Urinary Incontinence culprit medications and pharmacological therapy A

Urinary Incontinence - culprit medications and pharmacological therapy A learning module for clinicians Jillian Alston, MD, FRCPC

This module is part of the sf. Care approach This module follows the Urinary Incontinence introductory module for clinicians Power. Point Presentation 8. 5 x 11 Poster Patient Handout 2

Objectives 1. Summarize the physiology of bladder control Objectives 2. Describe age-related changes to the genitourinary Physiology of bladder control system 3. Apply knowledge of bladder physiology in order to: Age-related changes • Classify and identify medications that contribute to urinary incontinence (UI) and urinary symptoms • Classify and identify pharmacological treatments used for UI Medications to treat incontinence 4. Identify the side effect profile of medications used to Case study Medications causing incontinence treat UI Summary 5. Apply a senior friendly approach to optimizing Senior friendly approach medications in an older person with UI 3

Physiology of Bladder Control Brain (micturition centre) Objectives Sympathetic nervous system (SNS) (beta-adrenergic receptors) Physiology of bladder control SNS inhibition Age-related changes Detrusor muscle Spinal cord (thoracic and lumbar regions) Bladder Internal sphincter External (alphasphincter adrenergic receptors) Urethra Medications causing incontinence Medications to treat incontinence Parasympathetic nervous system (PNS) (cholinergic receptors) Case study Summary Somatic (pudendal) nerve Demaagd, G. , & Davenport, T. C. (2012). Management of urinary incontinence. P & T : a peer-reviewed journal formulary management, 37 6, 345 -361 H. (Sacral region) Senior friendly approach Tannenbaum. Chapter 10. Evidence. Based Geriatric Medicine. 2012. 4

Physiology of Bladder Control Nervous System Control of Bladder Control Objectives Sympathetic Nervous System (SNS) – Stores Urine: § Alpha-adrenergic constricts internal sphincter § Beta-adrenergic relaxes detrusor muscle Physiology of bladder control Age-related changes Somatic Input (via pudendal nerve): § External sphincter contraction prevents release Medications causing incontinence Pa. Rasympathetic Nervous System (PNS)- Releases Urine: § Cholinergic activation contracts detrusor § Coordination with SNS for sphincter relaxation Medications to treat incontinence Case study Frontal lobe and pontine micturition centre § Inhibit until physiologically and socially acceptable Summary Senior friendly approach Tannenbaum. Chapter 10. Evidence-Based Geriatric Medicine. 2012. 5

Physiology of Bladder Control - Simplified Objectives Physiology of bladder control Age-related changes Medications causing incontinence Medications to treat incontinence Case study a Summary Senior friendly approach Tannenbaum. Chapter 10. Evidence-Based Geriatric Medicine. 2012. 6

Age-Related Changes to the Genitourinary System that Impact Continence Objectives § Bladder wall fibrosis/ impaired collagen and elastin of bladder wall bladder capacity, post-void residual volume from impaired contractility Physiology of bladder control Age-related changes § Detrusor instability Medications causing incontinence § Altered outflow tract characteristics ( urethral tone, mostly in women) → stress incontinence Medications to treat incontinence § diurnal Anti-Diuretic Hormone (ADH) release ADH at night nocturia Case study Summary Senior friendly approach Geriatric Review Syllabus 9 – Urinary Incontinence Siroky MB. The aging bladder. Rev Urol. 2004; 6 Suppl 1(Suppl 1): S 3–S 7. 7

Medications that Cause Urinary Incontinence and Urinary Symptoms Medication Class Examples Alcohol Mechanism Objectives Frequency, urgency urge UI Physiology of bladder control Sedation, delirium, immobility functional UI α-Adrenergic agonists Midodrine, clonidine, methyldopa Age-related changes Outlet obstruction (men) overflow incontinence Medications causing incontinence α-Adrenergic blockers Alpha-1 blockers: Reduced internal sphincter tone Flomax and Prazosin (women) stress incontinence (selective), Trazadone (non-selective) Alpha 2: Mirtazapine ACE inhibitors SGLT-2 Inhibitors Ramipril, lisinopril, perindopril Associated cough worsens stress and possibly urge leakage in older adults with impaired sphincter function Empagliflozin, canagliflozin Urinary frequency, urinary tract infections Medications to treat incontinence Case study Summary Senior friendly approach Abrams et al. Incontinence. 5 th International Consultation on Incontinence. 5 th Edition, 2013. Geriatric Review Syllabus 9 – Urinary Incontinence 8

Medications that Cause Incontinence Medication Class Examples Mechanism Anticholinergics oxybutynin, amantadine Impaired emptying, retention overflow UI Delirium, sedation functional UI Constipation, fecal impaction retention overflow UI Antipsychotics Calcium channel blockers Cholinesterase inhibitors Risperidone, haloperidol, quetiapine, olanzapine Anticholinergic effects retention, overflow UI Nifedipine, amlodipine, diltiazem Impaired detrusor contractility and retention overflow UI Donepezil, rivastigmine Urinary frequency and urgency, potential interactions with anticholinergics Rigidity, sedation, and immobility functional UI Dihydropyridine agents can cause pedal edema, leading to nocturnal polyuria Objectives Physiology of bladder control Age-related changes Medications causing incontinence Medications to treat incontinence Case study Summary Senior friendly approach Abrams et al. Incontinence. 5 th International Consultation on Incontinence. 5 th Edition, 2013. Geriatric Review Syllabus 9 – Urinary Incontinence 9

Medications that Cause Incontinence Medication Class Examples Mechanism Narcotic analgesics* Hydromorphone, Urinary retention, fecal impaction urinary morphine, codeine retention overflow UI Objectives Physiology of bladder control Sedation, delirium functional UI NSAIDs Ibuprofen, naproxen Pedal edema causing nocturnal polyuria Sedative hypnotics* Lorazepam Sedation, delirium, immobility functional UI Thiazolidinediones Pedal edema causing nocturnal polyuria Tricyclic antidepressants Anticholinergic effects urinary retention, overflow UI Medications causing incontinence Medications to treat incontinence Sedation functional UI Loop diuretics furosemide Polyuria, frequency, urgency Lithium Polyuria from diabetes insipidus Estrogen (oral) Worsens stress and mixed leakage in women GABAergic agents* gabapentin, pregabalin Case study Summary Senior friendly approach Sedation, dizziness functional UI Pedal edema causing nocturnal polyuria Abrams et al. Incontinence. 5 th International Consultation on Incontinence. 5 th Edition, 2013. Geriatric Review Syllabus 9 – Urinary Incontinence Age-related changes 10

Pharmacological Management of Urinary Incontinence Objectives For most patients, trial of non-pharmacological treatment prior to drug therapy. Physiology of bladder control Consider starting on drug therapy earlier if: Age-related changes § Few medications Medications causing incontinence § Cognitively intact § Significant reduction in patient’s quality of life Medications to treat incontinence § Age <65 years old (more evidence about adverse effects, fewer adverse effects) Case study § Few comorbidities Summary Senior friendly approach Abrams et al. (2017). Incontinence, 6 th International Consultation on Incontinence. 11

Medications for Treating Urinary Incontinence Stress Urinary Incontinence: Objectives § Topical vaginal estrogen – may be useful for postmenopausal women with atrophy or estrogen deficiency • Oral/transdermal NOT recommended • Caution in women at increased risk of estrogen dependent cancers - Premarin (0. 625 mg/g vaginal cream) - 0. 5 g twice/week - Vagifem 10 mcg vaginal tab - 1 tab pv twice/week - Estring 2 mg vaginal ring – 1 ring PV every 90 days Physiology of bladder control Age-related changes Medications causing incontinence Medications to treat incontinence § No approved oral pharmacological therapies in Canada • Duloxetine (SNRI antidepressant) is approved in the UK - Consider to treat depression/UI concurrently - May reduce incontinence episodes - 1/3 patients report adverse effects Case study Summary Senior friendly approach NICE clinical guideline 40; October 2006: 1 - 14. 2 SOGC clinical practice guidelines. J Obstet Gynaecol Can 2012 Nov; 34(11): 1092 -101 Mariappan P. Cochrane Database of Systematic Reviews 2005, Issue 3 12

Medications for Treating Urinary Incontinence Mixed Urinary Incontinence: Objectives Treat as per the dominant category (urge/overactive bladder vs stress UI) Physiology of bladder control Age-related changes Medications causing incontinence Medications to treat incontinence Case study Summary Senior friendly approach 13

Medications for Treating Urinary Incontinence Urge Urinary Incontinence/ Overactive Bladder: Objectives § Two main classes • Antimuscarinics (aka anticholinergics) • Beta 3 -adrenoceptor agonist (mirabegron) Physiology of bladder control Age-related changes § Choice of medication based on the patient’s comorbidities, current medications, side effect profile of medications tolerability, ease of use, cost/if covered Medications causing incontinence § Consider vaginal estrogen in estrogen deficient women (may improve subjective symptoms) Medications to treat incontinence Case study Summary Senior friendly approach NICE clinical guideline 40; October 2006: 1 - 14. 2 SOGC clinical practice guidelines. J Obstet Gynaecol Can 2012 Nov; 34(11): 1092 -101 14

Antimuscarinics § Modest efficacy vs placebo • UI episodes and symptoms • Low cure rates Objectives Physiology of bladder control § Contraindications: gastric retention, urinary retention, untreated narrow angle closure glaucoma, myasthenia gravis and supraventricular tachycardia Age-related changes Medications causing incontinence § Avoid in those with dementia, those on cholinesterase inhibitors and those on anticholinergic agents Medications to treat incontinence § Associated with dementia § Cost: • Range from $14 per month (oxybutynin IR) to $102 per month (oxybutynin ER) • LU code 290 for all except oxybutynin Case study Summary Senior friendly approach Ann Intern Med. 2012; 156(12): 861 -874 SOGC clinical practice guidelines. J Obstet Gynaecol Can 2012 Nov; 34(11): 1092 -101 15

Antimuscarinic Agents § Start with the lowest dose • 4 -12 weeks for full effect • Titrate prn based on response and side effects Objectives Physiology of bladder control § Treatment failure: • Check adherence, check tolerability Age-related changes § Extended release (ER) preparations or patch minimize side effects, preferred over immediate release (IR) • IR– useful for prn continence at specific times Medications causing incontinence Medications to treat incontinence § Monitoring: side effects and signs of urinary retention Case study § Adverse effects: anticholinergic side effects such as dry mouth, constipation, blurred vision for near objects, tachycardia, drowsiness, falls and decreased cognitive function Summary Senior friendly approach Ann Intern Med. 2012; 156(12): 861 -874 Madhuvrata P. Cochrane Database Syst Rev. 2012 16

Antimuscarinic Agents Drug Dosing Oxybutynin (Ditropan – 2. 5 mg tab✗) • • • Tolterodine (Detrol) • • Fesoterodine (Toviaz) • • Notes ER (ditropan XL✗): 5 mg • daily, up to 30 mg daily • IR: 2. 5 mg BID, up to 5 mg • QID ($0. 10/tablet) Patch✗: 36 mg, twice/wk✗ Less selective ? more CNS side effects Reduce maximum dose for older adults CYP 3 A 4 metabolized ER (Detrol LA): 2 mg once daily, up to 4 mg once daily ($0. 49 / capsule) IR: 1 mg BID up to 2 mg BID dose for moderate renal or hepatic impairment, avoid in severe renal or hepatic impairment Metabolized by CYPs 3 A 4 and 2 D 6; max 2 mg daily with strong CYP 3 A 4 inhibitors QTc prolonging – avoid if on other QTc prolonging medications or if prolonged QTc • • • 4 mg, up to 8 mg ($1. 5 per • tablet) • * active metabolite of • tolterodine Avoid if soy allergy dose for moderate renal or hepatic impairment CYP 3 A 4 metabolized – max 4 mg with strong CYP 3 A 4 inhibitors ✗ =non-formulary IR = immediate release, ER = extended release - In most cases do not use IR Common CYP 3 A 4 inhibitors: Cyclosporine, grapefruit juice, protease inhibitors, “azole” antifungals, amniodarone, dronedarone, verapamil, diltiazem, clarithromycin, erythromycin, colchicine Ann Intern Med. 2012; 156(12): 861 -874 17

Antimuscarinic Agents Drug Dosing Notes Solifenacin* (Vesicare) 5 mg once daily, up to 10 mg • once daily • ($0. 30 per tab) • dose for moderate renal or hepatic impairment, avoid in severe hepatic impairment CYP 3 A 4 metabolized; max 5 mg daily with CYP 3 A 4 inhibitors QTc prolonging – avoid if on other QTc prolonging medications or if prolonged QTc Darifenacin* (Enablex) 7. 5 mg once daily, up to 15 mg once daily ($1. 61 per tablet) • CYP 3 A 4 metabolized; maximum 7. 5 mg daily with strong CYP 3 A 4 inhibitors dose for moderate hepatic impairment, avoid in severe hepatic impairment Trospium chloride* (Trosec) IR: 20 mg once daily, up to 20 mg BID ($0. 61 per tab) ER: 60 mg once daily • • Take on empty stomach, avoid ETOH for 2 hrs dose for reduced renal impairment, avoid in severe renal impairment No CYP metabolism *=newer agents, less blood brain barrier permeability Ann Intern Med. 2012; 156(12): 861 -874 18

Medications for Treating UI Beta 3 -adrenoceptor agonist: only option = mirabegron (Myrbetriq, $1. 46 per tab) Objectives Physiology of bladder control § Selective beta receptor stimulation of the detrusor muscle smooth muscle relaxation bladder capacity Age-related changes § Ontario Drug Benefits Limited Use (ODB – LU) code: 290 Medications causing incontinence § Clinical effectiveness similar to antimuscarinics Medications to treat incontinence § Contraindications: severe uncontrolled hypertension, severe hepatic impairment, urinary retention Case study § Potentially less dry mouth, constipation vs antimuscarinics Summary Senior friendly approach Wagg A, Ageing. 2014 Sep; 43(5): 666 -75. NICE https: //www. nice. org. uk/guidance/ta 290/chapter/4 -Consideration-of-the-evidence 19

Mirabegron Good candidates: Objectives § Those who do not tolerate or respond to antimuscarinic agents Physiology of bladder control Age-related changes § Sensitive to anticholinergic CNS impacts of antimuscarinics including: • Dementia patients • Those on cholinesterase inhibitors Medications causing incontinence Medications to treat incontinence § Contraindication to antimuscarinic § In combination with antimuscarinics when persistent symptoms (higher rates of retention) Case study Summary Senior friendly approach 20

Mirabegron § Dose: 25 mg daily • Increase to 50 mg daily if no effect by two to four weeks • If hepatic impairment or Cr. Cl 15 -29, max dose is 25 mg per day Objectives Physiology of bladder control Age-related changes § Side effects: • Urinary retention, diarrhea, dizziness, constipation, fatigue, increased blood pressure, increase heart rate, increased QTc Medications causing incontinence Medications to treat incontinence § Monitoring: • Monitor for urinary retention, consider routine PVR if available • Blood pressure elevation Case study Summary Senior friendly approach 21

Case study: Mrs. X is an 87 year old female, living alone with her husband. She has nocturia, stress leakage with chronic cough, urinary frequency and urgency with urge incontinence. Her urge symptoms are most bothersome. She has 2 -3 incontinence episodes a day and night time incontinence. Her symptoms impact her quality of life. Mrs. X comes to you to review her options for pharmacological management of her urinary incontinence. Objectives Physiology of bladder control Age-related changes Medications causing incontinence She has enacted all non-pharmacological strategies outlined in the “sf. Care Learning Series for Clinicians: Urinary Incontinence (introductory module)” including reduced caffeine, reduce fluid intake in the evening, physical exercise, kegels, pelvic physiotherapy and bladder training. Medications to treat incontinence Case study Summary Senior friendly approach 22

Case study: Mrs. X Medications Past Medical History § § § § Diabetes (well controlled) Hypertension Osteoarthritis of right knee Mild Alzheimer's Insomnia COPD Atrial Fibrillation Pedal edema § § § § § Ramipril 2. 5 mg bid Empagliflozin 10 mg daily Amlodipine 5 mg po daily Furosemide 40 mg daily Quetiapine 50 mg po qhs Donepezil 10 mg po daily Hydromorphone 0. 5 mg po q 8 h PRN Tiotropium 18 mcg inh daily Diltiazem 120 mg po daily Apixaban 5 mg po bid Objectives What is urinary incontinence? Prevalence and impact Causes How to treat Social History Case study § Retired nurse § Has private drug coverage under husband’s plan § Needs assistance with finances and scheduling, otherwise independent § Exercises 3 x/week Summary Senior friendly approach Questions 23

Case study: Mrs. X What approach would you take in regard to her current medications? Objectives Medication Plan Ramipril May lead to cough and worsen stress incontinence substitute for an angiotensin-ll receptor blocker (ARB) Empagliflozin Urinary frequency consider another anti-diabetic agent Amlodipine Pedal edema nocturia, furosemide prescription discontinue and optimize dose of ARB Furosemide Discontinue Quetiapine Anticholinergic effects, sedation taper and discuss nonpharmacological approaches to sleep Donepezil Urinary frequency and urgency discuss pros/cons of discontinuing What is urinary incontinence? Prevalence and impact Causes How to treat Case study Summary Senior friendly approach Hydromorphone Sedation taper and optimize OA without opioids (Tylenol, topical NSAIDs, intraarticular joint injections) Diltiazem Questions Ensure no overflow/retention, ensure constipation addressed 24

Case Study – Mrs. X What approach would you take in regard to prescribing medications for urinary incontinence? Objectives § Stress incontinence: • Optimize control of COPD, discontinue ACE-inhibitor • Try vaginal estrogen (Premarin cream twice weekly) • No indication for duloxetine What is urinary incontinence? Prevalence and impact § Urge urinary incontinence: • Antimuscarinics: special considerations - Mild dementia, use of cholinesterase inhibitor - Anticholinergic side effects – additive to quetiapine, tiotropium - Drug-drug interactions diltiazem = CYP 3 A 4 inhibitor (avoid tolterodine, darifenacin, solifenacin) - If this class chosen, trospium chloride likely best candidate – cost = (but drug coverage) Causes How to treat Case study Summary Senior friendly approach Questions • Mirabegron: ensure blood pressure well controlled 25

Case Resolution Making alterations to Mrs. X’s medications leads to partial relief of her symptoms. Objectives She tries per vaginal Premarin cream for 4 weeks which offers limited benefit. What is urinary incontinence? Prevalence and impact After discussing the pros and cons of the oral medications used to treat urge incontinence, she decides to try mirabegron. Causes How to treat Case study While she has no cure of her incontinence, she notes a clinically important reduction in incontinence episodes, reduced urinary urge and frequency, and improved quality of life. Summary Senior friendly approach Questions 26

Summary § The pathophysiology behind continence is complex but important to the understanding of how medications worsen or improve bladder control Objectives What is urinary incontinence? § Many common medications can contribute to UI in older adults Prevalence and impact § Antimuscarinics and beta-3 -adrenoreceptor agonists (mirabegron) can be used to improve urge UI symptoms, but cure rates are low. Balance with side effects and cost Causes How to treat Case study § There are no approved medications for stress UI Summary Senior friendly approach Questions 27

The senior friendly approach How all healthcare providers can address urinary incontinence using a senior friendly care approach Organizational Support Processes of Care Emotional & Behavioural Environment Prescribe medications impacting UI and treat UI in alignment with personal goals Ethics in Clinical Care and Research Do not deny access to research studies on medications for UI based on age Physical Environment Objectives Recruit healthcare providers with the knowledge, skills, and attitude to provide comprehensive medication review regarding UI What is urinary incontinence? Prevalence and impact Causes How to treat Case study Summary Senior friendly approach Ensure optimal environment for independent medication administration Questions 28

Discussion questions Objectives § What medications have you used to treat urinary incontinence? What have been your experiences with benefit and side effects? What is urinary incontinence? Prevalence and impact Causes § What is one thing you can do differently as a result of reviewing this module? How to treat Case study Summary Senior friendly approach Questions 29

The sf. Care Learning Series received support from the Regional Geriatric Programs of Ontario, through funding provided by the Ministry of Health and Long-Term Care. V 1 January 2020