Antimuscarinic agents: Implications and concerns in themanagement of overactive bladder in the elderly

Clinical Therapeutics/Volume 27, Number 1, 2005

Antimuscarinic Agents: Implications and Concerns in the Management of Overactive Bladder in the Elderly Gary G. Kay, PhD, 1 and LisaJ. Granville, MD 2

I Georgetown University School of Medicine, Washington, DC, and2Fforida State University Medical School, Gainesvilfe, Florida

ABSTRACT

Background: Overactive bladder (OAB) is a widespread problem that has a negative effect on quality of life, particularly among the elderly. Antimuscarinic agents are the only drug class with broad, accepted efficacy in the treatment of OAB. Their clinical usefulness, however; is limited by dose-dependent adverse effects. In the elderly, the most serious of these is central nervous system (CNS) dysfunction, including cognitive impairment. Objective: This article examines currently available antimuscarinic agents for the treatment of OAB in terms of their likelihood of causing CNS dysfunction by crossing the blood-brain barrier (BBB) and blocking muscarinic type 1 (M1) receptor sites in the brain. Methods: Pertinent studies were selected from a comprehensive review of the OAB literature with a focus on muscarinic receptor-associated mechanisms leading to CNS adverse effects and their potential impact on elderly patients. MEDLINE was searched for articles published in the past 10 years, and additional articles were obtained from the reference lists of identified publications. Also searched were abstracts of recent meetings of the International Consultation on Incontinence, International Continence Society, American Urological Association, and European Association of Urology. Results: Antimuscarinic agents control involuntary detrusor muscle contractions through cholinergic blockade at the muscarinic receptors. The prevalence of OAB is highest in the elderly, the population most likely to be taking multiple anticholinergic medications and most vulnerable to the CNS adverse effects of these agents. Nonselective antimuscarinic agents that bind to the M 1 receptor are most likely to cause significant cognitive adverse effects compared with the more selective antimuscarinic agents for the treatment of OAB. January200S

Conclusions: When considering use of an antimuscarinic agent for the treatment of OAB in elderly patients, prescribers should routinely consider the agent's receptor selectivity and ability to cross the BBB. The medical history should include all current medications that may contribute to the anticholinergic burden and cognitive impairment. Patients and caregivers should be educated to recognize anticholinergic adverse effects. (Clin Ther. 2005;27:127-138) Copyright © 2005 Excerpta Medica, Inc. Key words: antimuscarinic, anticholinergic, overactive bladder, elderly, adverse effects.

INTRODUCTION Antimuscarinic agents constitute the only drug class with broad, accepted efficacy in the treatment of overactive bladder (OAB). 1-3 Nonetheless, the clinical usefulness of these agents is consistently limited by dosedependent adverse effects (AEs), extensions of the drugs' therapeutic anticholinergic action. In otherwise healthy adults, common AEs include constipation, blurred vision, and dry mouth. 2,3 Because these AEs have their principal impact on drug tolerability, they may adversely affect compliance. However, in the elderly, the actual and potential problems associated with antimuscarinic therapy are of much greater concern. Among the most serious concerns is the possibility of central nervous system (CNS) dysfunction, including cognitive impairment, which may have consequences that prevent the patient from living independently. 4

Accepted for publication December7, 2004. ExpressTrack online publicationJanuary 24, 2005. doi:10.1016/j.clinthera.2005.01.006 0149-2918/05/$19.00 Printed in the USA. Reproduction in whole or part is not permitted. Copyright © 2005 Excerpta Me&ca, Inc.

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Because the prevalence of OAB and the sensitivity to anticholinergic drugs increase with age, s and because the elderly account for an increasing proportion of the population and an increased use of health care resources, the need for a therapeutic agent for OAB that has a good CNS safety profile in the elderly is becoming increasingly relevant. This article examines currently available antimuscarinic agents for the treatment of OAB in terms of their ability to cross the b l o o d - b r a i n barrier (BBB) and their activity at the muscarinic type 1 (M1) receptor in the brain, the blocking of which is associated with disruption of cognitive functioning. MATERIALS AND METHODS Pertinent studies were selected from a comprehensive review of the OAB literature with a focus on muscarinic r e c e p t o r - a s s o c i a t e d mechanisms that may lead to cognitive and other CNS impairment and the implications for treating OAB in the elderly. M E D L I N E was searched for articles published in the past 10 years, and additional articles were obtained from the reference lists of identified publications. Also searched were abstracts of recent meetings of the International Consultation on Incontinence, International Continence Society, American Urological Association, and European Association of Urology. PREVALENCE OF OVERACTIVE B L A D D E R

In 2001, the International Continence Society (ICS) defined OAB as a condition characterized by urgency with or without urge incontinence, usually with frequency and nocturia, and with no identifiable cause. 2,6 Although OAB was previously assumed to include incontinence, the broadened definition includes individuals who do not regularly experience incontinence. %s Prevalence estimates of OAB published in 2000 indicated - 1 7 million cases in the United States, 9 but experts now believe that these data reflect only some half of actual cases. Using the expanded ICS definition of OAB, National Overactive Bladder Evaluation Program survey data (2000-2001) identified up to 17% of the US population (16.9% of women; 16.0% of men), or 34 million people, with symptoms of OAB. 5,7,10 Although the overall prevalence of OAB based on the new criteria is only slightly higher in women than in men, the severity and nature of symptoms vary markedly by sex. OAB without 128

incontinence is more prevalent in men, whereas urge incontinence is more c o m m o n in women (both, P < 0.001). s The prevalence of OAB increases with age in both men and women. Table I shows rates of OAB by age and sex. 11 EFFECT O N Q U A L I T Y O F LIFE Quality-of-life survey instruments have been developed and validated for use in both men and w o m e n with OAB. Based on these instruments, study populations from Sweden, the United Kingdom, the United States, and other parts of N o r t h America have shown significant reductions in overall quality of life as a result of OAB (P < 0.001). 12 OAB sympt o m severity was shown to be inversely correlated with survey scores evaluating well-being (eg, general health, physical functioning, social functioning, vitality, mental health). The negative impact of OAB on quality of life occurs in patients with incontinence as well as in those who experience urgency or frequency without measurable urine loss. 13 To avoid embarrassment, patients with OAB tend to stop participating in social and physical activities they previously enjoyed. They often report feeling frustration, anxiety, and fear of odor. Common coping mechanisms include limiting travel, reducing fluid intake, and avoiding sexual intimacy. The effort to self-manage OAB through restriction of fluid intake can result in dehydration or highly concentrated urine leading to urinary tract infection9 Many individuals with OAB avoid discussing their symptoms with family members or medical providers. This reticence stems from embarrassment as well as a Table I. Prevalence (%) of symptoms of overactive

bladder, by age and sex, from a European population-based prevalence study. 11

Ag~ Group, y

Men

Women

(n - 704S)

(n - 972S)

40-44

3.4

4S 49

6.0

50-54

9.8

55-59 60 64 65-69 70-74

13.2 18.9 23.7 22.3

>7S All

41.9 15.6

8,7 I 0.6 11.9

16.9 16.9 17.5

22.1 31.3 1 7.4

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G.G. Kay and L.J. Granville

belief that no treatment is available for their condition. Patients often have the misconception that OAB is a normal part of the aging process. 9 A study in women aged >55 years with OAB symptoms found that those who believed that urinary incontinence was an unavoidable effect of aging were less likely to seek treatment for the condition. 14 The proportion of individuals with OAB who do not seek treatment is nearly the same among those with urgency and frequency alone (41%) and those with incontinence (34%). 7,11 It has been reported that patients typically experience OAB symptoms for up to 2 years before seeking treatment. Is Among those with symptoms who do seek medical care, OAB may remain undiagnosed in up to 30%, and as many as 80% may not receive treatment for OAB. 94s46 T H ERAP EUTIC CONSI DERATIONS The diagnosis of OAB is based on the presence of urologic symptoms in the absence of an identifiable cause. 2,8 Therefore, it is symptoms, not causes, that are targeted by current therapies, and the symptoms are addressed by forestalling involuntary detrusor muscle contractions. 1° The action of acetylcholine (ACh) at muscarinic receptors plays the main role in detrusor muscle contraction. Drugs that block the release of ACh restrict this efferent process. 17 Antimuscarinic agent may also reduce urgency through a yet-to-bedetermined afferent mechanism. Is The M z and M 3 muscarinic receptors of the detrusor muscle account for approximately two thirds and one third, respectively, of identifiable muscarinic receptors in the bladder. Although M z receptors are numerically predominant, animal studies indicate that both M 2 and M 3 receptors facilitate contraction in vivo. 19,20 The M 3 subtype is the receptor principally responsible for detrusor muscle contraction. 1°,39 Activation of the M 3 receptor directly causes detrusor muscle contraction, whereas activation of M 2 may contribute to contraction indirectly by reversing sympatheticmediated (beta-adrenoreceptor) relaxation. 2° The use of anticholinergic agents to treat the symptoms of OAB is complicated by several factors. First, muscarinic receptors (M1-M s subtypes) are distributed throughout the body, where they play distinct roles in various organ systems. 10,21 Next, nonselective muscarinic-receptor blockers not only disrupt activity in the detrusor muscle, but also interfere with muscarinic functioning in other organ systems (eg, eye, January2005

salivary system), z,3 Inhibition of the M 1 subtype in the brain is known to disrupt cognitive functions such as learning and memory. 2z,z3 Antimuscarinic agents vary in their ability to cross the BBB, and even agents that normally do not cross the BBB may do so under conditions in which the BBB becomes more permeable (eg, several disease states, normal aging). 24-z7 Finally, the use of antimuscarinics for OAB may add to the anticholinergic burden associated with the additive effect of the multiple drugs with anticholinergic activity frequently prescribed for the elderly, z8 O V E R V I E W O F T H E USE O F A N T I M U S C A R I N I C AGENTS FOR OVERACTIVE BLADDER The normal micturition reflex is generated by efferent parasympathetic nerve impulses through the neurotransmitter ACh. 1° Antimuscarinic agents block the neurotransmitter binding sites and, as such, represent the first line of pharmacotherapy for OAB. 3 Other classes of agents are sometimes prescribed, depending on the patient profile (eg, estrogen for women, alphaadrenergic-receptor antagonists for men, irnipramine for mixed urge and stress incontinence, desmopressin intranasal spray for primary nocturnal enuresis in children). 3 The antimuscarinic agents, however, are the only drug class with proven efficacy in the clinical treatment of OAB. 1 Table II lists some of the currently available antimuscarinic agents for the treatment of OAB by levels of evidence and clinical recommendation grades (Oxford system), z9,3° Of the agents listed, only oxybutynin, propiverine (not available in the United States), tolterodine, and trospium chloride have been accorded the highest level and grade of clinical recommendation for efficacy.3° Oxybutynin and tolterodine have been the most extensively studied of these agents. Oxybuwnin Oxybutynin is a nonselective antimuscarinic agent available in immediate-release (IR) or extendedrelease (ER) formulations and as a transdermal patch. The IR formulation, available as a generic, is taken 3 times daily. This formulation has been shown to reduce episodes of incontinence (defined as a 50% reduction in incontinence in 6 0 % - 8 0 % of patients), 3 but 72.9% of patients in clinical trials reported dry mouth. 31 Dry month, constipation, or blurred vision has led to treatment discontinuation in up to 25 % of 129

Clinical Therapeutics patients, depending on the dosage. 32 A comparative trial reported equivalent efficacy between the oncedaily ER formulation of oxybutynin and the IR formulation. 33 The proportions of study patients who were continent at completion of the study were 53 % for the ER formulation and 58% for the IR formulation. Those in the ER group experienced 43% fewer AEs. The oxybutynin transdermal patch has shown cornparable efficacy to the oral IR formulation: 66% continence was achieved with the patch, compared with 72% with the IR formulation. 34 Patients reported dry mouth significantly less often with the patch than with oral dosing (38% vs 94%, respectively; P < 0.001). The possibility of application-site skin reactions must be considered when prescribing the transdermal formulation. In one clinical trial, 3s pruritus at the application site was reported in 10.8% to 16.8% of patients in the patch group compared with 6.1% in the placebo group. The need to replace the patch on a 4-day cycle may cause problems with compliance. Tolterodine

Tolterodine is an antimuscarinic agent that is available in short-acting (2 mg BID) and long-acting (4 mg QD) formulations. A pooled analysis of four Table II. Efficacy of antimuscarinic drugs currently available for the treatment of overactive bladder: Levels of evidence and recommendation grades based on the Oxford system,a° Level of Evidence/ Recom m endati on Drug

Hyoscyamine Oxybutynin Propantheline Propiverine Tofferodine Trospi um chloride

Grade* 2/D 1/A 2/B 1/A 1/A 1/A

~Scoring system: 1 - evidence from randomized, controlled trials; 2 - evidence flora good-quality prospective cohort studies; 3 - evidence from good quality retrospective case-control studies; 4 - evidence flora good-quality case series+ Grading system: A- consistent level 1 evidence; Bconsistent level 2 or level 3 evidence or extrapolations from level-1 studies; C - level-4 evidence or extrapolations from level 2 or level 3 studies; D - inconclusive, inconsis tent, or nonexistent evidence, or evidence based on expert opinion only. 29

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12-week studies that evaluated the short-acting formulation found reductions in micturition frequency of 2.3, 2.0, and 1.4 per 24 hours for tolterodine 2 mg BID, oxybutynin 5 mg TID, and placebo, respectively (P < 0.001). 36 Episodes of urge incontinence were reduced by 1.6, 1.8, and 1.1 per 24 hours (P < 0.015). Although efficacy was comparable, the incidence of dry month was lower with tolterodine than with oxybutynin (40% vs 78%, respectively; P < 0.001). A placebo-controlled trial in 1529 patients with OAB compared the long- and short-acting formulations of tolterodine. 37 The once-daily formulation was 18 % more effective than the twice-daily formulation (P < 0.05) and was associated with fewer reports of dry mouth (P < 0.02). The OPERA (Overactive Bladder: Performance of Extended Release Agents) study compared the longacting (once-daily) formulations of tolterodine (4 mg QD) and oxybutynin (10 mg QD) in 790 patients at 71 centers in the United States. 38 No difference in the reduction of urge incontinence episodes was observed between drugs. However, oxybutynin was more effective than tolterodine with respect to the secondary end point of micturition frequency, with reductions in the number of micturitions per week of 28.4 and 25.2, respectively (P = 0.003). The incidence of dry mouth was significantly lower in patients receiving tolterodine compared with those receiving oxybutynin (22.3% vs 29.7%, respectively; P = 0.02). Trospium Chloride Trospium chloride was approved for use in the United States in May 2004. Clinical trials to date indicate that trospium chloride is as effective as oxybutynin IR and is associated with fewer AEs. 3 One study reported no significant difference in efficacy between these drugs, although the incidence of dry mouth was 33% with trospium chloride and 50% with oxybutynin (P < 0.02), and overall AEs occurred in 50% of patients receiving trospium chloride and 59% of patients receiving oxybutynin (P = 0.02). 39,4o A study in 180 patients compared micturition frequency after administration of trospium chloride, tolterodine, and placebo, and reported mean reductions of 3.4, 2.6, and 1.9 per 24 hours, respectively (lP < 0.05). 41 The overall incidence of AEs was comparable between trospium chloride and tolterodine (34% vs 32%, respectively), as was the incidence of gastrointestinal AEs (including dry mouth) (29% vs 27%). Volume 27~ Number 1

G.G. Kay and LJ. Gran~lle

ANTIMUSCARINIC RECEPTOR AFFINITY AND SELECTIVITY OF AGENTS FOR OVERACTIVE BLADDER

In general, the clinical efficacy of the antimuscarinic agents is affected by the occurrence of dose-dependent anticholinergic AEs, including constipation, blurred vision, and dry mouth, all of which may lead to noncompliance.2.3.42 A binding-affinity study using human recombinant muscarinic receptor subtypes (M1-Ms) evaluated the receptor specificity of darifenacin (approved by the US Food and Drug Administration in 2004 for the treatment of OAB), oxybutynin, propiverine, tolterodine, and trospium chloride. 43 Table III summarizes the M 3 selectivity of these agents. Among these agents, darifenacin exhibits the highest relative affinity for the M 3 receptor. Oxybutynin binds to both M 1 and M 3 receptors, 44 whereas tolterodine, propiverine, and trospium chloride are nonselective.43 The most important advantage of M 3 selectivity is the reduction in risk for M 1mediated CNS AEs and Me-mediated cardiac AEs. 45 T H E ROLE IN C O G N I T I O N O F C H O L I N E R G I C FUNCTION AND MUSCARINIC RECEPTORS

All muscarmic receptor subtypes (M1-Ms) are present in various regions of the human brain, with M 1 the most abundant subtype in the cerebral cortex and hippocampus, el,46 In the mouse CNS, cholinergic muscarinic receptors are involved in several processes, including memory, learning, control of movement, nociception, and regulation of circadian rhythmY ,47 Selective elimination of M 1 receptors (by mutation) in mice impairs hippocampal-cortical interaction specific to working memory and remote reference memory.22,23 The receptor-blocking antimuscarinic agent scopolamine has produced effects similar to those seen in the genetic studies. 48

In humans, blocking the action of ACh in the cerebral cortex impairs the encoding of new information (ie, recent memory). 49,s° For example, a functional magnetic resonance imaging study in 10 healthy men aged 23 to 35 years found that scopolamine diminished brain activity in regions associated with cornplex memory processes. 51 Measurements of activation in the hippocampal and frontal regions during 2 sessions of face-name recognition testing were a respective 15.7% and 10.8% lower with scopolamine (0.4 rag) than with placebo (saline solution) (P < 0.05). Another series of studies examined the effect of scopolamine on performance on a battery of neuropsychological tests in 10 healthy subjects aged 18 to 30 years and 10 subjects aged 60 to 85 years.4 Scopolamine impaired performance on measures of recent memory, visuospatial praxis, and response speed. The effect of scopolamine 0.43 mg/70 kg on neurocognitive functioning was more pronounced in the elderly group. Furthermore, older subjects were more vulnerable to the development of serious neuropsychiatric complications, including hallucinations and acute confusional syndromes (SH Ferris, MD, New York University School of Medicine, personal communication, April 2003). Because of these findings, caution is recommended when prescribing nonselective antimuscarinic agents-that is, agents that show little or no difference in receptor binding affinity in competitive-binding studies-for older adults. Agents that have known CNS anticholinergic effects are included in the Beers list of medications that are potentially inappropriate in the elderly, s2 The elderly are particularly vulnerable to the adverse CNS effects of anticholinergic medications.28 CNS cholinergic function declines with age, possibly because of reduced ACh activity or a decrease in the number of functioning muscarinic receptors. This reduction in cholinergic activity is thought to play a

Table III. M u s c a r i n i c - r e c e p t o r selectivity o f a n t i m u s c a r i n i c agents, measured as the r a t i o o f K i values. 43 Drug Darifenacin Oxybutynin Pro pive ri ne Tolterodine T r o s p i u m chloride

M 3 vs M 1

M 3 vs M 2

M 3 vs M 4

9,3 1.5 O, 6 0.6 1 .S

59,2 12.3 9, 6 3.6 1.3

59.2 6.9 2.8 7.3 2.0

M 3 vs M 5 12,2 27.0 0,8 6.3 4.6

Selectivity M3 M 1 and M 3 N o nsel ect ive Nonselective Nonselective

Ki - inhibition constant (a measure offhow strongly the antimuscarinic agent binds to the muscarinic receptor); M1-M s - muscarinic receptor su btypes÷

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major role in the nonpathologic decline in memory and cognitive function observed with normal aging, s3 These age-related changes must be differentiated from pathologic memory conditions (ie, dementias and arnnestic disorders), which lead to a severe loss of memory and marked disability,s4 The use of medications with CNS anticholinergic activity can exacerbate these normal age-related changes. Other factors that increase the vulnerability of older adults to the CNS effects of anticholinergic agents include changes in the distribution of muscarinic receptors, ss,s6 slower metabolism and elimination of m e d i c a t i o n s y polypharmacy with drugs that have anticholinergic activity, s7 and increased permeability of the BBB.27 The cumulative effect of taking multiple drugs with anticholinergic activity is referred to as the anticholinergic burden. In addition to drugs used specifically for their anticholinergic properties (eg, OAB medications), many other drugs have anticholinergic activity (eg, tricyclic antidepressants, older-generation antihistamines, antispasmodics for the gastrointestinal tract), s8 A survey of anticholinergic medication use by nursing home residents found that 21% to 32% of residents were taking :-2 drugs with anticholinergic activity, and 10% to 17% were taking :-3 drugs with anticholinergic activity,s7 In the early 1990s, Tune et al s9 analyzed the relative in vitro anticholinergic activity of 25 of the most commonly prescribed medications in the elderly. Fourteen of the drugs had some in vitro anticholinergic activity. In a subsequent article, Tune 6° noted that "anticholinergic toxicity is a common problem in the elderly" that is "often the result of the cumulative anticholinergic burden of multiple prescription medications and metabolites rather than of a single compound." In a recent study, 61 a significant association was observed between serum anticholinergic activity and scores on the Mini-Mental State Examination (MMSE). Patients with elevated serum anticholinergic activity (>90th percentile) were 13 times more likely than those with undetectable anticholinergic activity to have an MMSE score <24 (10th percentile) (P = 0.04). As noted by Mintzer and Burns, 6z "the concept of anticholinergic load illustrates that side-effects can be caused by combinations of drugs, even if the individual drugs do not cause obvious side-effects." An anticholinergic agent for OAB that spares the M 1 receptor would be expected to have less impact on CNS functioning than an Ml-selective agent. A 132

recent randomized, double-blind, 4-way crossover study compared the effect on cognitive functioning of darifenacin and dicyclomine, a smooth muscle relaxant with Ml-selective properties. 63 Performance on a battery of neuropsychological tests was comparable in those receiving darifenacin 7.5 or 15 mg or placebo, whereas dicyclomine produced significant impairment on measures of simple reaction time (P = 0.009), speed of spatial working memory (P = 0.048), speed of numeric working memory (P = 0.012), and speed and sensitivity of picture recognition (P = 0.040 and P = 0.030, respectively) compared with placebo. ANTICHOLINERGIC AGENTS AND THE PERMEABILITY OF THE BLOOD-BRAIN BARRIER

The extent to which an anticholinergic medication impairs CNS function depends on its ability to cross the BBB.64,6s All antimuscarinic agents have the potential to cross the BBB, and the likelihood of their doing so varies as a function of chemical properties that include molecular weight, lipophilicity, and polarity. 64,6s Table IV compares the antimuscarinic medications for OAB available in the United States with respect to the chemical properties influencing their ability to cross the BBB. 66-r° The chemical properties of oxybutynm--lipophilicity, small size, and neutral polarity--make it the most likely of OAB agents to cross the BBB. Because of its known sedating effects,6s this medication is prohibited for use by aviators (www.aviationmedicine.com) and is on the Beers list of potentially inappropriate medications for use in elderly patients (along with tolterodine), s2 Nevertheless, oxybutynin is widely used to treat OAB in older patients, rl The low cost of the generic formulation has given oxybutynin preferred status among health plans, even after newer agents with better AE profiles have become available. In some cases, a trial of generic oxybutynin must have failed before patients will be reimbursed for different OAB medications. 7z-74 The newer OAB medications are less likely to cross the BBB. Tolterodine is >3 0 times less lipophilic than oxybutynin and is thought to have a low potential for crossing the BBB.66,r° Darifenacin also has molecular characteristics that make it unlikely to cross the BBB.rs In addition, it is a substrate for P-glycoprotein, an active-transport system that can carry darifenacin Volume 27~ Number 1

G.G. Kay and L.J. Granville

back across the BBB. Trospium chloride is a highly polar molecule with the lowest lipophilicity of the OAB medications. This agent is considered the least likely to cross the BBB under normal conditions. 67 However, the permeability of the BBB is not uniform or stable throughout life. Furthermore, permeability increases in response to disease states such as type 2 diabetes mellitus24 and multiple sclerosis. 2s Permeability can be assessed by separating and measuring the quantity of albumin in the serum and cerebrospinal fluid (CSF) to calculate a representative ratio, called the permeability index (Qalb): Qalb = (CSF 1b/serum lb) X 103. The figure illustrates the ageassociated increase in the permeability of the BBB in serum and CSF from 120 male and female patients aged 20 to >70 years. 2r This phenomenon may partially explain why elderly patients are more vulnerable to the cognitive consequences of muscarinic-receptor blocking4; it has not been studied with antimuscarinics specifically. The simplest method for assessing the CNS depressant effect of medications (generally noted in the package insert in terms of somnolence, drowsiness, and fatigue) is the use of AE diaries. In addition to the diary method, which relies on patients' awareness of changes in CNS functioning, various physiologic and performance measures are sensitive to sedating effects. Electroencephalographic (EEG) changes are one of the biomarkers for drug-related changes in CNS functioning. A study by Todorova et a167 exam-

ined quantitative EEG power-frequency bands alpha-l, alpha-2, beta-l, beta-2, delta, and theta to explore the potential for CNS AEs in association with antimuscarinic drugs for OAB. Oxybutynin, unlike tolterodine and trospium chloride, caused significant changes in EEG activity (eg, decreased alpha activity; P < 0.01). Other studies have used polysomnography to evaluate the effect of OAB medications on sleep physiology. Recent studies by Diefenbach et a176,r7 have shown that oxybutynin and tolterodine suppressed rapid-eye-movement sleep, whereas the effect of trospium chloride on sleep physiology was comparable to that of placebo. The cognitive performance of individuals taking OAB medications has also been evaluated. In a study in geriatric patients, Katz et al rl compared the neurocognitive effects of oxybutynin IR 5 and 10 mg, diphenhydramine 50 mg, and placebo using a 4-way crossover design. The results showed a significant negative effect on cognitive performance with oxybutynin and diphenhydramine compared with placebo (both, P < 0.05). Studies of darifenacin63,rs and trospium chloride77 have demonstrated no cognitive impairment compared with placebo. USE O F A N T I M U S C A R I N I C AGENTS IN T H E ELDERLY: SPECIAL C O N S I D E R A T I O N S Although the AEs associated with antimuscarmic agents may cause some discomfort in otherwise healthy younger adults, these same AEs and their consequences are likely to be much more pronounced in

Table IV. Likelihood of selected antimuscarinic agents crossing the blood-brain barrier (BBB). 66 70 Likely to Cross BBB

Unlikely to Cross BBB

Oral Oxybutynin

Transdermal Oxybutynin

Dariflenacin

Tolterodine

Lipophilicity (solubility in alcohol)

Soluble ~

Soluble

Slightly soluble

Very slightly soluble

Low solubility

Molecular weight

Small (:393.9)

Small (:357.0)

Large (507.5)

Large (475.6)

Large (427.9)

Polarity

Neutral

Neutral

Positive (9.20 pKa)

Positive (9.87 pKa)

Highly polar

Characteristic

Trospium Chloride

~Solubilib/in alcohol is not reported in the package insert for oxybub/nin tablets. The solubility reported here is based on the package insert for transdermal oxybucynin (Watson Laboratories, Inc., Corona, California; 2003).

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the elderly. Dry mouth can reduce an elderly individual's ability to communicate, predispose him or her to malnutrition, and increase the risk of respiratory infection. Blurred vision and confusion can lead to falls, resulting in injuries that may include serious fractures. 2s Even modest cognitive AEs, such as memory lapses and mild confusion, may lead to functional dependence and thus the inability to live independently.2s Patients are not likely to be aware of drug-induced changes in memory and may mistakenly attribute their memory difficulties to aging or to cornorbid conditions associated with aging. Therefore, when selecting OAB therapies, health care providers must be aware of the potential anticholinergic burden. 62 Prescribers should anticipate elderly patients' likelihood of being particularly sensitive to anticholinergic Ats, 4 a sensitivity compounded by the high likelihood that they are receiving multiple anticholinergic agents, in some cases without the intent or knowledge of their health care provider(s). 62 Although they represent only 13% of the population, individuals aged >65 years consume a high volume of medications; the elderly account for 30% of prescription medications and 40 % of overthe-counter (OTC) medications used in the United States. 79 The elderly may fail to report to one physician medications prescribed by another for a different con-

dition, and they may forget to mention OTC medications even when asked specifically. Among common antimuscarinic agents that may not be reported by elderly patients are ophthalmic eye drops (often highly concentrated and directly absorbed), antidepressants (by some estimates, up to 25% of the elderly population have depression), and particularly first-generation antihistamines (commonly present in OTC allergy, sleep, "PM," and "extra-strength" pain medications)Y Some common medications associated with anticholinergic AEs are listed in Table V. The health care provider needs to be proactive in weighing the benefits against the risks of cumulative AEs when prescribing antimuscarinic agents for elderly patients. Some illnesses common in the elderly are complicated by treatment with antimuscarinics, and these must be documented carefully as part of the medical history (Table VI). 2s These illnesses include not only such specific diagnoses as Alzheimer's disease and Parkinson's disease, but also the more generalized diagnoses of dementia, depression, and sleep disturbance. 4>2%~° For example, acute anticholinergicinduced delirium has been reported within 1 to 2 weeks of adding tolterodine for the treatment of OAB to the daily regimen of patients with mild dementia receiving acetylcholinesterase-inhibitor therapy, sl These

6-

5 e-

4

E

3-

r~ e-

E -m <

2-

1 0 20 50

r

51 70

1

>70

1

Age (y) Figure. Age-associated increases in permeability of the blood-brain barrier to albumin, based on the albumin permeability index (Qalb): Qalb = (cerebrospinal fluidalb/serUmalb) X 103. A d a p t e d f r o m Pakulski e t al. 27

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G.G. Kay and L.J. Granville

patients had previously required only modest assistance and were able to dress and feed themselves; however; they became acutely delusional and aggressive, and in some cases fell repeatedly, after the addition of tolterodine. They returned to baseline behavior patterns within 24 to 48 hours after discominuation of tolterodine. Vigilance on the part of the prescriber, patiem, and caregiver team is necessary to ensure prompt recognition of any impairment associated with anticholinergic burden. The health care provider should instruct patients and caregivers to look for and report any of the symptoms listed in Table VII. 62 Even when symptoms are reported, however; the patient is likely to appear normal based on physical examination, laboratory tests, imaging studies, and scores on many standard cognitive screening tests, including the MMSE. A more sensitive memory screening test, the Hopkins Table V. Agents with anticholinergic adverse effects. 28

Anticholi nergic agents Anti em etics Antiparkinsonian drugs Antispasmodics Mydriatics/ cyclopI egics Other agents Antiarrhythm ics Antidepressants Antidiarrheals Anti histamines Anti psych oti cs Muscle relaxants

Table Vl. Common comorbid conditions in the elderly that may be complicated by antimuscarinic treatment for overactive bladder. 28

Angina pectoris Bronchitis (acute or chronic) Chronic airway disease Chronic renal failure Congestive heart iCailure Constipation Dementia Depression Diabetes mellitus Gait disturbance Glaucoma Sleep disturbance

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Verbal Learning Test-Revised, ~2 a 12-word list presented in 3 sequential trials, has detected memory impairment associated with OAB treatment when other indicators were normal, enabling the physician to link the memory deficit to anticholinergic activity and discontinue treatment. 83,84 This simple, rapidly administered test could be used to assess patients taking antimuscarinic treatment for OAB who may cornplain of memory impairment. 83,84 CONCLUSIONS

OAB is a widespread problem that negatively affects quality of life. Antimuscarinic agents that control involuntary detrusor muscle contractions through cholinergic blockade at the muscarinic receptors have proven efficacious and are considered first-line therapy for the urgency and frequency associated with OAB. However, the use of these agents is sometimes limited by anticholinergic AEs. Antimuscarinic agents that cross the BBB and bind to M 1 receptors in the brain present a risk for cognitive AEs, with impairment ranging from drowsiness to delirium. The most common of these AEs is a decline in recem memory. Elderly patiems have an increased risk for these cognitive AEs because of the increase in BBB permeability associated with normal aging, the effects of cornorbid conditions, and the use of multiple anticholinergic agents. Prescribers are therefore encouraged to routinely consider an agem's receptor selectivity and ability to cross the BBB when evaluating treatrnem options for OAB, particularly in elderly patients. Patients are often reluctant to report symptoms of urinary urgency, frequency, and incontinence. A proactive approach to the medical history, with spedfic questioning about possible bladder problems, can help identify OAB and lead to appropriate treatment of cases that might otherwise go unrecognized. Patients and their caregivers should be educated to recognize and report Table VII. Symptoms associated with increased cholinergic burden. 62

Dry mouth; difficulty speaking Pale, dry, cool skin Blurred vision Uncertain movement; stumbling or falling for no reason Increased anxiety with rapid, shallow breathing; tachycardia; cardiac arrhythmias

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anticholinergic AEs. In those w h o complain of changes in m e m o r y or other cognitive functions, a sensitive a n d brief m e m o r y t e s t - - t h e H o p k i n s Verbal Learning TestR e v i s e d - - m a y be useful to screen for or evaluate symptoms possibly related to anticholinergic medications.

AC K N O W L E DG M ENTS S u p p o r t for this s u p p l e m e n t w a s p r o v i d e d by N o v a r t i s I n t e r n a t i o n a l AG, Basel, Switzerland. Editorial assistance was p r o v i d e d by Accel H e a l t h c a r e C o m m u n i cations, N e w York, N e w York.

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Address correspondence to: Gary G. Kay, PhD, Washington Neuropsychological Institute, 4910 Massachusetts Avenue NW, Suite 100, Washington, DC 20016. E-mail: [email protected] Volume 27~ Number 1