Is There a Best Drug for Overactive Bladder in a Patient with Dementia? Todd Semla, MS, Pharm.D., BCPS, FCCP, AGSF National PBM Clinical Pharmacy Program Manager Mental Health & Geriatrics U.S. Department of Veterans Affairs Northwestern University Feinberg School of Medicine
Disclosures The views expressed are not necessarily those of the U.S. Department of Veterans Affairs or the U.S. Government Member of Omnicare, Inc. Pharmacy & Therapeutics Committee; Senior Editor, LexiComp, Inc; Member, AARP Caregiving Advisory Board Spouse an employee of AbbVie and owns stock in AbbVie, Abbott and Hospira.
The Clinical Conundrum 83 yo patient with Alzheimer s disease diagnosed 4 years ago; MMSE 18. Donepezil 10 mg daily. 23 year history of urinary incontinence, mixed type. Until recently managed with regular toileting and a pad. Recently, larger volumes lost, more frequently. Other problems: osteoarthritis managed with scheduled acetaminophen.
Dementia & OAB: Questions needing answers 1. Do anticholinergic agents developed to treat OAB improve continence in patients with dementia? 2. Do anticholinergic agents developed to treat OAB impair cognition in patients with dementia? 3. When part of the same regimen do anticholinergic agents negate the effects of acetylcholinesterase inhibitor on cognition? And vice versa? 4
Medications for OAB Generic name Oxybutynin chloride Oxybutynin chloride extended-release Oxybutynin chloride transdermal Oxybutynin gel Tolterodine tartrate Tolterodine tartrate extended-release Trospium chloride Trospium chloride ER Solifenacin succinate Darifenacin hydrobromide Fesoterodine fumarate Mirabegron Botulinum toxin Brand Ditropan Ditropan XL Oxytrol Gelnique Detrol Detrol LA Sanctura Sanctura XR Vesicare Enablex Toviaz Myrbetriq Various 5
What s the Evidence? Clinical report Chemical-physical properties Laboratory Observational studies Controlled trials
What Are the Consequences of Concurrent CI and Anticholinergic Use? Retrospective cohort study of AD patients stratified by anticholinergic use; all taking donepezil 10 mg QD Baseline MMSE: 22.6 ± 5.5 No anticholinergic use (n=53) 20.6 ± 4.0 Anticholinergic users (n=16) Change in MMSE Over Time 1 year 2 years No ACh ACh use No Ach Ach use -2.25 n=53 p=0.073-4.19 n=16-3.08 n=25 p=0.052-7.00 n=11 Lu C & Tune LE Am J Geriatr Psychiatry 2003;11:458-61 7
Muscarinic Receptor Subtypes: Location and Response Muscarinic Receptor Location Response M1 M2 M3 M4 Secretory glands, CNS, urethra, vascular smooth muscle Heart, respiratory tract, bladder, urethra, g.i. tract, uterus smooth muscle Smooth muscle and secretory glands; respiratory tract; bladder and the g.i. tract including salivary glands, eyes Smooth muscle and secretory glands; respiratory tract Smooth muscle contraction, gastric acid secretion, memory and learning Regulate heart rate and contractility; constipation Dry mouth, blurred vision Dry mouth M5 Ciliary muscle; eyes Dry mouth, blurred vision
Muscarinic Binding Affinities Agent Chemical amine M1 M2 M3 M4 M5 Uroselectivity Oxybutynin Tertiary amine 8.7 7.8 8.9 8.02 7.4 M3>M2, min Tolterodine Tertiary amine 8.8 8.0 8.5 7.7 7.7 None Trospium Quarternary amine 9.2 9.2 9.3 9.0 8.7 None Darifenacin Tertiary amine 8.2 7.4 9.1 7.3 8.0 M3 selective Solifenacin Tertiary amine 7.6 6.9 8.0 Unkn Unkn M3>M2, min. FESO, 5HMT Tertiary amine 9.5 9.2 8.9 8.7 9.02 Atropine Tertiary amine 9.6 8.9 9.6 8.9 9.2 -------------------
Relative Lipophilicity Log P and dipole moment 1. Darifenacin 2. Oxybutynin, Solifenacin 3. Tolterodine 4. Trospium Most Least Log D:octanol-H 2 O: 1. Oxybutynin 2. Darifenacin 3. Tolterodine 4. Solifenacin 5. Fesoterodine 6. Trospium
P-glycoprotein Substrate? Darifenacin Fesoterodine (5-HMT) Trospium? Tolterodine (5-HMT)? Oxybutynin No - Solifenacin
Brain Anticholinergic Activity 5 drugs AA measured by radiolgand ( 3 H-QNB) binding to rat muscarinic receptors over range of known serum concentrations. Highest Intermediate Lowest 5-HMT, tolterodine > oxybutynin > darifenacin, solifenacin Darifenacin lowest AA over entire concentration range 5-HMT most extensive AA low to high concentration Tolterodine largest change in AA low to high (ratio 37.3) Solifenacin least change in AA low to high (ratio 1.37) Jakobsen, et al. JAGS 2011;59:501-5
Concurrent Use of Oxybutynin or Tolterodine and CI: Effect on cognition and function Prospective cohort, merged SSA and MDS databases (January 2003 December 2004) N = 3,536 NH residents: 44% >85 years old; 75% women 3,141 CI only 395 CI and Anticholinergic (196 oxy, 231 tolterodine) Median dual use: 141 days (77-262) Measure change in MDS ADL and MDS-COG 47% severe or complete ADL dependence >50% severe or very severe cognitive impairment Sink KM, et al. JAGS 2008
Sink, et al.: Results Change in ADL Function Highest functioning quartile at baseline CI alone: 1.08 vs. CI + anticholinergic: 1.62 Rate of ADL decline: -0.53 change/quarter, p=.02 Change in Cognition No difference in rate of decline Oxybutynin vs. Tolterodine Rates of decline in ADLs and cognition did not differ or between IR and ER formulations Sink KM, et al. JAGS 2008
Cognitive, Behavioral and Physiological Changes in AD Patients as a Function of Incontinence Medications 9 patients with AD and urinary incontinence treated with oxybutynin or tolterodine 3 weeks on and off anticholinergic medication Cog. Assess. On ACh Off ACH p-value MMSE 16.44 17.44 0.017 ADAS-cog 28.00 29.00 0.155 Memory Behav. List 45.5 34.5 0.017 No difference in NPI, ADLs, CG burden, Urinary frequency, or incontinence episodes. Significant inverse relationship between serum AA and MMSE. Jewart RD, et al. Am J Geriatr Psychiatry 2005;13:324-8 15
CNS Effects of OAB Medications Darifenacin 3.75, 7.5, or 15 mg vs. placebo x 2 wks 1 No significant changes in memory, reaction time or word recognition sensitivity Alertness, calmness and contentment not affected Darifenacin 7.5, 15, or 20 mg vs. placebo x 7 days 2 27 healthy men, ages 19-44 years No significant changes in cognitive function vs. placebo Oxybutynin, tolterodine, trospium vs. placebo 3,4 Quantitative EEG changes seen with oxybutynin 1 Lipton RB, et al. J Urol 2005; 173:493-8 2 Kay G, et al. BJU Int 2005;96:1055-62 3 Todorva A, et al. J Clin Pharmacol 2001;41:636-44 4 Pietzko A, et al. Eur J Clin Pharmacol 1994;47:337-43 16
Oxybutynin ER vs. Placebo in Cognitively Impaired Elderly with Urinary Incontinence 50 female NH residents with mild to severe cognitive impairment and urinary incontinence Randomized to 4-weeks oxybutynin ER 5 mg or placebo once daily; no additional behavioral treatments for UI Confusion Assessment Method, MMSE, Severe Impairment Battery, Brief Agitation Rating Scale No SD between treatments in UI episodes, frequency or dryness No decline in cognition; well tolerated Lackner TE, et al. JAGS 2008 and JAMDA 2011 17
Solifenacin Single dose R, DB, PC, 3-way, X-over design Solifenacin 10 mg, oxybutynin IR 10mg 12 healthy adults >65; MMSE>27 Solifenacin Quality of Working Memory after 2 & 4 hours Oxybutynin after 6 hours significant impairment in attention, working memory, and self-rated alertness compared to placebo Wesnes, et al., Expert Opin Drug Safety 2009;8:615-626
Solifenacin in Patients with MCI R, DB, PC Triple X-over trial 26 subjects >75 years with MCI per criteria including MMSE >23 Solifenacin 5 mg QD, oxybutynin 5 mg BID, and placebo x 21 days Neither solifenacin or oxybutynin significantly changed cognitive function from baseline. NS difference: solifenacin vs. placebo Decreased continuity of attention: oxybutynin vs. placebo 1 hour post dose. Wagg et al. Euro Urol 2013;64:74-81
Trospium Ho: Trospium should not penetrate the BBB and should not impair cognitive function. 12 healthy subjects; 65-75 years old; MMSE>25 Trospium ER 60 mg daily for 10 days Hopkins Verbal Learning Test-Revised and Brief Visuospatial Memory Test-Revised at baseline, Days 0 and 10. CSF trospium concentrations Day 10 at 0,2,5,7,12 & 24h Findings: Trospium was undetectable in all CSF samples. Trospium demonstrated no significant effects on total or delayed recall. Statskin, et al. Int J Clin Pract 2010;64:1294-1300
Fesoterodine & Mirabegron 12-week R, DB, PC trial in vulnerable elderly subjects with urge UI 562 community-dwelling, >65 (mean 75) yrs., MMSE>20 Fesoterodine 4-8 mg/day (flexible dose) No deterioration in MMSE from baseline 2 reports of memory impairment with fesoterodine 1 withdrawal due to mild confusion (fesoterodine arm) Mirabegron DuBeau CE, et al. J Urol 2013;191:395-404 no data on cognitive function
Other Considerations Dose adjustment for renal function Mirabegron, tolterodine, trospium, solifenacin, fesoterodine Drug interactions CYP3A4 oxybutynin, tolterodine, darifenacin, fesoterodine, solifenacin CYP2D6 tolterodine, fesoterodine, darifenacin, mirabegron (inhibitor) Blood pressure mirabegron Do not take with food trospium Do not crush
Summary Medication Properties Control Trials Oxybutynin, oral Unfavorable EEG changes, negative control Oxybutynin, topical?? Tolterodine Unfavorable No EEG changes Trospium Favorable Undetectable CNS, no cog. Solifenacin Favorable Single dose, MCI Darifenacin Favorable NS cognitive changes Fesoterodine Fav/Unfav. No change in MMSE Mirabegron Favorable? No information 23
Which to Choose? All antimuscarinic OAB agents are superior to placebo None has been shown to be superior to the others Limited data on AChEI + OAB agents No clear winner Antimuscarinics lower doses, less risk Miragbegron intriguing choice, no data Monitor efficacy and safety. STOP if ineffective or suspected adverse effects. Try another agent