Editing Functional: Pharmacological Management of LUTS (section)

==== β3-adrenoreceptor agonists ====

* '''<span style="color:#ff0000">3 β-ARs subtypes (β1, β2, and β3) have been identified in the detrusor and urothelium.</span>'''
** Stimulation of β2- and β3-adrenergic receptors results in the direct relaxation of the detrusor smooth muscle
** '''<span style="color:#ff0000">β3-adrenergic receptor is the most highly expressed subtype</span>''' among α- and β-adrenoceptor subtypes at the mRNA level in human bladder

===== Mechanism of action =====
* '''Stimulates β3-adrenoceptor causing activation of adenylyl cyclase with the subsequent formation of cAMP, resulting in detrusor relaxation'''
** Recall that in erectile physiology, activation of guanyl cyclase results in increased cGMP, resulting in arterial wall smooth muscle relaxation
* '''Inhibits filling induced activity in both mechanosensitive Aδ and C-fiber primary bladder afferents,''' at least in an animal model.

===== Mirabegron =====

====== Metabolism ======
* Rapidly absorbed
* '''Metabolized in the liver via multiple pathways, mainly by cytochrome P450'''
** '''Subject to clinically relevant drug-drug interactions;''' should be used with caution in patients who are taking ketoconazole or other potent CYP3A4 inhibitors.
** Metabolites are inactive

====== Outcomes ======
* '''Increases bladder capacity, improves frequency, urgency, incontinence episodes'''
* '''Does not adversely affect flow rate, detrusor pressure at maximum flow rate, bladder contractile index, or residual volume'''

====== Contraindications(3):[https://www.astellas.com/ca/system/files/pdf/Myrbetriq_PM_EN.pdf §] ======
# '''<span style="color:#ff0000">Severe uncontrolled hypertension defined as systolic blood pressure ≥180 mm Hg and/or diastolic blood pressure ≥110 mm Hg.</span>'''
# '''<span style="color:#ff0000">Pregnancy</span>'''
# '''<span style="color:#ff0000">Hypersensitivity</span>'''

====== Dosage ======
* '''Starting dose of 25 mg and increasing to 50 mg, if needed, is recommended.'''
* '''Lowest dose is also recommended for renal and hepatic impairment'''

====== <span style="color:#ff0000">Adverse events[https://www.astellas.com/ca/system/files/pdf/Myrbetriq_PM_EN.pdf §]</span> ======
* '''<span style="color:#ff0000">≥1% (5)</span>'''
*# '''<span style="color:#ff0000">Hypertension</span>'''
*#* The mean increase (compared with placebo) in systolic and diastolic blood pressure after therapeutic doses of mirabegron once daily was ≈0.5-1 mm Hg and was reversible on discontinuation of treatment.
*#* In the clinical efficacy and safety studies, the change from baseline in mean pulse rate for mirabegron 50 mg was ≈1 beat/min and reversible on discontinuation of treatment.
*# '''<span style="color:#ff0000">Tachycardia</span>'''
*#'''<span style="color:#ff0000">Nasopharyngitis</span>'''
*#'''<span style="color:#ff0000">Urinary tract infection</span>'''
*#'''<span style="color:#ff0000">Headache</span>'''
*#'''<span style="color:#ff0000">Constipation</span>'''
*'''Does not cause increase QT interval'''
* '''Effects on HR and blood pressure need to be monitored when the drug is prescribed''', even if the cardiovascular effects of mirabegron observed in clinical studies have been minimal and clinically not relevant