How do beta-3 (beta 3) adrenergic receptor agonists work?

From the Guidelines

Beta-3 agonists work by selectively binding to beta-3 adrenergic receptors, primarily found in adipose tissue and the urinary bladder, leading to relaxation of the detrusor smooth muscle during the bladder filling phase, which increases bladder capacity and decreases urinary frequency and urgency. This mechanism of action is supported by the most recent and highest quality study, which found that mirabegron, a beta-3 agonist, improves frequency, urgency, and UUI episodes compared with placebo or tolterodine 1. The main beta-3 agonist medication currently approved is mirabegron (Myrbetriq), typically prescribed at doses of 25-50 mg once daily for overactive bladder.

Key Points

• Beta-3 agonists, such as mirabegron, are effective in improving urinary urgency, frequency, and/or urgency urinary incontinence, as recommended by the AUA/SUFU guideline on the diagnosis and treatment of idiopathic overactive bladder 1.
• The use of beta-3 agonists has been shown to have a mild improvement of urinary frequency and urgency episodes per day compared with alpha-1 adrenoceptor antagonists alone, when used in combination therapy 1.
• Beta-3 agonists generally cause fewer side effects like dry mouth and constipation, though they may cause mild hypertension in some patients, and are well tolerated in the elderly and in patients with multiple comorbidities, except in patients with severe uncontrolled hypertension 1.

Clinical Considerations

• Treatment with beta-3 agonists is usually long-term as symptoms often return when medication is stopped.
• Beta-3 agonists represent a different mechanism for treating overactive bladder by enhancing the storage phase of bladder function rather than inhibiting the contraction phase, making them particularly useful for patients who experience urinary urgency and frequency.
• The most frequent adverse effects of mirabegron are hypertension, UTIs, headache, and nasopharyngitis, and it does not affect voiding urodynamic parameters, with an overall small change in PVR 1.

From the FDA Drug Label

Mirabegron is an agonist of the human beta-3 adrenergic receptor (AR) as demonstrated by in vitro laboratory experiments using the cloned human beta-3 AR. Mirabegron relaxes the detrusor smooth muscle during the storage phase of the urinary bladder fill-void cycle by activation of beta-3 AR which increases bladder capacity Beta-3 agonists, such as mirabegron, work by:

• Activating the beta-3 adrenergic receptor in the detrusor smooth muscle
• Relaxing the detrusor smooth muscle during the storage phase of the urinary bladder fill-void cycle
• Increasing bladder capacity 2

From the Research

Mechanism of Action

• Beta 3 agonists, such as mirabegron, work by activating the β3-adrenergic receptor in the bladder, which leads to relaxation of the detrusor muscle 3, 4, 5, 6.
• This relaxation increases the bladder capacity, reducing the frequency of urination and improving symptoms of overactive bladder (OAB) 3, 4, 5, 6.
• The activation of the β3-adrenergic receptor also releases nitric oxide (NO) and an urothelial-derived inhibiting factor (UDIF), which further contribute to the relaxation of the detrusor muscle 6.

Efficacy

• Mirabegron has been shown to be effective in reducing the frequency of micturition and incontinence, as well as improving health-related quality of life (HR-QOL) in patients with OAB 3, 4, 7, 5.
• The efficacy of mirabegron is similar to that of antimuscarinics, but with a more favorable adverse effect profile 3, 4, 7.
• Mirabegron has also been shown to be effective in older patients and in patients who have not responded to antimuscarinic therapy 7, 5.

Benefits

• Beta 3 agonists, such as mirabegron, offer a new treatment option for patients with OAB who are intolerant of or have contraindications to anticholinergic agents 3, 4, 5.
• Mirabegron has a lower incidence of dry mouth compared to antimuscarinics, making it a more tolerable treatment option for some patients 3.
• The use of mirabegron may also improve treatment adherence and persistence due to its favorable adverse effect profile 7.