Gemtesa (Vibegron) Mechanism of Action
Vibegron is a selective beta-3 adrenergic receptor (β3-AR) agonist that increases bladder capacity by relaxing the detrusor smooth muscle during bladder filling. 1
Primary Mechanism
Vibegron selectively activates β3-adrenergic receptors in the bladder, which directly relaxes the detrusor smooth muscle during the filling phase, thereby increasing bladder capacity. 1
The drug demonstrates high selectivity for β3-AR across species, functioning as a potent, selective full agonist at these receptors. 2
Dual Mechanism of Action
Recent research has revealed that vibegron operates through two complementary pathways:
Inhibition of acetylcholine (ACh) release from cholinergic efferent nerves in the detrusor muscle, which reduces involuntary bladder contractions. 3
Afferent nerve inhibition via urothelial β3-AR activation, which dampens sensory signals that trigger urgency. 3
Afferent Pathway Modulation
In normal bladder conditions, β3-AR agonists predominantly inhibit mechanosensitive Aδ-fibers, preventing transmission of urgency signals to the central nervous system. 3
In pathologic conditions (such as spinal cord injury), the mechanism shifts to inhibit capsaicin-sensitive C-fibers. 3
This afferent inhibition prevents local signals (autonomous myogenic contractions, micromotions, or "afferent noises") from triggering coordinated urgency-related detrusor contractions during bladder filling. 3
Receptor Distribution
β3-adrenergic receptors are expressed in both the urothelium and detrusor smooth muscle of the bladder, allowing vibegron to act at multiple sites. 2
This dual localization enables both direct smooth muscle relaxation and modulation of sensory signaling pathways. 2
Clinical Pharmacodynamics
Vibegron's activation of β3-AR increases bladder capacity, decreases micturition pressure, and increases bladder compliance. 2
The drug does not significantly affect voiding urodynamic parameters or cause clinically meaningful changes in post-void residual volume. 4, 5
Unlike antimuscarinics, vibegron does not prolong the QT interval to any clinically relevant extent, even at doses 5.3 times the approved dose. 1
Pharmacokinetic Considerations
Vibegron has an effective half-life of 30.8 hours, allowing for once-daily dosing. 1
Steady-state concentrations are achieved within 7 days of once-daily administration. 1
Metabolism plays a minor role in elimination, with CYP3A4 being the predominant enzyme responsible for in vitro metabolism, though most drug is excreted unchanged (54% in feces, 19% in urine). 1