Medical Management for Overactive Bladder

Medical Management
for Overactive Bladder
How to choose which one to use
Kristy Borawski, MD
Disclosures

None
Off-Label Discussion

None
Overview

Anticholinergics
Side effects, cautions & contraindications
 Anticholinergics in certain disease states


Beta-3 agonist
Precautions/Contraindications
 Combination therapy safety


Overactive bladder (OAB): new ICS definition


“urgency, with out without urge incontinence, usually
with frequency and nocturia1”
Prevalence exceeding 16%

33 million adults in USA



12 million with urgency urge incontinence
21 million without incontinence2
Cost equivalent in US 2000 dollars


$19.5 billion for incontinence
$12.6 billion for OAB3
1Abrams,
et al. Neurourol Urodyn 2010: 29: 213-240. 2Dmochowski, et al. Curr Opin Urol 2011: 21.
3Hu, et al. Urol 2004: 63: 461-465.
Persistence and compliance with medical overactive
bladder syndrome therapy remain astoundingly low
both in the clinical setting and in large-scale
clinical trials
Rosenblum. Rev in Urol 2009, 11: 45-51.
Antimuscarinics

Most commonly prescribed class of medications
for overactive bladder
Cameron, et al. J Urol, 182: 1062, 2009. Stevens, et al. Eur Urol 52: 531, 2007.
Anticholinergics

Muscarinic Receptor Subtypes
Subtype
Distribution
Role
M1
Brain (cortex, hippocampus), Salivary
gland
Cognitive function, memory; saliva
secretion
M2
Heart, brain, smooth muscle
Regulation of heart rate & HR
variability; behavioral flexibility
M3
Smooth muscle, glands, eye
Smooth muscle contraction, iris
contraction, gland secretion
M4
Brain (forebrain, striatum)
Dopamine dependent behaviors
M5
Brain (substantia nigra), eye
Regulation of striatal dopamine release
Anticholinergics

Antimuscarinics & M3 Receptor Selectivity
Anticholinergics

Antimuscarinics & Common Side Effects
Dry mouth
 Constipation
 Blurred vision

Anticholinergics
Constipation
Dry Mouth
Enablex 7.5mg
14.8%
20.2%
15mg
21.3%
35.3%
5.4%
10.9%
13.4%
27.6%
8.5%
10.7%
7%
35%
4.2%
18.8%
6%
34.6%
Vesicare 5mg
10mg
Sactura XL 60mg
Detrol LA 4mg
Toviaz 4mg
8mg
Anticholinergics

Antimuscarinics & Feared Side Effects
Urinary Retention
 Cognitive Side Effects
 Cardiovascular Side Effects
 Drug Interactions

Urinary retention with
Anticholinergic Use
Anticholinergics: Retention
Anticholinergics: Retention

Kaplan, et al. JAMA 2006
Tolterodine + flomax, flomax only, tolterodine only
vs. placebo
 80% improvement in combination group

62% placebo
 71% flomax only
 65% tolterodine only

Kaplan, et al. JAMA 2006: 296(19): 2321.
Anticholinergics: Retention
Anticholinergics: Retention

Kaplan, et al. JAMA 2006

Low incidence of acute urinary retention
0.4% combination
 0.5% tolterodine only
 0% placebo
 0% flomax only

Kaplan, et al. JAMA 2006: 296(19): 2321.
Anticholinergics: Retention
Blake-James, et al. BJU Int 2006: 99: 85.
Cognitive Decline with
Anticholinergic Use
Anticholinergics:
Cognitive Side Effects

Merchant, et al.

Prevalence of cognitive impairment more than
doubled with the use of drugs with anticholinergic
activity in community dwelling older persons
CNS Penetration

Entry into the brain via BBB by passive
diffusion dependent on:


Molecular size, polarity, lipophilicity
Highly lipophilic, non polar small molecules will
more readily cross the BBB by passive diffusion
Oxybutynin: 357kDareadily passes BBB
 Darifenacin, solifenacin, tolterodine, fesoterodine all
>475kDa unlikely to pass via passive diffusion
 Tropsium (Sancura) hdrophilic, polar compound,
428kDa  low propensitiy for BBB penetration

Cognitive Impairment &
Receptor Selectivity

M1 & M2 receptors are important in cognitive
functioning and memory & behavioral flexibility
& learning
More data that central blockade of M1 receptors has
a key functional role in cognitive impairment
 Less M3 selectivity may be associated with increased
risk of cognitive impairment


Sanctura (tropsium): although relatively non-selective, low BBB
penetration should have low potential for cognitive risk as long
as BBB integrity is not compromised

Elderly are more likely to develop central
anticholinergic side effects
Age related deficit in central cholinergic transmission
 Deficient drug metabolism
 Numerous studies highlighting increased cognitive
impairment in the elderly (compared to younger
cohort) using anticholinergic drugs

Cancelli, et al. J Cl Psychopharm 28(6): 654, 2008
Cardiovascular Effects with
Anticholinergic Use
Anticholinergics:
Cardiovascular Side Effects

Andersson, et al

Patients with OAB more likely to have CV comorbidities compared with age/gender matched
non-OAB patients (39% vs. 21%)

HTN most common
Anticholinergics:
Cardiovascular Side Effects

M2 receptors
Modify pacemaker activity and atrioventricular
function, altering the contractile force in atrium &
ventricles
 Blockade of M2 receptor reduces down-regulation of
HR by lowering effect of acetylcholine on the
receptors

Leads to increased HR & possibly tachycardia 
increased oxygen demand by myocardium
 Evidence (not in OAB pts) that increased resting HR
correlates to increased mortality & morbidity

Anticholinergics:
Cardiovascular Side Effects
Rosa, et al. Exp Opin Drug Safety, 12(6): 815, 2013.
HR & Mortality

Even a small change in HR can be significant

Increase 5bpm: 16-17% increase mortality
Anticholinergics:
Cardiovascular Side Effects

Heart rate variability (HRV)
Used as a surrogate measure of autonomic
influences on the heart
 Decreased HRV associated with increased risk of
CV events (MI, HTN, CAD)

Anticholinergics:
Cardiovascular Side Effects


Darifenacin: does not significantly increase HR or
decrease HRV compared to placebo
Tolterodine: HR increased 1.84-2.24bpm compared to
darifenacin and 1.42 – 1.84bpm increased compared to
placebo

Decrease in HRV with tolterodine compared to darifenacin
placebo
Rosa, et al. Exp Opin Drug Safety, 12(6): 815, 2013.
Anticholinergics & Parkinson’s
Disease
Rosa, et al. Exp Opin Drug Safety, 12(6): 815, 2013.
ACh & Parkinson’s Disease

Neurogenic Detrusor Overactivity is very
prevalent in PD population
Dopaminergic mechanism though to play a central
role in normal micturition control
 D1 receptors in basal ganglia inhibits the mictuition
reflex


Cell depletion results in loss of this D1-mediated
inhibition
Mohammed, et al. Neurol Urodyn 30: 1258, 2011.
ACh & Parkinson’s Disease

No studies looking solely at PD & outcomes
with anticholinergics


VA study currently recruiting
Two main potential issues with Ach use
Anticholinergic properties of antiparkinsonian drugs
 Concurrent dementia

Anticholinergics & Alzheimer’s
Disease
Anticholinergics & Alzheimer’s
Disease


One of the leading cause of dementia in the
elderly
High rates of incontinence in elderly patients
with dementia
11-36% community dwelling
 40-53% mixed inpatient/outpatient
 78-90% long-term care/inpatient

Siegler, et al. Clin Pharmacol Ther 75: 484, 2004.
Anticholinergics & Alzheimer’s
Disease

Cholinesterase inhibitors are mainstay of
treatment for Alzheimer's disease

Initiating treatment with cholinesterase inhibitors
shown to have a 5-10% risk of urinary incontinence

Also may worsen pre-existing incontinence
Beier, et al. JAMDA, 413, 2005
Anticholinergics & Alzheimer’s
Disease


Combination treatment may lead to
pharmacologic antagonism
May precipitate increased confusion,
hallucinations and frank delirium
Beier, et al. JAMDA, 413, 2005
Anticholinergics & Alzheimer’s
Disease

Blood brain barrier may become “leaky” with
age and brain injury


May result in easier access of drugs into BBB despite
safe pharmacokinetic profiles
Studies showing significant decline in
Alzheimer’s patients usually involved oxybutynin
Steers, et al. Cur Urol Rep, 441, 2007.
Anticholinergics & Alzheimer’s
Disease


Awareness of anticholinergic properties of
medications
Avoid oxybutynin



Consider avoiding tolterodine
Consider hydrophilic (tropsium) vs. M3 selective
drug (darifenacin)
Warn caregivers/patient about potential risk &
have low threshold to stop anticholinergic
Steers, et al. Cur Urol Rep, 441, 2007.
Miscellaneous Concerns
Renal/Hepatic Impairment

Depending on drug, some dose adjustments or
limitations are required

Check with manufacturer’s prescribing information
Creatinine clearance <30mL/min
 Hepatic impairment (Child-Pugh > B)

Pregnancy/Breastfeeding

Ditropan: Category B




Unknown if it passes into breast milk
Vesicare: not recommended for pregnant or
breastfeeding patients
Enablex/Toviaz/Detrol: only use if perceived
benefit outweighs unknown risk for
pregnant/breastfeeding patient
Sanctura: Category C

Unknown if it passes into breast milk
Myrbetriq® (Mirabegron)

Beta-3 agonist
Promotes bladder relaxation
 FDA approved June 2012

Myrbetriq® (Mirabegron)

Contraindications

Severe uncontrolled HTN
>180 systolic
 >110 diastolic

End Stage Renal Disease
 Child-Pugh Class C Liver Failure

Myrbetriq package insert, available at astellas.com
Nitti, et al. Int J Clin Prac 2014
Myrbetriq® (Mirabegron)
Will it cause hypertension?

No
Myrbetriq 25
Myrbetric 50
Myrbetriq 100
Tolterodine
Systolic BP am
-0.5
-0.6
0.4
0.1
Systolic BP pm
-1.0
0.5
0.9
0
Diastolic BP am
-0.1
0.4
0.2
0.7
Diastolic BP pm
-0.3
0.4
0.5
1
Nitti, et al. Int J Clin Prac, 2014
Myrbetriq® (Mirabegron)
Will it cause tachycardia?

Rarely
Myrbetriq 25

Myrbetric 50
Myrbetriq 100
Tolterodine
Pulse rate am
0.9
1
1.9
1
Pulse rate pm
0.6
1
2.3
2.1
Patients with heart rate >100bpm
12 week study, 4.2% myrbetriq, 3.1% placebo, 3.2%
tolterodine
 1 year study: 4.5% myrbetriq, 6.5% tolterodine

Nitti, et al. Int J Clin Prac, 2014
Myrbetriq® (Mirabegron)
Will it cause retention?

Rates similar to placebo & tolterodine

2 cases of retention in myrbetriq group
Nitti, et al. Int J Clin Prac, 2014
Myrbetriq® (Mirabegron)
Combination therapy?

Flomax & Myrbetriq
No significant difference in adverse events
 No significant difference in pulse or blood pressure


Solifenacin & Myrbetriq
Improved mean volume voided per micturition in
combination group with decreased
frequency/urgency
 No additional safety /adverse findings

van Gelderen, et al. Int J Clin Pharm Th 2014. Abrams, et al. Eur Urol 2014
Myrbetriq® (Mirabegron)
Combination therapy?

Flomax & Myrbetriq
No significant difference in adverse events
 No significant difference in pulse or blood pressure

van Gelderen, et al. Int J Clin Pharm Th 2014
Myrbetriq® (Mirabegron)
Elderly?
Wagg, et al. Age Ageing, 2014.
Miscellaneous Concerns
Renal/Hepatic Impairment

Renal Insufficiency
CrCl 15 -30: Max dose 25mg daily
 ESRD: contraindicated


Hepatic Dysfunction
Child-Pugh Class B: max dose 25mg daily
 Child-Pugh Class C: contraindicated

Pregnancy/Breastfeeding

Pregnancy: Class C

Breastfeeding: myrbetriq is found in the milk of
nursing rats. Assume it will cross into human
milk & use extreme caution in nursing mothers