Anticholinergic in Urologic Conditions-Sibicky
Transcript of Anticholinergic in Urologic Conditions-Sibicky
7/8/21
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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
Parasympathetic Nervous SystemSympathetic
Nervous System (α-adrenergic)
Bladder Neck
Somatic Nervous System
Inhibitory Signal from Cortex
Detrusor Muscle
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
Parasympathetic Nervous SystemSympathetic
Nervous System (α-adrenergic)
Bladder Neck
Somatic Nervous System
Inhibitory Signal from Cortex
CONTRACTION (Closed)
CONTRACTION (Closed)
Bladder FillingDetrusor Muscle
RELAXATIONβ3
Handb Clin Neurol. 2019;167:495-509.Picture: http://iahealth.net/wp-content/uploads/2008/12/bladder-other.jpg
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Pathophysiology: Voiding PhaseUreters
Detrusor Muscle
External Sphincter
Internal Sphincter
Parasympathetic Nervous SystemSympathetic
Nervous System (α-adrenergic)
Bladder Neck
Somatic Nervous System
Inhibitory Signal from Cortex
Handb Clin Neurol. 2019;167:495-509.Picture: http://iahealth.net/wp-content/uploads/2008/12/bladder-other.jpg
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Pathophysiology: Voiding PhaseUreters
Detrusor Muscle
External Sphincter
Internal Sphincter
Parasympathetic Nervous SystemSympathetic
Nervous System (α-adrenergic)
Bladder Neck
Somatic Nervous System
Inhibitory Signal from Cortex
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
Handb Clin Neurol. 2019;167:495-509.
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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
Handb Clin Neurol. 2019;167:495-509.Med Clin North Am. 2011 Jan;95(1):253-64.
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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
Handb Clin Neurol. 2019;167:495-509.Med Clin North Am. 2011 Jan;95(1):253-64.
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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
Handb Clin Neurol. 2019;167:495-509.
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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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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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Pathophysiology: Voiding PhaseUreters
Detrusor Muscle
External Sphincter
Internal Sphincter
Parasympathetic Nervous SystemSympathetic
Nervous System (α-adrenergic)
Bladder Neck
Somatic Nervous System
Inhibitory Signal from Cortex
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
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
Urinary tract Bladder relaxation, sphincter closing
GI tract Constipation, dry mouth
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
M1Brain Cognitive impairment
GI tract Constipation, dry mouth
M2
Brain Cognitive impairment
Heart Tachycardia
Urinary tract Bladder relaxation, sphincter closing
M3
Urinary tract Bladder relaxation, sphincter closing
GI tract Constipation, dry mouth
Ophthalmologic Mydriasis
M4 Brain Balance impairment
Adapted from Zimmerman K, 2015.GI - gastrointestinal
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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
M1Brain Cognitive impairment
GI tract Constipation, dry mouth
M2
Brain Cognitive impairment
Heart Tachycardia
Urinary tract Bladder relaxation, sphincter closing
M3
Urinary tract Bladder relaxation, sphincter closing
GI tract Constipation, dry mouth
Ophthalmologic Mydriasis
M4 Brain Balance impairment
Adapted from Zimmerman K, 2015.GI - gastrointestinal
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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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Pathophysiology: Voiding PhaseUreters
Detrusor Muscle
External Sphincter
Internal Sphincter
Parasympathetic Nervous SystemSympathetic
Nervous System (α-adrenergic)
Bladder Neck
Somatic Nervous System
Inhibitory Signal from Cortex
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
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
Picture: http://sketchym edicine.com /2012/02/stress-urge-overflow-and-m ixed-incontinence/
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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
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Mixed Urinary Incontinence
Picture: http://sketchym edicine.com /2012/02/stress-urge-overflow-and-m ixed-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”
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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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• 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 .
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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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