Category:Overactive bladder medications: Difference between revisions
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The first effective pharmacological treatment was the non-selective antimuscarinic [[Oxybutynin|oxybutynin]], introduced by Marion Laboratories in 1975 on the rationale that the detrusor contraction was driven by parasympathetic acetylcholine acting on muscarinic receptors. Oxybutynin was effective but produced the full antimuscarinic toxidrome (dry mouth, blurred vision, constipation, somnolence, confusion in the elderly) at clinically useful doses; the immediate-release formulation has been progressively replaced by the extended-release tablet (1998), the transdermal patch (2003), and the topical gel (2009), each of which reduces peak concentrations and the corresponding dose-limiting adverse effects. | The first effective pharmacological treatment was the non-selective antimuscarinic [[Oxybutynin|oxybutynin]], introduced by Marion Laboratories in 1975 on the rationale that the detrusor contraction was driven by parasympathetic acetylcholine acting on muscarinic receptors. Oxybutynin was effective but produced the full antimuscarinic toxidrome (dry mouth, blurred vision, constipation, somnolence, confusion in the elderly) at clinically useful doses; the immediate-release formulation has been progressively replaced by the extended-release tablet (1998), the transdermal patch (2003), and the topical gel (2009), each of which reduces peak concentrations and the corresponding dose-limiting adverse effects. | ||
The next generation of antimuscarinics aimed for greater selectivity for the M3 receptor predominant on the detrusor, with less M1 affinity (the M1 receptor of the central nervous system and of the salivary acini accounts for much of the dry mouth and cognitive toxicity). [[wikipedia:Tolterodine|Tolterodine]] (Pharmacia, 1998), [[Solifenacin|solifenacin]] (Yamanouchi, 2004), [[wikipedia:Darifenacin|darifenacin]] (Pfizer, 2004, the most M3-selective of the class), fesoterodine (Pfizer, 2008, | The next generation of antimuscarinics aimed for greater selectivity for the M3 receptor predominant on the detrusor, with less M1 affinity (the M1 receptor of the central nervous system and of the salivary acini accounts for much of the dry mouth and cognitive toxicity). [[wikipedia:Tolterodine|Tolterodine]] (Pharmacia, 1998), [[Solifenacin|solifenacin]] (Yamanouchi, 2004), [[wikipedia:Darifenacin|darifenacin]] (Pfizer, 2004, the most M3-selective of the class), fesoterodine (Pfizer, 2008, hydrolysed in vivo to the active metabolite of tolterodine), and [[wikipedia:Trospium chloride|trospium]] (a quaternary amine that does not cross the blood-brain barrier and so produces less central toxicity) extended the class. Comparative meta-analyses show similar efficacy across the antimuscarinic class, with the differences principally in side-effect profile rather than in symptom reduction. | ||
The transformative agent in the 2010s was the first beta-3 adrenergic agonist. Detrusor smooth muscle, although under predominant parasympathetic stimulatory control through M3 receptors, also expresses beta-3 adrenoceptors whose activation produces relaxation; the receptor was poorly accessible to traditional adrenergic medicines because beta-3 selectivity is difficult to achieve. [[Mirabegron|Mirabegron]] (Astellas, 2012) was the first orally bioavailable selective beta-3 agonist; it reduced urge incontinence episodes and micturition frequency comparable to the antimuscarinics, without dry mouth or cognitive effect, although with a small but real signal of hypertension that has required blood-pressure monitoring on treatment.<ref name="khullar2013">Khullar V, Amarenco G, Angulo JC, Cambronero J, Høye K, Milsom I, Radziszewski P, Rechberger T, Boerrigter P, Drogendijk T, et al. Efficacy and tolerability of mirabegron, a beta(3)-adrenoceptor agonist, in patients with overactive bladder: results from a randomised European-Australian phase 3 trial. ''European Urology''. 2013 Feb;63(2):283-295. PMID 23182126.</ref> [[wikipedia:Vibegron|Vibegron]] (Urovant, 2020) followed with a similar efficacy profile and a smaller blood-pressure signal. The combination of a beta-3 agonist with an M3 antimuscarinic is now standard for symptoms not controlled on monotherapy, with the additive efficacy of two mechanisms and largely non-overlapping side-effect profiles. | The transformative agent in the 2010s was the first beta-3 adrenergic agonist. Detrusor smooth muscle, although under predominant parasympathetic stimulatory control through M3 receptors, also expresses beta-3 adrenoceptors whose activation produces relaxation; the receptor was poorly accessible to traditional adrenergic medicines because beta-3 selectivity is difficult to achieve. [[Mirabegron|Mirabegron]] (Astellas, 2012) was the first orally bioavailable selective beta-3 agonist; it reduced urge incontinence episodes and micturition frequency comparable to the antimuscarinics, without dry mouth or cognitive effect, although with a small but real signal of hypertension that has required blood-pressure monitoring on treatment.<ref name="khullar2013">Khullar V, Amarenco G, Angulo JC, Cambronero J, Høye K, Milsom I, Radziszewski P, Rechberger T, Boerrigter P, Drogendijk T, et al. Efficacy and tolerability of mirabegron, a beta(3)-adrenoceptor agonist, in patients with overactive bladder: results from a randomised European-Australian phase 3 trial. ''European Urology''. 2013 Feb;63(2):283-295. PMID 23182126.</ref> [[wikipedia:Vibegron|Vibegron]] (Urovant, 2020) followed with a similar efficacy profile and a smaller blood-pressure signal. The combination of a beta-3 agonist with an M3 antimuscarinic is now standard for symptoms not controlled on monotherapy, with the additive efficacy of two mechanisms and largely non-overlapping side-effect profiles. | ||