Current pharmacotherapy of overactive bladder

Kreydin, Evgenyi I.; Gomes, Cristiano M.; Cruz, Francisco

doi:10.1590/S1677-5538.IBJU.2021.99.12

Evgenyi I. Kreydin

Department of Urology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA

Cristiano M. Gomes Correspondence address: Cristiano Mendes Gomes, MD, Divisao de Clinica Urologica Hospital das Clínicas da Universidade de São Paulo, Avenida Dr. Eneas de Carvalho Aguiar, 255, Sala 710F, São Paulo, SP, 05403-000, Brasil. Fax: + 55 11 3064-7013. E-mail: crismgomes@uol.com.br

Divisão de Urologia, Departamento de Cirurgia, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil

https://orcid.org/0000-0002-8486-4003

Francisco Cruz

Departamento de Urologia, Hospital de S. João, Faculdade de Medicina do Porto, Porto, Portugal

i3S Instituto para Investigação e Inovação em Saúde, Porto, Portugal

Correspondence address: Cristiano Mendes Gomes, MD, Divisao de Clinica Urologica Hospital das Clínicas da Universidade de São Paulo, Avenida Dr. Eneas de Carvalho Aguiar, 255, Sala 710F, São Paulo, SP, 05403-000, Brasil. Fax: + 55 11 3064-7013. E-mail: crismgomes@uol.com.br

CONFLICT OF INTEREST

None declared.

Tables (6)

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Key Points Treatment principles Treatment options for OAB are divided by “lines of therapy” based on levels of invasiveness; First line includes lifestyle modifications and pelvic floor physical therapy; Second line consists of drug therapy with anticholinergics and/or beta-3 agonists; Third line includes intravesical botulinum toxin injection, SNM* and PTNS**; Treatment should ideally escalate from least to most invasive, but different modalities can be combined if single-therapy approach is not successful.

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Table 1
Antimuscarinic agents for adults with OAB.

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Key Points Antimuscarinics (AM) AM act mainly by blocking M3 receptors; Because there are no AM with significant selectivity for the bladder, adverse effects (AEs) of treatment are common; AM differ in molecular size, charge and lipophilicity; Quaternary AM have greater molecular charge and less lipophilicity which limit their passage into the central nervous system; Many AM are metabolized by the P450 enzyme system which may affect the plasma concentration of the AM and that of an interacting drug; All commercially available AM improve OAB symptoms and quality of life with comparable efficacy, but different tolerability profiles; The most frequent AEs are gastrointestinal, with dry mouth as the most common; Considering the starting oral dosages, a similar AE profile was observed for most AM, with the exception of oxybutynin which demonstrated higher AE rates; Immediate-release AM have a greater risk of side effects than extended-release formulations; Recommended AM dosages do not significantly inhibit voiding contraction; AM should be avoided in the elderly population since the cumulative use of medications with anticholinergic activity may be associated with the risk of dementia; Persistence in treatment with AM is low, with only 20% persisting after 1 year; Due to specific pharmacologic properties and dosing schedule, AM treatment must be individualized; Intravesical administration of oxybutynin is an option for patients with neurogenic dysfunction who perform intermittent catheterization.

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Key Points Beta-3 agonists β3-AR agonists promote detrusor relaxation through activation of adenylyl cyclase and formation of cAMP; Mirabegron improve OAB symptoms and quality of life and is recommended by current guidelines for the treatment of OAB; Some countries offer mirabegron in both 25mg and 50mg doses; 50mg shows some superiority over lower doses; The efficacy of Mirabegron and AM were never compared in well-powered studies; Persistence in treatment with mirabegron exceeds that of AM; Mirabegron does not inhibit voiding contraction; Mirabegron has a high safety profile including for cardiovascular events; Appearance or aggravation of hypertension is similar in subjects exposed to mirabegron or AM; Yet, mirabegron is contra-indicated in patients with uncontrolled hypertension and regular vigilance of blood pressure is recommended after its prescription; Rates of dry mouth and constipation are reduced compared to AM, especially in the elderly (≥75y); Patients exposed to mirabegron did not show evidence of cognitive deterioration; Vibegron (75mg/day) is a new β3-AR agonist that has recently been approved for use in OAB patients; Hypertension is similar in subjects exposed to Vibegron or placebo; The efficacy and safety profiles of vibegron have not been compared to mirabegron and there is a scarcity of studies evaluating its use in combination with other drugs.

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Key Points Drug combinations Adding Mirabegron to patients unsatisfied with monotherapy with an AM provides superior efficacy; Adding an AM to patients unsatisfied with monotherapy with mirabegron is also effective; Adding Mirabegron to men with LUTS unsatisfied with monotherapy with tadalafil provides superior improvement of OAB symptoms without significant AE; The efficacy and safety of combining vibegron with other agents has yet to be shown.

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Key Points New directions Lower urinary tract sensation and contractility are mediated by a multitude of mechanisms and receptors. Some of these are being investigated as potential targets for novel oral therapies for OAB; Altering afferent bladder signaling may be a novel approach to OAB therapy; Agonists and inhibitors of pain and mechanotransduction receptors such as TRPV and cannabinoid receptors are currently in preclinical and clinical studies and have shown some promise in certain patient populations.

Key Points

Treatment principles

Treatment options for OAB are divided by “lines of therapy” based on levels of invasiveness;
First line includes lifestyle modifications and pelvic floor physical therapy;
Second line consists of drug therapy with anticholinergics and/or beta-3 agonists;
Third line includes intravesical botulinum toxin injection, SNM* and PTNS**;
Treatment should ideally escalate from least to most invasive, but different modalities can be combined if single-therapy approach is not successful.

	Starting dose regimen^* * Recommended initial dose for adults with no liver or renal function impairment; Unless noted, regimens are once-daily dosing; bid: twice a day; tid: three times a day; IR: immediate release; ER: extended release;	Dose escalation^* * Recommended initial dose for adults with no liver or renal function impairment; Unless noted, regimens are once-daily dosing; bid: twice a day; tid: three times a day; IR: immediate release; ER: extended release;
Darifenacin	7.5mg	15mg
Fesoterodine	4mg	8mg
Imidafenacin	0.1mg bid	0.2mg bid
Oxybutynin^ Agents with mixed mechanism of action but predominant antimuscarinic action.	10mg ER or 5mg IR bid or tid	115-20mg ER or 5mg qid
Propiverine^ Agents with mixed mechanism of action but predominant antimuscarinic action.	30mg ER or 15mg IR bid	45mg ER or 15mg IR tid
Solifenacin	5mg	10mg
Tolterodine	4mg ER or 2mg IR bid	Not evaluated
Trospium	60mg ER or 20mg bid	Not evaluated

Key Points

Antimuscarinics (AM)

AM act mainly by blocking M3 receptors; Because there are no AM with significant selectivity for the bladder, adverse effects (AEs) of treatment are common;
AM differ in molecular size, charge and lipophilicity; Quaternary AM have greater molecular charge and less lipophilicity which limit their passage into the central nervous system;
Many AM are metabolized by the P450 enzyme system which may affect the plasma concentration of the AM and that of an interacting drug;
All commercially available AM improve OAB symptoms and quality of life with comparable efficacy, but different tolerability profiles;
The most frequent AEs are gastrointestinal, with dry mouth as the most common;
Considering the starting oral dosages, a similar AE profile was observed for most AM, with the exception of oxybutynin which demonstrated higher AE rates;
Immediate-release AM have a greater risk of side effects than extended-release formulations;
Recommended AM dosages do not significantly inhibit voiding contraction;
AM should be avoided in the elderly population since the cumulative use of medications with anticholinergic activity may be associated with the risk of dementia;
Persistence in treatment with AM is low, with only 20% persisting after 1 year;
Due to specific pharmacologic properties and dosing schedule, AM treatment must be individualized;
Intravesical administration of oxybutynin is an option for patients with neurogenic dysfunction who perform intermittent catheterization.

Key Points

Beta-3 agonists

β3-AR agonists promote detrusor relaxation through activation of adenylyl cyclase and formation of cAMP;
Mirabegron improve OAB symptoms and quality of life and is recommended by current guidelines for the treatment of OAB;
Some countries offer mirabegron in both 25mg and 50mg doses; 50mg shows some superiority over lower doses;
The efficacy of Mirabegron and AM were never compared in well-powered studies;
Persistence in treatment with mirabegron exceeds that of AM;
Mirabegron does not inhibit voiding contraction;
Mirabegron has a high safety profile including for cardiovascular events;
Appearance or aggravation of hypertension is similar in subjects exposed to mirabegron or AM;
Yet, mirabegron is contra-indicated in patients with uncontrolled hypertension and regular vigilance of blood pressure is recommended after its prescription;
Rates of dry mouth and constipation are reduced compared to AM, especially in the elderly (≥75y);
Patients exposed to mirabegron did not show evidence of cognitive deterioration;
Vibegron (75mg/day) is a new β3-AR agonist that has recently been approved for use in OAB patients;
Hypertension is similar in subjects exposed to Vibegron or placebo;
The efficacy and safety profiles of vibegron have not been compared to mirabegron and there is a scarcity of studies evaluating its use in combination with other drugs.

Key Points

Drug combinations

Adding Mirabegron to patients unsatisfied with monotherapy with an AM provides superior efficacy;
Adding an AM to patients unsatisfied with monotherapy with mirabegron is also effective;
Adding Mirabegron to men with LUTS unsatisfied with monotherapy with tadalafil provides superior improvement of OAB symptoms without significant AE;
The efficacy and safety of combining vibegron with other agents has yet to be shown.

Key Points

New directions

Lower urinary tract sensation and contractility are mediated by a multitude of mechanisms and receptors. Some of these are being investigated as potential targets for novel oral therapies for OAB;
Altering afferent bladder signaling may be a novel approach to OAB therapy;
Agonists and inhibitors of pain and mechanotransduction receptors such as TRPV and cannabinoid receptors are currently in preclinical and clinical studies and have shown some promise in certain patient populations.

[1] Correspondence address: Cristiano Mendes Gomes, MD, Divisao de Clinica Urologica Hospital das Clínicas da Universidade de São Paulo, Avenida Dr. Eneas de Carvalho Aguiar, 255, Sala 710F, São Paulo, SP, 05403-000, Brasil. Fax: + 55 11 3064-7013. E-mail: crismgomes@uol.com.br

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Current pharmacotherapy of overactive bladder

ABSTRACT