The lower urinary tract consists of the bladder, urethra, urinary or urethral sphincter, and surrounding musculofascial structures, including connective tissue, nerves, and blood vessels. The urinary bladder is a hollow organ composed of smooth muscle and connective tissue located deep in the bony pelvis in men and women. The urethra is a hollow tube that acts as a conduit for urine flow out of the bladder. An epithelial cell layer termed the urothelium, which is in constant contact with urine, lines the interior surface of both the bladder and the urethra. Previously considered inert and inactive, the urothelium may play an active role in the pathophysiology of many lower urinary tract disorders, including interstitial cystitis and UI10 and may be a targeted location for future pharmacologic therapeutic interventions for some types of lower urinary tract dysfunction.11 The urinary or urethral sphincter is a combination of smooth and striated muscle within and surrounding the proximal portion of the urethra adjacent to the bladder. In the male, the prostate gland lies just beyond the bladder outlet and is intimately associated with the urethral sphincter. Its location accounts for both the favorable effects of pharmacological manipulation on male lower symptoms as well as the risk of UI in males following some types of prostate surgery.
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To understand the principles of pharmacotherapy for UI, an understanding of the neuroanatomy and neurophysiology of the bladder and urethra is needed. The primary motor (efferent) input to the detrusor muscle of the bladder is parasympathetic and travels along the pelvic nerves emanating from spinal cord segments S2 to S4. Acetylcholine appears to be the primary neurotransmitter at the neuromuscular junction in the human lower urinary tract. Both volitional and involuntary detrusor contractions are mediated by activation of postsynaptic muscarinic receptors by acetylcholine. Of the five known subtypes of muscarinic receptors, the majority of bladder smooth muscle cholinergic receptors are of the M2 variety. In humans, the ratio of M2/M3 receptor numbers is approximately 3:1. However, M3 receptors are the subtype responsible for both emptying contractions of normal micturition as well as involuntary bladder contractions that may result in UI.10 Thus, most pharmacologic antimuscarinic therapy is primarily anti-M3 based.