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

Pamela Ellsworth; Eileen Kirshenbaum

Urol Nurs. 2010;30(1):29-39.

Abstract and Introduction

Abstract

Overactive bladder (OAB) is a common condition, affecting approximately 17% of females and males 40 years of age and older. Historically, oxybutynin was the only medication approved for use in the management of OAB. Over the past decade, several new antimuscarinics have been approved for the treatment of OAB. Although all are deemed to be effective in improving the bothersome symptoms of OAB, they differ in their molecular properties, metabolism, and tolerability/side effect profile. A greater understanding of the pathophysiology of OAB has led to approved and investigative therapies to treat refractory OAB, such as neuromodulation and intravesical injection of Botulinum toxin, respectively. A variety of pharmacologic agents are in clinical trials for OAB that target different components of bladder function, such as the urothelium, the afferent sensory nerve pathways, and the central nervous system. It is the intent of this article to highlight these aspects of OAB management.
Objectives
1. Define overactive bladder.
2. Explain the impact of overactive bladder on quality of life.
3. Discuss the management of overactive bladder, including behavioral and pharmacologic therapies.
4. List adverse effects of pharmacologic therapies.
5. Discuss future pharmacologic therapies.

Introduction

Overactive bladder (OAB) is a symptom syndrome characterized by the presence of urgency, with or without urgency urinary incontinence (UI), usually with frequency and nocturia. These symptom combinations are suggestive of urodynamically demonstrable detrusor overactivity but can be related to other forms of urethrovesical dysfunction. The symptoms of OAB are storage phase symptoms (Abrams et al., 2002). The International Continence Society (ICS) classifies OAB as a syndrome for which no precise cause has been identified (idiopathic), with conditions that may cause or mimic OAB ruled out by diagnostic evaluation (Abrams et al., 2002; Ouslander, 2004; van Kerrebroeck et al., 2002). Individuals with neurologic diseases, such as multiple sclerosis, spinal cord injury, and myelodysplasia, may have neurogenic OAB but would not be considered to have idiopathic OAB; their management will not be discussed in this article.

Urgency, the cardinal symptom of OAB, is the complaint of a sudden compelling desire to pass urine, which is difficult to defer. Incontinence associated with urgency is defined as urgency (urge) urinary incontinence (UUI). Urinary frequency is defined as eight or more micturitions per day, and nocturia is the complaint that the individual has to wake at night one or more times to void (Abrams et al., 2002).

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Table 1. Currently Approved Medictions for Overactive Bladder
Medications	FDA Approval Date
Ditropan® XL (oxybutynin extended release) (1R)	June 1999
Detrol® LA (tolterodine tart rate extended release) (1R)	December 2000
Oxytrol® ( tra n s d e rmal oxybutynin)	March 2004
Sanctura® IR (trospium chloride immediate release)	May 2004
Vesicare® ( Solifenacin)	November 2004
Enablex® ( Darifenacin)	December 2004
Sanctura® XR (trospium chloride extended release)	August 2007
Toviaz™ (fesoterodine)	October 2008
Gelnique™ (oxybutynin chloride gel 10%)	January 2009

Table 2. Adverse Effects of Antimuscarinic Agents Used for Overactive Bladder
Drug	Adverse Reaction	Drug AE %	Placebo AE %	Drug to Placebo Ratio
Darifenacin (Enablex®)
7.5 mg	Dry mouth Constipation Dizziness	20.2% 14.8% 0.9%	8.2% 6.2% 1.3%	2.5 2.4 0.7
15 mg	Dry mouth Constipation Dizziness	35.3% 21.3% 2.1%	8.2% 6.2% 1.3%	4.3 3.4 1.6
Fesoterodine (Toviaz™)
4 mg	Dry mouth Constipation Insomnia	18.8% 4.2% 1.3%	7.0% 2.0% 0.5%	2.7 2.1 2.6
8 mg	Dry mouth Constipation Insomnia	34.6% 6.0% 0.4%	7.0% 2.0% 0.5%	4.9 3.0 0.8
Oxybutynin chloride 10% gel (Gelnique™)	Dry mouth Constipation Application site reaction	7.5% 1.3% 5.4%	2.8% Not reported 1.0%	3.3 – 5.4
Solifenacin (Vesicare®)
5 mg	Dry mouth Constipation Dizziness Blurred vision	10.9% 5.4% 1.9% 3.8%	4.2% 2.9% 1.8% 1.8%	2.6 1.9 1.1 2.1
10 mg	Dry mouth Constipation Dizziness Blurred vision	27.6% 13.4% 1.8% 4.8%	4.2% 2.9% 1.8% 1.8%	6.6 4.6 1.0 2.7
Tolterodine LA 4mg (Detrol® LA 4mg)	Dry mouth Constipation Headache Dizziness Abnormal vision	23.0% 6.0% 6.0% 2.0% 1.0%	8.0% 4.0% 4.0% 1.0% 0.0%	2.9 1.5 1.5 2.0
Transdermal oxybutynin (Oxytrol®)	Dry mouth Constipation Application site Puritis Erythema	9.6% 3.3% 16.8% 5.6%	8.3% 0.0% 6.1% 2.3%	1.2 – 2.8 2.4
Trospium chloride IR (Sanctura®)	Dry mouth Constipation Headache	20.1% 9.6% 4.2%	5.8% 4.6% 2.0%	3.5 2.1 2.1
Trospium chloride XR (Santura® XR)	Dry mouth Constipation Dry eyes	10.7% 8.5% 1.6%	3.7% 1.5% 0.2%	2.9 5.7 8.0

* Oxybutynin IR and ER not included as prescribing information reports adverse effects (AEs) from multiple doses.

Table 3. Factors Affecting Likelihood of Central Nervous System Penetration
	Darifenacin M3 Selective	Tolterodine Non-Selective	Trospium Non-Selective	Oxybutynin M3, M1	Solifenacin M3, M1	Fesoterodine Non-Selective
Solubility in alcohol (lipophilicity)	Low	Slightly soluble	Low	Soluble	Freely Soluble	Low
Molecular size	507.5	475.6	427.9	357	480.6	527.7
Charge	Positive	Positive	Positive	Neutral	Not reported	Positive
PGP substrate	Yes	Yes	Not reported	Not reported	Not reported	Yes
Amine	Tertiary	Tertiary	Quarternary	Tertiary	Tertiary	Tertiary

Table 4. Metabolism, Dosing, and Pharmacokinetics of Overative Bladder Agents
Drug	Half-Life (Hour)	Time to Peak (Hour)	Route of Metabolism	Adult Dose	Dose Frequency
Darifenacin (Enablex®)	7 to 20	5 to 8	CYP450 CYP2D6 CYP3A4	7.5 mg to 15 mg	QD
Fesoterodine (Toviaz®)	7 to 8	5	Ester hydrolysis CYP450 CYP2D6 CYP3A4	4 mg to 8 mg	QD
Oxybutynin (Ditropan®)	2 to 3	< 1	CYP450 CYP3A4	2.5 to 5.0 mg	BID to TID
Oxybutynin XL (Ditropan® XL)	12 to 13	3 to 6	CYP450 CYP3A4	5 mg to 30 mg	QD
Oxybutynin chloride 10% gel (Gelnique™)	64 at steady state	Steady state concentrations achieved within 7 days of steady dosing	Liver CYP450 CYP3A4	1 gm dose of 100 mg/g oxybutynin chloride gel 1.14 ml	QD
Solifenacin (Vesicare®)	45 to 68	3 to 8	CYP450 CYP3A4	5 mg to 10 mg	QD
Tolterodine IR (Detrol® IR)	2 to 4	1 to 2	CYP450 CYP2D6 CYP3A4	1 mg to 2 mg	BID
Tolterodine LA (Detrol® LA)	7 to 18	2 to 6	CYP450 CYP2D6 CYP3A4	2 mg to 4 mg	QD
Transdermal oxybutynin (Oxytrol®)	7 to 8	10 to 48	CYP450 CYP3A4	36 mg patch delivers 3.9 mg/day	Twice weekly
Trospium chloride (Sanctura®)	18	5 to 6	Renal excretion Minimal hepatic metabolism	20 mg	BID 1 hour before meals
Trospium Chloride XR (Sanctura® XR)	36	5	Ester hydrolysis Renal excretion	60 mg	QD – 1 hour before breakfast

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