fesoterodine and darifenacin

Overactive bladder (OAB) is often treated with medications that block the cholinergic receptors in the bladder (known as anticholinergics). The effect of this medication class on cognition and risk of dementia has been increasingly studied over the past 40 years after initial studies suggested that the anticholinergic medication class could affect memory. Short-term randomized clinical trials demonstrated that the administration of the anticholinergic oxybutynin leads to impaired memory and attention, and large, population-based studies showed associations between several different anticholinergic medications and dementia. However, trials involving anticholinergics other than oxybutynin have not shown such substantial effects on short-term cognitive function. This discordance in results between short-term cognitive safety of OAB anticholinergics and the long-term increased dementia risk could be explained by the high proportion of patients using oxybutynin in the OAB subgroups of the dementia studies, or a study duration that was too short in the prospective clinical trials on cognition with other OAB anticholinergics. Notably, all studies must be interpreted in the context of potential confounding factors, such as when prodromal urinary symptoms associated with the early stages of dementia lead to an increase in OAB medication use, rather than the use of OAB medication causing dementia. In patients with potential risk factors for cognitive impairment, the cautious use of selected OAB anticholinergic agents with favourable physicochemical and pharmacokinetic properties and clinical trial evidence of cognitive safety might be appropriate.

Topics: Benzhydryl Compounds; Benzofurans; Cholinergic Antagonists; Cognition; Cognitive Dysfunction; Dementia; Humans; Mandelic Acids; Prodromal Symptoms; Pyrrolidines; Risk Assessment; Risk Factors; Solifenacin Succinate; Tolterodine Tartrate; Urinary Bladder, Overactive

To carry out a network meta-analysis of randomised controlled trials (RCTs) of anticholinergic drug treatment for people with overactive bladders.. Comprehensive searches for relevant RCTs were carried out starting with RCTs included in previous systematic reviews with the last search in February 2017. Searches included terms for the anticholinergic drugs tolterodine, oxybutynin, trospium, propiverine, solifenacin, darifenacin, imidafenacin, and fesoterodine. Data was extracted from the systematic reviews or reports of studies for cure or improvement, voids per 24 hr, leakage episodes per 24 hr and dry mouth. Data was analysed using frequentist network meta-analysis.. 128 studies were found. There was no clearly best treatment for cure or improvement. The differences between treatments for voids and leakages were small and unlikely to be of clinical importance. Transdermally delivered oxybutynin was clearly the best treatment for dry mouth but was still worse than placebo.. All the anticholinergic drugs were better than placebo but apart from dry mouth were similar in effect. Transdermal oxybutynin caused less dry mouth than the other treatments, so may be worth considering as the first treatment.

Topics: Benzhydryl Compounds; Benzilates; Benzofurans; Cholinergic Antagonists; Humans; Imidazoles; Mandelic Acids; Network Meta-Analysis; Pyrrolidines; Solifenacin Succinate; Tolterodine Tartrate; Treatment Outcome; Urinary Bladder, Overactive

Overactive bladder (OAB) is a common constellation of lower urinary tract storage symptoms that causes a significant impact on a person's quality of life. The elderly may be disproportionally impacted by these symptoms due to concomitant poor mobility, comorbid conditions such as diabetes and heart failure, and polypharmacy. While behavioral modification and pelvic floor muscle training should be considered first-line treatment options, pharmacotherapy remains the backbone of the therapeutic regimen. Trospium, oxybutynin, fesoterodine, and darifenacin all have unique properties that may confer certain advantages in the elderly population. The hydrophilicity and quaternary amine structure of trospium may limit its ability to cross the blood-brain barrier and thus minimize impact on cognition in the elderly. In its oral form, oxybutynin may have the most significant effect on cognition; however, the transdermal preparations may be favorable in the elderly population due to the ability to avoid first-pass metabolism and its limited antimuscarinic adverse effects. Fesoterodine may be the most extensively studied OAB medication in the elderly population. Darifenacin has a strong affinity for the M3 receptor in the bladder, while having a weak affinity for the M1 receptor commonly found in the brain. It must be noted that all muscarinic receptor antagonists are associated with common adverse effects to some degree, and frequent re-evaluation of the elderly patient is necessary to confirm the proper benefit-to-risk profile.

Topics: Aged; Aging; Benzhydryl Compounds; Benzofurans; Blood-Brain Barrier; Cognition; Female; Humans; Mandelic Acids; Pyrrolidines; Quality of Life; Urinary Bladder, Overactive

Urinary incontinence (UI) in women adversely affects quality of life.. To conduct a systematic literature review of drugs for urgency UI in women.. MEDLINE, the Cochrane Central Register of Controlled Trials, SCIRUS, and Google Scholar were searched for articles published from 1966 to November 2011.. Randomized, controlled trials (RCTs) reported in English.. Rates of outcomes and risk of bias were extracted by using a standardized form to pool absolute risk differences and calculate the number of attributable events per 1000 patients treated, with 95% CIs.. 94 RCTs were eligible. Pooled analyses showed that among drugs for urgency UI, per 1000 treated women, continence was restored in 130 with fesoterodine (CI, 58 to 202), 85 with tolterodine (CI, 40 to 129), 114 with oxybutynin (CI, 64 to 163), 107 with solifenacin (CI, 58 to 156), and 114 with trospium (CI, 83 to 144). Rates of treatment discontinuation due to adverse effects were 31 per 1000 treated with fesoterodine (CI, 10 to 56), 63 with oxybutynin (CI, 12 to 127), 18 with trospium (CI, 4 to 33), and 13 with solifenacin (CI, 1 to 26). The studies' inconsistent definitions of reduction in UI and quality of life hampered synthesis of evidence.. Evidence for quality-of-life improvements and comparative effectiveness with drugs was limited, and evidence for the effects of race, baseline severity of UI, and comorbid conditions on treatment success was insufficient.. Overall, drugs for urgency UI showed similar small benefit. Therapeutic choices should consider the harms profile. Evidence for long-term adherence and safety of treatments is lacking.

Topics: Benzhydryl Compounds; Benzilates; Benzofurans; Comparative Effectiveness Research; Cresols; Female; Humans; Mandelic Acids; Muscarinic Antagonists; Nortropanes; Phenylpropanolamine; Pyrrolidines; Quality of Life; Quinuclidines; Randomized Controlled Trials as Topic; Solifenacin Succinate; Tetrahydroisoquinolines; Tolterodine Tartrate; Urinary Incontinence

Antimuscarinics (AMs) are the mainstay of pharmacological treatment of overactive bladder (OAB), a symptom complex defined by the presence of urinary urgency, usually associated with frequency and nocturia, with or without urgency urinary incontinence. The AMs used to treat OAB differ in their pharmacological profiles, which may affect their potential for causing adverse effects (AEs).. The present article aims to review the literature about pharmacokinetics (PK) of the different AMs used in the treatment of OAB. Furthermore, the AEs related to the use of these drugs and their incidence are presented. This systematic review is based on material searched and obtained via Medline, Pubmed and EMBASE up to March 2012 using the search terms "adverse events, pharmacokinetics, tolerability" in combination with "darifenacin, fesoterodine, imidafenacin, oxybutynin, propiverine, solifenacin, tolterodine, and trospium.". Antimuscarinics are the first-line pharmacological treatment for OAB. Despite the development of new molecules that improve their efficacy/safety profile, there are some drugs that are pharmacokinetically more appropriate to be prescribed in specific populations such as patients with neurological disease or the elderly. Moreover, research should be encouraged in evaluating antimuscarinics in conjunction with other drugs such as estrogens or beta-agonists. The identification of prognostic criteria for pharmacological therapy would be helpful.

Topics: Benzhydryl Compounds; Benzilates; Benzofurans; Chronic Disease; Cresols; Drug Combinations; Female; Humans; Imidazoles; Mandelic Acids; Muscarinic Antagonists; Nocturia; Phenylpropanolamine; Pyrrolidines; Quinuclidines; Solifenacin Succinate; Tetrahydroisoquinolines; Tolterodine Tartrate; Urinary Bladder, Overactive; Urinary Incontinence

Anticholinergic drugs are commonly prescribed for symptomatic treatment of overactive bladder (OAB). While recent meta-analyses have characterized the prevalence of dry mouth among patients utilizing OAB medications, prevalence of constipation has not been systematically reviewed.. To provide an effect measure for constipation associated with anticholinergic OAB drugs versus placebo.. A meta-analysis of trials with darifenacin, fesoterodine, oxybutynin, solifenacin, tolterodine, and trospium was conducted. All randomized, placebo-controlled studies of anticholinergic OAB drugs published in English language and identified in Medline and Cochrane databases were considered for inclusion in this meta-analysis. Those meeting predetermined design characteristics and having sufficient duration (≥2 weeks) were included. Constipation-related data from all included studies were abstracted.. One hundred two English-language, randomized, placebo-controlled trials were originally identified. Thirty-seven studies were ultimately included in the analysis, involving 19,434 total subjects (12,368 treatment+7,066 placebo patients). The odds ratios for constipation compared with placebo were as follows: overall [odds ratio (OR) 2.18, 95% confidence interval (CI)=1.82-2.60], tolterodine (OR 1.36, 95% CI=1.01-1.85), darifenacin (OR 1.93, 95% CI=1.40-2.66), fesoterodine (OR 2.07, 95% CI=1.28-3.35), oxybutynin (OR 2.34, 95% CI=1.31-4.16), trospium (OR 2.93, 95% CI=2.00-4.28), and solifenacin (OR 3.02, 95% CI=2.37-3.84).. Our results demonstrate that patients prescribed anticholinergic OAB drugs are significantly more likely to experience constipation. Differences in muscarinic receptor affinities among individual agents may possibly account for the modest variation in constipation rates observed; however, such a determination warrants additional research.

Topics: Aged; Aged, 80 and over; Benzhydryl Compounds; Benzofurans; Cholinergic Antagonists; Constipation; Female; Humans; Male; Middle Aged; Pyrrolidines; Randomized Controlled Trials as Topic; Risk Factors; Urinary Bladder, Overactive

To compare the heart rate increase side effect of different antimuscarinic drugs used in overactive bladder (OAB).. Overall 341 patients were consecutively randomized to take seven different antimuscarinic drugs between January 2014 and June 2016 at three institutions, and 250 patients who completed the follow-up visits were accepted into this study. Ninety-one patients who never came to visits were excluded. Drugs were classified into two groups as selective (darifenacin hydrobromide, solifenacin succinate and oxybutynin hydrochloride) and non-selective (fesoterodine fumarate, tolterodine tartrate, trospium chloride and propiverine hydrochloride) antimuscarinic drugs. The cardiac pulse rates and the blood pressures were recorded during the baseline, first visit (1 week) and second visit (1 month). Data were compared for drugs and two groups (selective versus non-selective) by using ANOVA test.. Baseline characteristics were similar among the patients using different antimuscarinic drugs. Statistically significant increase in heart rate occurred in patients treated with non-selective antimuscarinic drugs compared to those treated with selective drugs (p < 0.001), and this increase was especially evident in patients treated with trospium chloride, tolterodine tartrate, fesoterodine fumarate and propiverine hydrochloride (p < 0.001, 0.003, 0.011 and 0.37, respectively). There was no statistical difference for the other side effects.. Our results showed that heart rate significantly increased in OAB patients treated with non-selective antimuscarinic drugs. Trospium chloride, tolterodine tartrate, fesoterodine fumarate and propiverine hydrochloride seem to have the most unfavorable properties with regard to increased heart rate side effect when compared to the other antimuscarinic drugs (darifenacin hydrobromide, solifenacin succinate and oxybutynin hydrochloride).

Topics: Adult; Aged; Benzhydryl Compounds; Benzilates; Benzofurans; Blood Pressure; Female; Heart Rate; Humans; Male; Mandelic Acids; Middle Aged; Muscarinic Antagonists; Nortropanes; Prospective Studies; Pyrrolidines; Solifenacin Succinate; Tolterodine Tartrate; Urinary Bladder, Overactive

Topics: Acetanilides; Adrenergic beta-3 Receptor Agonists; Aged; Aged, 80 and over; Benzhydryl Compounds; Benzofurans; Denmark; Female; Humans; Male; Mandelic Acids; Middle Aged; Muscarinic Antagonists; Norway; Practice Patterns, Physicians'; Prospective Studies; Pyrrolidines; Registries; Solifenacin Succinate; Sweden; Thiazoles; Tolterodine Tartrate; Urinary Bladder, Overactive

To investigate the pattern of use of anticholinergic drugs for overactive bladder among women in Norway with regard to persistence, adherence and switch rates.. Observational study.. Data from the Norwegian Prescription Database on prescriptions for tolterodine, solifenacin, darifenacin and fesoterodine filled in Norwegian pharmacies from 1 January 2004 to 31 December 2010.. Data from the database were analysed at an individual level, and drug persistence, discontinuation rates and switch rates during a follow-up period of 365 days after the first prescription were calculated.. Overall 1-year persistence for new users was 38.0%. Within the same period, a total of 10.3% switched from the index drug to another drug in the same group, whereas 51.7% discontinued without switching. Users of solifenacin and tolterodine were somewhat more persistent than users of darifenacin and fesoterodine. Persistence was lowest (20.9%) in the age group 18-39 years, increased with age and was highest in the age groups 70-79 years and 80 years and above (43.5 and 43.3%, respectively). In total, 31.9% filled only one prescription of the drug and, of these, only one of four women switched to another drug. The proportion who were adherent during treatment was 60.4%.. The discontinuation rate for anticholinergic drugs for overactive bladder in women is high. The reasons why patients stop using them remain obscure but could be related both to a limited clinical effect and an unacceptable adverse effect burden.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Benzhydryl Compounds; Benzofurans; Cholinergic Antagonists; Cresols; Databases, Pharmaceutical; Drug Substitution; Female; Follow-Up Studies; Humans; Medication Adherence; Middle Aged; Norway; Phenylpropanolamine; Pyrrolidines; Quinuclidines; Solifenacin Succinate; Tetrahydroisoquinolines; Tolterodine Tartrate; Urinary Bladder, Overactive; Young Adult

To compare the brain anticholinergic activities of five urinary spasmolytic drugs (USDs).. In vitro study.. Laboratory.. None.. A validated 96-well anticholinergic radio receptor bioassay using small incubation volumes (240 μL per well) was applied in the current study. The different USDs (tolterodine, oxybutynin, solifenacin, darifenacin, and 5-hydroxy-methyl-tolterodine (5-HMT; the active metabolite of fesoterodine) were dissolved in plasma in their respective therapeutic concentration ranges. The plasma samples were added directly to the wells of 96 filter plates, wherein the incubation, filtration, and counting of undisplaced radioactivity was performed. Standard curves with atropine were used as reference for estimations of anticholinergic activity (AA).. 5-HMT and tolterodine displayed the highest AA of the tested USDs. In the middle of the therapeutic concentration range, the central anticholinergic potency of 5-HMT and tolterodine was more than 10 times as high as that of oxybutynin, solifenacin, and darifenacin. Darifenacin exhibited the lowest AA at therapeutic serum concentrations (< one-third the AA of oxybutynin and solifenacin).. Tolterodine and fesoterodine appear to have the highest pharmacodynamic potential to induce central anticholinergic side effects of the tested USDs. Darifenacin displayed the lowest AA, and combined with a low degree of brain distribution, it has probably the most favorable pharmacological profile of the USDs with respect to risk of cognitive impairment in older adults.

Topics: Benzhydryl Compounds; Benzofurans; Biological Assay; Brain; Cognition Disorders; Cresols; Humans; In Vitro Techniques; Mandelic Acids; Muscarinic Antagonists; Phenylpropanolamine; Pyrrolidines; Quinuclidines; Solifenacin Succinate; Tetrahydroisoquinolines; Tolterodine Tartrate

This study provides antimuscarinic agents for overactive bladder (OAB) display variable association with side effects mediated by the central nervous system (CNS), which may be of particular concern in the elderly. Adverse effects on CNS functioning are related to muscarinic receptor subtype selectivity and the ability of the agent to cross the blood-brain barrier, where P-gp plays a role in limiting permeability.. This study provides a parallel investigation of CNS penetration of antimuscarinic OAB agents in vivo and assessment of physical properties and permeability in cell monolayers in vitro. It adds further understanding of the roles of passive transcellular permeability and P-gp in determining CNS penetration of antimuscarinic OAB agents. It also enables a comparison of CNS side-effect profiles of OAB agents with preclinical CNS penetration data.. To assess and compare the mechanisms of central nervous system (CNS) penetration of antimuscarinic overactive bladder (OAB) agents.. Physical properties were computed or compiled from the literature. Rats were administered 5-hydroxymethyl tolterodine (HMT), darifenacin, oxybutynin, solifenacin, tolterodine or trospium subcutaneously. At 1 h postdose, plasma, brain and cerebrospinal fluid (CSF) concentrations were determined using LC-MS/MS assays. Brain and plasma protein binding were determined in vitro. Permeability in the presence and absence of the efflux transporter P-glycoprotein (P-gp) was assessed in RRCK and MDCK-MDR1 transwell assays.. Oxybutynin displayed extensive CNS penetration, with brain:plasma ratios (B:P), unbound brain:unbound plasma ratios (Kp,free) and CSF:free plasma ratios each >1. Tolterodine (B:P = 2.95, Kp,free = 0.23 and CSF:free plasma = 0.16) and solifenacin (B:P = 3.04, Kp,free = 0.28 and CSF:free plasma = 1.41) showed significant CNS penetration but with some restriction from CNS as indicated by Kp,free values significantly <1. 5-HMT, darifenacin and trospium displayed much lower B:P (0.03-0.16), Kp,free (0.01-0.04) and CSF:free plasma (0.004-0.06), consistent with poor CNS penetration. Permeability in RRCK cells was low for trospium (0.63 × 10(-6) cm s(-1) ), moderate for 5-HMT (11.7 × 10(-6) cm s(-1) ) and high for darifenacin, solifenacin, tolterodine and oxybutynin (21.5-38.2 × 10(-6) cm s(-1) ). In MDCK-MDR1 cells 5-HMT, darifenacin and trospium, were P-gp substrates, whereas oxybutynin, solifenacin and tolterodine were not P-gp substrates.. Brain penetration was low for antimuscarinics that are P-gp substrates (5-HMT, darifenacin and trospium), and significant for those that are not P-gp substrates (oxybutynin, solifenacin and tolterodine). CNS adverse events reported in randomized controlled clinical trials show general alignment with the preclinical data described in this study.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B; Benzhydryl Compounds; Benzofurans; Blood-Brain Barrier; Brain; Cell Line; Chromatography, High Pressure Liquid; Cresols; Humans; Male; Mandelic Acids; Muscarinic Antagonists; Phenylpropanolamine; Pyrrolidines; Quinuclidines; Randomized Controlled Trials as Topic; Rats; Rats, Sprague-Dawley; Receptors, Muscarinic; Solifenacin Succinate; Tandem Mass Spectrometry; Tetrahydroisoquinolines; Tolterodine Tartrate; Urinary Bladder, Overactive

Recent studies have described muscarinic receptors on the mucosa and the detrusor of the human urinary bladder. Muscarinic receptor antagonists are effective in the treatment of overactive bladder (OAB), but their site(s) of action and actual therapeutic target are unclear. Our aim was to compare, in human bladder mucosa and detrusor, the radioligand binding characteristics of newer, clinically effective agents: darifenacin, its hydroxylated metabolite UK-148,993, fesoterodine, solifenacin, tolterodine, and trospium. Specimens were collected from asymptomatic patients (50-72 years old) undergoing open bladder surgery. Radioligand binding studies with the muscarinic antagonist [3H]quinuclidinyl benzilate (QNB) were performed separately on detrusor and mucosal membranes. All antagonists displayed high affinity when competing for [3H]QNB binding in both detrusor and mucosa. Inhibition constants were also obtained for all antagonists against individual muscarinic receptor subtypes expressed in Chinese hamster ovary cells. Here, fesoterodine showed anomalous binding results, suggesting that some conversion to its metabolite had occurred. Global nonlinear regression analysis of bladder binding data with five antagonists demonstrated 82% low-affinity sites in mucosa and 78% low-affinity sites in detrusor, probably representing M(2)/M(4) receptors. There was an excellent correlation (r(2) = 0.99) of low-affinity global estimates between detrusor and mucosa, whereas the corresponding high-affinity estimates ( approximately 20% of sites) were dissimilar. In conclusion, commonly used and clinically effective muscarinic receptor antagonists bind to receptors located on the bladder mucosa and the detrusor, providing support for the hypothesis that muscarinic receptors in the mucosa may represent an important site of action for these agents in OAB.

Topics: Aged; Benzhydryl Compounds; Benzofurans; Cresols; Cystectomy; Female; Humans; Male; Middle Aged; Mucous Membrane; Muscarinic Antagonists; Phenylpropanolamine; Prostatectomy; Pyrrolidines; Quinuclidines; Quinuclidinyl Benzilate; Radioligand Assay; Receptors, Muscarinic; Solifenacin Succinate; Tetrahydroisoquinolines; Tolterodine Tartrate; Urinary Bladder; Urinary Bladder, Overactive