8 randomized controlled trials

Study duration: 2-6 weeks

% cure: 0-14

% side effects: 5-33%

WITHDRAWN FROM MARKET due to report of


hemorrhagic stroke

Drug Treatment of Overactive


Bladder
Anticholinergic Drugs are mainstay
Oxybutynin IR 2.5-5 mg bid-qid
Ditropan XL 5-20 mg daily
Oxytrol patch TDS 3.9 mg 2x/wk
Tolterodine tartrate IR 1-2 mg bid
Detrol LA 2-4 mg daily
New Drugs:
Trospium chloride (Sanctura) 20 mg bid
Darifenicin (Enablex) 7.5-15 mg daily
Solefenicin (Vesicare) 5-10 mg daily

Muscarinic Receptors
M1 Brain (cortex, hippocampus), salivary,
glands, sympathetic ganglia
M2 Heart, hindbrain, smooth muscle (80% of
detrusor)
M3 Smooth muscle (20% of detrusor), salivary
glands, brain, eye (lens, iris)
M4 Brain (forebrain, striatum)
M5 Brain (substantia nigra), eye

Oxybutynin
Both anticholinergic and smooth
muscle relaxant properties
6/7 RCTs show benefit
15-58% greater reduction in urge UI
than placebo
Dose: 2.5 -5 mg qid, 20 mg/d
maximum

Oxybutynin Controlled
Release
Once daily dosing
RCT showed rate of daytime
continence similar to that for
immediate release (53 vs 58%)
Lower rate of dry mouth than
immediate release form

Tolterodine tartrate
Pure muscarinic receptor antagonist
Dry mouth most common side effect
3 RCT compared tolterodine (2 mg bid) to
oxybutynin (5 mg tid): Equally effective
and superior to placebo
Decreased urge UI in study of 293 pts:47%
tolterodine, 71% oxybutynin, 19% placebo,
dry mouth 86% oxybutynin, 50%
tolerodine

Trospium
Dose 20 mg bid
Renal metabolism
Nonselective for muscarinic receptors
Effective for detrusor overactivity in
placebo-controlled double-blind studies:
Trospium 20 mg bid vs tolterodine 2 mg bid
in 232 pts reduced voiding frequency and
number of UI episodes
Dry mouth 7% and 9% respectively

Darifenicin
Dose 7.5 to 15 mg daily
Selective M3 receptor antagonist
Several RCTs
Mundy et al 2001 Randomized
double-blind trial compared
darifenacin 15 mg and 30 mg to
oxybutynin 5 mg tid in 25 pts ,
similar efficacy
Side effects: Dry mouth,

Solefenacin
Dose 5 to 10 mg daily
Long acting muscarinic receptor
antagonist, selective for M3
Undergoes hepatic metabolism
involving cytochrom P450
Several multinational trials with
over 800 pts, vs placebo, showed
efficacy low side effects (2% dry
mouth)

Urinary
retention

Gastric
retention

Cardiac
arrhythmias
Contraindications
for
Anticholinergics

Bladder
outlet
obstruction

Narrow
angle
glaucoma

Desmopressin
Decreases urine production
Helps nocturia
Dose: 20-40 mcg intranasal spray
Double-blind crossover trial showed
decreased nighttime voids vs
placebo, 1.9 vs 2.6
Contraindications: CHF, HTN

Enuresis: Definition
DSM IV definition:
Repeated voiding of urine into bed or
clothes, whether involuntary or
intentional (American Psychiatric
Association, 2000).

Enuresis: Treatment
Pharmacological
Imipramine (Trofanil)
Tricyclic antidepressant
Once medication discontinued, bedwetting
resumes
Relapse rate varies from 60% to 90%

Duration of treatment varies without


consensus

Enuresis: Treatment
Pharmacological
Desmopressin Acetate (DDAVP)
Analogue of Vasopressin (ADH)
Supports urine concentration
Decreases urine volume during nighttime

Research findings yield mixed outcomes


Increased number of dry nights
Dryness may not maintain once terminate
DDAVP
Relapse rate varies from 50% to 95%

IPSS
Mild (score 0-7)
Moderate (score 8-19)
Severe (score 20-35)

Treatment Algorithm
I n it ia l P r e s e n t a t io n :
T y p ic a l M a n w it h L U T S s e c o n d a r y t o B P H
N o s u r g ic a l I n d ic a t io n s
M ild S y m p t o m s
S m a ll o r L a r g e P r o s t a te

M o d e ra te -S e v e re S y m p to m s
N o S ig n if ic a n t B o t h e r

M o d e r a te - S e v e re B o t h e r

S m a ll P r o s t a te

L a r g e P r o s t a te

S m a ll P r o s t a te

L a r g e P r o s t a te

W a t c h f u l w a it in g

W a t c h f u l w a it in g o r
c o n s id e r 5 -a lp h a re d u c ta s e th e ra p y

A lp h a b lo c k e r t h e r a p y
o r s u rg ic a l o p t io n

A lp h a b lo c k e r o r
5 a lp h a re d u c t a s e T rx
o r c o m b in a t io n
o r s u rg ic a l o p t io n

W a t c h f u l w a it in g

Medical Treatment
Alpha blockers
5-Reductase inhibitors
Combination Therapy

Medical Treatment
Alpha blockers

Initially used for treatment of


high blood pressure

The human prostate and bladder


base contain alpha-1adrenoreceptors and the prostate
contracts to corresponding
agonists. The contractile
properties of the prostate and
bladder neck are mediated
primarily by the subtype 1a
receptors

Alpha blockade improves both


objective and subjective
symptoms and signs of BPH in
some patients
Alpha blockers can be classified
according to their receptor
selectivity as well as their half-life

Alpha Blockers
Dosage
Alpha-1 short-acting:
Prazosin
BID
Alpha-1, long-acting:
Terazosin
OD
Doxazosin
OD
Alpha-1a selective:
Tamsulosin
OD

Oral

2mg

5 or 10
4 or 8

0.4 or 0.8

Medical Treatment
Alpha blockers

Short Acting: Prazosin

Long-acting: Alfuzosin, Doxazosin mesylate, Tamsulosin, Terazosin

Side Effects: dizziness, postural hypotension, fatigue, retrograde ejaculation,


rhinitis, and headaches. May potentiate other antihypertensive medications

Studies have shown that all of them have comparable effectiveness and the
future research is focused on improving convenience and tolerability

Terazosin and doxazosin may decrease the total cholesterol as well as LDL
fraction. Both may cause first-dose syncope so titration is required

Alfuzosin and tamsulosin -have alpha 1A selectivity and dose titration is not
required

Medical Treatment
Alpha blockers

A study performed at the University of Maryland, Baltimore,


USA, published in Jan. 2007, Title:A review of the clinical
efficacy and safety of 5alpha-reductase inhibitors for the
enlarged prostate

Conclusion: alpha-blockers in men with enlarged prostate


have reported improvements in total symptom scores of
10% to 20% compared with placebo

Do not reduce the risk of long-term complications nor


disease progression

Medical Treatment
5-Reductase inhibitors

Finasteride is a 5-reductase inhibitor that blocks the conversion


of testosterone to dihydrotestosterone. It affects the epithelial
component of the prostate, resulting in a reduction in the size of
the gland and improvement in symptoms
Six months of therapy are required to see the maximum effects on
prostate size (20% reduction) and symptomatic improvement
Several randomized, double-blind, placebo-controlled trials have
compared finasteride with placebo. Efficacy, safety, and durability
are well established
Symptomatic improvement is seen only in men with enlarged
prostates (> 40 mL)
Side effects include decreased libido, decreased ejaculate volume,
and impotence. Serum PSA is reduced by approximately 50% in
patients being treated with finasteride, but individual values may
vary, thus complicating cancer detection

Medical Treatment
5-Reductase inhibitors

Dutasteride: not enough data! In 3 double-blind trials it


reduced acute urinary retention (1.8% versus 4.2%placebo) and need for surgery (2.2% vs 4.1%) but increased
impotence ( 7.3% vs 4.0%), ejaculation disorder, and
gynecomastia and lowered libido

Medical Treatment
5-Reductase inhibitors

Significantly reduced the relative risk for acute urinary


retention(AUR) and enlarged prostate-related surgery,
slowed the disease progression, and showed greater relief
of symptoms compared to placebo
Dutasteride, improved symptom scores greater after 4
years of therapy compared with 2 years (-6.4 vs -4.3 points,
respectively) and flow rates were better (2.6 vs 2.3 mL/sec).
Finasteride showed maintenance of the decreased risk for
AUR and enlarged prostate-related surgery over 4 year
period
Generally well tolerated, with sexual dysfunction the most
frequently reported adverse effect (1%-8%)

Medical Treatment
Combination therapy

Short term
Veterans Affairs Cooperative Study, 1229 men with BPH
randomly assigned to placebo, finasteride, terazosin or both
for one year. Results as follow:
Terazosin lowered the symptom score and increased the
peak urinary flow rate when compared with placebo
Finasteride alone was no better than placebo
The combination of finasteride and terazosin was no better
than terazosin alone

Medical Treatment
Combination therapy

(contd)

Short term
PREDICT trial in which 1095 men were randomly assigned to
doxazosin, finasterid or both for one year. Resluts as follow:
Doxazosin more effective than finasteride or placebo for
urinary symptoms and flow rate
Combination no more effective than doxazosine alone
Conclusion: Combination treatment with an alpha-blocker
and a 5ARI is beneficial for immediate relief of symptoms
( with discontinuation of the alpha-blocker after several
months of therapy)

Medical Treatment
Combination therapy

(contd)

Long term

Medical Therapy of Prostatic Symptoms (MTOPS) trial-3047


men with BPH randomly assign to doxazosin, finasteride,
combination therapy or placebo were evaluated for
symptomatic improvement and overall clinical progression
of the BPH. Follow up 4.5 years. Results as follow:
Risk of overall progression- reduced to a similar degree by
doxazosin and finasteride (39% and 34% when compared to
placebo)
Combination therapy reduced the risk of clinical progression
by 66 %
Symptom scores improved with all therapies, but to a
greater degree with combined therapy

Combination Therapy for BPH ( MTOPS


Study )

Medical Treatment
Combination therapy(contd)

Combination therapy or finasteride alone (but not doxazosin alone),


reduced the risk of acute urinary retention and the need for invasive
therapy
NNT(# needed to treat) to prevent one instance of overall clinical
progression was 8.4 for combination therapy, 13.7 for doxazosin, and
15.0 for finasteride
AE -similar with combination therapy and monotherapy, with the
exception of abnormal ejaculation, peripheral edema, and dyspnea,
which were more common with combination therapy
Conclusion: long-term combination therapy lowered the risk of overall
clinical progression of BPH significantly more than treatment with
either drug alone. In addition, combination therapy or finasteride
alone (but not doxazosin alone), reduced the risk of acute urinary
retention and the need for invasive therapy

BPH Summary
Alpha-adrenergic antagonists provide immediate
therapeutic benefits and are first line treatment for
smaller prostates <40mL and mild symptoms
5-alpha-reductase inhibitors require long-term
treatment for efficacy and are beneficial for larger
prostates >40 mL mild to moderate symptoms
Combined alpha adrenergic antagonist and 5-alphareductase inhibitor therapy appears to be superior to
either agent alone for long-term Trx
The choice of medical treatment may be made on the
basis of cost and side-effect profile of the drug

Anatomy and Physiology of erection

Reproduced from Carson C, Holmes S, Kirby R. Fast Facts- Erectile Dysfunction. Oxford: Health Press Limited; 2002: 8

Anatomy and Physiology of erection


Parasympathetic nerves S2-4 mediate erection
Sympathetic nerves T11-L2 control ejaculation
and detumescence
Smooth muscle relaxation
Nitric oxide diffuses into cavernosal smooth muscle cells,
activates Guanylate cyclase converts guanosine
triphosphate to cGMP resulting in smooth muscle
relaxation. Effect of cGMP stopped by Phosphodiesterase
type 5 which exists primarily in corpora cavernosa.

Drugs for ED
Oral agents
Centrally acting dopamine-receptor
agonist Apomorphine (discontinued in
UK)
Phosphodiesterase type 5 inhibitors

Intra-cavernosal
Prostaglandin E1 Alprostadil

Intra-urethral
Alprostadil

PDE5 inhibitors

Sildenafil (Viagra) 25mg, 50mg, 100mg


1 hour before sexual activity
Absorption delayed by fatty meal
Tadalafil (Cialis) 10mg, 20mg
30 minutes before sexual activity
36 hour window
Absorption not affected by food
Tadalafil (Cialis) 5mg
daily
Vardenafil (Levitra) 5mg, 10mg, 20mg
30-60 minutes before sexual activity
4-6 hour window
Absorption delayed by fatty meal

PDE5 Physiology

Reproduced from Carson C,Holmes S,Kirby R. Fast Facts-Erectile Dysfunction. Oxford: Health Press Limited; 2002 : 40

PDE5 Inhibitors Side Effects

Facial flushing
Headache
Nasal congestion
Dizziness
Dyspepsia
Visual disturbance (blue halo)
Priapism
Non-arteritic anterior ischaemic optic neuropathy

PDE5 Contraindications

Recent cardiovascular event


Nitrates
Hypotension
Anatomical deformity
Angulation, cavernosal fibrosis, Peyronies

Predisposition to prolonged erection


Sickle cell disease
Multiple myeloma
Leukaemia

Intracavernosal Injections
Alprostadil (Caverject, Viridal) 5-40 mcg
Independent of intact nervous system
Manual dexterity, adequate vision, training
Contraindicated: bleeding disorders, sickle cell anaemia,
multiple myeloma, leukaemia
Side effects: penoscrotal pain, haematoma, fibrosis at
injection sites, priapism

Papaverine, Phentolamine, Aviptadil (vasointestinal peptide) been used sole or with


Alprostadil

Intracavernosal Injections

Reproduced from Carson C,Holmes S,Kirby R. Fast Facts-Erectile Dysfunction. Oxford: Health Press Limited; 2002 : 53

Intraurethral
Alprostadil (Muse) 125mg, 250mg,
500mg,1g
Pellet inserted with applicator
Massage penis to aid absorption
Side effects: Penile pain, dizziness,
priapism rare

Intraurethral Alprostadil

Reproduced from Carson C,Holmes S,Kirby R. Fast Facts-Erectile Dysfunction. Oxford: Health Press Limited; 2002 : 55