Beta 3 Agonist For Overactive Bladder

Section : Research Needs And Future Directions

Figure 4: OAB Patient Groups

Epidemiology. Studies assessing how OAB develops and its natural history and progression are required. The timing and circumstances around which OAB develops and associated risk factors are not yet well-understood. While not specifically targeting epidemiology of OAB, there are large community-based studies that assess prevalence of lower urinary tract symptoms and urinary incontinence.280, 281 By longitudinally studying these community cohorts, these investigators have developed a new hypothesis that lower urinary tract symptoms are likely related to other systemic diseases/conditions.282, 283 Continuation of these types of studies could lead to potential preventive interventions for OAB symptoms and/or utilization of treatments that target the associated systemic conditions rather than the bladder. Epidemiologic studies provide a better cross sectional estimation of the overall population impact of OAB-type symptoms.284

Clinical studies should use validated standardized measures to report subjective outcomes. Objective outcomes should include frequency, nocturia, urgency, incontinence episode frequency and reporting of the variance for each of these measures. Furthermore, the Guideline Panel’s meta-analytic efforts were hampered by lack of consistent reporting of variance information for baseline and post-treatment measurements.

Are Beta 3 Adrenergic Agonists Now The Preferred Pharmacologic Management Of Overactive Bladder

The current data supports beta 3 adrenergic agonists as the recommended pharmacological therapy for overactive bladder syndrome, according to this research. Mirabegron has an effectiveness profile equivalent to first-line antimuscarinics, as well as a benign adverse effect profile. In individuals who are at a higher risk of anticholinergic side effects, treatment with a beta-3 adrenergic agonist should be preferred. The effectiveness and tolerance of beta-3 adrenergic agonists in older OAB patients, whether treated alone or in combination with other antimuscarinics, have been repeatedly documented. Unless the symptoms are severe or refractory, mirabegron is a cost-effective treatment for OAB. Mirabegron combined with other medications has been shown to be effective in managing OAB symptoms without causing major side effects.

While beta-3 adrenergic agonists have benefits in the treatment of OAB, clinicians should undertake complete and cautious pre-treatment planning to maximize treatment benefits and adherence.

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How Are Beta3 Agonists Used

Beta3 agonists are administered as oral tablets or granules in suspensions, approved by the FDA for the treatment of the following conditions:

• Overactive bladder with symptoms of urge, incontinence, urgency, and frequency
• Pediatricneurogenic detrusor overactivity, a condition due to nerve damage or disease that causes overactivity of the bladder wall muscles, which normally relax to hold urine.

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Mechanism Of Action Of 3

Early studies using animal OAB models indicated that the effect of 3-ARAs was mainly through a direct relaxant effect on the detrusor, due to activation of cAMP and BKCa channels.12,13 This theory has been questioned by several studies documenting that plasma concentrations after oral administration of mirabegron do not reach the concentration necessary to achieve detrusor relaxation during in vitro experiments using both animal and human isolated bladder strips. Since abundant expression of 3-ARs has been documented at afferent nerve endings and interstitial cells in the suburothelial layer, as well as in the urothelium, it was proposed that a reduction in bladder afferent signaling could be the most important mechanism leading to detrusor relaxation.14 This theory was supported by an evident decrease in afferent activity of both A and C fibers after mirabegron administration, which was associated with decreased spontaneous phasic activity of the urinary bladder wall in animal studies.15

Fda Approves New Beta

The FDA recently approved vibegron , a beta-3 agonist for the treatment of overactive bladder in adults who have symptoms of urge urinary incontinence, urgency, and urinary frequency. Like other beta-3 agonists, vibegron works by increasing bladder capacity, causing the detrusor smooth muscle to relax during bladder filling. According to the American Urological Association 2019 guidelines, both beta-3 agonists and antimuscarinics are first-choice pharmacological treatments for overactive bladder, second only to nonpharmacological behavioral therapies.

Clinical trials leading to vibegrons approval showed that it had a statistically significant impact on the average daily number of micturitions, average daily number of urinary urge incontinence episodes, average daily number of urgency episodes, and average volume voided per micturition.

Vibegron comes as a 75mg tablet and is intended for once daily oral administration. Importantly, no dose modifications are required for those with impaired renal function, although the drug has not been studied in end-stage renal disease and should, therefore, be avoided in those with the condition. The tablet should be swallowed whole with a glass of water but may also be crushed and mixed with applesauce if desired.

References:

Food & Drug Administration. Gemtesa. 2020. Retrieved from:

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Vaginal Estradiol Vs Oral Beta

Background/significance: Overactive Bladder Syndrome is defined as urinary urgency, with or without urgency incontinence, and usually accompanied by frequency and nocturia. OAB remains an increasingly more prevalent disease, affecting over 45% of postmenopausal women over the age 65 within the United States. Epidemiological research continues to consistently highlight OAB’s impact on patience’s mental health, sleep quality, physical activity, occupational productivity and overall quality of life. OAB’s economic burden cannot be overstated as well as a US cost-of-illness study reported a total cost of $66 billion in 2007 and estimated cost of over $82 billion in 2021.

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Role Of 3 Adrenoreceptors In Bladder Control Under Physiological Conditions

The main role of the lower urinary tract is accumulation of urine during the storage phase and its periodical elimination during the voiding phase of the micturition cycle. The function of the LUT is under constant control of the neural system, including peripheral nerves, the spinal cord, and supraspinal centers in the brain. Any disruption of this control pathway may lead to development of LUT symptoms .4 At the peripheral nerve level, parasympathetic efferents are responsible for detrusor contraction during voiding, while sympathetic nerves drive detrusor relaxation during the storage phase.

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Beta 3 Agonists: A Much

Urology Times® is celebrating its 50th anniversary in 2022. To mark the occasion, we are highlighting 50 of the top innovations and developments that have transformed the field of urology over the past 50 years. In this installment, Ekene A. Enemchukwu, MD, MPH, discusses the development of 3 agonists for the treatment of overactive bladder . Enemchukwu is an assistant professor of urology and, by courtesy, of obstetrics and gynecology and medical director of the Stanford Pelvic Health Center, Stanford University, Palo Alto, California

Differences Of Persistence And Compliance Between Oab Drugs

In the pharmacologic treatment of OAB, a limitation is that available approved drugs are restricted to several antimuscarinics and the 3-adrenoceptor agonist, mirabegron. In general, persistence to OAB drugs is lower than for other types of chronic medications, such as antihypertensives and drugs for treatment of diabetes . Even if there seem to be no consistent differences in efficacy between antimuscarinics and the 3-adrenoceptor agonists, for long-term use it is desirable to establish if there are relevant differences in persistence and compliance not only between antimuscarinics and 3-adrenoceptor agonists , but also between different antimuscarinics. These issues have been discussed by several investigators , and recently in a study by Chapple et al. .

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Please Provide An Overview Of The Development Of 3 Agonists In Oab

The discovery of the 3 receptor subtype occurred in the late 1980s. At that time, researchers discovered that 3 agonists had activity in adipose tissue, so the initial indication for this class of medications was actually going to be obesity and diabetes. It wasn’t until the late 1990s, when evidence of 3 receptor subtype activity was linked to smooth muscle relaxation in the bladder, that the 3 agonist as a treatment for overactive bladder was conceived. In the late 1980s, the only medication available for the treatment of OAB was oxybutynin. That was approved by the FDA back in 1975. It wasn’t until 1998 that the FDA approved our second antimuscarinic, tolterodine. So for over 20 years, the only medication we had available to treat overactive bladder was oxybutynin. So to hear of a new drug target for OAB was really exciting. It was in 2001 that this first compoundwhat we now know today as mirabegron was studied and showed some preclinical efficacy in several models of OAB and a favorable human safety profile. Then, in 2011, there were phase 3 clinical trials, and in 2012, mirabegron received its FDA approval in the US and also in Europe. Last year, we actually had the approval of the second drug in this class: vibegron , which is also a selective 3 agonist.

Drug Therapy With Antimuscarinics

Antimuscarinics or Muscarinic receptor antagonists are a group of drugs which reduce the abnormal contractions of the bladder and improve urgency symptoms.

There are several MRAs. These work similarly, but they may have different side effects and be more or less tolerated by patients.

Taking antimuscarinics

Most antimuscarinics are taken by mouth once daily with or without food, although they can also be administered through a transdermal patch. The recommended dose for adults differs by the type of MRA. Start with the minimum dosage that gives you the beneficial effects of the drug with as few side effects as possible.

Antimuscarinics are not recommended for patients who are pregnant or those who suffer from conditions like:

• severe constipation

Possible drug interactions

When antimuscarinics are taken by mouth, interactions with other drugs can occur. Ask your doctor about drug interactions. Read the prescription instructions for your drug treatment carefully to make sure you take medications correctly.

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How To Improve Compliance And Persistence

More effective strategies for improving compliance and persistence with OAB pharmacotherapy are needed. Assessing the individualized needs of each patient and goal achievement for the most bothersome symptoms as well as patient support programs can be good strategies. Since the most common causes for discontinuation are lack of efficacy and adverse effects it is important to inform the patients on these issues to promote realistic expectations. It should be emphasized that drugs are second line treatment, and a combination of behavioral therapy and drug intervention seems to be the most efficacious in terms of patient satisfaction, perceived improvement, and reduction of bladder symptoms .

Anticholinergic/antimuscarinic And Beta 3

Acetylcholine is the primary excitatory neurotransmitter involved in bladder emptying. The two medication classes commonly used are anticholinergic/antimuscarinic and beta 3-adrenergic agonists . These medications reduce symptoms of OAB and UI with variable outcomes.29,30 A 2017 study found that prescribing of medications with anticholinergic properties to nursing home residents is common, despite an association with an increased risk of falls, delirium, and other outcomes.31

A systematic literature review of randomized controlled trials between 1966 and 2011 evaluating fesoterodine, tolterodine, oxybutynin, solifenacin, and trospium concluded that approximately 13% of participants achieved continence, and approximately 6% of participants discontinued treatment due to the severity of adverse effects .32 Improved quality of life was limited.

The newer medications, such as darifenacin, solifenacin, and trospium, are more targeted for bladder tissue, whereas transdermal delivery systems still produce unwanted anticholinergic effects in tissues other than the bladder.32

K. Sakamoto, in, 2010

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How Do Beta3 Agonists Work

Beta3 agonists are a relatively new class of medications prescribed to treat bladder overactivity which can cause urinary urgency and incontinence. Beta3 agonists ease the urination urge and increase bladder capacity by relaxing the bladders detrusor smooth muscle while the bladder is filling.

Beta3 agonists work by activating beta3 receptors, which are protein molecules on the detrusor musclecell membranes. Beta3 receptors are adrenergic receptors that relax the detrusor muscle when activated by the hormones, epinephrine, and norepinephrine.

Beta3 agonists may be prescribed as monotherapy or in combination with a muscarinic antagonist. Muscarinic antagonists bind to muscarinic receptors and block the activity of acetylcholine, a chemical that nerve endings secrete to make the detrusor muscle contract to release urine.

Clinical Efficacy In Specific Oab

Mirabegron in Men

Our current knowledge on the clinical efficacy of mirabegron in men is based mainly on pooled analysis of previously conducted phase II and III trials enrolling both men and women.29 Studies designed primarily to assess the efficacy of mirabegron in the treatment of OAB symptoms in men are rather sparse.30 A majority of placebo-controlled studies have documented statistically significant superiority of mirabegron on some end points. However the difference in most cases was small and the clinical value of such improvement questionable. In addition, data showing that female patients have better adherence to mirabegron treatment than men may implicate lower efficacy in men than women.31 This is consistent with previous findings demonstrating that male patients suffering from OAB symptoms generally have a lower response rate when treated using AChs than women. This probably reflects the fact that the etiology of male LUTSs is more complex, as it may include additional factors, such as bladder-outflow obstruction, resulting in urothelial dysfunction, chronic bladder ischemia, and inflammation.32

Mirabegron in Adults with Neurogenic Detrusor Overactivity

Mirabegron in the Elderly

Mirabegron in Children

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Increases In Heart Rate/blood Pressure

There appears to be a dose dependent increase in heart rate and blood pressure with the use of mirabegron. There was no significant increase in heart rate in mirabegron 25mg/day in either the morning or afternoon, 0.34 bpm and 0.49 bpm, respectively ,23 or in mirabegron 50mg/day in the morning or afternoon, 0.81.64 bpm and 0.71.12 bpm, respectively .23,25 In the BLOSSOM trial, subjects taking mirabegron 150mg BID had a 5bpm increase compared to no change in mirabegron 100mg BID and tolterodine ER 4mg/day.22 In trials of higher doses there were significant increases in heart rate. There was an increase of 1.62.5 bpm in the morning and 2.02.71 bpm in the afternoon in mirabegron 100mg/day .23,25 There was also a 4.634.66 bpm increase in the mirabegron 200mg/day group however, there were no reported cardiac adverse effects.23 Changes in heart rate were not reported in the ARIES trial.24

Clinical Efficacy Of Mirabegron In Combination Treatment

Both AChs and 3-ARAs are standard treatments for OAB. Given their different modes of action, simultaneous administration of both drug classes is a logical way to improve efficacy if monotherapy is unable to control OAB symptoms sufficiently. In addition, especially in older individuals, the combination of AChs and 3-ARAs allows for limiting unwanted ACh load. Combinations of AChs and 3-ARAs have been assessed in several large-scale, multicentric prospective, randomised phase II and III studies that recruited mostly women suffering from OAB wet . These trials documented the superiority of the combination over monotherapy on a majority of end points, showing a 31%50% higher likelihood of achieving continence using the combination than monotherapy.51 A pooled analysis of the BESIDE study of patients aged > 65 years documented that the combination of mirabegron and solifenacin was superior to solifenacin monotherapy without increasing the rate of adverse events.52

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