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There are currently five antimuscarinic (reversible muscarinic receptor antagonists) used clinically to treat the symptoms of an embarrassing disorder referred to as overactive bladder (OAB): oxybutynin, tolterodine, darifenacin, trospium, and solifenacin. Overactive bladder is estimated to afflict up to 20 million persons in the United States. This condition has previously been reviewed (Kosier, Newton, & Smith (2000). Solifenacin (VESIcare®) produced by Yamanouchi Pharmaceutical Co. with marketing partner GlaxoSmithKline was FDA approved in November, 2004. Darifenacin (Enablex®) and trospium (Sanctura(TM)) were also FDA approved in 2004. Solifenacin is a once-daily (5-10 mg) drug to treat symptoms of this condition such as urgency, frequency, and urge incontinence (involuntary loss of urine).
The pharmacologic strategy of targeting the cholinergic system in treating OAB stems from the prominent role of the parasympathetic nervous system in controlling the urinary bladder and the process of micturition. Lumbosacral parasympathetic innervation provides motor control of the smooth muscle of the urinary bladder (detrusor) via acetylcholine activation of M^sub 2^/M^sub 3^ muscarinic receptors. The M^sub 3^ receptors are mainly responsible for detrusor muscle contraction via coupling to calcium entry into the cells by activation of L-type calcium channels on the smooth muscle cell membrane (Scheider, Fetscher, Krege, & Michel (2004). New evidence also points to an important role of muscarinic receptors on the urothelium and suburothelial interstitial cells. They mediate the release of various neurotransmitters which function as modulators of both detrusor muscle contraction as well as mediate sensory information to the central nervous system when triggered by stretching the bladder wall (De Groat, 2004; Gillespie, Harvey, & Drake, 2003). OAB is thought to involve an imbalance within one or more aspects of this cholinergic control system resulting in overstimulation of the detrusor muscle and the observed symptoms of OAB (De Groat, 1997). Symptoms are urinary frequency (having to urinate eight or more times daily), urgency (the need to urinate immediately), and urinary incontinence (leaking or wetting accidents).
Solifenacin relieves the symptoms of OAB by relaxing the smooth muscle of the bladder. It competitively antagonizes the muscarinic receptors in the urinary bladder (primarily M^sub 3^) leading to smooth muscle relaxation. Solifenacin possesses marginal selectivity for the M^sub 3^ receptor subtype not seen with tolterodine, which does not have selectivity towards any of the five...