Pharmacolo gic Ma nagement of Urinar y Incontinence, Voiding Dysfunction, and Overactive Bladder Emily K. Saks, MD*, LilyA. Arya, MD, MS KEYWORDS Urinary incontinence Overactive bladder Female Medication Treatment
The bladder and urethra comprise the female lower urinary tract and function in concert to store and expel urine at the proper times. Urinary incontinence and voiding dysfunction are the result of an inability to appropriately store or empty urine. The capability of the female lower urinary tract to efficiently store urine and release it at appropriate intervals requires an intact and functioning nervous system. The female bladder and urethra are supplied by the somatic (pudenal) and autonomic (sympathetic and parasympathetic) nerves (Fig. 1).1 The pudendal nerve, originating from the anterior horn of the second, third, and fourth sacral nerve roots, supplies the external urethral sphincter and is under voluntary control. The parasympathetic nerves are derived from dorsolateral ganglion of the second, third, and fourth sacral segments of the spinal cord and have long preganglionic nerves that synapse close to the bladder. The short postganglionic nerves end primarily on muscarinic receptors of the detrusor muscle. Sympathetic nerve supply of the bladder is derived from the thoracolumbar segments (T10–L2) of the spinal cord. The short preganglionic fibers synapse in the sympathetic trunk and the long postganglionic fibers terminate in adrenergic receptors of the urethra and the bladder neck. The pharmacologic treatment of urinary incontinence and voiding dysfunction is focused on modulating sphincter function or detrusor contractility through its effect on the nerve supply of the lower urinary tract.
Division of Urogynecology and Pelvic Reconstructive Surgery, Department of Obstetrics and Gynecology, University of Pennsylvania School of Medicine, 1000 Courtyard, Philadelphia, PA 19104, USA * Corresponding author. E-mail address: emily.saks@uphs.upenn.edu (E.K. Saks). Obstet Gynecol Clin N Am 36 (2009) 493–507 doi:10.1016/j.ogc.2009.08.001 0889-8545/09/$ – see front matter ª 2009 Elsevier Inc. All rights reserved.
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Brain hyp etic path Sym
T10–L2
e nerv tric ogas
M2 (80%) M2
M3 (20%)
Bladder detrusor smooth muscle
M3 e ic nerv tic pelv mpathe Parasy
S2–S4
M2
Urethral smooth muscle Striated urethral sphincter
Somatic pudendal nerve
Levator Ani skeletal muscle Urethral smooth muscle
Fig.1. Neurophysiology of the lower urinary tract. (Adapted from Wein AJ. Pharmacological agents for the treatment of urinary incontinence due to overactive bladder. Expert Opin Investig Drugs 2001;10(1):65–83; with permission. Data from Abrams P, Andersson KE, Buccafusco JJ, et al. Muscarinic receptors: their distribution and function in body systems, and the implications for treating overactive bladder. Br J Pharmacol 2006;148(5):565–78; and Benson JT, Walters MD. Neurophysiology and pharmacology of the lower urinary tract. In: Walters MD, Karram MM, editors. Urogynecology and reconstructive surgery. 3rd edition. Philadelphia: Mosby and Elsevier; 2007. p. 33.).
STRESS URINARY INCONTINENCE
Numerous drugs have been investigated as potential treatments for stress urinary incontinence, but unfortunately few have made significant impact. This is likely because the main underlying cause of stress urinary incontinence is mechanical displacement of the bladder neck and urethra.2 Pharmacologic therapies for stress urinary incontinence are targeted toward improving urethral muscle tone by stimulation of adrenergic receptors at the urethra and bladder neck, where a-adrenoceptors predominate over b-adrenoceptors.3 Adrenergic agonists, such as pseudoephedrine and ephedrine, have long been used off-label for stress urinary incontinence with some beneficial results in uncontrolled studies.4 A recent Cochrane review5 concluded that the potential of serious side effects, such as hypertension, arrhythmias, and cardiovascular events, severely limits the use of these medications for stress urinary incontinence. Imipramine inhibits reuptake of norepinephrine and serotonin and is thought to improve contraction of urethral smooth muscle. Imipramine may also have some benefit in the treatment of detrusor hyperactivity because it exerts weak antimuscarinic properties in the bladder. There are no well-conducted studies proving efficacy of the drug in stress or urge incontinence.6–8 Additionally, there is concern regarding associated side effects including peripheral antimuscarinic effects, hypertension, and orthostatic hypotension, especially in older adults. Duloxetine, an antidepressant, inhibits presynaptic reuptake of serotonin and norepinephrine in the sacral spinal cord, which leads to increased activity of the urethral striated sphincter. Duloxetine may also reduce detrusor overactivity and increase bladder capacity through a central mechanism.9 Although randomized clinical trials have shown overall decreases in the frequency of stress and urge incontinence episodes and improvements in quality of life, it remains unclear whether these effects are sustainable.10–12 High rates of nausea lead to significant dropout (over
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50%) in the clinical trials.13 The drug is not approved for urinary incontinence in the United States and carries a black box warning regarding suicidal tendencies during early use. Because of the limited efficacy of medications in women with stress urinary incontinence, pharmacotherapy should be used in conjunction with behavioral therapies. Behavioral treatments and surgical procedures remain the mainstay of treatment for stress urinary incontinence. URGE URINARY INCONTINENCE AND OVERACTIVE BLADDER
Antimuscarinic medications serve as the foundation of therapy for urge urinary incontinence and overactive bladder and have been used for several decades. Recently, with the development of slow-release and transdermal formulations, and novel antimuscarinic medications, a variety of treatment options have emerged. Multiple studies have established their safety and tolerability. Although these drugs produced significant improvements in symptoms and quality of life as compared with placebo,14 the overall cure rate (ie, the number of patients reporting no urinary leakage) is low. Acetylcholine, the main contractile neurotransmitter of the detrusor muscle, acts by stimulation of the muscarinic receptors.15 Antimuscarinic agents act during the fillingstorage phase of the micturition cycle by inhibiting afferent (sensory) input from the bladder, and directly inhibiting smooth muscle contractility. Clinically, antimuscarinic agents reduce urinary frequency, urgency, and the number of incontinence episodes, while increasing the warning time to get to the bathroom and the volume of each void. Antimuscarinic medications may be prescribed for overactive bladder when behavioral measures, such as caffeine restriction, fluid manipulation, bladder retraining, and pelvic physical therapy, have failed to control symptoms. Five subtypes of muscarinic receptors are found throughout the human body including the central nervous system, salivary glands, heart, and bowel.16 Urinary smooth muscle and urothelium contain mainly M2 and M3 receptors. Although M2 receptors account for 80% of the receptors in the urinary tract, M3 receptors are primarily responsible for bladder contraction. Unfortunately, M2 and M3 receptors are also present in other tissues of the body (eg, M3 in bowel, salivary glands, and eye; M2 in cardiac smooth muscle), making it difficult to develop purely uroselective drugs. Most of the current antimuscarinic medications used in the treatment of urge incontinence produce varying degrees of common antimuscarinic side effects, such as dry mouth, blurred vision, confusion, constipation, and rarely increased heart rate. Although these medications have varying selectivity for the different subtypes of muscarinic receptors, it is unclear whether this results in clinically significant differences in efficacy and tolerability. Historical antimuscarinics, such as urospas, propiverine, and flavoxate, are no longer recommended because of lack of efficacy. Data on the efficacy of tricyclic antidepressants, a-adrenergic agonists, afferent nerve inhibitors, prostaglandin antagonists, b-adrenergic agonists, and calcium channel blockers for overactive bladder are lacking and are generally not used.17 Currently, six main anticholinergic drugs are available in the United States for the treatment of urge urinary incontinence and overactive bladder. The receptor selectivity, dose, and pharmacodynamics of these drugs are listed in Table 1. Oxybutynin18 is one of the earliest medications used for the treatment of overactive bladder and has a combination of antimuscarinic, antispasmodic, and local anesthetic properties.19 The drug seems to have the greatest affinity for M1 and M3 receptors, but may have more selectivity for salivary gland tissue than bladder smooth muscle20
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Table 1 Dose, receptor selectivity, and pharmacodynamics of antimuscarinic medications
a b
Peak Plasma Levela
Elimination Half-Lifea
Generic Name
Brand Name
Subtype of Muscarinic Blockade20
Dose
Darifenacin
Enablex
Relatively selective for M3
7.5–15 mg daily
7h
13–19 h
Fesoterodine
Toviaz
Similar block of M3 and M2
4–8 mg daily
3–8 h
45–68 h
Oxybutinin IR
Ditropanb
Relatively selective for M3 and M1
5 mg two to four times daily
1h
2–3 h
Oxybutinin ER
Ditropan XLb
Relatively selective for M3 and M1
5–30 mg daily
4–6 h
13 h
Oxybutinin transdermal patch
Oxytrol
Relatively selective for M3 and M1
One patch every 3–4 d
10 h
7–8 h
Oxybutinin transdermal gel
Gelnique
Relatively selective for M3 and M1
1g gel daily
7–8 h
64 h
Solifenacin
Vesicare
Relatively selective for M3 and M1
5–10 mg daily
3–8 h
45–68 h
Tolterodine IR
Detrol
Similar block of M3 and M2, relatively nonselective
1–2 mg twice a day
0.5–2 h
2.4 h
Tolterodine ER
Detrol LA
Similar block of M3 and M2, relatively nonselective
2–4 mg daily
2–6 h
7–9 h
Tropsium IR
Sanctura
Similar block of M3 and M2, relatively nonselective
20 mg twice a day
5–6 h
20 h
Tropsium ER
Sanctura XR
Similar block of M3 and M2, relatively nonselective
60 mg daily
4–5 h
35 h
Pharmacodynamic data obtained from drug prescribing information. Generic form also available.
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as reflected in the significantly high rates of dry mouth. Most of the side-effects of oxybutynin are caused by its active metabolite, N-desethyloxyloxybutynin, produced through the extensive first-pass metabolism in the gut.21 Alternate formulations of oxybutynin, such as an extended-release formulation,22 a transdermal patch,23 and a new transdermal gel,24 produce lower levels of N-desethyloxyloxybutynin by reducing the first-pass effect. They have similar efficacy rates with fewer side effects than the immediate-release oral preparation. The transdermal patches have been associated with local skin irritation, such as pruritis and erythema.23 Because of its local anesthetic properties, oxybutynin may be of some benefit in patients with urgency, frequency, and bladder pain.25 Tolterodine26 was the first drug to be developed specifically for treatment of overactive bladder. It is a relatively nonselective muscarinic receptor antagonist, but may have more affinity for the receptors of the bladder than of the salivary gland, likely contributing to the reports of significantly less dry mouth than oxybutynin.20 The extended-release formulation was developed to reduce side effects. In clinical trials, the extended-release formulation was 18% more effective and had a 27% decrease in the rate of dry mouth than the immediate-release formulation.22 Trospium27 was approved for use in the United States in 2004 but has been approved in Europe for over 25 years. In contrast to other antimuscarinics, which are negatively charged tertiary amines, tropsium is a positively charged, hydrophilic, quaternary amine.28 This structure results in impaired absorption from the gut that is even worse if taken with food. It does not cross the blood-brain barrier and very few effects on the central nervous system have been reported in clinical trials. It is the only drug, other than fesoterodine, not metabolized by the liver and has lower potential for side effects. Because it is excreted by the kidneys, there is concern for toxicity in patients with renal impairment.28 It does not seem, however, that the dose needs to be adjusted in elderly patients.29 The drug binds to all muscarinic receptors with similar affinity and the extended-release formulation has fewer side effects than the immediate-release drug. Solifenacin30 primarily blocks M1 and M3 receptors and may be more selective for M3 receptors on bladder smooth muscle cells than for salivary gland tissue, explaining the low rate of dry mouth in clinical trials.31 As compared with placebo, there is a reduction in the mean number of voids and daily incontinence episodes and an increase in the mean voided volume. As compared with tolterodine extended-release, slightly improved efficacy, fewer side effects, and lower drug discontinuation rates were observed with solifenacin.32 Darifenacin33 is a relatively selective M3 muscarinic receptor antagonist. Consistent with its low relative affinity for M1 and M2 receptors, it has few effects on cognitive function or the cardiovascular system. Darifenacin is metabolized by the liver and is not recommended for patients with severe liver impairment.34 It is unclear if improved M3 selectivity of darifenacin correlates with improved efficacy and tolerability. Festoterodine,35 the newest antimuscarinic compound for the treatment of overactive bladder and urge urinary incontinence, was approved by the Food and Drug Administration in October of 2008. It is a prodrug of tolterodine that is nonhepatically metabolized and has demonstrated acceptable efficacy and safety with both the 4and 8-mg doses in two recent, placebo-controlled, phase three trials.35,36 Fesoterodine was found to be superior to placebo in decreasing the number of voids, number of incontinence, and urgency episodes in a 24-hour period and increasing mean voided volume. Side effects of fesoterodine are similar to that of other antimuscarinic medications.
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INTERPRETATION OF CLINICAL TRIAL DATA
Most clinical trials on antimuscarinic medications assess efficacy by using objective measures, such as pad counts, pad weights, voiding diary variables, and urodynamic parameters. It is clear that improvements in some of these objective measures may not correspond to the patient’s perception of improvement in symptoms or address the most disabling aspects of urinary incontinence. Currently, few clinical trials include patient-reported outcomes and there are insufficient data to compare the effects of individual antimuscarinic medications on health-related quality of life.37 Future welldesigned clinical trials should routinely include validated instruments to measure symptomatic improvements and treatment-related enhancement in quality of life. COMPLIANCE
Although numerous well-performed studies have demonstrated the efficacy of antimuscarinic medications, their effectiveness in real life is limited by poor adherence. Because overactive bladder is a symptom-based disease, adherence may be an overall marker of the efficacy/side effect ratio, with women likely to continue the drug if they experience significant improvement. Studies have reported discontinuation rates of up to 80% at 1 year.38–40 Side effects along with patient perception of inadequate relief of symptoms may be contributing factors to high discontinuation rates.41 WHICH ANTIMUSCARINIC?
To help guide clinicians in their choice of antimuscarinic drugs, a Cochrane review42 analyzed 49 randomized clinical trials that compared two formulations of antimuscarinic medications or one antimuscarinic drug with another and concluded that overall efficacies of the varied antimuscarinic drugs are similar. Chapple and coworkers43 recommended that if one drug does not seem to provide satisfactory relief of symptoms, the clinician should choose an alternate drug. The initial choice of antimuscarinic agent should be based on its side effect profile. Major studies comparing different antimuscarinic medications are summarized in Table 2. CONSIDERATIONS IN THE ELDERLY
Although the prevalence of overactive bladder increases with age, there are relatively little data on the safety and the efficacy of antimuscarinic medications in older women. In a community-based study in women 65 years and older, side effects were similar to those observed in younger women with no increase in serious adverse events.44 Although drug absorption is generally unchanged with aging, drug distribution may change because of decreased muscle mass with decreased water content and renal impairment. These factors become particularly important in the frail elderly, and in women with comorbidities or on multiple medications. When prescribing antimuscarinic medications to older women, care should be taken regarding the overall antimuscarinic burden because several other medications used in older women (eg, those for Parkinson’s disease or dementia) also have antimuscarinic effects. There is significant concern for cognitive side effects with antimuscarinics in older women and studies have shown impaired memory recall and immediate learning with oxybutynin.45 Darfenicin, transdermal oxybutynin, tolterodine,46 and solifenacin47 have been shown to have relatively few cognitive side effects in clinical studies of older women. Close monitoring is required when these medications are prescribed to elderly women, especially in long-term care facilities.
Pharmacologic Management of Urinary Incontinence
Table 2 Comparative efficacy of different antimuscarinic medications Study
Drugs Compared
Efficacy
Side Effects
Pooled data (Cochrane, 2005)42
Oxybutinin and tolterodine
Similar in most outcome variables
Slightly less dry mouth and withdrawals with tolterodine
Pooled data (Cochrane, 2005)42
Oxybutinin ER and tolterodine ER
Similar in most outcome variables
Slightly less dry mouth with tolterodine ER
OPERA (Diokno et al, 2003)22
Oxybutinin ER and tolterodine ER
Similar in most outcome variables
Slightly less dry mouth with tolterodine ER, overall tolerability similar
Trospium and oxybutinin (Halaska et al, 2003)82
Oxybutinin and trospium
Similar in most outcome variables
Slightly less dry mouth with trospium
STAR (Chapple et al, 2005)31
Solifenacin and tolterodine ER
Solifenacin had slightly better efficacy than tolterodine ER
Similar rates of side effects
Tolterodine and fesoterodine (Chapple et al, 2008)83
Tolterodine and fesoterodine
Fesoterodine had slightly better efficacy than tolterodine ER
Slightly less dry mouth with tolterodine ER
BOTULINUM-A TOXIN
Injection of botulinum toxin into the detrusor muscle for the treatment of neurogenic detrusor overactivity was first described by Schurch and coworkers.48 Botulinum toxin, a potent neurotoxic protein produced by the bacterium Clostridium botulinum, binds to the presynaptic terminals of motor neurons and impedes the fusion of synaptic vesicles with the neuronal membrane.49 This inhibits the release of neurotransmitters, including acetylcholine, causing an interruption in neuronal transmission that affects both the efferent and the afferent branches of the micturition reflex and inhibits detrusor contractions. It may also decrease sensory input to the bladder by down-regulating the neurotransmitter receptors of afferent neurons in the detrusor muscle.50 In clinical practice, the technique for botulinum injection has not been standardized. It usually involves multiple injections of the drug into the detrusor muscle of the bladder under cystoscopic guidance using local anesthesia, with sparing of the trigone. Botulinum toxin injections have been shown to be beneficial in several conditions associated with neurogenic detrusor overactivity, including neurogenic detrusor hyperreflexia and detrusor external sphincter dyssynergia. In a large review of patients with neurogenic detrusor overactivity, there was marked reduction in the number of incontinence episodes in between episodes of clean intermittent self-catheterization with improved quality of life.50 The effects were noted within 1 to 2 weeks of treatment
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and lasted for 8 to 9 months. Urodynamics showed reduced mean detrusor pressures with increased postvoid residual volumes. There were minimal injection sites or systemic adverse effects. The role of botulinum toxin injection has also been investigated in the treatment of refractory, idiopathic, urge incontinence in neurologically normal women.51 In a clinical trial investigating botulinum injection in women with urge incontinence refractory to at least two other first-line treatments, significant improvement in symptoms were noted in 60% women with sustained clinical effects for almost 1 year. Unexpectedly high rates of urinary retention and urinary tract infections led to early discontinuation of the trial. The clinical significance of asymptomatic increased postvoid residual volume remains unclear. A Cochrane review52 evaluating botulinum toxin for both neurogenic and idiopathic overactive bladder concluded that although the drug can improve symptoms of overactive bladder, too little data exist on safety and efficacy compared with placebo and other treatments. A clear consensus on use of the drug in clinical practice including optimal dose, location, and number and timing of initial and repeat injections has not yet emerged. Experts recommend use of the drug in treatment of refractory symptoms in neurogenic and idiopathic detrusor overactivity53 but recommend caution because the risk of voiding difficulty and duration of effect have not yet been accurately evaluated.54 DRUGS TO DECREASE AFFERENTS
The afferent nerve input for the voiding reflex from bladder to brain requires stimulation of the A delta fibers that detect bladder fullness and increased wall tension and C fibers that detect noxious stimuli and initiate painful sensations. Abnormal detrusor contractions may be triggered by hypersensitive C fiber afferent neurons.55 Intravesical instillation of vanilloid neurotoxins, resiniferatoxin and capsaicin, have been investigated for the treatment of refractory neurogenic and nonneurogenic idiopathic detrusor overactivity. Intravesically administered neurotoxin, such as capsaicin and its analog resiniferatoxin, bind to vanilloid receptors in the bladder epithelium and desensitize the C fiber sensory neurons while sparing the A delta unmyelinated fibers involved in the normal micturition reflex.15 Both drugs have similar rates of reduced urinary frequency and incontinence episodes; however, resiniferatoxin causes less side effects, such as acute pain and irritation, than capsaicin.55 Because of the lack of well-designed randomized controlled trials, neither is approved for use in the United States. A small study showed that botulinum toxin may be better than resiniferatoxin in the treatment of refractory detrusor overacitivity.56 The use of either resinferatoxin or botulinum toxin for overactive bladder is off-label, should be considered experimental, and probably restricted to patients who have failed conventional therapies.57 Desmopressin nasal spray,58 an oxytocin analog, is currently the only medication approved for nocturia. Nocturia is common in older women and often coexists with sleep disorders, such as insomnia and sleep apnea.59 Because of the risk of hyponatremia, the drug should be prescribed with extreme caution in older women. VOIDING DYSFUNCTION
Anatomic bladder outlet obstruction is rare in women and is usually iatrogenic (postsurgical). Functional causes of bladder outlet obstruction including detrusor sphincter dysynnergia, and primary bladder neck obstruction along with other causes of urinary retention, such as impaired detrusor contractility and detrusor hyperactivity with
Pharmacologic Management of Urinary Incontinence
impaired contractility, are treated primarily with clean intermittent self-catheterization. Drug therapy has a small secondary role in their management. Detrusor sphincter dyssynergia, characterized by a lack of coordination of detrusor muscle contraction with external sphincter relaxation, usually occurs as a result of a neurologic lesion caudal to the pontine micturition center. It is usually treated with clean intermittent self-catheterization to prevent increased intravesical pressures and overflow incontinence. Intraurethral injections of botulinum toxin may be beneficial in improving voiding function as suggested in several small studies of patients with spinal cord injury and detrusor sphincter dysynnergia.60–62 Attempts have also been made to decrease outlet resistance with baclofen or diazepam.15 Primary bladder neck obstruction has an unclear etiology in women. Suggested underlying causes include hypertrophy of the bladder neck or increased tone of urethral smooth muscle from an increased number of a-adrenergic receptors.63 Most treatment options for primary bladder neck obstruction in women, including pharmacologic and surgical therapies, are based on anecdotal evidence. Although some studies suggest that a-adrenergic antagonists, such as terazosin or doxazosin, may be effective, there are little available scientific data.64,65 Postural hypotension is a significant side effect. Impaired detrusor contractility may be a side effect of various drugs and the first-line treatment should be to stop these medications if possible. If the condition persists, the mainstay of treatment is clean intermittent self-catheterization while attempting to improve detrusor contractions with muscarinic agonists or b-adrenergic antagonists.66 Bethanechol, a muscarinic agonist, has been used anecdotally, but does not have proved efficacy.67 Detrusor hyperactivity with impaired contractility is a condition characterized by urge incontinence and retention of urine with prominent detrusor trabeculations on cystoscopy and is common in older women with overactive bladder.68 Patients with detrusor hyperactivity with impaired contractility may benefit from antimuscarinic medications or botulinum toxin,69 recognizing that women may require intermittent catheterization even after injection. ESTROGEN
The increased prevalence of urgency, frequency, and incontinence in postmenopausal women may at least partially be caused by the urogenital effects of estrogen loss including thinning of mucosa, loss of sphincter muscle tone, and alteration of the urethrovesical angle.70 Although oral estrogen replacement seems to improve some urogenital symptoms, such as urgency, frequency, and recurrent urinary tract infections in menopausal women, estrogen does not improve incontinence symptoms.71,72 In two large clinical trials, women taking oral hormone-replacement therapy reported significantly more incontinence symptoms when compared with controls.73,74 Vaginal estrogen may be the most useful form of administration for reducing irritative voiding symptoms and recurrent infections.71 ROLE OF BEHAVIORAL THERAPIES WITH PHARMACOLOGIC MANAGEMENT
A recent Cochrane review reported that in women with overactive bladder, symptom improvement is greater when antimuscarinics are combined with bladder training as compared with each therapy alone.75 Studies have also suggested additive effects of behavioral therapy when combined with pharmacologic agents in the treatment of stress urinary incontinence. A recent trial comparing antimuscarinic medication alone with combined medication and behavioral therapies in the treatment of
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overactive bladder found no difference in the number of women who remained off antimuscarinics or reported a reduction in incontinence episodes among the two groups, but women who received both behavioral treatment and antimuscarinic medications reported greater satisfaction as compared with the women who received antimuscarinics alone.76 NEW HORIZONS
Several neurotransmitters are being recognized as having a role in urinary storage and voiding through their effect on central and peripheral pathways. These include glutamate and serotonin for central pathways and norepinephrine, nitric oxide, tachykinins, and dopamine for peripheral pathways. Several new drugs, targeted toward these neurotransmitters, are currently under investigation for the treatment of overactive bladder. Preclinical studies suggest that b3-adrenergic receptors predominate in the detrusor muscle77 and preliminary data evaluating solabegron, a b3-adrenergic agonist, seem promising.57 Two additional clinical trials assessing mirabegron78 and solabegron79 were completed earlier this year and results should be available shortly. Gabapentin, which binds to calcium channels, is being investigated in patients with neurogenic and idiopathic detrusor overactivity.57 Tramadol is a weak m-receptor agonist that also inhibits serotonin and norepinephrine reuptake. Both actions may inhibit bladder contractions and improve the symptoms of overactive bladder.80 Tachykinins including substance P and neurokinins A and B play a role in the mincturition reflex. Neurokinin receptors are found on neurons of the dorsal horn and it is thought that upregulation of tachykinin-mediated bladder-spinal reflex signaling may lead to urge urinary incontinence. Initial clinical trials with aprepitant, a neurokinin-1 receptor antagonist, have shown promising preliminary results in the treatment of urge urinary incontinence.81 SUMMARY
Most pharmacologic agents used for the treatment urinary incontinence and voiding dysfunction exert their effect on the neuromuscular transmission of the central or peripheral nervous system. Surgery remains the mainstay of treatment for stress urinary incontinence. Several different antimuscarinic medications are available for the treatment of overactive bladder. Despite multiple routes of administration, most of these drugs have similar efficacy and tolerability. Overall adherence to the medications is low. Despite the high prevalence of overactive bladder in the elderly, studies regarding safety and efficacy of these drugs in this population are lacking. Several medications with different mechanisms of action are being investigated for urge urinary incontinence and overactive bladder and are still in the preclinical phase. Clean intermittent self-catheterization is the mainstay of treatment for voiding dysfunction with medications playing a small secondary role. REFERENCES
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