1

Medications for
Urinar y 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
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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
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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
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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
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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
7. Botox - Botulinum toxin A
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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
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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
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 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,
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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 hyperref lexia
 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
(a
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
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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
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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
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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
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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
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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
ti d
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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
 Overactive Bladder Syndrome (OAB) – in adults

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
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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%).
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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 at night)
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
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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 tolerated

 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
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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
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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
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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
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 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 adherence to treatment

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
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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 uninhibited detrusor
contractions
 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
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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
 Electromotive drug administration (EMDA)
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 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
 26

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 suspended in a gel carrier

 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 infection.

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
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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