Mechanism of Action of Mirabegron (Beta-3 Adrenergic Receptor Agonist)
Mirabegron works primarily by selectively activating beta-3 adrenergic receptors in the detrusor smooth muscle, causing relaxation during the bladder filling/storage phase and increasing bladder capacity. 1
Primary Mechanism
- Mirabegron is a selective agonist of human beta-3 adrenergic receptors (β3-AR), as demonstrated through in vitro laboratory experiments using cloned human β3-AR 1
- By activating β3-AR, mirabegron relaxes the detrusor smooth muscle specifically during the storage phase of the urinary bladder fill-void cycle 1
- This relaxation mechanism increases overall bladder capacity, reducing symptoms of urgency, frequency, and urgency incontinence 1, 2
Molecular Pathway
- Activation of β3 adrenergic receptors by mirabegron leads to:
Selectivity Profile
- Mirabegron demonstrates high selectivity for β3-AR with nanomolar EC50 values in biochemical assays 4
- It shows very low intrinsic activity for human β1-AR and β2-AR at therapeutic doses 1
- At higher doses (200 mg, which exceeds the maximum recommended dose), some β1-AR stimulation can occur in humans 1
Physiological Effects
- Inhibits afferent nerve signals by predominantly affecting mechanosensitive Aδ-fibers in the normal bladder 5
- In pathological conditions (e.g., spinal cord injury), it may also inhibit capsaicin-sensitive C-fibers 5
- In bladder outlet obstruction models, mirabegron prevents acetylcholine release through parasympathetic prejunctional mechanisms 5
- Unlike antimuscarinic agents, mirabegron does not block muscarinic receptors, resulting in fewer anticholinergic side effects such as dry mouth 6
Clinical Pharmacodynamics
- Urodynamic studies in 200 male patients with lower urinary tract symptoms (LUTS) and bladder outlet obstruction (BOO) showed that mirabegron administration for 12 weeks did not adversely affect maximum urinary flow rate or detrusor pressure 1
- At therapeutic doses (50 mg), mirabegron causes minimal increases in heart rate (approximately 1 bpm in clinical efficacy studies) 1
- Blood pressure effects are dose-dependent, with the maximum recommended dose of 50 mg causing approximately 4.0/1.6 mm Hg increase in systolic/diastolic blood pressure compared to placebo 1
Mirabegron represents a first-in-class therapy for overactive bladder that works through a different mechanism than traditional antimuscarinic agents, offering an alternative treatment approach with a distinct side effect profile 6, 3.