anticholinergic in urologic conditions-sibicky

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The Impact of Anticholinergic Burden in Urologic Conditions

Stephanie L. Sibicky, PharmD, MEd, BCGP, BCPS, FASCP

Associate Clinical Professor

Northeastern University | Bouvé College of Health Sciences

School of Pharmacy | Boston, MA

@stephsibicky

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Meet the Speaker:Stephanie L. Sibicky, PharmD, MEd, BCGP, BCPS, FASCP

• Associate Clinical Professor, Northeastern University School of Pharmacy, Boston, MA• Clinical Pharmacy Faculty in Internal

Medicine at Brigham and Women’s Hospital, Boston, MA

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Disclosure

• I have no potential or actual conflicts of interest to disclose

• Off-label use of medications will be identified

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Learning Objectives

• Recognize urology conditions and complications that emerge in the older adult population• Discuss strategies to review medication management to ensure that

urinary conditions and perceived complications are not the result of other conditions (diuretic use, uncontrolled diabetes mellitus, urinary tract infections, etc.)• Compare and contrast treatments for urgency, frequency, urinary leakage,

urge incontinence, and dysuria• Discuss the adverse effect potential of currently available medications for

these issues and their impact on polypharmacy in older adults• Create a safe non-pharmacologic and pharmacologic treatment plan for an

older adult that lowers the risk of anticholinergic burden and the polypharmacy that may result

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Anatomy & PathophysiologyUreters

Detrusor Muscle

External Sphincter

Internal Sphincter

Parasympathetic Nervous SystemSympathetic

Nervous System (α-adrenergic)

Bladder Neck

Somatic Nervous System

Capacity ≈ 300 ml

Handb Clin Neurol. 2019;167:495-509.Picture: http://iahealth.net/wp-content/uploads/2008/12/bladder-other.jpg

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Pathophysiology: Storage PhaseUreters

External Sphincter

Internal Sphincter



Bladder Neck


Inhibitory Signal from Cortex

Detrusor Muscle


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Pathophysiology: Storage PhaseUreters

External Sphincter

Internal Sphincter



Bladder Neck



CONTRACTION (Closed)

CONTRACTION (Closed)

Bladder FillingDetrusor Muscle

RELAXATIONβ3


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Pathophysiology: Voiding PhaseUreters

Detrusor Muscle

External Sphincter

Internal Sphincter



Bladder Neck




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Detrusor Muscle

External Sphincter

Internal Sphincter



Bladder Neck



MICTURITIONRELAXATION

(Open)

AChM3

RELAXATION (Open)

Ach – acetylcholine Handb Clin Neurol. 2019;167:495-509.

Picture: http://iahealth.net/wp-content/uploads/2008/12/bladder-other.jpg

CONTRACTION

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The Aging Urinary TractPhysiologic Change Results In…

↓ bladder elasticity Less capacity for volume

↑ residual volume Incomplete emptying

↑ nocturnal sodium and fluid excretion Nighttime awakening to urinate

↑ urethral resistance (enlarged prostate, men) Weak stream, difficulty urinating

↓ urethral resistance (↓ estrogen, women) Urgency, going too much

Weakened pelvic floor muscles Inadequate support of external sphincter, leakage

↑ involuntary bladder contractions Urgency, got to go NOW!

All contribute, but none alone precipitates incontinence

Handb Clin Neurol. 2019;167:495-509.

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Urologic Conditions in Older AdultsConditions

Voiding dysfunction

Benign prostatic hyperplasia

Incontinence

Nocturia

Malignancies

Bladder

Kidney

Prostate

Dysuria

Cystitis/ Pyelonephritis

Urethritis

Vaginitis

Erectile dysfunction


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0%

20 %

40 %

60 %

80 %

C o mm u n ity re g u la r UI C o mm u n ity a n y UI C o mm u n ity a n y UI C o mm u n ity fra i l o ra cu te ho s pi ta l

Nu rs in g ho m e

% p

reva

lenc

e

Epidemiology of Urinary Incontinence (UI)

♂♀

2.5X more common in women

Handb Clin Neurol. 2019;167:495-509.Med Clin North Am. 2011 Jan;95(1):253-64.

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Consequences of IncontinenceMedical

Risk of cystitis, urosepsis, pressure

sores, perineal rashes, sleep disturbances, dehydration, falls

PsychosocialEmbarrassment,

isolation, depression, predisposition to

institutionalization

EconomicCost of supplies,

medications, home health aide/care at

home, nursing facility


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Evaluation and Diagnosis of UI

HISTORY

• Symptoms (onset, type, frequency, timing)• Bladder record or voiding diary• Comorbidities (e.g., cognitive

impairment, Parkinson’s disease)• Lifestyle• Environment• Patient perception of incontinence• Medications

PHYSICAL

• Mobility issues and frailty• Gynecological and urological

evaluation• Tests

• Urinalysis and urine cultures• Blood chemistries (including glucose,

vitamin D, B12)• Renal function• Catheterization or bladder ultrasound

(residual volumes)• Cystoscopy and flow studies• Urinary stress test

Med Clin North Am. 2011 Jan;95(1):253-64.JAMA. 2017 Oct 24;318(16):1592-1604.

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Goals of Therapy of UI

• Minimize signs and symptoms most bothersome to the patient1. Non-pharmacologic techniques2. Medications3. Surgical intervention

• Set realistic expectations• Total elimination of symptoms may not be feasible• Communicate most common side effects• Balance patient goals, expectations, and risks

JAMA. 2017 Oct 24;318(16):1592-1604.

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Types of Urinary Incontinence

Acute/Transient UIReversible causes

Medication-induced

Chronic/Persistent UIUrge

StressMixed

OverflowFunctional

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Classification: Acute/Transient

• Signs and symptoms with recent onset• May be associated with an acute medical problem• Infection• Heart failure• Acute confusion or altered mental status• Constipation• Surgical procedures

• Can also alter/exacerbate chronic UI


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Reversible Causes & ManagementCondition Management

Delirium Treat underlying cause

Restricted mobility, injury, restraint Scheduled toileting, assistive devices, environment changes

Infection

• Urinary tract infection • Antibiotics (not asymptomatic bacteriuria)

• Atrophic vaginitis/urethritis • Topical estrogen

• Prostatectomy • Behavioral, no additional surgery within first year

Stool Impaction Anti-constipation medications, increase fluid intake, manual disimpaction

Polyuria

• Metabolic (hyperglycemia, hypercalcemia) • Control diabetes, treat underlying cause

• Excess intake • Fluid restriction, reduce diuretic fluids (e.g., caffeine)

• Volume overload • Diuretics

• Venous insufficiency/edema • Compression stockings, leg elevation, sodium restriction, diuretics

Pharmaceuticals Discontinue, change, decrease dose, timing, polypharmacy


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Medication-Induced IncontinenceStress

• α-blockers • Atypical antipsychotics• ACE inhibitors • Sedative-hypnotics

Urge• Antidepressants • Hormone replacement• 5HT4 (serotonin)-agonists• Direct or indirect parasympathomimetics (cholinesterase inhibitors)

Overflow• Anticholinergics • α-agonists• Antiparkinson drugs • Opioids• β-agonists • Calcium channel blockers

Functional• Histamine antagonists • Opioids• Antipsychotics • Alcohol• Benzodiazepines • Antidepressants

Increase Urine Production

• Diuretics • Thiazolidinediones• Lithium • Muscle relaxants• NSAIDs • Alcohol

Handb Clin Neurol. 2019;167:495-509.ACE – angiotensin-converting enzyme; NSAIDs – non-steroidal anti-inflammatory drugs

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Case BW

• BW is a 72-year-old female who presents to the clinic complaining of increased frequency (every 2 hours), urgency, and moderate leakage• PMH includes diabetes, uncontrolled hypertension, osteoporosis, and

hypothyroidism• Medications include metformin, HCTZ, amlodipine, calcium + vitamin

D, and levothyroxine• When asking her about OTC use, she mentions needing to take

Miralax daily

HCTZ – hydrochlorothiazide; OTC – over-the-counter

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Case BW, cont.

After removing the potential acute causes of UI, BW continues to have symptoms. She mentions that she has leakage when she sneezes and

often needs to “race to the ladies' room” throughout the day.

How would you classify BW’s incontinence?

a) Urgeb) Stressc) Overflowd) Mixed

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Types of Urinary Incontinence

Acute/Transient UIReversible causes

Medication-induced

Chronic/Persistent UIUrge

StressMixed

OverflowFunctional

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Classification: Chronic/Persistent UIUrge Stress Overflow Functional

Cause Detrusor muscleoveractivity

Weakened pelvic floor muscles

Bladder distensiondue to obstruction

(BPH, fecal impaction)

Underlying physical or mental

impairment impacting ability to

toilet

Common Symptoms

Urgency with or without

incontinence, frequency, nocturia

or enuresis

Incontinence with coughing, sneezing, laughing, exercise,

activities that increase abdominal pressure, frequency

Incomplete voiding, frequency, hesitancy,

abdominal fullness, straining

Incontinence –looks like urge

Mixed = usually combination of urge and stress incontinence

Med Clin North Am. 2011 Jan;95(1):253-64.

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Urge Urinary Incontinence (UUI)

• Involuntary voiding preceded by a brief warning• Causes:• Detrusor muscle instability (involuntary

contraction) • Two hypotheses

• Neurogenic• Myogenic

• Overactive bladder (OAB)• Syndrome including urgency, frequency, and nocturia• With or without urge incontinence

Picture: http://sketchym edicine.com /2012/02/stress-urge-overflow-and-m ixed-incontinence/

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UUI Treatment Strategy

• Identify and mitigate any reversible causes

• Non-pharmacologic• Lifestyle (e.g., diet, behavior)• Surgical

• Pharmacologic• Expectation of 4-8-week response• If no response, can switch to another agent in same class

JAMA. 2017 Oct 24;318(16):1592-1604.

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Non-pharmacologic Treatment of UUI

• Diet (monitoring fluid, caffeine, bladder irritants)• Exercise and weight loss • Smoking cessation• Scheduling regimens:

• Timed voiding• Bladder training and scheduling

• Muscle rehabilitation:• Pelvic floor muscle exercises (e.g., Kegel exercises)• Biofeedback, electrical stimulation• Acupuncture

• Surgery NEJM. 2009;360(5):481-90.BJU Int. 2003;92(1):69-77.

Cochrane Database Syst Rev. 2014; May 14;(5):CD005654.Pictures: https://www.healthlinkbc.ca/sites/default/libraries/healthwise/

m edia/m edical/hw/h9991505_001.jpg; https://www.liberatorm edical.com /purewick/im g/purwick_works.jpg

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External Urine CollectionCondom Catheter (Men) PureWick™ (Women)

https://youtu.be/xSOuvcShikw

Pictures: https://www.healthlinkbc.ca/sites/default/libraries/healthwise/m edia/m edical/hw/h9991505_001.jpg;

https://www.liberatorm edical.com /purewick/im g/purwick_works.jpg

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https://youtu.be/xSOuvcShikw

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Urinary Prosthesis (Women)

• Draws urine out of the bladder and blocks urine flow out• Inserted by physician, then by patient or caregiver• Replace every 29 days• Use remote control to void• Informational videos:

http://vesiflo.com/videos/

Picture: http://www.thedailynarrative.com /wp-content/uploads/2014/10/20141014-FG30001014FDA-H.jpg?33fdec /

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Detrusor Muscle

External Sphincter

Internal Sphincter



Bladder Neck




(Open)

AChM3

RELAXATION (Open)



CONTRACTION

β3

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UUI Treatment: Anticholinergics

• Reduce cholinergic transmission to bladder, inhibit involuntary detrusor contraction, increase bladder capacity, decrease frequency of urination• Side effects: dry mouth, visual disturbances, constipation, dry skin• Precautions: arrhythmias (QT-prolongation with solifenacin,

tolterodine), cardiovascular disease, gastrointestinal motility issues, dementia, and older adults• Contraindications: gastrointestinal obstruction, closed and narrow

angle glaucoma

JAMA. 2017 Oct 24;318(16):1592-1604.

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Anticholinergic Side Effects/Toxidrome Poem

Blind as a bat... (mydriasis)Mad as a hatter... (confusion)Red as a beet... (flushed skin)Hot as a hare... (hyperthermia)Dry as a bone... (dry mouth/urinary retention)the bowel and bladder lose their tone... (absent bowel sounds/less bladder contraction)...and the heart runs alone! (tachycardia)

Picture: https://sketchym edicine.com /wp-content/uploads/2012/01/20120129-123248-293x400.jpg

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UUI Treatment Targets: Non-selectiveReceptor Anatomical Location Result of Antagonism

M1Brain Cognitive impairment

GI tract Constipation, dry mouth

M2

Brain Cognitive impairment

Heart Tachycardia

Urinary tract Bladder relaxation, sphincter closing

M3



Ophthalmologic Mydriasis

M4 Brain Balance impairment

Adapted from Zimmerman K, 2015.GI - gastrointestinal

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UUI Treatment Targets: Non-selectiveReceptor Anatomical Location Result of Antagonism



M2


Heart Tachycardia


M3






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Non-selective AnticholinergicsMedication Formulations Adverse Effects Additional Comments

Oxybutynin IR tablets (Ditropan®) MOST Reference standardGradual dose escalation

ER tablets (Ditropan XL®) Better tolerated than IR

Patch (Oxytrol®) OTC for women onlyBypasses 1st pass

Gel (Gelnique®) Bypasses 1st pass

Tolterodine IR tablets (Detrol®) CYP2D6 > CYP3A4 metabolismRenal dose adjustments

ER capsules (Detrol® LA) Better tolerated than IR

Fesoterodine ER tablets (Toviaz®) Adjustments for renal impairment and 3A4 and 2D6 inhibitors

Trospium IR tablets (Sanctura®) Dose adjustment for CrCl < 30 ml/min

ER tablets (Sanctura XR®)LEAST

Better tolerated than IRAvoid in renal impairment

JAMA. 2017 Oct 24;318(16):1592-1604.IR – immediate release; ER – extended release; OTC – over-the-counter; CrCl – creatinine clearance

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UUI Treatment Targets: SelectiveReceptor Anatomical Location Result of Antagonism



M2


Heart Tachycardia


M3






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Selective AnticholinergicsSolifenacin

• IR tablets (Vesicare®)• M3 selectivity > M2• Efficacy

• Non-inferior to oxybutynin IR• Superior to tolterodine IR

• Side effects• Less than oxybutynin and tolterodine• More than darifenacin

• Maximum 5 mg/day• Renal impairment (CrCl < 30 ml/min)• Moderate and severe hepatic impairment

• CYP2D6 and 3A4 substrate

Darifenacin

• ER tablets (Enablex®)• Truly selective for M3• Efficacy

• Non-inferior to oxybutynin IR• More effective than tolterodine IR at 12

weeks

• Fewer side effects than oxybutynin• No renal dose adjustment• Hepatic impairment

• Moderate – max 7.5 mg/day• Not evaluated in severe

JAMA. 2017 Oct 24;318(16):1592-1604.IR – immediate release; ER – extended release; CrCl – creatinine clearance

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UUI Treatment: Efficacy

• Similar efficacy between agents although limited head-to-head trials • Anticholinergics have a modest benefit over placebo• Reduction in 0.5-0.7 UI episodes/day • Reduction of UI episodes for drug therapy alone (58%) v. in combination with

behavioral interventions (69%)

• Continuation rates• 50% of patients still unhappy or frustrated with symptoms after treatment• 60-70% of women discontinue within 6 months• 50% continue at 3 months, 25% at 12 months, 10% beyond 2 years

• Most agents need to be tried for 4-8 weeks to see effect AHRQ 2012. Ann Intern Med. 2012;156(12):861.

Drugs Aging. 2018 Sep;35(9):773-776.JAMA. 2017 Oct 24;318(16):1592-1604.

Cochrane Database Syst Rev. 2012 Jan 18;1:CD005429.

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Anticholinergic BurdenAdverse effects

Extended-release lower rate than immediate release

Higher doses associated with increased incidence

FrailtyLack of robust evidence for effect on frail, older adults

Potential safety concern

Polypharmacy

Nearly 600 medications with anticholinergic effects

50% of older adults prescribed one anticholinergic medication

Multiple scoring tools available to quantify anticholinergic burden

Cognitive decline

Observational studies suggest increased probability with anticholinergics

2019 AGS Beers Criteria® recommends avoiding medications with high anticholinergic burden in dementia or cognitive impairment

Drugs Aging. 2018 Sep;35(9):773-776.J Am Geriatr Soc. 2011;59(8):1477–83.

J Am Geriatr Soc. 2015 Jan;63(1):85-90.J Clin Psychiatry. 2001;62 Suppl 21:11–4.

J Am Geriatr Soc. 2019 Apr;67(4):674-694.AGS – American Geriatrics Society

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AGS Beers Criteria® Strong AnticholinergicsAmitriptyline Darifenacin Imipramine Propantheline

Amoxapine Desipramine Loxapine Protriptyline

Atropine (not ophth.) Dexbrompheniramine Meclizine Pyrilamine

Belladonna alkaloids Dexchlorpheniramine Methscopolamine Scopolamine (not ophth.)

Benztropine Dicyclomine Nortriptyline Solifenacin

Carbinoxamine Dimenhydrinate Olanzapine Thioridazine

Chlorpromazine Disopyramide Orphenadrine Trifluoperazine

Clemastine Doxepin (> 6 mg) Oxybutynin Trihexyphenidyl

Clidinium-chlordiazepoxide Doxylamine Paroxetine Trimipramine

Clomipramine Fesoterodine Perphenazine Triprolidine

Clozapine Flavoxate Prochlorperazine Trospium

Cyclobenzaprine Homatropine (not ophth.) Promethazine Tolterodine

Cyproheptadine Hydroxyzine

J Am Geriatr Soc. 2019 Apr;67(4):674-694.

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Anticholinergics and DementiaGray et al., 2015

Objective Association between 10-year cumulative AC use and risk of dementia

Study Design Prospective cohort study of 3,434 people in Washington

Baseline Characteristics

Median age 74.4, 91.4% white, 59.6% women, 78.3% with 1 fill for AC medication in 10 years before study entry

Findings • Mean follow up 7.3±4.8 years, 23.2% patients developed dementia with 79.9% with probable or possible AD

• TSDD > 1095 increased risk of dementia (HR 1.54, 95% CI 1.21-1.96) and AD (HR 1.63, 95% CI 1.24-2.14) compared to non-use

Other Conclusions Person taking an AC (e.g., doxepin 10 mg, oxybutynin 5 mg) daily for > 3 years would have greater risk of dementia

AC – anticholinergic; AD – Alzheimer’s disease; TSDD – total standardized daily doses; OR – odds ratio JAMA Intern Med. 2015;175(3):401-407.

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Anticholinergics and Dementia, ContinuedCoupland et al., 2019

Objective Association between cumulative AC use and risk of dementia including analysis of prescriptions 20 years before diagnosis

Study Design Nested case-control study of 58,769 patients with dementia matched with 225,574 controls in England

Baseline Characteristics

Mean age 82.4±7 years, 97% white, 63.1% women, 56.6% with any AC medication in 1-11 years before index date

Findings • Adjusted OR associated with cumulative AC exposure increased from 1.06 (95% CI 1.03-1.09) for 1-90 TSDD to 1.49 (95% CI 1.44-1.54) for > 1095 TSDD compared to non-use

• Increased risk associated with bladder antimuscarinics; in those > 1095 TSDD OR 1.65 (95% CI 1.56-1.75) compared to non-use

Other Conclusions • Stronger association when diagnosed with dementia < 80 years old• Similar risk to other modifiable risk factors for dementia

AC – anticholinergic; AD – Alzheimer’s disease; TSDD – total standardized daily doses; OR – odds ratio JAMA Intern Med. 2019;179(8):1084-1093.

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Detrusor Muscle

External Sphincter

Internal Sphincter



Bladder Neck




(Open)

AChM3

RELAXATION (Open)



CONTRACTION

β3

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β3-agonist: Mirabegron

• ER tablet (Myrbetriq®)• Reduces bladder contractions via

relaxation of detrusor muscle through β3-agonism• Moderate inhibition of CYP2D6,

substrate of 2D6, 3A4, p-glycoprotein• Maximum 25 mg/day if

CrCl < 30 ml/min• Side effects: hypertension,

nasopharyngitis, UTI, constipation, tachycardia, headache

Efficacy:

• Full in 4-8 weeks• Reduction in 0.5 episodes/day

at 50 mg dose• Mirabegron + solifenacin v.

solifenacin alone (71% v. 54% reduction, p=0.03)

• Mirabegron + solifenacin v. mirabegron alone (71% v. 61% reduction, NSS)

ER – extended release; CrCl – creatinine clearance; UTI – urinary tract infection; NSS – not statistically significant

BJU Int. 2017 Oct;120(4):562-575.JAMA. 2017 Oct 24;318(16):1592-1604.

Mirabegron [package insert]. Northbrook, IL: Astellas Pharma US, Inc.; 2018.

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β3-agonist: Vibegron

• Crushable, 75 mg tablet (Gemtesa®) available starting April 2021• Use not recommended if

eGFR < 15 mL/min/1.73 m2

• No CYP2D6 interactions• No blood-brain barrier penetration

in animal studies• Side effects: headache,

nasopharyngitis, diarrhea, nausea

Efficacy (at 12 weeks):

• Mean CFB of 0.5 micturitions/day (-1.8 vs. -1.3 placebo, p < 0.001)

• Mean CFB of -0.6 incontinent episodes/day (-2 vs. -1.4 placebo, p < 0.0001)

• Statistically significant reduction in secondary outcomes including reduction in urgency episodes, volume per micturition, proportion of incontinent patients with a ≥ 75% reduction in UUI episodes

• No increase in hypertensive episodes

J Urol. 2020 Aug;204(2):316-324.Expert Opin Pharmacother. 2021 Jan;22(1):9-17.

Vibegron [package insert]. Irvine, CA: Urovant Services, Inc; 2020.eGFR – estimated glomerular filtration rate; CFB – change from baseline

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Other Pharmacologic Treatment

• Tricyclic Antidepressants (e.g., imipramine)• Increases bladder capacity and outlet resistance, anticholinergic properties• Side effects: weakness, fatigue, postural hypotension, hip fractures

• Botox® (onabotulinumtoxinA)• Muscle paralytic when injected into detrusor muscle• Injected into 20 sites via urethra every 6-12 weeks• Decreases 1.6-1.9 episodes/day• Risks include urinary retention and infection

JAMA. 2017 Oct 24;318(16):1592-1604.

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(A reminder…) Case BW

• BW is a 72-year-old female who presents to the clinic complaining of increased frequency (every 2 hours), urgency, and moderate leakage• PMH includes diabetes, uncontrolled hypertension, osteoporosis, and

hypothyroidism• Medications include metformin, HCTZ, amlodipine, calcium + vitamin

D, and levothyroxine• When asking her about OTC use, she mentions needing to take

Miralax daily

HCTZ – hydrochlorothiazide; OTC – over-the-counter

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Case BW, cont.

Besides non-pharmacologic options, which treatment for urge UI would be most appropriate for BW?

a) Mirabegronb) Oxybutynin IRc) Darifenacind) Tolterodine ER

IR – immediate release; ER – extended release

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Stress Urinary Incontinence (SUI)

• Involuntary leakage due to increased intra-abdominal pressure that overcomes urethral resistance

• Causes• Weak pelvic floor muscles• Sphincter incompetence• Trauma/damage to urethra• Women >>> Men


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Stress Urinary Incontinence Triggers

Pictures: http://www.health.com /health/gallery/0,,20358279_2,00.htm l; http://assets.nydailynews.com /polopoly_fs/1.166883.1314026304!/im g/

httpIm age/im age.jpg_gen/derivatives/landscape_635/alg-laughing-jpg.jpghttp://im g.webm d.com /dtm cm s/live/webm d/consum er_assets/site_im ages/articles/

health_tools/incontinence_in_wom en_slideshow/getty_rm _photo_of_wom an_after_sneezing.jpg

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Non-Pharmacologic Treatment for SUIPelvic floor muscle training Pessaries

JAMA. 2017 Oct 24;318(16):1592-1604.Pictures: http://1qghdw20tywd2qc5uw1w82ap-wpengine.netdna-ssl.com /wp-content/uploads/2016/09/vagina.jpg;

http://2nznub4x5d61ra4q12fyu67t.wpengine.netdna-cdn.com /im g/54645ert.jpghttp://www.seekwellness.com /m ystore/products_pictures/stepfree%20weights.jpg

http://m civerclinic.com /im ages/uploads/pessary.jpg

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Pharmacologic Treatment for SUI

• No agent is FDA approved for the treatment of SUI in the United States• Duloxetine (Cymbalta®)• Serotonin and norepinephrine reuptake inhibitor

• Involved in control of urethral smooth muscle in cats and rats• Facilitates pathway between bladder and sympathetic nervous system• Increases sphincter tone during storage phase

• Off-label in US due to increased suicidality, indicated in UK• Side effects (diminish with time): nausea, dry mouth• Older adults underrepresented in studies

GOALIncrease contraction and tone of urethral

sphincter

JAMA. 2017 Oct 24;318(16):1592-1604.Curr Med Res Opin. 2010;26(2):253-61.

FDA – Food and Drug Administration; US – United States; UK – United Kingdom

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Pharmacologic Treatment for SUI

• α-Adrenergic agonists • Pseudoephedrine, phenylephrine• Caution in older adults due to side effects• Contraindicated in hypertension or obstruction

• Topical estrogen (creams, vaginal tablets, rings)• SUI + vaginitis or urethritis due to estrogen deficiency• NO systemic therapy • Used in combination with α-agonists

• Imipramine

Int Urogynecol J. 2015;26(4):477-85.JAM A. 2017 Oct 24;318(16):1592-1604.

Cochrane Database Syst Rev. 2012 Oct 17;10:CD001405.

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Overflow Urinary Incontinence (OUI)

• Volume of urine in bladder overcomes closing pressure• Symptoms:• Diminished stream• Straining to void• Sense of incomplete emptying

• Causes:• Neurogenic bladder• Atonic bladder• Obstruction (BPH, strictures, impaction)

• Interrupted flow• Hesitancy

Picture: http://sketchym edicine.com /2012/02/stress-urge-overflow-and-m ixed-incontinence/ BPH – benign prostatic hypertrophy

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Treatment of OUI

• Obstruction removal (surgery)• Bladder training and voiding schedule• Self-catheterization (3-4 times/day) or surgical placement

Non-pharmacologic

• αA1-receptor antagonists (tamsulosin, silodosin)᠆ Located in bladder neck, urethra, and periurethral tissues᠆ Treatment of BPH in men or use in women for OUI᠆ Concern for orthostatic hypotension

• 5α-reductase inhibitors (if BPH, finasteride)• 5-phosphodiesterase inhibitors (tadalafil)• Bethanechol (Urecholine®)

Pharmacologic

Med Clin North Am. 2011 Jan;95(1):253-64.BPH – benign prostatic hypertrophy

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Functional Incontinence

• Person is unable or unwilling to reach the toilet• Causes:• Musculoskeletal disorders/weakness• Disabilities, vision loss• Cognitive impairment• Physical restraints• Psychological impairments• Environment• Medications (e.g., sedatives, neuroleptics)

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Treatment for Functional UI

• Scheduled or prompted toileting• Removal of barriers and obstacles• Physical therapy• Assistive devices • Bedside commode• Urinals• Elevated toilet seats

Pictures: https://im ages.hom edepot-static.com /productIm ages/02ba2a43-32b9-4632-9ab9-bab8c459ec3a/svn/gray-powder-coated-drive-com m odes-11148-1-64_1000.jpg;

https://www.healthykin.com /im ages/Product/large/1429.jpg; https://i.ebayim g.com /im ages/g/nSM AAOSwy1ddW x4E/s-l300.jpg;

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Mixed Urinary Incontinence


URGE/STRESS

STRESS/URGE/FUNCTIONAL

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Treatment of Mixed UI

• Initial therapy depends on predominant symptoms

• Can use combination of treatment strategies for UUI and SUI in the absence of obstruction• Pelvic floor muscle training and bladder training• Behavioral interventions• Medications

JAMA. 2017 Oct 24;318(16):1592-1604.

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Dysuria

• Pain, burning, stinging, itching of urethra or urethral meatus with urination• Urine contacts inflamed mucosal lining of urethra stimulating pain

receptorsInfectious

• Urinary tract infections• Urethritis• Kidney/prostate• Sexually-transmitted• Vaginal

Non-infectious

• Skin conditions• Foreign body/ stone• Trauma• BPH• Malignancy

Other

• Interstitial nephritis• Medications• Anatomic abnormalities• Menopause• Atrophic vaginitis

Dysuria. StatPearls [Internet]. 2020.BPH – benign prostatic hypertrophy

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Treatment of DysuriaInfectious

• Urinary tract infections• Urethritis• Kidney/prostate• Sexually-transmitted• Vaginal

Non-infectious

• Skin conditions• Foreign body/ stone• Trauma• BPH• Malignancy

Other

• Interstitial nephritis• Medications• Anatomic abnormalities• Menopause• Atrophic vaginitis

Antibiotics (only if symptomatic)

Self-limited (small stones)Lithotripsy/nephrolithotomy

Alpha blockers 5-alpha reductase inhibitors

Transurethral resection of prostate

DiscontinueSeek alternative agents

Topical estrogen

Dysuria. StatPearls [Internet]. 2020.BPH – benign prostatic hypertrophy

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Case BW, cont.

After removing the potential acute causes of UI, BW continues to have symptoms. She mentions that she has leakage when she sneezes and

often needs to “race to the ladies' room” throughout the day.

How would you classify BW’s incontinence?

a) Urgeb) Stressc) Overflowd) Mixed

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Choosing Pharmacologic Therapy

Most have similar efficacies

New is not always better!!!

Consider symptoms, comorbidities, drug

interactions, side effects, etc.

Formulary restrictions and insurance coverage

Adherence and regimen complexity

“The Sibicky Square”

Picture: https://previews.123rf.com /im ages/nicklander/nicklander0701/nicklander070100056/716194-an-old-happy-businessm an-isolated-on-white-.jpg

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Treatment Approach in Older AdultsINITIATING• Determine if there is another

underlying cause• Start low and go slow

• Dose adjust for renal and hepatic impairment

• Titration based on side effects and tolerability

• Trial of one agent for up to 2 months• Consider switch to another agent if

no improvement and treatment is still necessary

DEPRESCRIBING• Assess necessity of medication• Wean with non-pharmacologic

strategies• 25-50% of dose every 1-4 weeks• Faster if serious adverse effects

• Check response• No withdrawal? Continue wean then

stop• Worsening confusion? Stop• Slow weaning (12.5%) when final

lowest dose, continue for 2 weeks• Consider every-other-day dosing

depending on dosage form

Deprescribing Guide For Anticholinergic Drugs for UrinaryIncontinence (Antimuscarinics). NSW Government, 2019.

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Counseling Tips for UI

• Reduce intake of fluid during the day, especially in the evening (after 6 pm)

• Avoid caffeinated beverages

• Minimize the use of artificial sweeteners, acidic and spicy foods

• Let your pharmacist know about new medications you are taking to see if they contribute to your symptoms

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Case BW, cont.

Four weeks after starting darifenacin, BW returns to the clinic because this medication is not working. She has seen commercials for a new medication called “My bears tricks” and asks if this is a better option.

Her blood pressure today is 122/78.

How would you proceed?

a) Check with her insurance first to see if it is coveredb) Counsel her that an effect can take up to 2 monthsc) Recommend a switch to solifenacin instead

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Take Home Points

• UI is a prevalent condition with the potential to have a significant impact on older adults• Treatment for UI should include non-pharmacologic approaches

before initiating pharmacologic agents to reduce risk of side effects and polypharmacy• Efficacy, adverse events, including anticholinergic burden, and patient

preference need to be considered when developing a treatment plan• Pharmacists can monitor for efficacy and help mitigate adverse effects

for patients with UI

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[email protected]

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References• Jo h n so n T M 2 n d , V au g h an C P . U ro lo g ica l fu n ctio n an d d ysfu n ctio n in ag in g : D iag n o sis an d tre atm e n t. H an d b C lin N e u ro l. 2 0 1 9 ;1 6 7 :4 9 5 -5 0 9 .

• G u zzo T J, D rach G W . M ajo r u ro lo g ic p ro b le m s in g e ria trics: asse ssm e n t an d m an ag e m e n t. M e d C lin N o rth A m . 2 0 1 1 Jan ;9 5 (1 ):2 5 3 -6 4 . d o i: 1 0 .1 0 1 6 /j.m cn a.2 0 1 0 .0 8 .0 2 6 . P M ID : 2 1 0 9 5 4 2 8 .

• Lu kacz E S , S an tiag o -Lastra Y , A lb o M E , B ru b ake r L . U rin ary In co n tin e n ce in W o m e n : A R e v ie w . JA M A . 2 0 1 7 O ct 2 4 ;3 1 8 (1 6 ):1 5 9 2 -1 6 0 4 . d o i: 1 0 .1 0 0 1 /jam a.2 0 1 7 .1 2 1 3 7 . P M ID : 2 9 0 6 7 4 3 3 .

• S u b ak LL , W in g R , W e st D S , e t a l. P R ID E In ve stig ato rs. W e ig h t lo ss to tre at u rin ary in co n tin e n ce in o ve rw e ig h t an d o b e se w o m e n . N E n g l J M e d . 2 0 0 9 Jan 2 9 ;3 6 0 (5 ):4 8 1 -9 0 . d o i: 1 0 .1 0 5 6 /N E JM o a0 8 0 6 3 7 5 .

• D allo sso H M , M cG ro th e r C W , M atth e w s R J, e t a l. Le ice ste rsh ire M R C In co n tin e n ce S tu d y G ro u p . T h e asso c iatio n o f d ie t an d o th e r life sty le facto rs w ith o ve ractive b lad d e r an d stre ss in co n tin e n ce : a lo n g itu d in a l stu d y in w o m e n . B JU In t. 2 0 0 3 Ju l;9 2 (1 ):6 9 -7 7 .

• D u m o u lin C , H ay-S m ith E J, M ac H ab é e -S é g u in G . P e lv ic flo o r m u sc le tra in in g ve rsu s n o tre atm e n t, o r in active co n tro l tre atm e n ts, fo r u rin ary in co n tin e n ce in w o m e n . C o ch ran e D atab ase S yst R e v. 2 0 1 4 M ay 1 4 ;(5 ):C D 0 0 5 6 5 4 . d o i: 1 0 .1 0 0 2 /1 4 6 5 1 8 5 8 .C D 0 0 5 6 5 4 .p u b 3 .

• Z im m e rm an K . M e d icatio n s fo r U rin ary In co n tin e n ce : W o rth a D ro p ? 5th A n n u a l In te rd isc ip lin ary S e n io r C are S ym p o siu m . O cto b e r 2 2 , 2 0 1 5 .

• S h am liyan T , W ym an JF , R am akrish n an R , e t a l. B e n e fits an d h arm s o f p h arm aco lo g ic tre atm e n t fo r u rin ary in co n tin e n ce in w o m e n : a syste m atic re v ie w . A n n In te rn M e d . 2 0 1 2 Ju n ;1 5 6 (1 2 ):8 6 1 -7 4 .

• E ffe ctive H e a lth C are P ro g ram . N o n su rg ica l T re atm e n ts fo r U rin ary In co n tin e n ce in A d u lt W o m e n : D iag n o sis an d C o m p arative E ffective n e ss. A g e n cy fo r H e a lth care R e se arch Q u a lity 2 0 1 2 . A va ilab le at: h ttp ://e ffe ctive h e a lth care .ah rq .g o v/e h c/p ro d u cts/1 6 9 /1 0 2 1 /C E R 3 6 _ U rin ary-In co n tin e n ce _ e xe csu m m .p d f (A cce sse d o n N o ve m b e r 1 9 , 2 0 1 2 ).

• M ad h u vrata P , C o d y JD , E llis G , H e rb iso n G P , H ay-S m ith E J. W h ich an tich o lin e rg ic d ru g fo r o ve ractive b lad d e r sym p to m s in ad u lts. C o ch ran e D atab ase S yst R e v. 2 0 1 2 Jan 1 8;1 :C D 0 0 5 4 2 9 . d o i: 1 0 .1 0 0 2 /1 4 6 5 1 8 5 8 .C D 0 0 5 4 2 9 .p u b 2 . P M ID : 2 2 2 5 8 9 6 3 .

• W o o d fo rd H J. A n tich o lin e rg ic D ru g s fo r O ve ractive B lad d e r in F ra il O ld e r P atie n ts: T h e C ase A g a in st. D ru g s A g in g . 2 0 1 8 S e p ;3 5(9 ):7 7 3 -7 7 6 . d o i: 1 0 .1 0 0 7 /s4 0 2 6 6 -0 1 8 -0 5 7 5 -x . P M ID : 3 0 0 9 7 9 0 8 .

• S a lah u d e e n M S , H ilm e r S N , N ish ta la P S . C o m p ariso n o f an tich o lin e rg ic r isk sca le s an d asso c iatio n s w ith ad ve rse h e a lth o u tco m e s in o ld e r p e o p le . J A m G e riatr S o c. 2 0 1 5 Jan ;6 3 (1 ):8 5 -9 0 . d o i: 1 0 .1 1 1 1 /jg s.1 3 2 0 6 . P M ID : 2 5 5 9 7 5 6 0 .

• T u n e LE . A n tich o lin e rg ic e ffe cts o f m e d icatio n in e ld e rly p atie n ts. J C lin P sych iatry . 2 0 0 1 ;6 2 S u p p l 2 1 :1 1– 4 .

• F o x C , R ich ard so n K , M aid m e n t ID , e t a l. A n tich o lin e rg ic m e d icatio n u se an d co g n itive im p airm e n t in th e o ld e r p o p u latio n : th e m e d ica l re se arch co u n cil co g n itive fu n ctio n an d ag e in g stu d y. J A m G e riatr S o c. 2 0 1 1 ;5 9 (8 ):1 4 7 7 – 8 3 .

• G ray S L , A n d e rso n M L, D u b lin S , e t a l. C u m u lative U se o f S tro n g A n tich o lin e rg ics an d In c id e n t D e m e n tia : A P ro sp e ctive C o h o rt S tu d y. JA M A In te rn M e d . 2 0 1 5 ;1 7 5 (3 ):4 0 1 -4 0 7 . d o i:1 0 .1 0 0 1 /jam ain te rn m e d .2 0 1 4 .7 6 6 3

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References• C o u p lan d C A , H ill T , D e n in g , T , e t a l. A n tich o lin e rg ic D ru g E xp o su re an d th e R isk o f D e m e n tia : A N e ste d C ase -C o n tro l S tu d y. JA M A In te rn M e d . 2 0 1 9 ;1 7 9 (8 ):1 0 8 4 -1 0 9 3 .

d o i:1 0 .1 0 0 1 /jam ain te rn m e d .2 0 1 9 .0 6 7 7 .

• M irab e g ro n [p ackag e in se rt]. N o rth b ro o k, IL : A ste llas P h arm a U S , In c .; 2 0 1 8 .

• S task in D , F ran ke l J , V aran o S , e t a l. In te rn atio n a l P h ase III, R an d o m ize d , D o u b le-B lin d , P lace b o an d A ctive C o n tro lle d S tu d y to E va lu atio n th e S afe ty an d E fficacy o f V ib e g ro n in P atie n ts w ith S ym p to m s o f O ve ractive B lad d e r: E M P O W U R . J U ro l. 2 0 2 0 A u g ;2 0 4 (2 ):3 1 6 -3 2 4 . d o i: 1 0 .1 0 9 7 /JU .0 0 0 0 0 0 0 0 0 0 0 0 0 8 0 7 .

• R ach b e rg e r T , W ró b e l A . E va lu atin g v ib e g ro n fo r th e tre atm e n t o f o ve ractive b lad d e r. E xp e rt O p in P h arm aco th e r. 2 0 2 1 Jan ;2 2 (1 ):9 -1 7 .

• V ib e g ro n [p ackag e in se rt]. Irv in e , C A : U ro van t S e rv ice s, In c ; 2 0 2 0 .

• H e rsch o rn S , C h ap p le C R , A b ram s P , A rlan d is S , M itch e so n D , Le e K S , R id d e r A , S to e lze l M , P a ire d d y A , van M aan e n R , R o b in so n D . E fficacy an d safe ty o f co m b in atio n s o f m irab e g ro n an d so life n ac inco m p are d w ith m o n o th e rap y an d p lace b o in p atie n ts w ith o ve ractive b lad d e r (S Y N E R G Y stu d y). B JU In t. 2 0 1 7 O ct;1 2 0 (4 ):5 6 2 -5 7 5 . d o i: 1 0 .1 1 1 1 /b ju .1 3 8 8 2 . E p u b 2 0 1 7 Ju n 8 . P M ID : 2 8 4 1 8 1 0 2 .

• C ard o zo L , Lan g e R , V o ss S , e t a l. S h o rt- an d lo n g -te rm e fficacy an d safe ty o f d u lo xe tin e in w o m e n w ith p re d o m in an t stre ss u rin a ry in co n tin e n ce . C u rr M e d R e s O p in . 2 0 1 0 F e b ;2 6 (2 ):2 5 3 -6 1 . d o i: 1 0 .1 1 8 5 /0 3 0 0 7 9 9 0 9 0 3 4 3 8 2 9 5 .

• M ala llah M A , A l-S h a iji T F . P h arm aco lo g ica l tre atm e n t o f p u re stre ss u rin ary in co n tin e n ce : a n arrative re v ie w . In t U ro g yn e co l J. 2 0 1 5 A p r;2 6 (4 ):4 7 7 -8 5 . d o i: 1 0 .1 0 0 7 /s0 0 1 9 2 -0 1 4 -2 5 1 2 -9 . E p u b 2 0 1 5 Jan 2 9 .

• C o d y JD , Jaco b s M L, R ich ard so n K , e t a l. O e stro g e n th e rap y fo r u rin ary in co n tin e n ce in p o st-m e n o p au sa l w o m e n . C o ch ran e D atab ase S yst R e v. 2 0 1 2 O ct 1 7 ;1 0 :C D 0 0 1 4 0 5 . d o i: 1 0 .1 0 0 2 /1 4 6 5 1 8 5 8 .C D 0 0 1 4 0 5 .p u b 3 .

• M e h ta P , R e d d ivari A K R . D ysu ria . [U p d ate d 2 0 1 9 N o v 1 2 ]. In : S tatP e arls [In te rn e t]. T re asu re Is lan d (F L): S tatP e arls P u b lish in g ; 2 0 2 0 Jan -. A va ilab le fro m : h ttp s://w w w .n cb i.n lm .n ih .g o v/b o o ks/N B K 5 4 9 9 1 8 /

• B y th e 2 0 1 9 A m e rican G e riatrics S o c ie ty B e e rs C rite ria® U p d ate E xp e rt P an e l. A m e rican G e riatrics S o c ie ty 2 0 1 9 U p d ate d A G S B e e rs C rite ria® fo r P o te n tia lly In ap p ro p riate M e d icatio n U se in O ld e r A d u lts. J A m G e riatr S o c. 2 0 1 9 A p r;6 7 (4 ):6 7 4 -6 9 4 . d o i: 1 0 .1 1 1 1 /jg s.1 5 7 6 7 . E p u b 2 0 1 9 Jan 2 9 . P M ID : 3 0 6 9 3 9 4 6 .

• D e p re scrib in g G u id e F o r A n tich o lin e rg ic D ru g s fo r U rin ary In co n tin e n ce (A n tim u scarin ics). N S W G o ve rn m e n t, 2 0 1 9 . A va ilab le at h ttp s://w w w .n sw tag .o rg .au /w p -co n te n t/u p lo ad s/2 0 1 8 /0 6 /1 .6 -D e p re scrib in g -G u id e -fo r-A n tich o lin e rg ic -d ru g s-fo r-U rin ary-In co n tin e n ce -A n tim u scarin ics.p d f

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The Impact of Anticholinergic Burden in Urologic Conditions

Stephanie L. Sibicky, PharmD, MEd, BCGP, BCPS, FASCP

Associate Clinical Professor

Northeastern University | Bouvé College of Health Sciences

School of Pharmacy | Boston, MA

@stephsibicky

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anticholinergic in urologic conditions-sibicky

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