Muscarinic receptor subtypes and management of the overactive bladder

Abstract Anticholinergic agents are the most widely used therapy for urge incontinence despite exerting adverse effects, such as constipation, tachycardia, and dry mouth, that limit their use. These adverse effects result from a lack of selectivity for the bladder over other organs. Although M 2 -muscarinic receptors are the predominant cholinoreceptor present in urinary bladder, the smaller population of M 3 -receptors appears to be the most functionally important and mediates direct contraction of the detrusor muscle. M 2 -receptors modulate detrusor contraction by several mechanisms and may contribute more to contraction of the bladder in pathologic states, such as bladder denervation or spinal cord injury. Prejunctional inhibitory M 2 -receptors or M 4 -receptors and prejunctional facilitatory M 1 -muscarinic receptors in the bladder have also been reported, but their relevance to the clinical effectiveness of muscarinic antagonists is unknown. In clinical studies, tolterodine, a nonselective muscarinic antagonist, has been reported to be equally effective to oxybutynin but to induce less dry mouth. Controlled-release and intravesical, intravaginal, and rectal administrations of oxybutynin have all been reported to cause fewer adverse effects. Conversely, darifenacin, a new M 3 -selective antagonist, has been reported to have selectivity for the bladder over the salivary gland in vivo. Whether M 3 -selective or nonselective muscarinic antagonists will be the most clinically effective for the overactive bladder—preserving the best balance between efficacy and tolerability—has yet to be established, and comparative clinical trials between compounds, such as darifenacin (M 3 selective) and tolterodine (nonselective) will be required.