Review of Nonneurogenic Overactive Bladder

Release Date: August 1, 2014

Expiration Date: August 31, 2016

FACULTY:

Muideen Adigun, PharmD, BCPS, BCPP
Clinical Coordinator and Program Director
Pharmacy Practice Residency
Howard University Hospital
Washington, D.C.
Assistant Professor, Howard University
College of Pharmacy
Department of Clinical and Administrative
Pharmacy Sciences

Adebola Adesoye, PharmD
PGY-1 Pharmacy Practice Resident
Howard University Hospital
Washington, D.C.

Ayotunde Ayoola, PharmD
PGY-1 Pharmacy Practice Resident
Howard University Hospital
Washington, D.C.

Louis Lteif, PharmD
PGY-1 Pharmacy Practice Resident
Howard University Hospital
Washington, D.C.

Onyebuchi Amaechi, PharmD
PGY-1 Pharmacy Practice Resident
Howard University Hospital
Washington, D.C.

FACULTY DISCLOSURE STATEMENTS:

Drs. Adigun, Adesoye, Ayoola, Lteif, and Amaechi have no actual or potential conflicts of interest in relation to this activity.

Postgraduate Healthcare Education, LLC does not view the existence of relationships as an implication of bias or that the value of the material is decreased. The content of the activity was planned to be balanced, objective, and scientifically rigorous. Occasionally, authors may express opinions that represent their own viewpoint. Conclusions drawn by participants should be derived from objective analysis of scientific data.

ACCREDITATION STATEMENT:

Pharmacy
acpePostgraduate Healthcare Education, LLC is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.
UAN: 0430-0000-14-029-H01-P
Credits: 2.0 hours (0.20 ceu)
Type of Activity: Knowledge

FEE INFORMATION:

Payment of $6.50 required for exam to be graded.

TARGET AUDIENCE:

This accredited activity is targeted to pharmacists. Estimated time to complete this activity is 120 minutes.

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DISCLAIMER:

Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients' conditions and possible contraindications or dangers in use, review of any applicable manufacturer's product information, and comparison with recommendations of other authorities.

GOAL:

To inform pharmacists on available treatment options for adult patients with overactive bladder (OAB), in order to optimize patient care.

OBJECTIVES:

After completing this activity, the participant should be able to:

  1. Identify the symptoms and clinical presentation of nonneurogenic OAB.
  2. Understand that the first-line recommended treatment for nonneurogenic OAB is behavioral therapy.
  3. Discuss the pharmacist's role in providing patient education to caregivers and patients for the management of nonneurogenic OAB.

ABSTRACT: Overactive bladder (OAB) disorder is a condition with a prevalence that increases with age. Frequently, patients afflicted with OAB experience symptoms of urinary incontinence, including increased urinary frequency and nocturia. Nonpharmacologic therapy such as behavioral therapy is considered first-line treatment, while second-line treatments include the use of antimuscarinic medications and the novel ß3-adrenergic agonist, mirabegron. These agents focus on associated symptoms of OAB to improve patients' quality of life by increasing the bladder's capacity and decreasing urinary bladder contraction. Pharmacists are essential in the management of OAB by providing education to patients and practitioners alike regarding key aspects of current treatment modalities that include, but are not limited to, adverse drug events, drug-drug interactions, and appropriate use of medications.

Overactive bladder (OAB) is characterized by the International Continence Society (ICS) and the American Urological Association (AUA) as multiple bothersome urinary symptoms, usually urinary urgency with or without urinary incontinence that is generally accompanied by frequency and nocturia, in the absence of urinary tract infection or other obvious pathology.1-6 OAB is often associated with urinary incontinence, which is defined as an ivoluntary loss of urine and may be further defined based on symptoms (TABLE 1). Notably, urinary incontinence is often absent in approximately 50% of patients with symptoms of OAB.7 One of the concerns of OAB is its significant impact on quality of life (QOL). It affects not only patients but also their family members; its impact extends socially, sexually, interpersonally, and professionally.2


table1

In the management of OAB, the goal of treatment is to attain relief of symptoms without affecting the emptying phase of the micturition cycle.4 These options include behavioral therapy, bladder retraining therapy, and pharmacologic therapy, as well as surgical intervention. Pharmacologic therapy is aimed at blocking muscarinic receptors in the bladder.10-12

EPIDEMIOLOGY

The underwhelmingly low proportion of patients seeking medical care for OAB for reasons that include social and cultural factors, particularly when urinary incontinence is present, has led to an underestimation of its true prevalence.8 The EPIC study, which included 19,000 participants in five countries, demonstrated that lower urinary tract symptoms (LUTS) are highly prevalent in men (62.5%) and women (66.6%) at least 40 years of age, with an increasing prevalence with advancing age.5,9 The study also showed that storage symptoms were reported more often than voiding or postmicturition symptoms; nocturia was reported as the most common storage symptom (men 48.6%; women 54.5%), followed by urgency (men 10.8%; women 12.8%).9

ETIOLOGY AND PATHOPHYSIOLOGY

The primary etiology of nonneurogenic OAB in the majority of patients remains unknown, though age does appear to be the most important risk factor. One proposed etiology of OAB include the possible exaggerated effect of acetylcholine (ACh), a neurotransmitter released from the urothelium during bladder distention, or increased sensitivity of sensory receptors in the urothelium to ACh.2 Subsequently, feedback to the central nervous system (CNS) creates the sensation of urgency, promoting the symptoms observed in OAB.2 A number of CNS disorders have been associated with OAB, including stroke, spinal cord injury, Parkinson's disease, and multiple sclerosis; however, these are considered to be of a neurogenic etiology.

In contrast, the neurogenic etiology of OAB may include damaged axonal paths in the spinal cord, increased LUT afferent nerve input, loss of peripheral inhibition, and enhancement of excitatory neurotransmission in the micturition reflex pathway.3 Additionally, myogenic etiology is related to patients with bladder outlet obstruction resulting from increased bladder pressure, which consequently causes partial neurologic denervation of the bladder smooth muscle.3

The pathophysiology of OAB syndrome is considered complex.13 The bladder, a urinary organ primarily made up of smooth muscle known as the detrusor muscle, is composed of two parts: the body (or dome) and a base. At the dome, beta-adrenergic and cholinergic receptors predominate, while alpha-adrenergic receptors predominate at the base and the proximal urethra (FIGURE 1).14


figure 1

The peripheral neurotransmitter predominantly responsible for bladder contraction, ACh, interacts with muscarinic receptors on the detrusor muscle. Of the five muscarinic subtypes (M1–M5), M2 and M3 are the primary muscarinic receptors located on the bladder, with M3 receptors predominating in the mediation of detrusor contraction.15 Sympathetic nerves inhibit bladder contraction and stimulate contractility of the urethra to promote urinary storage, while parasympathetic nerves stimulate bladder contraction and relax the bladder outlet to promote urinary emptying.16 Bladder filling causes an increase in sympathetic tone, which inhibits bladder parasympathetic motor nerves; this causes contraction of the urethra. Disorders of any of these structures may contribute to the symptoms of overactive bladder.

In addition to ACh, other neurotransmitters such as growth factors, serotonin, dopamine, glutamate, and prostaglandins have been studied in the voiding cycle. Serotonergic activity facilitates urine storage by enhancing the sympathetic reflex pathway. Dopamine D1 receptors appear to have a role in suppressing bladder activity, whereas dopamine D2 receptors appear to facilitate voiding, and glutamate controls the lower urinary tract, inhibiting the parasympathetic voiding pathway.17

CLINICAL PRESENTATION AND DIAGNSOSIS

The symptoms of OAB consist of four components: urgency, frequency, nocturia, and urgency (or urge) incontinence.1 OAB symptoms may include daytime urinary frequency, stress incontinence, nocturnal enuresis (involuntary loss of urine during sleep), or nocturia (urinary frequency, urgency, and urgency incontinence that only occurs at night).1,18

Diagnosis of OAB is based on patient symptomatology, where patients typically present with a complex of LUTS similar to thos of many other diseases such as urinary tract infections (UTIs). Therefore, initial evaluation should include a review of the patient's LUTS in order to exclude other causes.1,19 This includes a focused history, physical examination, urinalysis, and urinary diary, and may also include postvoid residual volume measurement, urodynamics, and cystoscopy as deemed necessary; the latter three are discouraged in the initial workup of an uncomplicated patient.1

A focused history of bladder symptoms, bladder storage problems, bladder emptying, fluid intake (type and amount), and past genitourinary disorders, including prostatic enlargement in older men, should be obtained.1,19 Focused physical examination includes assessment of abdomen, pelvis (including pelvic floor muscle function), neurologic function, and rectal/genitourinary.1,19 In addition, menopausal women may be assessed for atrophic vaginitis as a contributor to incontinence symptoms.1,19 A clean urine specimen should be obtained for urinalysis to rule out hematuria and/or urinary tract infection.1,18,19 Urinalysis positive for nitrites/leukocyte esterase, pyuria, and bacteriuria would warrant a urine culture and appropriate treatment.1

It is encouraged that patients with OAB maintain a urinary diary for 3 to 7 days to assist in determining baseline symptoms, contributing factors, pattern of voiding, and efficacy of treatment.1,18 Contents of the diary would include voiding times and amount, episodes of incontinence, and any circumstances or reasons associated with it, number of pads used, and the type and amount of liquid intake.1,20 Additionally, patients may also include a rating for the degree of each episode.1 Questionnaires such as the Urogenital Distress Inventory (UDI), the Incontinence Impact Questionnaire (II-Q), and the Overactive Bladder Questionnaire (OAB-q) assist in quantifying and following patients' baseline symptoms and response to treatment.1

MANAGEMENT

The Overactive Bladder Guidelines Panel of the American Urological Association Education and Research, Inc., henceforth referred to as The Panel, provided a clinical framework intended to assist clinicians in selecting appropriate treatment for patients with nonneurogenic OAB.1 These guidelines highlight the importance of recognizing OAB as a symptom complex that affects QOL rather than a life-threatening disease.1 Therefore, when selecting a treatment plan for a patient, the clinician should carefully weigh the potential benefits and risks of a particular treatment.1 Taking into consideration a balance of both the potential benefits and the adverse events, the guidelines document grouped treatment options into first, second, third, fourth, and fifth line.1

There are various factors to consider when selecting an appropriate treatment plan, including the patient's ability to remain motivated and maintain compliance, the availability of and access to specific treatments, patient allergies, and patient sensitivity to adverse events.1 A patient's urinary diary may be utilized in guiding treatment selections and monitoring efficacy.1 And treatment failure can be considered when the patient does not have the desired change in symptoms or is intolerable of treatment-associated adverse events.1

Nonpharmacologic treatment options include the recommended first-line option, behavioral therapies, and other options usually reserved for refractory patients, such as percutaneous tibial nerve stimulation and sacral neuromodulation.1 Pharmacologic treatment options include the antimuscarinics, beta3-adrenergic receptor (AR) agonist, onabotulinumtoxinA, and other alternatives such as hormonal therapy or tricyclic antidepressants.

First-Line Treatments

The Panel recommends behavioral therapies as the first-line treatment option when considering a treatment plan for patients presenting with OAB.1 These include a group of therapies aimed at changing the patient's behavior or environment and should be individualized to the patient's unique needs, keeping in mind that the patient's willingness and compliance will play a significant role in treatment efficacy.1 The Panel recommends two approaches to behavioral therapy: first, to focus on modifying bladder function by changing voiding habits, such as with bladder training and delayed voiding; and second, to focus on bladder outlet and pelvic floor muscle exercises to improve strength and control and the techniques for urge suppression.1

Components of behavioral therapy can include the following: self-monitoring (bladder diary); scheduled voiding; delayed voiding; double voiding; pelvic floor muscle training (PFMT) and exercise; urge-control techniques or bladder training (voiding schedules done with distraction and self-assertions); normal voiding techniques; biofeedback; electrical stimulation; fluid management (reduction in fluid intake reduces frequency and urgency); caffeine reduction (reduces voiding frequency); dietary changes (avoidance of bladder irritants such as alcohol or caffeine); weight loss (reduces urgency incontinence); and other lifestyle changes.1,21,22

Behavioral therapies are relatively noninvasive, associated with virtually no risk of adverse events, and can also be combined with other therapeutic alternatives.1 Evidence has demonstrated that the use of bladder training and behavioral training (PFMT with urge-suppression techniques) is just as effective as antimuscarinics, without associated adverse effects, in significantly reducing episodes of incontinence in both men and women.1,21-24 PFMT is the cornerstone of behavioral therapy for urinary incontinence of OAB.1,21 This focuses on teaching the patient how to properly contract pelvic floor muscles while relaxing other muscles, such as abdominal muscles, that may increase pressure on the bladder or pelvic floor with a goal of increasing pelvic muscle strength.21 Biofeedback, on the other hand, is a technique often used to help the patient identify pelvic floor muscles and how to appropriately exercise them or inhibit detrusor contractions; this requires special equipment and professional expertise, which may be costly and time-consuming.21 Patients with very weak pelvic floor muscles may benefit from combination of electrical stimulation and PFMT to improve efficacy.21

Second-Line Treatments

When selecting treatment options for patients with OAB, careful consideration should be given to deciding whether pharmacologic therapy should be added to behavioral therapy.1 The purpose of combining these treatments would be to optimize symptom control and QOL.25,26 However, a combination of behavioral treatment and pharmacotherapy requires an assessment of risks versus benefit, including the risk of potential adverse effects and increased pill burden. The Panel recommends oral antimuscarinics or a beta3-AR agonist as second-line therapy for management of OAB; these agents should be considered as the initial agent of choice when selecting a pharmacologic therapy.1 Other, less commonly used pharmacologic agents include tricyclic antidepressants, alpha-blockers, and intradetrusor onabotulinum-toxinA injections.

Antimuscarinics: Available anticholinergic agents include oxybutynin, tolterodine, solifenacin, darifenacin, trospium, and fesoterodine (TABLE 2). These agents act by decreasing urinary bladder contraction and detrusor muscle pressure and increasing residual urine volume through the inhibition of ACh at the M3 receptors, resulting in decreased urgency, frequency, and involuntary contractions. Although most of these agents have demonstrated functional selectivity to detrusor M3 receptors over salivary receptors, the newer agents (i.e., darifenacin, solifenacin, trospium, and fesoterodine) appear to be more selective than older agents offering better side-effect profiles and improved compliance.27 The Panel does not indicate any preference for one antimuscarinic agent over the other. However, The Panel does encourage dose modification or trial of another antimuscarinic in patients who experience inadequate symptom control before determining therapy failure.1


table2

Extensive randomized controlled trials and meta-analysis that compared the six different antimuscarinics to each other and to placebo suggest subtle differences in efficacy. When oxybutynin was compared to tolterodine, both agents seemed to decrease urinary frequency and incontinence with similar rates.30 Similarity in results was also seen between the two forms of oxybutynin, with no significant difference noted between the immediate-release (IR) and extended-release (ER) formulations.31 The ER formulation of tolterodine, however, appeared to be slightly more efficacious in urge incontinence and frequency than its IR formulation.32 When darifenacin was compared to oxybutynin IR, both agents were similar regarding OAB symptom control, and both were superior to placebo.33 Solifenacin, on the other hand, was found to be superior to both tolterodine and placebo in a randomized international multicenter trial.34 No significant difference was found when trospium was compared to both oxybutynin and tolterodine.35,36 Fesoterodine was found to be superior to tolterodine ER as early as 3 weeks after dose escalation.37

Associated side effects of antimuscarinic agents result from the inhibition of M1, M2, and M3 receptors external to the bladder and urethra. The inhibition of M1 receptors found in the CNS, salivary glands, and eyes resulted in decreased cognitive function, salivation, and production of tears, respectively. Similarly, blockage of the M2 receptors, mainly present on the heart and bronchial smooth muscles, may produce tachycardia and bronchodilation.

When comparing the ER formulations of oxybutynin and tolterodine to their IR counterparts, less dry mouth was reported due to constant levels of the parent drugs as well as lower rates of conversion to active metabolite in the stomach and small intestine (see TABLE 3 for tolerability of oxybutynin, tolterodine, and other anti-muscarinic agents).27,29,31,38 Additionally, oxybutynin, when compared to tolterodine, was associated with significantly more dry mouth.32 Similar tolerability was observed when oxybutynin was compared with darifenacin, the latter being associated with lower rates of dry mouth.33 Alternatively, tolterodine was associated with higher rates of dry mouth when compared to solifenacin both 5 mg and 10 mg.34 Unlike other agents, trospium, the only hydrophilic quaternary ammonium antimuscarinic agent, does not cross the blood-brain barrier, thus reducing CNS–related adverse effects. A systematic review also reported trospium with less dry mouth when compared to oxybutynin.39 The same systematic review concluded that fesoterodine was not associated with high rates of dry mouth when compared to other antimuscarinic agents.39 Because oxybutynin is the only agent available as a topical formulation, pruritus is another associated side effect with this agent. However, dry mouth rates of topical oxybutynin were lower than with oral formulations.39


table3

Antimuscarinics are contraindicated in patients at risk of or with known urinary or gastric retention or uncontrolled narrow-angle glaucoma. Additionally, they are all cautioned in patients with myasthenia gravis. Because of the risk of gastric retention and decreased gastrointestinal motility, caution should be used in patients with severe constipation, ulcerative colitis, and obstructive gastrointestinal disorders. Likewise, the American Geriatrics Society Beers Criteria for Potentially Inappropriate Medication Use in Older Adults caution clinicians against the use of antimuscarinics in patients aged >65 years owing to the possibility of causing worsened constipation; incidence of constipation differs among the antimuscarinics, and an alternative agent should be considered if constipation develops.40 Solifenacin and tolterodine have been associated with QT interval prolongation; therefore, caution and close monitoring are recommended in patients with a history of QT prolongation or in those on concomitant QT-prolonging drugs.29

Oral oxybutynin should be cautioned with concurrent bisphosphonate use or with drugs that cause or exacerbate esophagitis. Finally, darifenacin, oxybutynin, and solifenacin are metabolized by CYP3A4, and potential drug interactions could result with strong inhibitors; thus, dose adjustments are needed for darifenacin, soli-fenacin, fesoterodine, and tolterodine when given concomitantly with strong CYP3A4 inhibitors (e.g., keto-conazole, clarithromycin).29

Mirabegron: Mirabegron is the first beta3-AR agent of its class to be FDA approved for the management of OAB.41 It is thought to exert its effect on the beta3-AR present on the detrusor muscle, producing a dose-dependent relaxation of the detrusor muscle during the bladder-filling phase and inhibiting bladder overactivity.19,41 Its overall effect is to increase the bladder's capacity with no change in micturition pressure or residual volume. Physiologically, the release of endogenous norepinephrine from sympathetic nerves stimulates the beta3-AR to induce the production of adenyl cyclase, which in turn increases intracellular levels of cyclic adenosine monophosphate (cAMP), thereby causing relaxation of the detrusor smooth muscles.4,42 Mirabegron is recommended at a starting dose of 25 mg once daily, which can be increased to 50 mg once daily after 8 weeks based on efficacy and tolerability.29,41

A systematic review and mixed treatment analysis showed that mirabegron was equally effective to all antimuscarinics in reducing micturition episodes per day, except for solifenacin 10 mg, which demonstrated greater efficacy in both frequency and incontinence episodes.43

All antimuscarinics were associated with higher incidence of dry mouth compared to mirabegron, which had similar rates compared to placebo. Constipation rates were similar to both placebo and antimuscarinics. More concerning adverse effects such as QT prolongation and hypertension did not occur significantly at therapeutic doses; however, caution is needed when administering it concomitantly with other QT-prolonging agents, and mirabegron is not recommended in patients with severe, uncontrolled hypertension, as it was not studied in this population.44 Though there are no major clinical drug interactions noted for mirabegron, caution should be taken when administering CYP2D6 (desipramine, class I-C antiarrhythmics) and P-glycoprotein (Pgp) substrates, as mirabegron is a moderate CYP2D6 inhibitor and has weak Pgp inhibition activity.

Third-Line Treatments

Botulinum toxin: Intradetrusor injection of onabotu-linumtoxinA, or botulinum toxin, is an FDA-approved alternative for patients with OAB who are refractory to, or intolerant of, anticholinergics.1 The Panel recommends this agent as a third-line treatment option for selected patients who have been refractory to first- and second-line treatment options for OAB.1 Botulinum toxin exerts its action by hindering the attachment and fusion of ACh-containing synaptic vesicles to the cell membrane in the terminal nerve endings of the neuromuscular junction, preventing the exocytosis of ACh into the synaptic cleft and thereby inhibiting muscle contraction.41,45 This is especially useful in patients presenting with bladder-storage symptoms, indicating detrusor overactivity that is usually characterized by involuntary detrusor contraction during bladder filling.5,45

When compared to placebo, onabotulinumtoxinA showed significant improvements in bladder capacity, and episodes of incontinence at 2 and 4 weeks post treatment in patients with neurogenic OAB; onabotulinumtoxinA also showed significant improvements in bladder capacity, urinary frequency, and episodes of urge incontinence at 12 weeks post treatment in patients with nonneurogenic OAB.41 The Panel recommends this as a third-line option due to the rate of adverse events (UTIs, elevated postvoid residual urine [PVR], gross hematuria, dry mouth, impaired vision, and eyelid, arm, torso, and leg weaknesses) that could affect a patient's QOL.1 The effect of onabotulinumtoxinA is only temporary, and repeated injections will be necessary.1,18

Percutaneous Tibial Nerve Stimulation (PTNS) and Sacral Neuromodulation (SNS): More invasive procedures, such as PTNS and SNS, could be offered to selected refractory patients who fail behavioral and pharmacologic therapies or who are not candidates for pharmacologic agents.1 PTNS could be administered to patients with moderately severe baseline urinary incontinence (average of three episodes per day) and frequency (11.8 to 16.5 episodes per day).1 PTNS is a minimally invasive procedure that involves neuromodulation of the bladder through insertion of a fine needle electrode through the tibia. The most common protocol utilized in trials and endorsed by the AUA guidelines was a once-a-week, 30-minute session for 12 weeks and was associated with relatively uncommon and mild side effects.1,46 This protocol was compared to tolterodine ER 2 mg to 4 mg daily and showed similar to better improvements in voiding parameters.46 Another study compared combining PTNS to tolterodine 4 mg daily versus tolterodine alone, and results favored the combination approach.47 A patient's compliance plays a significant role in the efficacy of the protocol.1

SNS is an even more invasive surgical procedure that involves the implantation of a subcutaneous stimulator; this option could be offered to selected refractory patients characterized with baseline severe incontinence (5 to 11.6 episodes per day) and frequency (>13 episodes per day). Several studies evaluated the efficacy of SNS, and all showed improvements in outcomes and QOL.48-50 An on-demand version of the protocol driven by patients, in which the apparatus could be turned off for several hours a day, was also tested and showed positive outcomes in an attempt to reduce adverse effects and limit nervous system adaptation.51 Patients should be advised of potential side effects associated with SNS including pain at the stimulator and lead site, electric shock, infection/ irritation, and need for periodic surgical revisions and replacements.1 Patients should also be cautioned against the use of diagnostic MRI with the placement of SNS.1 In very rare cases, after trial of other invasive procedures, augmentation cytoplasty or urinary diversion may be considered for refractory patients, but these are more often reserved for neurogenic patients.1

Additional Treatments

Estrogen: The role of estrogen on urinary incontinence has been challenged by recent data; it is believed that estrogen deficiency and inflammation from atrophic vaginitis and urethritis may contribute to the LUTS in menopausal and postmenopausal women.1,19,52 The use of systemic estrogen or combination estrogen therapy in the management of LUTS remains controversial because of evidence suggesting a worsening effect on incontinence.18,41,52 However, local application of estrogen therapy (e.g., estrogen vaginal creams) in women with vaginal atrophy may improve incontinence, decreasing symptoms of frequency and urgency.18,41,52 Further clinical evaluation is warranted on the role of estrogen therapy in the management of OAB.

Alpha-adrenergic receptor antagonist: Benign or malignant prostate enlargement may contribute to symptoms of bladder overactivity; therefore, alpha1-adrenergic receptor antagonist such as tamsulosin or alfuzosin may be used in older males who have benign prostatic hyperplasia (BPH) or in whom urinary obstruction and prostate cancer have been ruled out.19,53 These agents work by blocking the alpha1a-adrenergic receptor on the bladder neck and urethra, causing a smoother urinary flow and improving voiding symptoms.19,54 To reduce the risk of postural hypotension, the agent may be taken at bedtime, and gradual dose titration must be done carefully, particularly in patients on other antihypertensive agents.19 Men who are unresponsive or intolerable to alpha1-adrenergic receptor antagonists and who are not candidates for surgical intervention may benefit from an antimuscarinic trial with adequate monitoring for urinary rentention.19 Combination of alpha1-adrenergic receptor antagonists with an antimuscarinic may also be considered in men in whom monotherapy was insufficient.19,54

Imipramine: Imipramine, which has FDA approval for nocturnal enuresis, may have clinical benefit in the treatment of urinary incontinence.24 Imipramine exerts its effect by decreasing bladder contractility through its anticholinergic effects on the detrusor muscle and by increasing outflow resistance through its action of the alpha1-adrenergic receptor on the bladder neck.24 Currently the use of imipramine in the management of OAB lacks sufficient clinical evidence; thus, it is not included in The Panel's recommendations.

Desmopressin (DDAVP): DDAVP is an oral synthetic antidiuretic hormone (ADH) that has been extensively studied and is FDA-approved for primary nocturnal enuresis.41,53 This agent exerts its action by increasing water reabsorption for up to 10 hours, thereby reducing urine production.53 The use of DDAVP at a dose of 0.2 mg orally in 88 adults suffering from OAB was found to decrease voiding and episodes of urgency as compared to placebo.55 Use of DDAVP has only a short-term role in the management of primary nocturnal enuresis in patients without any underlying electrolyte disturbance or risk factors for hyponatremia.41 The use of this drug in elderly patients is generally not recommended owing to the risk of hyponatremia.41

ROLE OF THE PHARMACIST

The accessibility of pharmacists in both community and institutional settings allows them to play a key role in providing pharmacotherapeutic and nontherapeutic education to patients, physicians, and nurses alike when managing OAB. Of note, pharmacists may assist in providing education regarding lifestyle changes that may reduce symptoms of OAB. For example, cigarette smoking, increased consumption of beverages, and obesity are documented as risk factors of OAB.56 Lifestyle modifications such as limiting daily fluid intake, consuming less than 400 mg of caffeine daily, losing weight, and quitting smoking have shown to decrease urgency and frequency in patients with mixed urinary incontinence symptoms.56

In the elderly, when considering the use of oxybutynin, severe adverse effects have been associated due to its nonselectivity, which may lead to adherence concerns. Recommendations to increase adherence include switching patients to tolterodine, which is slightly more selective than oxybutynin and has a less intense side-effect profile.2 Thus, providing proper education assists patients in identifying and managing potential medication side effects (i.e., dry mouth, dizziness, constipation, drowsiness, etc.). Chronic therapy is essential for symptom stabilization when managing OAB. Hence, pharmacists provide unique opportunities to enhance treatment outcomes in the overall management of OAB.

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