Glycopyrrolate as a substitute for atropine in neostigmine reversal of muscle relaxant drugs.
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Anesthesia↗
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Oxybutynin and the overactive bladder.
Oxybutynin is a tertiary amine, which undergoes an extensive first-pass metabolism. It has an active metabolite, N-desethyl oxybutynin, and the effect of oral oxybutynin is to a large extent exerted by this metabolite. Oxybutynin has both an antimuscarinic and a direct muscle relaxant effect, and, in addition, local anesthetic actions. Most probably, oral oxybutynin exerts its effects on the overactive bladder (OAB) by an antimuscarinic action. Several studies have shown that oral oxybutynin is effective in controlling OAB. Admininistred intravesically, it can increase bladder capacity and produce clinical improvement both in patients with hypereflexia and in other types of OAB with few side effects. Adverse effects related to the antimuscarinic activity occur frequently and can necessitate treatment discontinuation in up to 25% of patients, depending on the dosage. A controlled-release preparation has recently been introduced. Oxybutynin has a well-documented efficacy in the treatment of detrusor overactivity, and is a drug of first choice in patients with this disorder.
Humans↗
[Intravesical therapy for overactive bladder].
INTRODUCTION: Despite recent advances in the field of anticholinergic drugs, lack of efficiency and side effects are still the main reasons for discontinuation of treatment. The introduction of botulinum A toxin was a milestone in the treatment of detrusor overactivity. The treatment, however, is invasive, the duration of the treatment effects is limited, and long-term results are not yet available. The following addresses therapeutic alternatives to local treatment of overactive bladder. MATERIALS AND METHODS: A total of 52 patients received intravesical oxybutynin. In 16 patients, capsaicin was instilled in the bladder and 28 patients were treated with EMDA. RESULTS: Intravesical oxybutynin was successful in 86%; the success rate of capsaicin instillation was 47%. EMDA was successful in 78%. Two transient ischemic attacks following EMDA were observed as significant side effects. CONCLUSION: Besides botulinum A toxin, several effective treatment options are available for patients with detrusor overactivity refractory to oral anticholinergic treatment. Therefore, in each individual patient, possible risks and complications of the different treatment options should be considered thoroughly to find the optimal method in each case.
Administration, Intravesical↗
[Intravesical treatment of overactive bladder syndrome].
Overactive bladder and urgency incontinence are common conditions generally treated with oral anticholinergic medication. Despite the development of new antimuscarinic substances, many patients are refractory to or cannot tolerate the oral therapy due to severe side effects. Intravesical instillation therapy can provide an alternative method to manage detrusor overactivity. Intravesical instillation of anticholinergics such as oxybutynin and trospium chloride can achieve cholinergic blockade without producing systemic side effects. Botulinum toxin type A injections into the detrusor have been shown to increase bladder capacity and to decrease detrusor overactivity for 6 or more months. Intravesical local anesthetics such as lidocaine and bupivacaine block the conduction of unmyelinated C fibers which results in an increase of functional bladder capacity. Intravesical capsaicin and resiniferatoxin also affect the afferent C fiber innervation of the bladder, leading to a decrease in detrusor overactivity and also an increased bladder capacity. The use of intravesical anticholinergics and of local anesthetic medications, both known for their short-term efficacy, is limited due to the necessity of daily intermittent catheterization. In conclusion, intravesical therapies can provide an alternative treatment for the management of overactive bladder.
Administration, Intravesical↗
A comparison of extended-release oxybutynin and tolterodine for treatment of overactive bladder in women.
Women with urge or mixed incontinence were randomized to a daily dose of 10 mg extended-release oxybutynin chloride (qd) or tolterodine tartrate 4 mg (2 mg bid) for 12 weeks. Subjects completed 7-day voiding diaries at baseline and at 12 weeks. A total of 315 women were treated. At the end of the study, extended-release oxybutynin chloride was more effective than twice-daily tolterodine tartrate as measured by urge and total incontinence episodes (p=0.038, p=0.030, respectively). Overall, the reduction in micturition frequency between groups was not significantly different. In women aged 64 years and younger (comprising 63% of the population) extended-release oxybutynin was more effective than tolterodine for urge (p=0.005) and total incontinence (p=0.005), and for micturition frequency (0.024). Adverse events were infrequent, mostly mild, and similar between treatment groups. We concluded that daily extended-release oxybutynin chloride (10 mg) was more effective than tolterodine tartrate (2 mg bid) in treating urge and total incontinence. The incidences of dry mouth, CNS events, and other adverse events were similar for both drugs.
Aged↗
The puzzle of overactive bladder: controversies, inconsistencies, and insights.
Overactive bladder (OAB) affects millions of individuals and may severely impair the quality of life of those affected. The contribution of human behavior to manifestations of this symptom complex remains poorly understood. Continued evolution of our understanding of the pathophysiology of OAB has identified contributory mechanisms, which in turn may open new therapeutic avenues. Recent improvements in drug delivery systems represent advances in the management of OAB. However, more complete symptom control with greater tolerability is desirable; this awaits the development of agents specific for newly emerging and as yet unidentified pathophysiologic pathways. Importantly, as understanding of outcomes assessment in OAB matures, refined assessments of disease severity, response to intervention, and patient preference should be possible.
Animals↗
Effectiveness and tolerability of extended-release oxybutynin vs extended-release tolterodine in women with or without prior anticholinergic treatment for overactive bladder.
The efficacy and the tolerability of extended-release oxybutynin chloride, 10 mg daily, and extended-release tolterodine tartrate, 4 mg daily, in women with or without prior anticholinergic treatment for overactive bladder (OAB) were compared in a post-hoc analysis of data from the Overactive Bladder: Performance of Extended Release Agents (OPERA) trial. The patient population and study methods have been described previously (Diokno et al., for the OPERA Study Group, Mayo Clin Proc 78:687-695, 2003). Among the group with anticholinergic experience, extended-release oxybutynin was significantly more effective than extended-release tolterodine in reducing micturition frequency at last observation (p=0.052). Complete freedom from urge incontinence was reported by significantly more patients taking oxybutynin than tolterodine at last observation (23.6 vs 15.1%, p=0.038). In addition, among patients completing a full 12 weeks of oxybutynin treatment, significantly greater reductions were observed compared with those taking tolterodine on the primary efficacy variable, number of urge incontinence episodes (p=0.049), and the combined total of urge and non-urge episodes (p=0.012), although the differences between treatment groups were not significant at last observation. In the anticholinergic-naïve group, efficacy and tolerability outcomes were similar across treatments, except that oxybutynin was associated with a significantly lower frequency of micturition at last observation (p=0.035). No efficacy differences favoring tolterodine were observed, and tolerability of the treatments was comparable. Dry mouth (mostly mild to moderate in severity) was reported significantly more often among participants taking extended-release oxybutynin than extended-release tolterodine (32.2 vs 19.2%, p=0.004), but only among those with previous anticholinergic experience. Discontinuation rates were comparably low across groups. The results demonstrate the appropriateness of initiating treatment for OAB with extended-release oxybutynin, particularly in women presenting with incontinence.
Adult↗
Stoller afferent nerve stimulation in woman with therapy resistant over active bladder; a 1-year follow up.
AIM: In this prospective observational study, we investigated the efficacy of Stoller afferent nerve stimulation (SANS) in subjects with overactive bladder who failed anticholinergic treatment. METHODS: Thirty-five subjects with overactive bladder who failed therapy with oxybutynin participated in this study. Treatment (n = 35) was given once a week for 30 minutes for overall 10 weeks. In treatment, SANS device (Urosurge) was used. Subjects were assessed with 3-day voiding diary, SEAPI quality of life questionnaires and cystometry before therapy after completion of therapy and at one-year follow-up. RESULTS: In 54% (n = 19) of subjects complete recovery was obtained after treatment. Urgency and SEAPI were reduced significantly whereas urine volume increased significantly (p < 0.01). Complete recovery was maintained in eight of the 19 subjects at one year. CONCLUSIONS: SANS treatment has a short-term positive effect in patients with resistant overactive bladder. However, it was also established that efficacy was maintained at 1 year in only 23% of subjects.
Adult↗
Rehabilitation vs drug therapy for urge urinary incontinence: short-term outcome.
The objective of this study was to compare the short-term effectiveness of rehabilitation treatment with a standard drug treatment for urge urinary incontinence (UUI). The study design includes parallel clinical trial in an outpatient urogynecologic clinic setting. The subjects were 44 women who suffered from UUI and who were systematically assigned to a rehabilitation group (REH) (N=24) or a medication group (MED) (N=20). The intervention for REH was consisted of five visits during a 3-month period of pelvic floor muscle training and behavioral training, whereas for MED was extended release oxybutynin at 5 mg/day, for 3 months. The urinary symptoms considered were frequency of voiding per day and night (freq/day and freq/night), number of incontinent episodes per week based on a bladder diary, and data based on the Incontinence Quality of Life Instrument (I-QoL). In the within-group comparison, both groups had improved significantly over time with respect to urinary symptoms and I-QoL (p<0.01). In addition, there was a significant group-time interaction effect on freq/day. While REH improved during the 3-month follow-up period, the MED group deteriorated to mean baseline value (p<0.01). A significant negative association was found between the urinary symptoms and the I-QoL at the end of follow-up (r (p)=-0.35 to -0.62, p<0.05). Three months after the intervention, both groups maintained the achievements of the intervention period. In addition, the REH group demonstrated additional improvement in mean freq/day while the condition of MED patients deteriorated to baseline values.
Aged↗
Clinical efficacy and safety of tolterodine compared to oxybutynin and placebo in patients with overactive bladder.
This study compared the clinical efficacy (determined from micturition diaries) and safety of 12 weeks' treatment with either tolterodine 2 mg twice daily, oxybutynin 5 mg three times daily or placebo in patients with an overactive bladder. A total of 277 patients were randomized and treated at 25 centers. Both tolterodine and oxybutynin significantly increased volume voided/micturition compared to placebo. Both treatment groups evoked greater decreases in micturitions per 24 hours and incontinence episodes per 24 hours compared to placebo; however, only tolterodine was significantly better than placebo in reducing micturition frequency. Tolterodine and oxybutynin were equivalent in their effectiveness. Tolterodine was significantly better tolerated than oxybutynin when adverse events (particularly frequency and intensity of dry mouth), dose reduction and patient withdrawals were considered. Oxybutynin is an effective drug whose frequent adverse effects limit its clinical usefulness. Tolterodine has equivalent efficacy to oxybutynin, but with less severe adverse effects. This will allow patients to receive more effective treatment for their condition, with better compliance.
Adult↗
M(3) receptor antagonism by the novel antimuscarinic agent solifenacin in the urinary bladder and salivary gland.
The antimuscarinic profile of the experimental drug solifenacin/YM905 [(+)-(1 S,3' R)-quinuclidin-3'-yl 1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate] for the treatment of overactive bladder was compared with the commonly prescribed agent oxybutynin. In radioligand binding assays, p K(i) values of solifenacin for M(1), M(2), and M(3) receptors were 7.6, 6.9, and 8.0, respectively. These values for oxybutynin were 8.6 (M(1)), 7.7 (M(2)), and 8.9 (M(3)). Solifenacin and oxybutynin antagonized the contractile effect of carbachol (CCh) on isolated guinea pig urinary bladder smooth muscle (detrusor), displaying the negative logarithm of antagonist apparent affinity constant (p K(b) value) of 7.1 for solifenacin and 7.4 for oxybutynin. To study the tissue selectivity between bladders and salivary glands, guinea pig detrusor and mouse submandibular gland cells were stimulated with CCh and monitored for intracellular Ca2+, as determined by Fura 2 fluorescence. Ca2+ mobilization of detrusor cells was inhibited equipotently by solifenacin (p K(i)=8.4) and oxybutynin (p K(i)=8.6), whereas that of the gland cells was antagonized less potently by solifenacin (p K(b)=7.4) than by oxybutynin (p K(b)=8.8), although the M(3) subtype mediated both cell responses. In anesthetized rats, solifenacin (63-2100 nmol kg(-1) or 0.03-1 mg kg(-1)) dose-dependently inhibited CCh-stimulated increases in urinary bladder pressure, while its inhibitory effects on salivation and bradycardia were apparent only at a dose of 2100 nmol kg(-1). In contrast, oxybutynin within a dose range of 77-770 nmol kg(-1) (0.03-0.3 mg kg(-1)) inhibited responses of the bladder and salivary gland slightly more potently than that of the heart. In addition, inhibitory effects of darifenacin indicated a major role of M(3) receptors in the bladder and salivary gland. Therefore, M(3) receptor antagonism by solifenacin could be bladder-selective. This selectivity remains to be elucidated and may provide new approaches to the pharmacotherapy of overactive bladder.
Animals↗
Treatment of the overactive bladder syndrome with muscarinic receptor antagonists: a matter of metabolites?
Antagonists of muscarinic acetylcholine receptors, such as darifenacin, oxybutynin, propiverine, solifenacin, tolterodine, and trospium, are the mainstay of the treatment of the overactive bladder syndrome. Fesoterodine is a newer drug awaiting regulatory approval. We briefly review the pharmacological activity of their metabolites and discuss how active metabolites may contribute to their efficacy and tolerability in vivo. Except for trospium, and perhaps solifenacin, all of the above drugs form active metabolites, and their presence and activity need to be taken into consideration when elucidating relationships between pharmacokinetics and pharmacodynamics of these drugs. Moreover, the ratios between parent compounds and metabolites may differ depending on genotype of the metabolizing enzymes, concomitant medication, and/or drug formulation. Differential generation of active metabolites of darifenacin or tolterodine are unlikely to influence the overall clinical profile of these drugs in a major way because the active metabolites exhibit a similar pharmacological profile as the parent compound. In contrast, metabolites of oxybutynin and propiverine may behave quantitatively or even qualitatively differently from their parent compounds and this may have an impact on the overall clinical profile of these drugs. We conclude that more comprehensive studies of drug metabolites are required for an improved understanding of their clinical effects.
Benzhydryl Compounds↗
Effect of food on the bioavailability of oxybutynin from a controlled release tablet.
OBJECTIVE: The effect of food on the bioavailability of oxybutynin was assessed in a randomised cross-over study in 23 healthy volunteers. A single oral 10 mg dose of a controlled release oxybutynin tablet was administered after a high fat breakfast and to fasting subjects. The AUC, Cmax, tmax, t1/2 and MRT of oxybutynin and its active metabolite N-desethyloxybutynin were determined. RESULTS: Breakfast did not change the AUC of oxybutynin but increased the AUC of N-desethyloxybutynin by about 20%. The Cmax of oxybutynin and N-desethyloxybutynin were two-fold higher when the drug was administered after breakfast compared to the fasting state. CONCLUSION: Breakfast significantly reduced the MRT of oxybutynin and N-desethyloxybutynin.
Adult↗
Itraconazole moderately increases serum concentrations of oxybutynin but does not affect those of the active metabolite.
OBJECTIVE: Oxybutynin has low oral bioavailability due to an extensive presystemic metabolism. It has been suggested that the biotransformation of oxybutynin is dependent on CYP3A. Because itraconazole, a widely used mycotic, is a potent inhibitor of CYP3A4, we wanted to study a possible interaction between oxybutynin and itraconazole. METHODS: In this double-blind, randomized, two-phase cross-over study, ten healthy volunteers received either 200 mg itraconazole or placebo for 4 days. On day 4, each volunteer ingested a single dose of 5 mg oxybutynin. Serum concentrations of oxybutynin, its active metabolite N-desethyloxybutynin, and itraconazole were monitored over 24 h. RESULTS: Itraconazole significantly increased both the area under the serum drug concentration-time curve (AUC0-t) and the peak concentration of oxybutynin twofold. The AUC0-t and the peak concentration of N-desethyloxybutynin were not significantly affected by itraconazole. Itraconazole did not change the peak time or the elimination half-life of either oxybutynin or N-desethyloxybutynin. The occurrence of adverse events after oxybutynin administration was not increased by itraconazole. CONCLUSIONS: Itraconazole moderately increases serum concentrations of oxybutynin, probably by inhibiting the CYP3A-mediated metabolism. However, the concentrations of N-desethyloxybutynin were practically unchanged. Since about 90% of the antimuscarinic activity of oxybutynin is attributable to N-desethyloxybutynin, any interaction of oxybutynin with CYP3A4 inhibiting drugs has only minor clinical significance.
Adolescent↗
The pharmacokinetics of oxybutynin is unaffected by gender and contraceptive steroids.
OBJECTIVE AND METHODS: The effect of gender and concomitant use of contraceptive steroids on the absorption and metabolism of oxybutynin was investigated in 49 healthy volunteers, 24 females and 25 males. Serum concentrations of oxybutynin and its active metabolite, N-desethyloxybutynin, were measured for up to 48 h after ingestion of a single dose of 10 mg oxybutynin. RESULTS: Intake of oral contraceptive steroids had no significant effect on the pharmacokinetic parameters of oxybutynin or its metabolite. Both in males and females, the mean area under the curve (AUC0-t) of N-desethyloxybutynin was about 13 times higher and the peak concentration (Cmax) 15 to 19 times higher than the AUC0-t and Cmax of the parent oxybutynin, with no significant differences between males and females. CONCLUSIONS: The pharmacokinetics of orally administered oxybutynin shows a considerable interindividual variability, but is unaffected by gender and use of contraceptive steroids.
Administration, Oral↗
Oxybutynin disrupts learning and memory in the rat passive avoidance response.
BACKGROUND: oxybutynin, a drug for pollakisuria and urinary incontinence, has a potent antimuscarinic activity. This study was aimed to determine whether this drug disrupts learning and memory in rats, because antimuscarinic activity in the central nervous system is considered to cause amnesia in humans. METHODS: male Wistar rats were given oxybutynin or scopolamine as a reference drug, and subjected to the acquisition trial of step-through passive avoidance response (PAR). Twenty-four hours later the retention test for each rat was performed and the latency time in the PAR was measured. RESULTS: oral administration of oxybutynin at 30 mg/kg or higher and intraperitonial injection of scoplamine at 0.5 mg/kg caused a significant decrease in the latency time in the retention test. CONCLUSIONS: oxubutynin caused a decrease in the retention time of the PAR in a manner similar to scopolamine, indicating that oxybutynin may cause disruption of learning and memory.
Administration, Oral↗
Controlled, double-blind, multicentre clinical trial to investigate long-term tolerability and efficacy of trospium chloride in patients with detrusor instability.
Our objectives were to ascertain the tolerability and efficacy of trospium chloride in doses of 20 mg twice daily for long-term therapy (52 weeks) in patients with urge syndrome. The trial comprised a total of 358 patients with urge syndrome or urge incontinence. After randomisation in the ratio of 3:1, participants were treated continuously for 52 weeks with either trospium chloride (20 mg twice daily) or oxybutynin (5 mg twice daily). At intervals of 4-8 weeks, patients were physically examined with measurements of blood pressure and pulse rate, were questioned about any adverse events, checked for compliance and underwent relevant laboratory tests. As an additional safety measure, an ECG was made at 26 and 52 weeks. Urodynamic measurements were performed at the beginning, and at 26 and 52 weeks to determine the maximal cystometric bladder capacity. Among others things, the frequencies of micturition, incontinence and number of urgency events were recorded in patient diary protocols in weeks 0, 2, 26 and 52. The evaluation of vital parameters, laboratory results and ECGs did not show any relevant changes attributable to the action of the anticholinergics. Analysis of the micturition diary clearly indicated a reduction of the micturition frequency, incontinence frequency, and a reduction of the number of urgencies in both treatment groups. Mean maximum cystometric bladder capacity increased during treatment with trospium chloride by 92 ml after 26 weeks and 115 ml after 52 weeks (P=0.001). Further comparison with oxybutynin did not reveal any statistically significant differences in urodynamic variables between the drugs. Adverse events occurred in 64.8% of the patients treated with trospium chloride and 76.7% of those treated with oxybutynin. The main symptom encountered in both treatment group was dryness of the mouth. For patients on trospium chloride, the estimated risk of an unexpected adverse event was 0.027 per patient per week for all adverse events and 0.009 for dryness of the mouth, resulting in a considerably lower risk during treatment given with trospium chloride than with oxybutynin (0.045 and 0.021, respectively). An overall assessment for each of the drugs reveals a comparable efficacy level and a better benefit-risk ratio for trospium chloride than for oxybutynin due to better tolerability.
Adult↗
Health-related quality of life of Japanese patients with overactive bladder treated with extended-release tolterodine or immediate-release oxybutynin: a randomized, placebo-controlled trial.
Overactive bladder (OAB) has a significant impact on a patient's health-related quality of life (HRQoL). This study assessed the HRQoL of Japanese OAB patients following 12 weeks' treatment with tolterodine extended release (ER) or oxybutynin. A total of 293 patients with symptoms of OAB were randomized for treatment with tolterodine ER 4 mg once daily (n=114), oxybutynin 3 mg three times daily (n=122) or a placebo (n=57). Treatment efficacy and safety assessments were made over the 12-week period. HRQoL was assessed using the King's Health Questionnaire (KHQ). Patients receiving tolterodine ER or oxybutynin showed a significant (P<0.05) improvement in the Incontinence Impact, Role Limitations and most other KHQ domains compared with the placebo. These changes in HRQoL corresponded with significant (P<0.05) improvements in micturition diary variables for patients receiving tolterodine ER and oxybutynin compared with placebo. Our findings demonstrate that Japanese OAB patients receiving tolterodine ER or oxybutynin experienced overall improvement in their quality of life.
Adult↗