Abstract
Mirabegron is used for the treatment of symptoms associated with overactive bladder syndrome. It selectively stimulates the β3-adrenoreceptor, which relaxes the detrusor muscle. This improves urine storage by distension of the bladder body.
In this series we draw attention to medicines that have entered the European market with an entirely new mechanism of action. Publication is not to be confused with endorsement of use in clinical practice. Copyright to the images belongs to Leiden University, but use of the images (also available at http://coo.lumc.nl/trc and in the app stores) is free.
Introduction
Overactive bladder (OAB) is a syndrome characterized by urgency, with or without urge incontinence, usually with frequency and nocturia 1. The prevalence of OAB is high in the general population (16.5%) and increases with age 2.
Mechanism
The function of the lower urinary tract is regulated by the diametric opposition of sympathetic and parasympathetic innervation (Figure1) 3. Sympathetic nerve endings promote urine storage by releasing noradrenaline (NA), which activates β3-adrenoreceptors 4. This relaxes the detrusor muscle in the urinary bladder wall 5. Mirabegron is a selective β3-adrenoreceptor agonist, with a comparable mechanism of action. It relaxes the detrusor muscle enabling the bladder wall to remain distended and allowing for the storage of urine 6.
Figure 1.
Sympathetic and parasympathetic innervation diametrically regulates the function of the lower urinary tract. Sympathetic nerve activity triggers the release of noradrenaline (NA), which relaxes the detrusor muscle and promotes contraction of the urethra, thereby promoting the storage of urine. During urination, parasympathetic nerve activity predominates; the release of nitric oxide (NO) inhibits contraction of the urethra, and acetylcholine (ACh) release triggers contraction of the detrusor muscle. Like noradrenaline, mirabegron acts on the β3-adrenoreceptor, triggering detrusor muscle relaxation and improved urine storage
Indication
Mirabegron is indicated for the treatment of the following symptoms associated with OAB: urgency, urge incontinence and increased urination frequency 3.
Clinical application
In clinical trials, mirabegron reduced both the frequency of urination and the number of daily incontinence episodes. These improvements in objective treatment outcomes also correlated with patient-reported outcomes, such as health-related quality of life 7. Importantly, although the efficacy of mirabegron was similar to the efficacy of the anticholinergic drug tolterodine (4 mg), the incidence of dry mouth, a common side effect of anticholinergics, was three to five-fold lower with mirabegron 3,8. A recent post hoc analysis of pooled data from 1740 patients enrolled in three phase 3 trials suggested that the efficacy of mirabegron increases with increasing incontinence severity 8. The recommended daily dose of mirabegron in adults is 50 mg 3. A modest increase in mirabegron exposure (measured as the area under the curve) was observed in healthy volunteers who were co-medicated with a strong functional inhibitor of CYP3A and P-gp activity 3,8. Thus, dose adjustments are not recommended when mirabegron is combined with inhibitors of CYP3A and/or P-gp. A reduction in dose to 25 mg day–1 is recommended for patients who have mildly impaired hepatic or renal function and are taking a strong CYP3A inhibitor 3.
Adverse effects
The most common side effects reported among patients treated with mirabegron include tachycardia and urinary tract infection 3. Serious but uncommon side effects include atrial fibrillation (in 0.2% of patients) 3. In a study with healthy volunteers, mirabegron increased both heart rate and blood pressure in a dose-dependent manner, although these side effects appear attenuated among patients with OAB 9.
Competing Interests
All authors have completed the Unified Competing Interest form at http://www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare no support from any organization for the submitted work, no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years and no other relationships or activities that could appear to have influenced the submitted work.
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