1) Mirabegron and antimuscarinics are both effective treatment options for overactive bladder, with mirabegron offering fewer anticholinergic side effects such as dry mouth. 2) Combination therapy with solifenacin and mirabegron provides greater improvement in overactive bladder symptoms compared to monotherapy, though it is associated with more anticholinergic side effects. 3) Efficacy and safety of solifenacin, mirabegron, and their combination is maintained in elderly patients over 65 years old with overactive bladder, with combination therapy demonstrating the greatest benefit.

1. Anticholinergic and
Mirabegron
In Detrusor Overactivity.
Siddesh Dhanaraj

2. • In the 2013 dataset, the prevalence of OAB was 7.2%
(Male: 7.7%; Female: 6.7%).
• Prevalence was the highest among those aged more
than 74 years (9.3%), identifying as White (7.4%), and
residing in urban areas (7.5%).
• By 2027, OAB is projected to increase by 48.1%
World Wide

3. World Wide

4. World Wide

5. World Wide

6. Total population Men Women

7. O
A
B Table -1 Table -2

8. O
A
B
Diagnostics Assessment
 History (Bladder diary in selected patients)
 Physical Exam
 Women: Cough test for stress incontinence
 Men: Noninvasive flow rate
 Measurement of voiding flow rate
 Postvoid residual volume determination
 Urinanalysis

9. O
A
B
Treatment Options
 Behavioural interventions
• Pelvic floor muscle exercises.
• Healthy weight.
• Scheduled toilet trips
• Intermittent catheterization
• Absorbent pads
• Bladder training
 Medications
 Bladder injections (OnabotulinumtoxinA)
 Nerve stimulation
 Surgery
• Surgery to increase bladder capacity.
• Bladder removal.

10. • Antimuscarinics/Anticholinergic
• Beta-3 adrenergic
• Antispasmodic
• Hormones
• OnabotulinumtoxinA (Botox)
Medication available for the treatment of OAB -

11. Antimuscarinic drugs for the treatment of OAB -

12.  Muscarinic receptors are
distributed to most of the
organs in the body.
 Antimuscarinics have
important sites of action
outside the bladder that
cause effects limiting
their clinical use.

13. Fesoterodine is
not available in
India
Antimuscarinic drugs for the treatment of OAB -

14. 1. Treatment for overactive bladder using antimuscarinics in adults
aged 65 or older resulted in significant increases in risk for several
AEs compared to placebo including anticholinergic and non-
anticholinergic AEs. (Arch Gerontol Geriatr.2017;69:77-96).
2. Heart rate significantly increased in OAB patients treated with non-
selective antimuscarinic drugs. Trospium chloride, tolterodine tartrate,
fesoterodine fumarate and propiverine hydrochloride seem to have the
most unfavorable properties with regard to increased heart rate side
effect when compared to the other antimuscarinic drugs (darifenacin
hydrobromide, solifenacin succinate and oxybutynin hydrochloride).
• Int Urol Nephrol. 2019;51(3):417-424.
3. Which anticholinergic is best for people with overactive bladders? A
network meta-analysis
(Int Urogynecol J.2019;30(10):1603-1617).
 All the anticholinergic drugs were better than placebo but apart from
dry mouth were similar in effect. Transdermal oxybutynin caused less
dry mouth than the other treatments, so may be worth considering as
the first treatment.
Antimuscarinic AE’s-

15. Mirabegron: clinical considerations in OAB*
 First b3-adrenoceptor agonist approved for OAB
 Once-daily oral administration
 Reduces the frequency of micturition, incontinence
and urgency and improves HR-QOL
 Sustains these improvements over 52 weeks’ therapy
 Generally well tolerated
Beta-3 adrenergic drug for the treatment of OAB -

16. • Sympathetic and parasympathetic
innervation diametrically regulates the
function of the lower urinary tract.
• Sympathetic nerve activity triggers the
release of noradrenaline (NA),which relaxes
the detrusormuscle and promotes
contraction of the urethra, thereby
promoting the storage of urine.
• During urination, parasympathetic nerve
activity predominates; the release of nitric
oxide (NO) inhibits contraction of the
urethra, and acetylcholine (ACh) release
triggers contraction of the detrusor muscle.
• Like noradrenaline, mirabegron acts on the
β3-adrenoreceptor, triggering detrusor
muscle relaxation and improved urine
storage
* Br J Clin Pharmacol-2015,80:4; 762–764
Beta-3 adrenergic drug MOA* -

17. Patients with OAB
Anticholinergic/
Antimuscarinic drugs
β3 – adrenoceptor agonist
(Mirabegron)
Effective and Tolerate
treatment
1. Insufficient efficacy
2. Poor tolerability
Anticholinergic/
Antimuscarinic drugs
Possible utilisation of Mirabegron in the treatment of patients with OAB -*

18. Pharmacologic Management
Consider dose modification or alternate
medication if initial treatment is effective but
adverse events or other considerations preclude
continuation; consider combination therapy
with an anti-muscarinic and ß3-adrenoceptor
agonist for patients refractory to monotherapy
with either.
Diagnosis & Treatment Algorithm: AUA/SUFU Guideline on Non-
Neurogenic Overactive Bladder in Adults*-2019

19. 1. Impact of body mass index on treatment efficacy of mirabegron
for overactive bladder in females* (Eur J Obstet Gynecol Reprod Biol. 2016 Jan;196:64-8).
CONCLUSIONS:
This study provides evidence in support of documented data obtained do
not confirm hypothesis that the body weight influences the treatment
outcome of mirabegron.
2. The β3-adrenergic receptor agonist mirabegron improves glucose
homeostasis in obese humans* (J Clin Invest.2020 Jan 21).
CONCLUSION:
Mirabegron treatment significantly improves glucose tolerance in
obese, insulin resistant humans. Since β-cells and skeletal muscle do not
express β3-ARs, these data suggest that the beiging of SC WAT
(subcutaneous white adipose tissue) by mirabegron reduces adipose
tissue dysfunction, which enhances muscle oxidative capacity and
improves β-cell function.
Diabetes Mellitus Type 2
Possible utilisation of Mirabegron in the treatment
of patients with OAB -*

20. M3 & Beta-3 combination in OAB management -

21. Objective
To evaluate the potential of solifenacin 5 mg combined with Mirabegron 25 or 50 mg to deliver superior efficacy
compared with monotherapy, with acceptable tolerability, in the general overactive bladder (OAB) population with
urinary incontinence (UI).
Conclusion
• In the largest OAB study to date, combined therapy with solifenacin 5 mg + mirabegron 25 mg and solifenacin 5
mg + mirabegron 50 mg provided consistent improvements in efficacy compared with the respective
monotherapies across most of the outcome parameters, with effect sizes generally consistent with an additive
effect
• Most effects of combined therapy vs monotherapy were observable by week 4.
• The clinical relevance of the improvements seen with combined therapy for several objective OAB outcome
measures was also supported by the improvements of combined therapy vs monotherapy in the responder
analyses.
Efficacy and safety of combinations of Mirabegron and solifenacin compared with monotherapy and placebo in
patients with overactive bladder (SYNERGY study) - BJU Int 2017; 120: 562–575.

22. Objective:
To assess efficacy and tolerability of mirabegron 50 mg versus antimuscarinic monotherapies
and combination therapies.
Patient summary:
This study assessed the efficacy and tolerability of different drug treatments for
OAB. Mirabegron 50 mg was as effective as antimuscarinic therapy, with fewer common, bothersome
side effects such as dry mouth, constipation, and urinary retention. Combination treatment of
solifenacin 5 mg plus mirabegron 25 or 50 mg was more effective than mirabegron 50 mg alone,
but with more anticholinergic side effects.
Conclusion
The relief of key OAB symptoms produced by mirabegron 50 mg is significantly better than placebo, and similar to a
range of common antimuscarinics, with the benefit of significantly fewer bothersome anticholinergic side effects
such as dry mouth. Combination treatment of solifenacin 5 mg plus mirabegron 25 or 50 mg appears to provide an
efficacy benefit compared with mirabegron 50 mg, with the expected side effects of individual antimuscarinics.
Efficacy and Tolerability of Mirabegron Compared with Antimuscarinic Monotherapy or Combination Therapies
for Overactive Bladder: A Systematic Review and Network Meta-analysis
-Eur Urol. 2018 Sep;74(3):324-333.

23. Objective: To ensure efficacy and safety is maintained in older patients (>65 yr), who usually experience greater symptom
severity and comorbidities, a prespecified subanalysis stratified by age group was conducted.
Design, setting, and participants: Patients remaining incontinent (episode during 3-d diary) following 4-wk single-blind
daily solifenacin 5 mg were randomized 1:1:1 to a daily double-blind combination (solifenacin 5 mg and mirabegron 25 mg,
increased to 50 mg at wk 4), solifenacin 5 mg or 10 mg for 12 wk. Four cohorts stratified by age (<65 yr, 65 yr and
< 75 yr, 75 yr) were investigated.
Conclusion
Efficacy and safety in the overall population is maintained in older ( 65 yr) and elderly ( 75 yr) patients treated
with a combination of solifenacin and mirabegron, or solifenacin monotherapy; irrespective of age, combination was
associated with the greatest improvement in overactive bladder symptoms.
Patient summary: This study investigated the effectiveness and safety of a combination of two different treatments
(mirabegron 50 mg and solifenacin 5 mg) or solifenacin (5 mg or 10 mg) alone in patients aged <65 yr or 65 yr,
and <75 yr or 75 yr with overactive bladder. Symptoms of overactive bladder, such as the urgent need to visit the
toilet, incontinence, and frequent urination, were improved with all treatments regardless of the patient’s age, but
combination treatment demonstrated the greatest benefit, and was well tolerated.
Treating Overactive Bladder in Older Patients with a Combination of Mirabegron and Solifenacin:
A Prespecified Analysis from the BESIDE Study - Eur Urol Focus.2017 Dec;3(6):629-638.

24. Cholinergic pelvic nerves release acetylcholine
(ACh), which, via activation of muscarinic M3
receptors, induce contraction of the detrusor
muscle and emptying of the bladder.
Anti-muscarinic agents (e.g., solifenacin) block the
muscarinic receptor and reduce detrusor muscle
contractions. Hypogastric adrenergic nerves release
norepinephrine (NE), which causes urinary
retention by activating β3-adrenergic receptors in
the detrusor muscle and alpha-adrenergic
receptors in the internal sphincter of the urethra.
Mirabegron, a β3-adrenergic receptor agonist,
reduces bladder contractions in patients with
neurogenic detrusor overactivity.
Of note, the classical nomenclature of the sacral
autonomic outflow has been recently challenged
Sites of action and mechanisms of therapeutic agents used for the treatment of neurogenic overactive bladder
- Mov Disord. 2018 Mar; 33(3): 372–390.

25. Treatment Recommended dosing regimen Adverse events Receptor selectivity CNS penetration
Anticholinergic agents
Darifenacin 7.5 or 15 mg/day Constipation, dry mouth, urinary retention M3 selective Low
Trospium
20 mg twice a day
60 mg/day (extended release form)
Constipation, dry mouth, dry eyes, headache, urinary
retention
Non-selective Low
Solifenacin 5 or 10 mg/day
Constipation, dry mouth, blurred vision, nausea,
dyspepsia, urinary retention
M3 and M1 selective Moderate
Oxybutinin
5 mg up to 4 times/day
5-30 mg/day (extended release form)
3 pumps once a day (gel)
1 patch every 3-4 days (patch)
Constipation, dry mouth, blurred vision, nausea,
dyspepsia, urinary retention
M3 and M1 selective Moderate
Tolterodine
2 mg twice a day
2 or 4 mg/day (long acting form)
Constipation, dry mouth, dyspepsia, dizziness, blurry
vision, urinary retention
Non-selective Moderate
Fesoterodine 4 or 8 mg
Constipation, dry mouth, dyspepsia, dizziness, blurry
vision, urinary retention
Non-selective Moderate
β3-adrenergic agonists
Mirabegron 25 or 50 mg/day
Hypertension, irregular heart rate, abdominal or pelvic
pain, worsening dyskinesias in PD (one case report)
β3-selective Low
Pharmacological treatments for neurogenic detrusor overactivity
Mov Disord. 2018 Mar; 33(3): 372–390.

26. β3-adrenergic agonists-
 β3-adrenergic receptors contribute to detrusor muscle relaxation.
 Mirabegron, a selective β3-adrenergic receptor, elicits relaxation of the detrusor muscle during the
storage phase, thereby improving bladder capacity without impeding bladder voiding.
 Mirabegron is available in most countries.
 Oral mirabegron administered once daily (25-50 mg) is effective to improve urinary frequency,
urgency, and incontinence in patients with overactive bladder.
 Mirabegron is devoid of anticholinergic adverse events but can cause urinary retention,
pelvic/abdominal pain, and hypertension

27. Antimuscarinic agents-
 Antimuscarinic drugs improve symptoms of detrusor overactivity by reducing cholinergic output to the bladder
and, thus, relaxing the detrusor muscle and reducing the urge to urinate.
 Antimuscarinic agents can worsen the post-void residual volume and cause urinary retention, dry mouth, dry
eyes, gastroparesis and constipation.
 There are several antimuscarinic agents, the majority of which are available in most world regions: they share
mechanism of action but differ in selectivity of M3 receptors, and CNS permeability.
 Centrally acting antimuscarinic (e.g., atropine or scopolamine) or predominantly peripheral with CNS penetrance
(oxybutynin, fesoterodine) can cause/aggravate cognitive impairment and should be avoided.
 Peripherally acting antimuscarinics with low CNS penetrance (e.g., trospium, darifernacine) are preferable.
 Only solifenacin 5-10 mg daily has been specifically studied in a randomized placebo-controlled trial of patients
with PD showing a significant reduction in urinary frequency compared to placebo.

28. Other treatments-
 Alpha-adrenergic blockers (Tamsulosin, Silodosin) should be used very cautiously, or not at all, in patients with
autonomic dysfunction as they can aggravate OH and increase the risk of falls and syncope.
 Open label studies showed that intramural botulinum toxin injections in the bladder can improve refractory
neurogenic detrusor overactivity in patients with PD and MSA; potential adverse events include urinary
retention.198-200 Nocturnal natriuresis in patients with supine hypertension and nOH should be distinguished
from neurogenic detrusor overactivity.

29. Treatment of detrusor underactivity-
 Incomplete bladder emptying as a consequence of detrusor underactivity is common in MSA (multiple system
atrophy) and seldom reported in patients with PD (Parkinson disease), DLB (dementia with Lewy bodies) or PAF
(pure autonomic failure).
 Estimation of the post-void residual (PVR) bladder volume is a simple and useful test in patients with MSA; even
though their urinary complaints may be limited to urinary urgency or frequency, patients are usually unaware
that their bladders do not empty completely. PVR can be measured by ultrasound echography or transurethral
catheterization.
 If the patient has a PVR > 100 ml, clean intermittent self-catheterization must be recommended. Either the
patient or the caregiver can usually perform this after education is provided. In patients with advanced disease
and severe neurological disability, a permanent indwelling catheter, usually suprapubic, may be required.
 Antimuscarinic or β3-adrenergic treatment to reduce bladder overactivity should be added regardless of the
PVR. The caveats are the same as with the treatment of overactive bladder. Replaceable remote-controlled intra-
urethral prosthesis for women with underactive bladder have been recently approved by the U.S. FDA;209 these
do not require surgery, increase quality of life, and reduce the risk of urinary complications, although the
experience in patients with MSA is still limited

30. Incomplete bladder emptying as a consequence of detrusor
underactivity is common in multiple system atrophy (MSA)
but seldom reported in patients with other synucleinopathies.
Estimation of the post-void residual (PVR) bladder volume is
a simple and useful test in patients with MSA; even though
their urinary complaints may be limited to urinary urgency or
frequency, patients are usually unaware that their bladders do
not empty completely.
PVR can be measured by ultrasound echography or
transurethral catheterization. If the patient has a PVR > 100
ml, clean intermittent self-catheterization must be
recommended. Either the patient or the caregiver can usually
perform this after education is provided. In patients with
advanced disease and severe neurological disability, a
permanent indwelling catheter, usually suprapubic, may be
required. Antimuscarinic or β3-adrenergic treatment to
reduce bladder overactivity should be added regardless of the
PVR. (*) Replaceable remote-controlled intra-urethral
prosthesis for women with underactive bladder have been
recently approved by the Food and Drug Administration. Our
experience in women with MSA, although limited, is very
positive.
Algorithm for the management of underactive bladder in patients with synucleinopathies
Mov Disord. 2018 Mar; 33(3): 372–390.