Medications

for
Urinary Incontinence
(UI)
Introduction
The International Continence Society (ICS) defined
urinary incontinence (UI) as the complaint of any
involuntary leakage of urine. This can range from an
occasional leakage of urine, to a complete inability to hold
any urine
 The involuntary loss of urine - social or hygienic problem
Brain signals are key to coordinating the urinary function:
1. Autonomic nervous system control
Nerves coming from spinal cord and go directly to
bladder
When bladder is full, signals are sent to the brain
2. CNS - Voluntary control to choose when to void
BOTH ARE ALTERED BY AGING OR NEUROLOGICAL
DISEASE
Prevalence of UI:
200 million of adults worldwide suffer from UI
Prevalence increases with age
80% of urinary incontinence can be cured or
improved
85% of UI patients are women
UI Is More Prevalent Than Other Chronic
Diseases in Women:
Incontinence 30%
Hypertension 25%
Depression 20%
Diabetes 16%
”Causes of UI “DIAPPERS
D – Delirium/dementia
I – Infection – e.g., UTI, bladder infection
A – Aging, Atrophic vaginitis/urethritis or atonic bladder
P – Pharmacological agent – e.g., diuretics,
P – Psychological disorders – (e.g., depression), polyuria
E – Endocrine disorders or excessive urine output – e.g.,
excess fluid intake, volume overload, hyperglycemia,
diabetes insipidis
R – Restricted/reduced mobility – i.e., functional
incontinence or reversible urinary retention
(anticholinergic drugs)
S – Stool impaction
Risk factors
Pregnancy – childbirth, vaginal delivery, episiotomy
Menopause
Genitourinary surgery, bladder cancer, BPH, stone
High impact exercise, chronic cough
Stroke, diabetes, MS, parkinsonism, Alzheimer
Age related change in urinary tract – Pelvic muscle
weakness
Physical damage to the pelvic floor muscle (typically
after trauma)
Obesity, smoking
Drinking alcohol or caffeinated beverages
UI Impacts Quality of Life
Depression, anxiety, avoidance
Social isolation, decreased life-space
Financially burdensome, unable to work outside home
and loss of money spent on protective garments
Falls, hip Fractures
Nursing home admission, and loss of independence
37% of working women reported urine leakage during
the previous 30 days
88% of women with severe urine leakage reported UI
negatively impacted their abilities at work ; e.g.
concentration, self-confidence, ability to complete
work without interruption
 Types of incontinence

Stress urinary
incontinence (SUI)

Urgency urinary
incontinence (UUI)

Mixed urinary
incontinence (MUI)
Stress incontinence (SUI)
Complaint of involuntary leakage of urine on effort or
physical exertion, e.g., sporting activities, sneezing or
coughing
It is a storage bladder problem
Occurs in absence of bladder contraction and is due to
inadequate urethral sphincter function:
Loss of anatomical support: weakened pelvic muscles
that support bladder and urethra with
Urethral hypermobility and intrinsic urethral
sphincter deficiency (ISD)
 The sphincter is not able to prevent urine flow when there
is increased abdominal pressure during certain
activities
This result in small amounts of urine to leak
when stress is placed on the bladder. It can be a
few drops of urine to a tablespoon or more
SUI can be mild, moderate or severe
Most common type of incontinence in older
women, affecting more than half of all women
aged 60 years or more
SUI is less common in men, where it is often a
complication following prostate surgery, such as
radical prostatectomy or transurethral resection of
the prostate (TURP)
MANAGEMENT OF SUI
Weight reduction
Pelvic floor exercises
Physiotherapy
Electrical stimulation
Pharmacotherapy – duloxetine,
imipramine
Surgery
Devices
Urge incontinence (UUI)/Overactive
bladder syndrome (OAB)
Inability to hold flow of urine, when feeling the urge to void
A complaint of involuntary loss of urine accompanied
by or immediately preceded by urgency, frequency and
nocturia, in the absence of other pathology such as UTI
Involuntary loss of urine resulting from an increase in
bladder pressure secondary to bladder contraction
It may be caused by:
Detrusor overactivity – idiopathic
Detrusor hyper-reflexia – disturbance of neural
mechanisms; overactive dyschronous nerves in
bladder wall triggering involuntary muscle contractions
with resultant frequency and leakage
OAB is a chronic condition, affecting especially the
elderly population
The leakage can be large in amounts with the inability
to stop it once it starts

Multiple pathophysiologic mechanisms

proposed:
primary detrusor dysfunction (detrusor overactivity)
overactivity of the afferent arm of micturition reflex
a urothelial dysfunction
primary dysfunction of higher CNS inhibitory
centers
 Treatment of the OAB
Behavioural therapy and life-style changes
Drug therapy
Muscarinic receptor antagonists/antimuscarinics
 beta-3-agonists are as an effective and safe alternative
to antimuscarinic drugs
Botulinum toxin A detrusor injections for patient
refractory or intolerant to oral drugs
Intravesical medication
Transdermal medication (oxybutynin)
Surgical management
Sacral neuromodulation, Bladder augmentation
Mixed Incontinence (SUI and
OAB)
MUI is the complaint of involuntary leakage
associated with urgency and also with exertion,
effort, sneezing, or coughing.
Contains components of both stress and urge
incontinence
Non-pharmacological therapy
Lifestyle advice (weight loss and dietary changes)
Avoidance of urethral compression during voiding
1. Lifestyle changes
Moderating fluid intake during the day
Urinating on a scheduled basis
Avoiding jumping or running
Avoiding alcohol and caffeine
Losing weight if overweight
Avoiding food (spicy foods) and drinks (caffeine,
carbonated drinks) that could irritate the bladder
2. Pelvic floor exercises, to strengthen pelvic
floor muscles by squeezing them
“Kegel exercises,” that strengthen the urinary
sphincter and pelvic floor muscles.
These exercises can both improve stress
incontinence, and prevent the condition from
worsening.
They can also help suppress the urge to urinate
for urge incontinence
Bladder retraining, that involves gradually
increasing the interval time between trips to the
bathroom
3. Medical Devices and absorbent products
Penile clamp, vaginal Pessary, urinary catheter
Radiofrequency therapy, Electrical stimulation
Urethral bulking agents

4. Surgery
If the above treatments don't provide enough
relief, surgery may help
Pharmacological Therapy
1. Anticholineric - calm overactive bladders and may
help patients with urge incontinence
Oxybutynin, Tolterodine, Solifenacin, Fesoterodine,
Darifenacin, Trospium
2. Antidepressant
 Imipramine, Tipramine, Duloxetine

3. Topical estrogen - may reinforce tissue in the

urethra and vaginal areas and lessen some of the
symptoms
4. Beta-3 agonists - Mirabegron
5. 5-alpha reductase inhibitors
6. Phosphodiesterase-5 inhibitors
 Antimuscarinics
(anticholinergics) drugs
The most common types of antimuscarinic drugs
used to treat urge incontinence include:
Oxybutynin (Ditropan XL, Oxytrol, Gelnique)
Tolterodine (Detrol, Detrol LA)
New drugs
Trospium - (Sanctura) - nonselective
Darifenacin - (Enablex)
Solifenicin (Vesicare, Vesicare LS)
Ach actions on Urinary
bladder
Acetylcholine (Ach) released from cholinergic
nerves stimulates muscarinic receptors and
mediates the main part of voiding contractions in
humans
Contracts the detrusor muscle (M3 receptor)
Relaxes the trigonal sphinter (causes urination)
Five subtypes of muscarinic receptors (M1-M5)
identified
Muscarinic Receptors
M1 – Brain(cortex, hippocampus), salivary
glands, sympathetic ganglia
M2 – Heart, brain, 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
The M2 and M3 subtypes - detected in human
bladder and, despite the predominance of M2
receptors, pharmacologically defined M3
receptors mediate bladder contraction
Mechanism of action
Anticholinergic drugs block the action of Ach
that causes abdominal bladder contractions
Antimuscarinics (AMs) are now widely used as
the pharmacological therapy for overactive
bladder (OAB) and/or urgency incontinence
Chemically, these drugs, being tertiary or
quaternary amines, are structurally similar
to acetylcholine
It can take several weeks before symptoms
begin to improve on an anticholinergic drug. It
might take 2-12 weeks to see the full effect of drug
Characteristics of Antimuscarinic Drugs
for Urgency Urinary Incontinence
Adverse effects
Anticholinergic adverse effects: common
Dry mouth, constipation, somnolence,
drowsiness, and blurred vision, which
impact on both compliance and persistence
with long-term treatments
Dry mouth being the most common
An extended-release form taken once a day
might cause fewer adverse effects
Other less common side effects include
heartburn, rapid heartbeat, flushed skin and
urinary retention
Neurological adverse effects are of great
concern, particularly in elderly patients because of
an increase in blood–brain barrier (BBB)
permeability with aging
Alzheimer disease and dementia – with
cumulative anticholinergic use. The use of
anticholinergic agents for ≥3 months appears to
increase the risk of dementia by an estimated 46%
Cognitive impairment in the elderly - dementia
and confusion with increased risk with oral
oxybutynin, and tolterodine. By contrast, little
to no cognitive impairment associated with
fesoterodine, solifenacin, or trospium
Although all antimuscarinic drugs are comparable
in terms of efficacy, immediate release (IR)
preparations were associated with more side-
effects
Extended release (ER) formulations showed
statistically significant lower rates of dry
mouth –
extended release (ER) formulations of
oxybutynin (40%) and tolterodine (18%)
compared with the IR formulations of both
medications (68% and 28%, respectively)
Transdermal oxybutynin (patch and gel) - skin
reactions were the commonest reason for
treatment discontinuation
Contraindications
Untreated narrow angle glaucoma – may be
aggravated by anticholinergic drugs
Urinary retention or significant bladder outflow
obstruction
GIT disorders - gastric retention, severe decreased
gastrointestinal motility, partial or complete
obstruction of GIT, gastroesophageal reflux disease,
paralytic ileus, intestinal atony of the elderly or
debilitated patient, megacolon, ulcerative colitis
Myasthenia gravis
Obstructive uropathy
Hypersensitivity to the drug
Preacutions
Patients should be monitored for signs of CNS
effects, particularly in the first few months after
beginning treatment or when increasing the dose
If a patient experiences anticholinergic CNS effects, dose
reduction or drug discontinuation should be considered
used with caution in patients with preexisting
dementia treated with cholinesterase inhibitors due
to risk of aggravation of symptoms
should be used with caution in the frail elderly, in
patients with hepatic or renal impairment, and in
patients with myasthenia gravis
Urinary Retention
Gastrointestinal Disorders /gastroesophageal reflux
Drug interactions
with other anticholinergic drugs (atropine,
scopolamine), other antispasmodic drugs (such
as dicyclomine, propantheline), certain anti-
Parkinson's drugs (trihexyphenidyl), mifepristone –
may increase frequency and/or severity of adverse
effects (dry mouth, constipation, drowsiness)
Anticholinergic agents may alter absorption of some
concomitantly administered drugs their effects on GIT
motility
Drugs that may affect the heart rhythm (QT
prolongation, including amiodarone, quinidine,
procainamide, sotalol, macrolide antibiotics (such
as erythromycin), others
CYP 3A4: Interactions with macrolides,
ketoconazole
antimycotic agents (ketoconazole,
miconazole)
 macrolide antibiotics (erythromycin and
clarithromycin),
drugs used to treat HIV
potent CYP3A4 inhibitors may alter
anticholinergic drugs mean pharmacokinetic
parameters (plasma concentrations, Cmax and
AUC)
Caution should be used when such drugs are co-
administered
 OXYBUTYNIN (Ditropan)
It is a nonselective anticholinergic agent
available in short- and long-acting oral forms
(Ditropan), as a transdermal patch (Oxytrol) and
as a topical gel (Genlnique)
It has :
moderate selectivity for M3 relative to the
M2 muscarinic receptor
direct muscle relaxant effects. It is therefore
classified as an antimuscarinic drug with a
‘mixed’ action’
Oxybutynin was also shown to have local
anaesthetic properties
These actions together form the basis for its use as
a therapeutic option in patients with overactive
detrusor function - either idiopathic detrusor
instability (DI) or detrusor hyperreflexia
It exhibits one-fifth of anticholnergic activity
of atropine on detrusor muscle, but four to ten
times the antispasmodic activity
No blocking effects occur at skeletal
neuromuscular junctions or autonomic ganglia
(antinicotinic effects)
Pharmacokinetics
Rapidly absorbed after oral administration, Cmax in an
hour, and half-life of about 2-3 hrs
Bioavailability is about 6% - increased with food by 25%
Oxybutynin is a tertiary amine that undergoes extensive
first-pass metabolism to an active metabolite, N-
desmethyl oxybutynin - responsible for part of action
parent drug
It is metabolized primarily by cytochrome P450 enzyme,
CYP3A4 in liver and gut wall. Its metabolic products
include desethyloxybutynin (pharmacologically active)
CYP 3A4: Interactions with macrolides, ketoconazole
Indications
Relief of symptoms of bladder instability – in
uninhibited neurogenic or reflex neurogenic
bladder
In OAB, oxybutynin decreased the number of
incontinence episodes and increased average
voided volume. There was no difference between
transdermal oxybutynin and extended-release oral
tolterodine
Treatment of overactive bladder
The short-acting preparation is approved for children
older than 5 years
Oxybutynin Controlled Release - once daily dosing, has
lower rate of dry mouth than immediate release form
Oxybutynin 5 mg orally 1 hour before surgery
reduced the incidence and severity of
postoperative bladder discomfort
Oxybutynin is available as a tablet, a syrup, and an
extended-release (long-acting) tablet
Transdermal oxybutynin, was as effective as oral
tolterodine and caused fewer anticholinergic side
effects, presumably because of the “smoother”
release of the drug from a transdermal patch
Use in pregnancy appears safe but has not been
well studied while use in breastfeeding is of
unclear safety
Adverse effects
Anticholinergic adverse effects – frequent and troublesome
to necessitate treatment discontinuation in up to 25% of
patients, depending on dosage
Serious side effects may include urinary retention and an
increased risk of heat stroke
 Elevated body temperature - more likely to occur in elderly
 Oxybutynin's tend to reduce sweating and increases the risk of
heat exhaustion and heat stroke
Development of dementia in those over 65 years of age
N-Desethyloxybutynin - an active metabolite of oxybutynin
that is thought responsible for much of adverse effects
associated oxybutynin.
In overflow incontinence due to diabetes or neurological
diseases like multiple sclerosis or spinal cord trauma,
oxybutynin can worsen overflow incontinence since the
fundamental problem is that the bladder is not contracting
Contraindications
Untreated or uncontrolled narrow angle glaucoma - anticholinergic
drugs may aggravate these conditions
Urinary retention/significant bladder outflow obstruction
Gastric retention
 Partial or complete obstruction of GIT, intestinal atony, paralytic ileus,
megacolon, ulcerative colitis or Crohn's disease
 Digestive problems such as heartburn, gastroesophageal reflux disease
Myasthenia gravis
Kidney or liver diseases - affect disposition of drug, dosage
reduction necessary in patients with substantially reduced renal or
hepatic function
Heart diseasess, including long QT syndrome, heart failure,
irregular or slow heartbeats or cardiomyopathy
Hypersensitivity to the drug substance or other components of the
product
Pregnancy (Category B) and lactation
Drug interactions
Anticholinergic drugs (atropine, scopolamine),
antispasmodic drugs
(dicyclomine, propantheline), certain anti-
Parkinson's drugs (trihexyphenidyl),
anticholinesterases (for dementia) - may increase
frequency and/or severity of such effects
Anticholinergic agents may potentially alter
absorption of some concomitantly administered
drugs due to anticholinergic effects on GI motility.
This may be of concern for drugs with a narrow
therapeutic index
Drugs that may affect the heart rhythm (QTc
prolongation), including amiodarone,
procainamide, quinidine, sotalol,
macrolide antibiotics (such as erythromycin),
among others
Inhibitors of CYP 3A4
antimycotic agents (ketoconazole,
itraconazole, miconazole), macrolide
antibiotics (erythromycin, clarithromycin) may
alter oxybutynin mean pharmacokinetic
parameters (plasma concentrations, Cmax and
AUC)
Pediatric Use
The safety and efficacy of DITROPAN
administration have been demonstrated for
pediatric patients 5 years of age and older
Geriatric Use
In general, starting at low end of dosing range
(2.5 mg), due to decreased hepatic, renal, or
cardiac function, and of concomitant disease or
other drug therapy
 TOLTERODINE
Tolterodine Tartrate (Detrol and Detrol LA)
Synthetic tertiary amine antimuscarinic agent
Selective anticholinergic agent
Has relatively more action on cholinergic receptors in
bladder than in salivary glands and other organs
Tolterodine and its active metabolite, 5-hydroxymethyl-
tolterodine, act as competitive antagonists at M2 and M3
subtypes of muscarinic receptors
Selectively and competitively binds to muscarinic M3
receptors in bladder inhibition of bladder
contraction, decrease in detrusor muscle tone,
incomplete emptying of bladder and increasing internal
urethral sphincter tone increase volume of urine
the bladder can hold and control the release of urine
Pharmacokinetics
Upon oral administration, it undergoes first-pass
metabolism, where CYP2D6 metabolizes drug to
its active form, 5-hydroxymethyl derivative -
major pharmacologically active metabolite, that
exhibits antimuscarinic activity similar to that of
tolterodine, and contributes significantly to
therapeutic effect
Tolterodine begins to work within 3 to 8 hours
but it may take up to 4 weeks before it takes full
effect
Hepatic metabolism - metabolized principally
by CYP2D6
It is available in short- and long-acting oral forms -
immediate-release (IR) and extended-release
(ER)
Long-acting formulations are preferred over the
short-acting counterpart - more effective in
controlling incontinence symptoms, cause fewer
anticholinergic side effects
short-acting oxybutynin - slightly more effective
in controlling incontinence, but long-acting
tolterodine has fewer anticholinergic side effects
and is better tolerated
Tolterodine administration
Orally as tablets or Extended release capsules

Transdermal Topical Gel Formation

(proniosomes) –
Transdermal patches demonstrated similar
therapeutic effects as the oral dose form, but
it showed a decrease in the adverse effects,
such as dry mouth and constipation
It is effective for over 72 hours after the
application because of constant entry into
systemic circulation through patch
Indications
Management and treatment of OAB -
serves as a gold standard treatment for OAB, and
has a decreased level of adverse effects compared to
other alternatives, such as oxybutynin
decreases daily number of voids and incontinence
episodes, while increasing the total volume per void.
Clinical studies have shown that combination
therapy of tolterodine with an alpha-blocker,
(tamsulosin), significantly improves symptoms
Treatment of bedwetting in children (nocturnal
enuresis) - although it is not FDA approved for
children but is often used in children intolerant
to oxybutynin
Adverse effects
Adverse effects of tolterodine are significantly
lower than that of other antimuscarinic drugs
Patient tolerance is significantly better than
oxybutynin regarding incidence and severity of
dry mouth.
Also, fewer dropouts of patients occur with
tolterodine as compared to oxybutynin.
Dry mouth, is less common due to its functional
selectivity for bladder over salivary glands
In women with overactive bladder, dry mouth
occurred significantly more often with
oxybutynin (30% versus 22%)
Disturbances in the cardiac and central
nervous systems
Low doses of tolterodine can cause an increase
in heart rate by acting on M1 tachycardia,
palpitations, and cardiac rhythm disorders.
Used with caution in pts with any heart-related
problems
Because tolterodine is slightly lipophilic, it
does not penetrate significantly CNS and
exhibits a low frequency of cognitive side
effects
In rare cases, it's possible to have a serious
allergic reaction (anaphylaxis) to tolterodine -
swelling of face, throat, tongue, lips, and eyes and
difficulty swallowing or breathing

If a patient is about to perform a potentially

dangerous task, this medication should not be
administered, as it can cause drowsiness and
blurred vision
Contraindicated in pregnancy, or breastfeeding
Drug interactions
Anticholinergic drugs
CYP 3A4 inhibitors
CYP 2D6 inhibitors: interactions with TCAs,
fluoxetine - increased tolterodine concentrations
 SOLIFENACIN (Vesicare)
Long acting muscarinic receptor antagonist, selective
for M3. It acts by relaxing the bladder muscles
 Solifenacin starts to work within 3 to 8 hrs, but it can
take up to 4 weeks to reach its full effect
Undergoes hepatic metabolism involving CYP3A4
Solifenacin is used to treat symptoms of an
overactive bladder including urinary urgency, urinary
frequency (urinary incontinence)
Several clinical trials showed efficacy and low side
effects (2% dry mouth).
It is available also combined with tamsulosin, a
drug for prostate problems; taken as 1 tablet once a day
 DARIFENACIN
(Enablex®, Emselex)

Darifenacin is a selective M3 receptor

competitive antagonist. It has greater affinity for
the M3 receptor than for the other known
muscarinic receptors
Blocking the M3 muscarinic Ach receptor, which is
primarily responsible for bladder muscle
contractions and thereby decreases the urgency
to urinate
Pharmacokinetics
Well absorbed from GIT, undergoes extensive first-
pass metabolism in liver, bioavailability - 15-19%
Peak plasma in 7 hrs and steady state in about 6
days, highly bound to plasma proteins (98%)
Mainly metabolized in liver by two enzymes: CYP3A4
and CYP2D6 into various metabolites, some of which
are active and may contribute to the drug’s effects
Darifenacin and its metabolites are eliminated
through urine (60%) and feces (40%)
The elimination half-life is about 14-19 hrs for the
extended-release tablet
Indications
Treatment of OAB
To prevent urgent, frequent, or uncontrolled
urination
Reduces muscle spasms of bladder and urinary
tract
Available as oral tablet (15 mg) and extended-
release (7.5 mg) tablet taken once a day with
plenty of liquid and may be taken with or without
food
Studies showed that darifenacin 15 mg and 30 mg
showed similar efficacy to oxybutynin 5 mg tid
 FESOTERODINE
Nonselective antimuscarinic prodrug that used in
the treatment of overactive bladder
fesoterodine prodrug is broken down into its active
metabolite, 5-hydroxymethyl tolterodine (5-HMT), by
plasma esterases - acts as a competitive antagonists at
muscarinic receptors
5-HMT is metabolized in the liver by CYP2D6 and
CYP3A4 to inactive metabolites that is excreted in
urine
Half-life: 7-8 hours for the active metabolite 5-HMT
Indications:
Neurogenic Detrusor Overactivity - pediatric patients
≥ 6 years old weighing > 25 kg
 Selection of one
anticholinergic agent
Short-acting oxybutynin - slightly more effective in
controlling incontinence, but short-acting tolterodine
has fewer anticholinergic side effects and is better
tolerated
Comparing long-acting oxybutynin (10 mg) with long-
acting tolterodine (4 mg) in patients with urge
incontinence - had similar reductions in incontinence
episodes, but oxybutynin-treated patients had a 50
percent higher rate of moderate or severe dry mouth
Transdermal oxybutynin: as effective as tolterodine
and caused fewer anticholinergic side effects, because of
“smoother” release of drug from a transdermal patch
Cutaneous side effects were frequent: 20% of patients
reported moderate to severe reactions
The choice between long-acting oral tolterodine
and long-acting oral oxybutynin is more difficult and
depends largely on whether more emphasis is put on
having slightly better control of incontinence (in
which case oxybutynin is preferred) or minimizing
anticholinergic side effects (in which case tolterodine
is preferred).
Common side effects include
 constipation and dry mouth (unpleasant, dental caries)
 Anticholinergic agents may worsen cognitive function and
should be used with caution in patients with dementia
 They are contraindicated in patients with angle-closure
glaucoma and urinary outflow obstruction
 Latest developments
Novel antimuscarinic molecules were developed
with the intention of attaining better M3 affinity
and improving side effect profiles
 Imidafenacin
developed to improve the tolerability of therapy by
a higher affinity for the M1 and M3 receptor subtypes
and lower affinity for M2 subtype.
Its efficacy and safety for treatment of OAB was
similar to that of tolterodine with no significant
change in mean number of incontinence and daytime
incontinence episodes
The most frequent Adverse effects were GI disorders
Has similar efficacy to other AMs, but imidafenacin
caused fewer nocturia episodes, lower dry mouth rate,
lower constipation rate and fewer withdrawals, making
imidafenacin preferable for patients who need long-
term medications
 Tarafenacin
Has the highest selectivity of human M3 vs M2 subtype
and with a less marked inhibiting effect on M3
activation in submandibular gland than in
bladder, indicating a very favorable selectivity index
between both tissues
It produced improvement in OAB symptoms, but
the rate of dry mouth was somewhat higher for
tarafenacin (64%) than other reported anticholinergics
(29%)
the rate of constipation of tarafenacin (2%) was
comparatively lower than other agents (7.7%).
ANTIDEPRESSANTS
Introduction
Tricyclic antidepressants (TCA):
amitriptyline, imipramine, duloxetine

Block both central and peripheral cholinergic

muscarinic receptors and inhibit the neuronal
reuptake of monoamines, in particular
noradrenaline and serotonin
Imipramine (Tofranil)
TCA, anticholinergic and alpha-agonist effects - relax
bladder muscle, contract smooth muscles at the
bladder neck. This is useful for facilitating urine
storage by decreasing bladder contractility and
increasing bladder outlet resistance
It is useful for nocturia and mixed incontinence
caused by detrusor overactivity and bladder outlet
incompetence
Imipramine can cause drowsiness, so it's often taken
at night. Because of this, imipramine may be useful for
nighttime incontinence
Acceptable as temporary adjunctive therapy to
reduce enuresis in children aged ≥ 6 years (bed-wet
Adverse effects
irregular heartbeat and dizziness or fainting from
postural/orthostatic hypotension (specially in
Children and older adults)
Other side effects may include dry mouth, blurry
vision drowsiness, excessive sweating, delayed
orgasm, and constipation
hepatic dysfunction, rash, and arrhythmias
 Duloxetine
(Cymbalta, Drizalma Sprinkle)
Antidepressant, useful for treatment of stress and
urge/OAB incontinence
Centrally acting, inhibits presynaptic re-uptake of
serotonin (5-HT) and noradrenaline (NA). In the
sacral spinal cord, an increased concentration of 5-HT
and NE in synaptic cleft increases stimulation of 5-HT
and NE receptors on the pudendal motor neurons,
which in turn increases the resting tone and
contraction strength of the urethral striated
sphincter and increases urethral closure pressure
during urine storage phase of the micturition cycle -
a potential benefit in stress incontinence
Duloxetine reverses the symptoms of overactive
bladder co-existing with depression acting via the
central pathways
Long-term treatment was characterized by a high
patient withdrawal rate, caused by a lack of
efficacy and high incidence of adverse events,
including nausea and vomiting (40% or more of
patients), dry mouth, dizziness, constipation,
insomnia and fatigue
Beta -3-agonists
Introduction
Beta-3 adrenergic receptor (β3-AR) represents the
most common subtype of β-ARs in the human
bladder where it mediates noradrenaline-induced
detrusor relaxation
The development of β3-AR agonists was originally
aimed at the treatment of diabetes mellitus
Mirabegron (Myrbetriq)
Used as an alternative if antimuscarinics (AMs)are
unsuitable for treatment of OAB, or have
unpleasant side effects
It significantly improved the rates of treatment
satisfaction and symptoms in patients with OAB,
the response rate of treatment satisfaction at 12
weeks was 69%
Mirabegron showed comparable overall efficacy
versus antimuscarinic treatments, but it has a
good safety profile and causes no side effects
typical of anticholinergics - significantly better
It works by activating beta-3 adrenergic receptors
in bladder, which relaxes smooth muscle and
increases the bladder capacity.
This reduces symptoms of urinary urgency,
frequency, and incontinence. It may also
increase the amount of urine excreted at one
time, helping to empty the bladder more
completely
Taken by mouth once a day, and it can be used
alone or in combination with other drugs for
overactive bladder, such as solifenacin
Adverse Effects
Common: nausea, dizziness, urinary tract infection,
headache, and diarrhea
Others include hypertension (7%)
Contraindicated in patients with severe uncontrolled
high blood pressure (systolic ≥180/110 mm Hg)
No cognitive side effects
Dry mouth, constipation and urinary retention -
significantly lower compared with almost all other
active treatments
Treatment persistence with mirabegron was
significantly longer than that with AMs
 Vibegron (Gemtesa®)
It is a new, oral, potent, and selective β3-AR agonist
that is created for treatment of obesity (2000s). While
efficacy for treatment of obesity was not achieved, the
compound was instead used for the treatment of OAB
Indicated for treatment of OAB with signs of urge
urinary incontinence (UUI), urgency and urinary
frequency in adults
Clinically, once-daily 75 mg demonstrated clear
efficacy on key symptoms of OAB, with a response rate
exceeding 50%
It is the first beta-3 agonist available as a once-daily
pill which does not require dose titration
Vibegron showed a favorable safety profile:
did not have any increase in the adverse
event of hypertension compared to placebo
did not show any induction and inhibitory
effects on CYP enzymes (mirabegron inhibits
CYP2D6), suggesting no risk of drug−drug
interaction
has no interactions with medications
metabolized by CYP2D6
Phosphodiesterase-
5 Inhibitors
Introduction
Phosphodiesterase 5 inhibitors (PDE5i) have
traditionally been used in treatment of erectile
dysfunction.
PDE-5i prolong the physiological effects of
nitric oxide (NO)/cyclic guanosine
monophosphate (cGMP) signaling in tissues
through the inhibition of cGMP degradation, an
important mediator of smooth muscle tone
Tadalafil - showed a potential therapeutic use in
the treatment of OAB and male LUTS
Tadalafil may ameliorate bladder overactivity
through increase of nitric oxide synthase (eNOS)
activity in bladder mucosa, and restoration of
urinary NO availability and detrusor cGMP level
In men, tadalafil 5 mg/day, when compared with
fesoterodine 8 mg/day, significantly improved
urgency incontinence episodes
Tadalafil 5 mg/d was well-tolerated and no serious
adverse reaction was observed, possibly due to the
low doses of the drug
Desmopressin
Introduction
Desmopressin is a synthetic vasopressin
analogue
It has strong anti-diuretic effects without
altering blood pressure
Decreases urine production
It reduces urine flow by inhibiting reabsorption
of water by the kidney tubules
Indications:
Primary nocturnal enuresis (bed wetting)
Nocturia associated with multiple sclerosis
Cranial diabetes insipidus
Adverse effects
Nasal irritation, rhinitis, congestion, abdominal
cramps, urge defecate, fluid retension, ulceration,
nausea, pallor, backpain in females, (due to uterine
contraction)
Contraindications:
CHF, HTN, ASCVD
Hypersensitivity, impaired renal function
Cautions
 in CV disease, edema, hypertension, fluid and
electrolyte imbalance, pregnancy and lactation
 Vaginal estrogens
Ovestin, Vagitem, Ortho-gynest
After menopause, the body produces less estrogen

weakening of supportive tissues around

bladder and urethral urine passage. This can
contribute to stress incontinence
The rationale for estrogen therapy is its ability to:
increase urethral vascularity and thickness,
sensitize α-adrenergic receptors in bladder
neck and improves urinary sphincter tone
both of which could improve urethral closure
Helpful for stress incontinence in women
Topical products are recommended, since
systemic treatment may produce serious side
effects
The medication comes in the form of a vaginal
cream, ring or patch
Applying low-dose, topical estrogen may help
restore the tissues in the vagina and urinary tract
to relieve some symptoms.
Topical estrogen might not be safe for people with
a history of breast cancer, uterine cancer or
both
 Combination Therapy
Combination therapy’s advantage lies in acting
simultaneously on different pharmacological
pathways, with additive and/or synergistic effects

Anticholinergic medication with mirabegron:

For OAB, combination therapy of solifenacin with
mirabegron improves, in a statistically significant
manner, urinary frequency, urgency, and urgency
incontinence compared to monotherapy solifenacin or
mirabegron alone
Combination of tadalafil and mirabegron
For OAB, the total OAB symptoms score of
combination therapy was significantly decreased
by 1.78 (95%) points compared with that of
monotherapy

Alternative strategies, in patients refractory to

first-line antimuscarinic monotherapy, are
combination of two antimuscarinics or
antimuscarinic cycling - refers to the practice of
periodically rotating or switching between
different antimuscarinic medications
combinations of trospium and solifenacin
result in decreases in urinary urgency and urgency
incontinence.
one-year cyclic therapy with a trospium and
solifenacin combination
provided a high compliance level (76–84%),
while continuous therapy with standard doses of
trospium and solifenacin resulted in low
adherence and high rates of treatment
withdrawal (⩾66%) despite satisfactory clinical
and urodynamic results
This cycling approach aims to address several
potential issues:
1. Tolerance
Some patients may develop tolerance to a specific
antimuscarinic medication over time, leading to
diminished effectiveness. By switching to a different
antimuscarinic agent, tolerance to the initial
medication may be avoided or minimized
2. Receptor selectivity

3. Side effects
Switching to a different medication with a different
side effect profile may improve tolerability and
4. Optimization of dosing
Cycling between different antimuscarinic
medications allows for adjustments in dosing
regimens, such as titrating dose or changing the
dosing schedule, to optimize efficacy while
minimizing side effects

5. Placebo effect
In some cases, switching to a different medication
may have a placebo effect, leading to subjective
improvement in symptoms
 Botulinum Toxin (Botox)
There are seven subtypes of botulinum toxin (BoNT),
of which subtype A (BoNT-A) is clinically the most
relevant
Four different commercial forms of BoNT-A are
available: onabotulinumtoxin A, abobotulinumtoxin
A, incobotulinumtoxin A and prabotulinumtoxin A
onabotulinumtoxinA (Botox®)
Intradetrusor injections are currently the only FDA
approved botulinum toxin treatment for patients
with OAB and/or UUI, who have failed first-line
pharmacological treatment
Mechanism of action
The mechanism of action of BoNT in nerve
terminals:
Blockade of neuromuscular transmission by
binding to receptor sites on nerve terminals and
preventing neurosecretory vesicles from
docking/fusing and releasing ACh and other
neurotransmitters from the axon endings
Botox blocks the actions of acetylcholine and
paralyzes the bladder muscle
Long-lasting neuronal blockade leading to
decreased muscle contractility and chemical
de-nervation at the injection site
 Indications
Onabotulinumtoxin A is injected cystoscopically.
It is used to treat adults with overactive bladder or
neurogenic urge incontinence if they have an
inadequate response to or cannot tolerate
anticholinergic drugs.
Intradetrusor injections of aboBoNT-A (750U)/12
weeks, useful in patients with neurogenic detrusor
overactivity
significant decrease in number of UI episodes per day,
significant increase in maximum cystomanometric
capacity,
significant increase in proportion of patients with no
The efficacy and safety of onaBoNT-A for OAB and
urgency incontinence was established leading to the
approval of a treatment starting dose of 100 U (10 ml)
in patients with idiopathic OAB
BoNT showed significantly greater reductions in
UI than AMs in both patients with idiopathic OAB
and patients with neurogenic OAB
Botox significantly improves symptoms of
incontinence and causes few side effects. The most
common adverse event was UTI (17% after the first
treatment)
Treatment is repeatable, being safe and effective
even in the long term
Median duration of effect was 7.6 months
 Latest developments
In recent years, there has been growing interest in
the search for new drug delivery approaches
(Figure), based on the finding that the potency of
intradetrusor onaBoNT-A injections is sensitive to
injection volume and depth
Intravesical delivery of botulinum toxin:
Liposomes (lipid vesicles)
Intravesical thermosensitive hydrogels
Dimethyl sulfoxide (DMSO)
Protamine
TAT peptide

Different approaches for intravesical delivery of botulinum toxin.
Abbreviations: DMSO, dimethyl sulfoxide; EMDA, electromotive
drug administration; LESW, low energy shock waves.
Liposomes (lipid vesicles)
onaBoNT-A complexed with liposomes was
protected from proteolytic degradation exerted by
urine proteases
lipo-botulinum toxin instillation was associated
with a statistically significant decrease in
micturition events per 3 days and statistically
significant decrease in urgency severity scores
compared to placebo, with no urinary retention
events and with a risk of UTI similar to placebo
Intravesical thermosensitive hydrogels
developed to increase the residence time of
drugs within bladder. Its unique rheological
property allows the instillation to be liquid at room
temperature (25°C), and then semi-solid at body
temperature
The hydrogel within the bladder allowed a gradual
release of 200 U of onaBoNT-A for up to 6–8 hrs
compared to typical 2 hrs for saline instillation
efficacy lasts for a few weeks, with transient and
mild AEs, the most common being constipation.
in patients with painful bladder syndrome
Dimethyl sulfoxide (DMSO)
an organic solvent that has been used to facilitate
delivery of several anticancer drugs into animal bladders
by increasing urothelium permeability
Protamine
an arginine rich polycationic peptide used as an
antidote to heparin overdoses
Protamine internalizes into cells through heparin
sulfate mediated endocytosis
This effect on the urothelium was used to enhance the
uptake of onaBoNT-A into the bladders
TAT peptide
Protein transduction domain (PTD) derived from
human immunodeficiency virus (HIV), which was
successfully employed for uptake of peptide
nucleic acids, conjugated with TAT peptide, into
rat bladders
Electromotive drug administration
(EMDA)
Physical approach to increase bladder permeability
to instilled drug molecules through electromotive
forces (EMF). EMF involves the placement of
electrodes, one inside the bladder and one outside on
the abdomen to create a potential difference driving
the diffusion of instilled drugs
Macroplastics
Macroplastics
Macroplastique is an injectable soft-tissue
bulking agent that is commonly used for treating
stress urinary incontinence in females
It is typically used on people who have intrinsic
sphincter deficiency (ISD), which is when the
sphincter becomes diseased or damaged
The procedure aims to strengthen and support the
sphincter
It is a medical grade silicone combined with a
water-soluble gel. It is composed of tiny beads of
non-absorbable, biocompatible silicone elastomer
When injected into tissues around urethra, these
beads provide structural support and bulk,
improving closure of urethra and reducing urinary
leakage
This provides strength and support.
The bulking agent works through stabilising and
“bulking” the tissue ↓ urinary leakage
during activities that increase abdominal pressure
The increase in tissue bulk also provides
surrounding muscles with increased urine
capacity, improving control over urination
Procedure
The procedure is typically performed in an
outpatient setting under local anesthesia
The surgeon uses a cystoscope or a visualizing tube
to view the urethra and bladder, which is filled
partly with water to improve the process
it involves injecting the Macroplastique substance
into specific locations around the urethra using a
cystoscope or specialized needle
The procedure is fairly short, and can be performed
in 30 minutes
Antibiotics can be used to reduce the risk of
Adverse effects
They are often temporary and resolved within 30
days after treatment.
Possible complications of macroplastique include
the following:
Bladder infection
Slowed urine stream
Urinary retention
Strong desire to urinate
Hesitancy
Who is Macroplastique
Ideal For?
More suited for women who desire long-term
significant improvement or cure of their SUI

The surgery is also ideal for those who prefer a

minimally invasive procedure with low morbidity

Considered as an alternative to other surgical

treatments for SUI such as midurethral slings
Advantages
It can be performed under local anesthesia
Side effects are rarely reported
Studies show the surgery to be highly effective
and safe - with an 84% success rate for the
outpatient procedure from 12 to 24 months
It is minimally invasive
It has a short recovery time
The majority of patients report better quality
of life after procedure. QOL scores improved
significantly throughout the 24 months