Original ArticlesMuscarinic receptor antagonists in the treatment of overactive bladder
Section snippets
Rationale for the use of antimuscarinic agents in overactive bladder
The etiology of overactive bladder remains unknown, and may involve both neurologic and myogenic causes.7, 8 It is well established, however, that acetylcholine-induced stimulation of post-ganglionic muscarinic receptors on detrusor smooth muscle is involved in both normal and involuntary bladder contraction.9 This profile explains the therapeutic efficacy of muscarinic receptor antagonists in overactive bladder.
Muscarinic receptors are heterogeneous in nature and widely distributed throughout
Oxybutynin
Oxybutynin was originally identified in the 1960s as a potential treatment for gastrointestinal hypermotility.23, 24 Further investigation showed that it was effective in inhibiting uncontrolled bladder contractions.25 Subsequently, oxybutynin became the most widely used pharmacologic agent for the treatment of overactive bladder.
New approaches to improve tolerability
New approaches to improving the tolerability of oxybutynin include alternative routes of administration, use of extended-release oral formulation technology, and stimulation of salivation. Clinical development of the S-enantiomer of oxybutynin has also been advocated.
Tolterodine
Tolterodine is the first drug to have been specifically developed for the treatment of patients with overactive bladder presenting with frequency, urgency, and urge incontinence. Given the complexity of the role of muscarinic receptors in bladder function, this agent was developed using a functional approach to achieve bladder selectivity, rather than relying on muscarinic receptor subtype selectivity.
Darifenacin
Given the major involvement of M3 receptors in bladder contraction,12 compounds selective for this subtype may prove effective in the treatment of overactive bladder without the systemic adverse effects caused by blockade of M1 and M2 receptors.104 Darifenacin is a new agent, currently undergoing clinical trials, that was identified for development by using this subtype-selectivity rationale.
Conclusions
There is little doubt that compounds with antimuscarinic properties are effective in the treatment of overactive bladder, and so form the mainstay of treatment for this common and distressing condition. However, the usefulness of previously available agents, such as oxybutynin, has been limited by the occurrence of treatment-limiting adverse events, principally dry mouth. Intravesical instillation of oxybutynin overcomes many of the tolerability problems associated with oral therapy, but this
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2018, Pharmacology and TherapeuticsCitation Excerpt :In agreement with this observation, Cappon et al. (2008) showed that tolterodine had little effect on memory in the mouse passive-avoidance model. In clinical studies, the incidence of CNS side effects of tolterodine was shown to be lower than that of oxybutynin and similar to that of a placebo (Scheife and Takeda, 2005; Chapple, 2000; Clemett and Jarvis, 2001). Thus, these findings suggest that solifenacin, tolterodine, and darifenacin have advantages in the treatment of OAB owing to fewer CNS effects.
Fesoterodine: Pharmacological properties and clinical implications
2018, European Journal of PharmacologyCitation Excerpt :Such pharmacological data suggesting a very low risk of penetrating the blood-brain barrier is confirmed by clinical trials evaluating the cognitive functions of patients treated with fesoterodine. They show no impairment of cognitive functions (Geller, 2012; Chapple, 2000). The non-reliance on hepatic first-pass metabolism to obtain the active form of fesoterodine is also an important characteristic, resulting in constant concentrations irrespective of any liver conditions.