**5.2 Pharmacological agents**

Traditionally, drug therapy is commenced at the same time as behavioral therapy. Drug treatment plays an important role in the management of women with OAB, although many drugs currently in use have not been subjected to controlled clinical trials in the treatment of OAB. From a review of the literature, it is clear that there is no ideal drug. (Hay-Smith et al., 2005) Current pharmacological approaches to improving the treatment of OAB include delayed release formulations of existing oral agents, new pharmaceutical agents with greater specificity/selectivity, and alternative routes of administration. New generation pharmacological treatments provide better or comparable efficacy with fewer adverse drug events. (Shaw & Burrows, 2011)

### **5.2.1 Antimuscarinic (anticholinergic) drugs**

There are many different antimuscarinic compounds licensed for use for patients with OAB. Oxybutynin was the first drug of this class used specifically to treat the symptoms of OAB. This class of drugs has been considered the "gold standard" in the treatment of OAB for many years. However, there is little or no evidence to help clinicians choose between particular anticholinergic drugs. To add to the difficulty with studying this class of drugs, compliance with antimuscarinics is generally poor. (Brubaker et al., 2010)

Traditionally, it was thought that these drugs act by blocking the muscarinic receptors on the detrusor muscle. This resulted in decreased bladder contractions and thus reduced the symptoms of OAB. However, it appears that antimuscarinic drugs act primarily during the storage phase of the micturition cycle, decreasing urgency and increasing bladder capacity. During this phase, there is normally no parasympathetic input to the LUT. (Abrams & Andersson, 2007)

A recent Cochrane review assessed the various anticholinergics available for the treatment of OAB in adults. The conclusions of this review were when the prescribing choice is between oral immediate-release oxybutynin and tolterodine, tolterodine might be preferred due to a reduced risk of dry mouth. In addition, they concluded that if extended-release preparations of either drug are available, they would be preferred to the immediate-release preparations because of the decreased risk of dry mouth and better compliance. There were insufficient data from trials of other anticholinergic drugs to draw any conclusions. (Hay-Smith et al., 2005) The most commonly prescribed anticholinergic drugs and their dosages in the treatment of OAB are listed in Table 1. (Shaw & Burrows, 2011)

#### **5.2.1.1 Oxybutynin**

172 Urinary Incontinence

defined as the frequency of leakage (0 *=* never to 4 *=* always) during 9 activities that can

Patients may have additional improvement in learning to appropriately do PFMT with the use of vaginal weighted cones. These cones are inserted in the vagina by the patient and she

Biofeedback is used to teach patients how to control normal physiologic responses of the bladder and pelvic floor muscles that mediate urinary incontinence. Biofeedback for OAB consists of bladder-pressure biofeedback as well as the pelvic floor's muscular activity

Behavioral therapy requires the active participation of motivated patients and a practitioner well-trained in behavioral therapy. Behavioral therapy does not cause permanent changes in bladder function; therefore, regular adherence and long-term compliance are needed for

Traditionally, drug therapy is commenced at the same time as behavioral therapy. Drug treatment plays an important role in the management of women with OAB, although many drugs currently in use have not been subjected to controlled clinical trials in the treatment of OAB. From a review of the literature, it is clear that there is no ideal drug. (Hay-Smith et al., 2005) Current pharmacological approaches to improving the treatment of OAB include delayed release formulations of existing oral agents, new pharmaceutical agents with greater specificity/selectivity, and alternative routes of administration. New generation pharmacological treatments provide better or comparable efficacy with fewer adverse drug

There are many different antimuscarinic compounds licensed for use for patients with OAB. Oxybutynin was the first drug of this class used specifically to treat the symptoms of OAB. This class of drugs has been considered the "gold standard" in the treatment of OAB for many years. However, there is little or no evidence to help clinicians choose between particular anticholinergic drugs. To add to the difficulty with studying this class of drugs,

Traditionally, it was thought that these drugs act by blocking the muscarinic receptors on the detrusor muscle. This resulted in decreased bladder contractions and thus reduced the symptoms of OAB. However, it appears that antimuscarinic drugs act primarily during the storage phase of the micturition cycle, decreasing urgency and increasing bladder capacity.

compliance with antimuscarinics is generally poor. (Brubaker et al., 2010)

learns to contract the pelvic floor muscles to hold the cone in place.

trigger urge incontinence.

**5.1.5 Biofeedback** 

effectiveness.

**5.1.4 Weighted vaginal cones** 

feedback. (Burgio et al., 1985)

**5.2 Pharmacological agents** 

events. (Shaw & Burrows, 2011)

**5.2.1 Antimuscarinic (anticholinergic) drugs** 

**5.1.6 Limitations of behavioral therapy** 

As mentioned above, oxybutynin was the first anticholinergic widely used for the treatment of OAB. It is an anticholinergic agent that has antimuscarinic, antispasmodic, and potential local anesthetic effects. Oxybutynin has been shown to have a high affinity for the M1 & M3 receptors and much less affinity for the M2 receptor. (Hughes et al., 1992 and Nilvebrant & Sparf, 1986) It is available in immediate release (IR), extended release (ER), transdermal patch and topical gel formulations. In general, the efficacy is similar for all formulations. The initial dosage for IR is 2.5 mg two to three times daily, followed by titration as needed up to 20 mg/day in divided doses. The ER formulation is started at 5 mg once daily and titrated up to 20 to 30 mg once daily.

The transdermal patch (equivalent to 3.9 mg/day) applied to the abdomen, hip, or buttock is changed twice a week. The topical 10% gel is applied as 1 gm (approximately 1 mL) daily to the thigh, abdomen, upper arm, or shoulder. Currently, oxybutynin IR and ER are available as generic formulation in the United States. Oxybutynin IR is associated with high rates of anticholinergic adverse effects. Dry mouth is a particularly bothersome side effect for patients that can limit therapy with oxybutynin IR. This side affect is less frequent with the ER and transdermal preparations (Anderson et al., 1999; Davila et al., 2001; Versi et al., 2000) Irritation and pruritus at the application site has been reported in approximately 15 percent of patients using transdermal oxybutynin and 5 percent using the topical gel. (Dmochowski et al., 2002)

#### **5.2.1.2 Tolterodine**

Tolterodine has been shown to be a competitive muscarinic receptor antagonist with some selectivity for bladder muscarinic receptors [59]. It is available in immediate- and extendedrelease forms. Tolterodine is administered at 1 to 2 mg twice a day for the IR preparation or 2 to 4 mg per day using the ER preparation. It has similar efficacy when compared to other antimuscarinics. Both formulations have shown efficacy for symptoms of OAB in a large study population (Choo et al., 2008).

One of the few "head to head" studies between anticholinergic drugs was The STAR trial. In this study the investigators directly compared solifenacin (discussed below) at a flexible 5 or 10 mg once daily dose with tolterodine extended release 4 mg once daily in a randomized

Diagnosis and Treatment of Overactive Bladder 175

Fesoterodine is metabolized to 5-hydroxymethyl tolterodine, (the active metabolite of

Similar to solifenacin, the newer antimuscarinic drug darifenacin is more selective for M-3 muscarinic receptors in the bladder. Drifenacin is administered 7.5 mg daily and can be increased to 15 mg daily. In a randomized trial of darifenacin versus placebo, median incontinence episodes were show to significantly decrease with darifenacin. (Zinner et al., 2006) However, dry mouth and constipation rates were similar when compared to other

As noted above, the most common side effects associated with darifenacin are mild to moderate dry mouth and constipation. This drug has been studied in patients who were dissatisfied with prior OAB treatment with oxybutynin ER or tolterodine ER. The authors found significant improvements in OAB symptoms with darifenacin. (Zinner et al., 2008) Additionally, long-term studies have shown persistence of continuation with darifenacin therapy and well-maintained treatment benefits (over 2 years in duration). (Haab et al., 2006

Because of its' selectivity for the M3 receptor darifenacin minimizes the risk of side effects due to blockade of other muscarinic subtypes, such as M1 mediated cognitive impairment. (Foote et al., 2005) This is important in relation to the treatment of elderly populations who

Fesoterodine Toviaz 4 mg daily, can be increased to 8 mg daily Oxybutynin extended release Ditropan XL 5 mg daily, titrate up to 20-30 mg daily Oxybutynin gel Gelnique Topical 10% gel applied as 1 g daily to

Oxybutynin transdermal Oxytrol Applied to abdomen, hip or buttock and

Detrol LA 2-4 mg daily

Sanctura 60 mg daily

Detrol 1-2 mg twice daily

Sanctura 20 mg twice daily

thigh, abdomen, upper arm or shoulder

changed twice per week (equivalent to 3.9

titration as needed u to 20 mg/d in

Ditropan 2.5 mg 2-3 times daily, followed by

divided doses

mg/d)

anticholinergics (29% dry mouth and 18% constipation).

may be more susceptible to cognitive impairment and CNS effects.

Darifenacin hydrombromide Enablex 7.5 to 15 mg daily

Solifenacin succinate Vesicare 5-10 mg daily

Table 1. Commonly prescribed anticholinergic drugs for treatment of OAB

Generic name Brand Name Dosage & Administration

tolterodine).

**5.2.1.6 Darifenacin** 

& Hill et al., 2007)

Oxybutynin immediate

Tolterodine tartrate extended

Trospium chloride extended

Trospium chloride immediate

Tolterodine tartrate immediate release

release

release

release

release

controlled trial. (Chapple et al., 2005) The authors found that the flexible dose of solifenacin showed marked advantages over the single dose of tolterodine extended release. In a reanalysis comparing only the patients in the trial taking solifenacin 5 mg once daily with the patients in the tolterodine arm the authors found a more modest benefit. (Chapple et al., 2007) Solifenacin 5 mg once daily was superior for incontinence episodes and pad usage, but showed no difference in urge incontinence or dryness rates. Notably in both analyses, the main advantage for solifenacin was minimizing rates of dry mouth and constipation. However, there were slightly more withdrawals due to adverse events in the solifenacin group.
