Update on the Pharmacologic Management of Overactive Bladder: The Present and the Future

Pamela Ellsworth; Eileen Kirshenbaum

Disclosures

Urol Nurs. 2010;30(1):29-39. 

In This Article

Management of OAB

Behavioral Therapy

First-line therapies for the management of OAB include behavioral and pharmacologic therapies. The best results can be obtained if a combination of the two therapies is used (Burgio, Locher, & Goode, 2000). There are multiple components to behavioral therapy (see Figure 2), which can be an important part of treatment for patients with OAB and is most useful in motivated individuals who are willing to make lifestyle and dietary changes (Ouslander, 2004; Sussman, 2007). Components of behavioral therapy include education, timed voiding, delayed voiding, dietary modifications, and pelvic floor muscle exercises.

Figure 2.

Components of Behavioral Therapy

Behavioral therapy starts with education. Patients need to be educated regarding normal bladder function and normal voiding habits. Timed voiding involves voiding at set intervals, regardless of the urge to void, which may help to decrease the risk of UUI and urgency (Wyman & Fantl, 1991). In some individuals, caffeinated, spicy, and acidic foods and drinks may exacerbate symptoms, and thus, dietary restrictions may lead to improvement in symptoms. Normalizing fluid intake may also prove helpful; too much or even too little fluid may exacerbate symptoms because concentrated urine may act as a bladder irritant.

Individuals suffering fro murgency and frequency, but not UUI, may benefit from urgency suppression techniques and delayed voiding, which involves trying to hold urine for progressively longer periods of time by consciously suppressing the urge to void, as well as tightening pelvic floor muscles. Finally, pelvic floor muscle exercises may also help decrease urgency and UUI when properly performed (Miller & Sand, 2007; Shafik & Shafik, 2003). A bladder diary is a useful adjunct in behavioral therapy because it allows patients to track their responses and identify possible factors that exacerbate their symptoms.

Pharmacologic Therapy

Pharmacologic therapy remains a mainstay in the management of OAB. As with behavioral therapy, the goal of pharm acologic therapy is to improve OAB symptoms. Individuals suffering from OAB are rarely "cured " with pharmacologic therapy; however, clinically significant improvements in symptoms may be achieved.

Antimuscarinic agents are U.S. Food and Drug Adminstration (FDA)-approved pharmacologic therapies for OAB. Initially, it was believed that these agents worked primarily at the level of the detrusor muscle, inhibiting the binding of acetylcholine to the muscarinic receptors in the detrusor smooth muscle cells, and thus, stabilizing the detrusor muscle and incre a sing bladder capacity. More recently, muscarinic receptors have been identified in the urothelium. Antimuscarinic agents may also function by inhibiting sensory receptors in the urothelium, thereby decreasing afferent nerve activity (Abrams & Wein, 1998; Andersson, 2004; de Groat, 2004; Wang, Luthin, & Ruggieri, 1995). There are five muscarinic receptors located throughout the body. In the bladder, the M2 muscarinic receptors are the most common, and the M3 receptor has been demonstrated to play a significant role in normal detrusor function.

There are currently 11 FDA-approved antimuscarinic agents for the treatment of OAB in the U.S., including immediate-release and generic formulations (see Table 1). Fesoterodine and oxybutynin chloride 10% gel are the newest antimuscarinic agents. The fesoterodine molecule is rapidly hydrolyzed by non-specific esterases to the active metabolite of tolterodine, 5-hydroxymethyl tolterodine (5-HMT) by ester hydrolysis. This conversion is rapid and extensive; no fesoterodine is detected in the serum after oral administration (Malhotra, Guan, Wood, & Gandelman, 2008; Michel, 2008). Fesoterodine is available in two doses, 4 mg and 8 mg. Oxybutynin chloride 10% gel (Gelnique™) is a transdermal formulation of oxybutynin applied to the thigh, abdomen, upper arm, or shoulder. A 1 gm (1 ml) dose of 100 mg/g Gelnique delivers a consistent dose of oxybutynin through the skin over a 24-hour period (Alberti, Grenier, Kraus, & Carrara, 2005).

Comparison of Currently Approved OAB Medications. A recent update of a systematic review and meta-analysis of the effects of antimuscarinic treatments in OAB (Chapple et al., 2008) concluded that antimuscarinic agents are efficacious, safe, and well-tolerated; improve health-related QOL; and currently remain as first-line pharmacologic treatment for OAB. Despite this, the ceiling may have been reached with respect to the therapeutic efficacy of antimuscarinics, with the only new innovation being that of dose flexibility with the newer antimuscarinics, such as darifenacin, solifenacin, and fesoterodine. Dose flexibility allows individual titration to provide maximum efficacy and tolerability (Chapple et al., 2008).

There appear to be differences in the tolerability and safety profiles of these agents, which may prove to be clinically significant in different patient populations. Although not statistically validated, one way to compare the various OAB agents with respect to tolerability is to look at the drugto-placebo ratio (see Table 2). This comparison is based on the rationale that individuals receiving a placebo agent should respond similarly in the various trials. To calculate the drug-to-placebo ratio, the drug response is divided by the placebo response in the trial (drug incidence %/placebo incidence %).

Other areas where agents may differ include the potential for drug-drug interactions, the ability to cross the blood-brain barrier (and in turn, cause unwanted CNS effects), the impact on heart rate (governed by the M2 receptor), the concentration of drug in the urine, and the muscarinic receptor selectivity (Wein & Rackley, 2006). Whether or not these differences prove to be clinically significant may vary with diff e rent patient populations; the first three of these effects are described in greater detail in the following section.

Potential for CNS Adverse Effects. Antimuscarinic agents may cause adverse effects in the CNS, such as dizziness, somnolence, and insomnia, and in some individuals, cognitive impairment (memory loss). The risk of developing such adverse effects may be affected by the likelihood of the antimuscarinic agent to penetrate the blood-brain barrier, the integrity of the blood-brain barrier, alterations in drug metabolism, polypharmacy, and the muscarinic receptor selectivity of the antimuscarinic agent, M1 being the receptor in the brain involved with cognitive function and memory (Kay et al., 2006; Kay & Granville, 2005; Scheife & Takeda, 2005).

Properties of the drugs, such as molecular size and structure, polarity, and lipophilicity, may govern the likelihood of an agent crossing the blood-brain barrier and vary between the diff e rent antimuscarinics (see Table 3). Molecules that have a small linear molecular size are neutral in charge and liphophilic, and are more likely to penetrate an intact blood-brain barrier. Most FDA-approved agents are tertiary amines. While trospium chloride is a quarternary amine, tertiary amines have three of the hydrogen atoms of the ammonia replaced by an organic group and are neutral in charge. In a quarternary amine, the nitrogen atom has four groups bonded to it and carries a positive charge. Positive-charged molecules are less likely to penetrate the CNS. Darifenacin is more selective for the M3 receptor and has less affinity for other muscarinic receptors than the other agents.

In the brain and other organ systems in the body, there is an active efflux transport system, the P-glycoprotein transport system. In the brain, if a molecule is able to cross the blood-brain barrier and enter the CNS and if it is recognized by the P-glycoprotein transport system, it is transport e d back into the vasculature. Some of the antimuscarinic agents are recognized by the P-glycoprotein transport system, and others have not been evaluated. Older adults may be at greater risk for adverse effects of the CNS due to underlying comorbidities that may affect the permeability of the blood-brain barrier (such as cerebrovascular disease), alterations in muscarinic receptor densities in the brain, age-related changes in drug elimination, and polypharmacy (Abrams et al., 2006).

Drug-drug Interactions. Most antimuscarinic agents are metabolized by the CYP450 system. Thus, patients taking medications that are known inhibitors of the CYP450 system may require a lower dose of the antimuscarinic and/or be more likely to experience a drug-drug interaction (see Table 4). Conversely, trospium chloride is primarily secreted intact in the urine and is at low risk for such drug-drug interactions; however, its effects on other drugs eliminated by the kidneys is limited. Studies with concomitant administration of digoxin and tropsium chloride have not demonstrated any increased incidence of adverse events (Sandage et al., 2006).

Heart Rate and QT Effects. Heart rate is affected by the M2 receptor, and thus, M2 receptor agents may lead to an increase in heart rate. Some OAB agents may lead to small increases in heart rate (ranging from 2 to 9 beats per minute depending on the agent), which should be taken into consideration when treating patients (Andersson, Kahler, & Ebinger, 2007; Olshansky, Ebinger, Brum, & Egermark, 2008). However, no definite data prove that drugs that raise heart rate are necessarily linked to a poor outcome (Kowey, 2007). The effect of the various antimuscarinic agents on the QT interval (the time interv a l between the Q and T waves on an electrocardiogram) is not related to muscarinic receptor antagonism; rather, it is related to a specific effect of each molecule on specialized potassium channels in the heart (Kowey, 2007). Darifenacin, fesoterodine, and trospium chloride have no effect on the QT interval; tolterodine and solifenacin have led to small increases in the QT interval (see manufacturers' prescribing information for each agent). No information on the QT effects of oxybutynin is available.

Improving Compliance with Pharmacologic Therapy. Persistence with antimuscarinic therapy is poor (D'Souza, Smith, Miller, Doyle, & Ariely, 2008; Haab & Castro-Diaz, 2005; Yu, Nichol, Yu, & Ahn, 2005). A variety of factors may affect persistence, including unrealistic expectations, tolerability, and efficacy-related issues. Identifying the patient's expectations regarding treatment and setting realistic expectations is important. Since dry mouth and constipation are the more commonly encountered side effects in this class of medications, it is important to educate patients on how to manage these side effects. In individuals prone to constipation, proactive management of constipation is important because there is evidence that constipation can potentiate OAB symptoms (Rosenberg, Newman, Tallman, & Page, 2007). Individuals who do not respond to or who have difficulty adhering to the regimen for one antimuscarinic agent may benefit from a trial of another agent, particularly one with dose flexibility.

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