Mirabegron Mode of Action
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 without interfering with the voiding phase. 1
Molecular Mechanism
Mirabegron acts as an agonist of the human beta-3 adrenergic receptor (AR), as demonstrated through in vitro experiments using cloned human beta-3 AR. 1
The drug specifically targets beta-3 receptors in the bladder, showing very low intrinsic activity for cloned human beta-1 AR and beta-2 AR at therapeutic doses, though beta-1 AR stimulation can occur at supratherapeutic doses (200 mg). 1
Beta-3 receptor activation leads to accumulation of cyclic adenosine monophosphate (cAMP), which increases intracellular calcium and triggers the release of nitric oxide (NO). 2
Physiological Effects on the Bladder
The primary therapeutic effect is detrusor smooth muscle relaxation during the storage phase of the urinary bladder fill-void cycle, which increases bladder capacity. 1
Beyond direct muscle relaxation through nitric oxide release, mirabegron may also stimulate the release of an urothelial-derived inhibiting factor (UDIF) that further inhibits bladder contractions. 2
The mechanism is fundamentally different from antimuscarinic agents: mirabegron enhances bladder storage function without interfering with the parasympathetic-regulated voiding phase, which explains its lower incidence of voiding dysfunction compared to antimuscarinics. 3, 4
Clinical Implications of the Mechanism
Urodynamic studies in 200 male patients with lower urinary tract symptoms demonstrated that mirabegron administered once daily for 12 weeks did not adversely affect mean maximum flow rate or mean detrusor pressure at maximum flow rate. 1
The selective beta-3 mechanism results in a distinct adverse effect profile compared to antimuscarinics, with lower rates of dry mouth, constipation, and blurred vision. 5, 4
At therapeutic doses (25-50 mg), cardiovascular effects are minimal, with mean pulse rate increases of approximately 1 bpm in clinical efficacy studies, though dose-dependent increases in heart rate and blood pressure occur at supratherapeutic doses. 1
Receptor Distribution and Additional Effects
Beta-3 adrenergic receptors are present not only in the detrusor muscle but also in the urothelium itself, interstitial cells, and ureteric smooth muscle. 6
Stimulation of beta-3 receptors in the ureter decreases intraluminal pressure, which has led to investigation of mirabegron as a potential medical expulsive therapy for ureteral stones, though this remains investigational. 6
Mirabegron may also reduce activity in sensory nerves within the bladder, contributing to its efficacy in reducing urgency symptoms beyond simple muscle relaxation. 5