Mechanism of Action of Mirabegron
Mirabegron is a selective beta-3 adrenergic receptor agonist that relaxes the detrusor smooth muscle during the bladder storage phase by activating beta-3 adrenergic receptors, which increases bladder capacity. 1
Primary Mechanism
Mirabegron acts as an agonist of the human beta-3 adrenergic receptor (beta-3 AR), as demonstrated in laboratory experiments using cloned human beta-3 AR. 1
The drug specifically relaxes the detrusor smooth muscle during the storage phase of the urinary bladder fill-void cycle through beta-3 AR activation, resulting in increased bladder capacity. 1
This mechanism is fundamentally different from antimuscarinic agents, providing an alternative pathway for treating overactive bladder symptoms. 2, 3
Receptor Selectivity Profile
Mirabegron demonstrates very low intrinsic activity for cloned human beta-1 AR and beta-2 AR at therapeutic doses. 1
However, beta-1 AR stimulation can occur at supratherapeutic doses of 200 mg (four times the maximum recommended dose), which explains the dose-dependent cardiovascular effects observed at higher doses. 1
The selective targeting of beta-3 adrenoreceptors allows mirabegron to improve bladder storage function without significantly altering void contractions. 4
Additional Mechanisms
Beyond direct beta-3 receptor activation, mirabegron may also act by binding other targets in the bladder and potentially reducing activity in sensory nerves. 3
This multi-target activity may contribute to its efficacy in reducing urgency symptoms and improving overall bladder function. 3
Clinical Implications of the Mechanism
The beta-3 agonist mechanism results in detrusor muscle relaxation without the anticholinergic side effects (dry mouth, constipation, cognitive impairment) commonly seen with antimuscarinic drugs. 5, 2
Mirabegron does not adversely affect maximum urinary flow rate or detrusor pressure at maximum flow rate in urodynamic studies of male patients with lower urinary tract symptoms and bladder outlet obstruction. 1
The mechanism allows for symptomatic relief from overactive bladder without disturbing the normal micturition cycle. 4
Cardiovascular Effects Related to Mechanism
At therapeutic doses (25-50 mg), mirabegron causes minimal increases in heart rate (approximately 1 bpm mean change) and modest blood pressure elevations (maximum mean increase of approximately 4.0/1.6 mm Hg for systolic/diastolic blood pressure). 1
These cardiovascular effects are dose-dependent and become more pronounced at supratherapeutic doses due to beta-1 AR stimulation. 1