US Pharm. 2007;32(6):34-44.
Urinary incontinence (UI) is best defined as a variety of abnormalities of the urinary tract that result in the inability to experience normal micturition, leading to involuntary loss of bladder control. Approximately 40% of community-dwelling elderly and hospitalized patients are afflicted with this disorder.1-3 Sixty percent of nursing home patients experience this disorder, and it is often the reason for their admittance.4 Due to the social stigma associated with UI, the actual incidence in the community may be underestimated. Urinary incontinence may be associated with significant medical complications, creating issues for both patients and caregivers.1,5,6 The economic impact that results from UI influences both direct and indirect costs, placing a significant burden on the health care system.7,8
CAUSES OF URINARY INCONTINENCE
The causes of urinary incontinence are numerous and may involve age-related changes in the bladder and urethra, including declines in outlet resistance in females and prostate enlargement in males. Causes may also be secondary to a variety of cerebral insults or diseases, including cerebrovascular disease (strokes), spinal cord lesions, Alzheimer's disease, and Parkinson's disease. Reversible causes are numerous and include urinary tract infections, stool impaction, and numerous other triggers, described by the acronym DIAPPERS in Table 1.9-14 Numerous medication and medication classes can cause or exacerbate an existing incontinence and are described in Table 2 .12,13 Pharmacists should be aware of these potential disease–drug interactions when monitoring their patients' drug therapy.
OVERVIEW OF THE ANATOMY AND PHYSIOLOGY OF THE
A basic understanding of the bladder's anatomy and pathophysiology is important in order to understand the various UI types and their pharmacological management.11,14 Figure 1 describes the anatomy and physiology associated with bladder function, including the detrusor muscle in the bladder body and the internal and external sphincters, along with their nervous system connections. The bladder fills when sympathetic nervous system control results in a relaxed detrusor muscle and closed sphincters at the bladder outlet. When the bladder reaches a certain volume (200-400 mL), signals move from the spinal cord to brain centers, resulting in the sensation of urge. During voiding, the parasympathetic nervous system releases acetylcholine, which acts on the bladder detrusor smooth muscle to create contractions, and, concurrently, the sympathetic nervous system and somatic systems allow the sphincters to open. The result of these complex processes is the release of urine (micturition) from the bladder. 14-18
DIAGNOSIS AND TREATMENT OVERVIEW
The evaluation and diagnosis of UI requires a complete medical examination to rule out reversible causes and may require the participation of physicians trained in urological evaluation.13 Correct diagnosis is important since drugs utilized for one incontinence type may exacerbate other types. 18,19 From a pharmacist's perspective, a good understanding of the medications used to treat incontinence and the medications (Table 2) that may exacerbate this disorder are important.9-13 In addition, since many urinary incontinent patients are elderly, drug use can be challenging and requires an understanding of the pharmacokinetic and pharmacodynamic changes that occur in this population.20
CLASSIFICATION OF INCONTINENCE
The various types of UI include those listed in Table 3, although many patients may experience mixed etiologies. This article will provide an overview of the three major types of UI and their treatments, including urge, stress, and overflow types.6,13,21-26
Urge UI is the most common cause of incontinence in the elderly and is best described by features of urgency that result in loss of urine. Urge incontinence is often referred to as overactive bladder (OAB), although an important distinction needs to be made from OAB since approximately two thirds of patients with OAB are not incontinent of urine.13,27-30 The pathophysiology is primarily due to detrusor muscle overactivity, resulting in uncontrolled, uninhibited, or involuntary bladder muscle contractions. 30-32a Clinically, patients describe a sudden desire to urinate, which is difficult to defer and results in leakage of urine occurring at various times during the day and night.6,29,30 The causes may be secondary to neurogenic insults including stroke, trauma, and neurologic diseases in addition to reversible causes such as drugs and infections.6,9-13,26 The treatments for urge incontinence include bladder training, behavioral treatments, pelvic floor exercises (Kegels), pads for temporary support, surgery, and pharmacotherapy.33-35
Pharmacotherapy with Anticholinergic Drugs
The basis of pharmacotherapy for urge incontinence is controlling bladder detrusor muscle overactivity with drugs that act as acetylcholine (cholinergic) antagonists on bladder muscarinic (M) receptors, specifically the M2 and M3. The result is a reduction in urgency symptoms and improvements in bladder control.36 Since muscarinic receptors are also located in other organ systems throughout the body and since these antimuscarinic drugs are nonselective, numerous other effects and/or adverse effects may result from their use.
Anticholinergic or antimuscarinic side effects include both peripheral and central adverse reactions as noted in Table 4 . These adverse effects, including confusion, delirium, constipation, and urinary retention, are especially concerning in the more vulnerable elderly population.11,36,41,42 Contraindications to these agents are documented elsewhere and include narrow-angle glaucoma, urinary/gastric obstructive disorders, and dementia. Drug interactions include other anticholinergic drugs, acetylcholinesterase inhibitors, and numerous other agents. All of the antimuscarinic agents discussed below, except trospium, are metabolized by the cytochrome P-450 (CYP-450) system, and inhibitors of this system can potentiate their side-effect profiles.11,36 Monitoring for anticholinergic side effects, drug interactions, and potential contraindications, especially in patients who are taking multiple drugs with these properties, is essential for all health care professionals, including pharmacists.
A number of anticholinergic drugs are utilized in the treatment of urge incontinence. Older agents such as propantheline, dicyclomine, and flavoxate are still available but are rarely used because of their questionable efficacy and side-effect profiles. The tricyclic antidepressants (TCAs), including imipramine, have been used in urge incontinence and may have a role in mixed forms of stress and urge due to their duel antimuscarinic and alpha-adrenergic properties.36,43-47 The major agents used today in the treatment of urge incontinence include oxybutynin chloride (OBC), tolterodine (TD), and the three newest agents--trospium chloride (TC), darifenacin (DAF), and solifenacin (SFA)--along with a transdermal formulation of oxybutynin. Results from two large meta-analyses reported similar clinical efficacy among the available agents measured as reductions in episodes of urgency, frequency, daily micturitions, nocturnal awakenings, increase volume per void, and patient satisfaction. 44,48 Comparison trials with these agents are limited, however, and will be discussed below in a brief overview.49-51
Oxybutynin chloride: Oxybutynin chloride is the oldest of the agents presently used for urge incontinence and is available in regular-release and long-acting oral products, in addition to a patch formulation. Clinical trials indicate similar efficacy to other agents in the class, and the significance of OBC's proposed additional muscle relaxation properties is not clear.52 The oral extended-release formulation and patch formulations may offer improved tolerability, due to less formation of the active metabolite desethyloxybutynin (DES).53-57 The adverse effects include dose-related anticholinergic effects as described above, along with the addition of erythema and pruritus associated with the transdermal patch. Dry mouth with this agent is reported to be as high as 50% to 70% and may be due to greater binding to the parotid gland.52-57 Drug interactions include the expected additive side effects when used with other anticholinergic agents. In addition, CYP-450 2D6 and 3A4 pathway inhibitors (e.g., fluconazole and erythromycin) may potentiate its side-effect profile. Monitoring and reviewing patients' medication profiles are important when oxybutynin is prescribed with other agents.36,52,57
Tolterodine (Detrol, Detrol LA): Tolterodine is available in both regular-release tablets and long-acting products, and they may offer improved tolerability versus regular-release oxybutynin, with similar efficacy and tolerability to the other available agents.57,58 Tolterodine's bioavailability (BA) and elimination is dependent on the CYP-450 2D6 metabolism phenotype, with extensive metabolizers having a lower BA and less excretion of drug in the urine. Drug interactions are similar to those reported with oxybutynin, above.59-62
Newer Agents Released in 2004
The search for drugs with improved tolerability led to the development, approval, and release of three new drugs in 2004.49-51 Although these agents appear equal in efficacy to oxybutynin and tolterodine, they may have some individual advantages in pharmacokinetic profile and/or tolerability, although there is limited evidence to support a clinical advantage.63-65
Trospium (Sanctura): The first of the new agents, trospium chloride, has a quaternary amine structure resulting in a hydrophilic molecule, with less blood–brain barrier penetration and a reduced potential for central nervous system (CNS) side effects. The BA of this agent is poor, and administration should be on an empty stomach. Hepatic metabolism is limited, resulting in lack of CYP-450 involvement and associated drug interactions. Elimination is via tubular secretion, requiring dose adjustments in patients with creatinine clearances (CrCl) less than 30 mL/minute.51,64,65 Trospium's efficacy is reported to be similar to other drugs in the class, although it may be better tolerated in some patients. 64,66-68 Drug interactions may involve competition for tubular secretion (metformin, digoxin) and drugs with an additive anticholinergic side-effect profile. Contraindications are similar to those of other anticholinergic agents as discussed above.51,69-71
Solifenacin (VESIcare): Solifenacin, another of the new antimuscarinics, is dosed once daily and has excellent BA. Solifenacin is metabolized primarily by CYP-450 3A4 and has some dependence on renal clearance, requiring adjustments in patients with a CrCl less than 30 mL/minute.50,72 Efficacy is reported to be similar to that of the other available anticholinergic agents,72-76 with one trial reporting fewer micturitions per 24 hours with solifenacin versus tolterodine.63 Adverse effects are similar to those of the other agents, along with reports of prolonged QTc intervals at higher doses, suggesting caution with patients at risk for this adverse event. As noted with oxybutynin and other drugs mentioned above, drug interactions, adverse effects, and contraindications are similar along with the added QTc concern. 50,77
Darifenacin (Enablex): Darifenacin, the third of the newer agents released in 2004, is also dosed once daily. Darifenacin's BA is poor and depends on the CYP-450 2D6 metabolism phenotype. Extensive metabolizers have a lower BA and more dependence on the CYP-450 3A4 pathway. Dosage adjustments are recommended in patients with hepatic impairment, and caution is suggested in patients with renal disease. 49,78
Darifenacin is reported to have a higher affinity for bladder M3 receptors, suggesting greater selectivity and tolerability, although clinical evidence of this advantage is lacking.78-80 Clinical trials with darifenacin have reported similar efficacy to the other agents, with improved tolerability versus oxybutynin.81-84 As noted with oxybutynin and the others above, metabolism involves the CYP-450 system, and adverse effects and contraindication are also similar.49
The anticholinergic/muscarinic drugs described above have a role in the management of urge incontinence. Doses should be started low, especially in elderly patients, and titrated slowly with careful monitoring for adverse effects and drug interactions. An adequate trial of four to eight weeks is recommended, with no clear advantage in terms of efficacy between the five agents discussed, although tolerability differences may exist.47,48,81,82 Patient counseling when dispensing these agents should include a review of potential side effects, drug interactions, and education on dosing and onset of action.
Stress incontinence, the most common form of UI in elderly women, is primarily a problem with bladder sphincter function, resulting in urine leakage at inappropriate times. Risk factors are numerous, including aging changes, multiple childbirths, medications (Table 2), obesity, trauma, or neurogenic problems.13,26,59,85-88 Although the economic costs are high, the social costs and impact on elderly women are also significant. 89-91 Clinically, patients describe involuntary loss of urine triggered by coughing, sneezing, or rising quickly. Patients with pure stress incontinence may lack urgency and nocturia, although many of these patients may have mixed forms of incontinence with features of urgency.87,88,92,93 The treatment of stress incontinence includes temporary pads for social situations, behavioral interventions, and Kegel exercises, along with a number of surgical options.37,94-99 There are limited agents and data available for the pharmacological management of pure stress incontinence. Unlabeled uses of alpha-adrenergic agonists (e.g., pseudoephedrine and phenylephrine) are based on the urethral smooth-muscle response to alpha stimulation, resulting in improved control of the internal sphincter and reduced urine loss. Lack of proven efficacy with these agents and concerns with adverse effects including insomnia, anxiety, hypertension, arrhythmias, and stroke limits their utility.13,26,59,100-102 The tricyclic antidepressant imipramine has been used in the treatment of stress or mixed incontinence, due to its alpha-adrenergic agonist and anticholinergic properties. Low doses may provide relief in some patients, especially if they have a mixed disorder with stress and urgency symptoms. With its anticholinergic side-effect profile, the use of this agent in elderly patients may be problematic.11,26,36,85,86
Although the loss of estrogen in postmenopausal woman may contribute to symptoms of stress incontinence due to estrogen's influence on sphincter control, there is limited clinical evidence to support its use. Estrogen therapy has been proposed to increase urethral resistance via stimulation of estrogen receptors. If treatment is utilized, local or topical treatments are recommended and include creams (Table 3), vaginal tablets, or elastomer ring formulations, which may be beneficial for improving irritative symptoms and discomfort in some patients. 85,86,103-107 The use of oral estrogen for stress incontinence is not recommended due lack of benefit, along with the small but significant increased risk of other comorbidities.108
The most recent agent being evaluated for stress incontinence is duloxetine, a dual norepinephrine (NE) and serotonin (5HT) reuptake blocker approved for depression. The proposed mechanism in this disorder is through duloxetine's action on receptors in the Onuf's nucleus of the spinal cord and on the pudendal bladder nerve to improve urethral sphincter muscle contractions and tone.109
Overflow incontinence is best described as an overfilled bladder secondary to obstruction, bladder prolapse, or alignment problems, most commonly seen in males with benign prostatic hyperplasia (BPH).11,13,26,110 Men with BPH are usually found to have an enlarged prostate on physical exam, and in some cases further evaluation may be warranted to rule out prostate cancer or other obstructions.110 The clinical presentation of overflow incontinence is described by lower urinary tract symptoms including difficulty starting urination and/or having a weak urine stream, a sense of incomplete emptying, nocturia, and dribbling. A complicating feature of this disorder is that two thirds of patients with BPH may also have urgency symptoms, which can make diagnosis and treatment challenging.110,111 Treatment for overflow incontinence caused by BPH may include watchful waiting and eliminating potential triggers, including alcohol and/or caffeine. Surgical options may include transurethral resection of the prostate (TURP) or newer, less-invasive laser procedures.110,112-116
Drug therapy for the treatment of overflow incontinence secondary to BPH includes the peripheral alpha-adrenergic blockers and the 5-alpha-reductase inhibitors.110,112 The alpha-adrenergic blockers include the older, nonselective agents originally approved to treat hypertension and the newer prostate selective agents, which have minimal effects on blood pressure.117-119 The alpha-adrenergic blockers are usually the choice therapy in early mild disease due to their faster onset of action, usually within six weeks.118-121 Their mechanism of action is through their blocking action at the prostate alpha 1A receptor, resulting in improved urine outflow and relief of the symptoms described above.
These agents are metabolized by the hepatic CYP-450 system, and monitoring for drug interactions is necessary. Adverse effects include dizziness, peripheral edema, sedation, ejaculatory dysfunction, flulike symptoms, headaches, and gastrointestinal effects. Contraindications include heart failure, hypotension, and the potential to exacerbate stress incontinence in females. Individual differences between these agents include selectivity, dosing frequency, and cost issues related to brand name products. The selective agents may be better choices in patients without hypertension or in elderly patients at risk for orthostatic hypotension. The nonselective agents may be appropriate choices in younger BPH patients with concurrent hypertension. Patient counseling when dispensing these agents should include a review of potential side effects, especially effects on blood pressure, sedation, and dizziness.110,112,118
The alpha-reductase inhibitors finasteride and dutasteride are also used to treat overflow incontinence secondary to BPH. Their mechanism of action is through inhibiting the conversion of testosterone to dihydrotestosterone, resulting in reduced androgenic prostate stimulation and leading to reduced gland size and improved urine outflow. Although usually considered a second-line therapy, they may be used first-line in patients with contraindications to the alpha-blockers (hypotension or heart failure) or in combination with alpha-blockers in progressive or more moderate-to-severe disease, e.g., large glands. Although effective in treating the symptoms of BPH, their side-effect profile (e.g., decreased libido, impotence, dry sex, and gynecomastia) and slower onset of action, which may take up to six to 12 months, limits their use in mild disease.110,112,118,122-124 Similar efficacy for both agents has been reported in clinical trials, and potential differences in selectivity for reductase enzymes have not been demonstrated clinically.125 Although these agents are not indicated in women, they are classified as pregnancy category X, and avoidance of drug contact by any potential route (handling broken tablets, semen transfer) with pregnant women or those seeking to become pregnant is recommended. 110,112,118
Other therapies that have been utilized in the management of overflow incontinence secondary to BPH include the herbal saw palmetto, which is reported to have 5-alpha-reductase inhibitor activity and the cholinergic agonist bethanechol, which may be used for acute management after TURP procedures11,36 Investigational therapies include combinations of anticholinergic drugs with alpha-blockers for patients who have urgency associated with their BPH symptoms.111,126 The use of the erectile dysfunction drugs (e.g., phosphodiesterase inhibitors [sildenafil] and botulinum toxin) are also being evaluated in the treatment of overflow incontinence secondary to BPH.127,128 As noted in Table 3, other types of incontinence include functional incontinence secondary to patients' inability to reach the bathroom due to a physical disability and atonic bladder, where complete loss of bladder innervation and control secondary to various diseases or insults, including stroke or diabetes, requires the use of intermittent catheterizations. Mixed UI may occur in up to 20% to 30% of patients and, due to the various clinical presentations and symptoms, may require extensive evaluation and therapeutic trials to determine appropriate therapies.6,11,13,18,24-26,59,88
The pharmacological management of UI requires appropriate evaluation by qualified clinicians. Pharmacists can offer educational support to patients by questioning and monitoring the effectiveness and tolerability of the various pharmacotherapies. Taking time to get to know your patients in the ambulatory and clinical settings allows the pharmacist the opportunity to provide valuable education, intervention, and recommendations to improve patient care outcomes in the management of this complex disorder.
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