Renal

Antimuscarinic drugs to treat overactive bladder

BMJ 27 March 2012
د. حسين محمد جمعه
اختصاصي الامراض الباطنة
البورد العربي
كلية طب الموصل
2012

This is one of a series of occasional articles on therapeutics for common or serious conditions, covering new drugs and old drugs with important
new indications or concerns. The series advisers are Robin Ferner, honorary professor of clinical pharmacology, University of Birmingham
and Birmingham City Hospital, and Philip Routledge, professor of clinical pharmacology, Cardiff University. To suggest a topic for this series,please email us at practice@bmj.com

A 45 year old woman presents to her general practitioner complaining of troublesome urinary symptoms increasingly affecting her quality of life. She is currently voiding more than 10 times a day and rising three times at night. In addition she
notices a sudden urgent desire to void and on two occasions has leaked urine before reaching the toilet. She gives no history of urinary tract infection or haematuria. Her periods remain regular.


In the past she has had two vaginal deliveries, has no significant medical history, and is not taking any medication. Pelvic examination is unremarkable and urine analysis normal.
Ultrasound examination shows no post-void residual urine.
Based on the history, clinical examination, and basic
investigations you make a symptomatic diagnosis of overactivebladder.
After discussing her bladder symptoms, you offer lifestyle advice including the moderation of fluids and reduction of caffeine intake. In addition you refer her for bladder retraining and start treatment with antimuscarinic drugs.

What is overactive bladder?

Overactive bladder is the term used to describe the symptom complex of urinary urgency, usually accompanied by frequency and nocturia, with or without urge urinary incontinence, in the absence of urinary tract infection or other obvious pathology.
Epidemiological studies in North America have reported aprevalence of overactive bladder in women of 16.9%, and the prevalence increases with age—from 4.8% in women under years to 30.9% in those aged over 65 years.

Prevalence data from Europe are similar, with frequency the most commonly reported symptom (85%), and 54% reporting urgency and 36% urge incontinence.
The symptoms of overactive bladder are most likely due to
involuntary contractions of the detrusor muscle during the filling phase of the micturition cycle; abnormalities in afferent sensation may also play a role. Detrusor overactivity is mediated by acetylcholine induced stimulation of muscarinic receptors in the bladder, under the control of the parasympathetic nervous system.

Although the cause of detrusor overactivity is unknown, there is evidence to support both neurogenic and myogenic causes. Antimuscarinic drugs used to treat overactive bladder (see box 1) act by blocking muscarinic receptors at the neuromuscular junction and thus prevent acetylcholine mediated bladder contraction.
Consequently, overactive bladder is a symptom based diagnosis, and detrusor overactivity can be diagnosed only after urodynamic investigation.

The two terms are not synonymous:

64% of women with overactive bladder have urodynamically proved detrusor overactivity, while 83% of women with detrusor overactivity have symptoms suggestive of overactive bladder.

How well do antimuscarinic drugs work?

Several antimuscarinic drugs are licensed and available in the UK. These have all been recently recommended by the International Consultation on Incontinence to treat overactive bladder syndrome (box 1) and all have level I evidence8 and a
grade A recommendation (see box 2 for definitions).
The clinical effectiveness of antimuscarinic agents was first questioned in a systematic review of 32 randomised controlled trials including 6800 participants.


Cure or improvement after treatment were all significantly in favour of antimuscarinic drugs
(relative risk 1.41 (95% confidence interval 1.29 to 1.54), P<0.0001), although the differences from placebo were small and of questionable clinical significance. A subsequent Cochrane review of 61 randomised controlled trials including 11 956
patients was supportive of these findings, with a significantly greater cure or improvement rate in the antimuscarinic group compared with placebo (relative risk 1.39 (1.28 to 1.51)).

Importantly, there was also a significant improvement in quality of life, implying clinical as well as statistical significance. The overall number needed to treat (NNT) was seven.
The most recent meta-analysis of 83 randomised controlled trials, including 30 699 patients and six different drugs (fesoterodine, oxybutynin, propiverine, solifenacin, tolterodine, and trospium), also supports the efficacy of antimuscarinic drugs in the treatment of overactive bladder.

Overall there was asignificantly higher return to continence with active treatment

compared with placebo—the pooled relative risk across different studies and different drugs was 1.3–3.5 (P<0.01). Antimuscarinic therapy was also shown to be significantly more effective in reducing the daily number of incontinence episodes (pooled differences in mean change 0.4–1.1), micturitions (0.5–1.3),
and urgency episodes (0.64–1.56).

While these data confirm the efficacy of antimuscarinic drugs, the evidence for comparing different drugs is less robust. Some
randomised controlled data suggest that extended release oxybutynin and tolterodine may have superior efficacy to the immediate release preparations In addition, solifenacin is as
effective as extended release tolterodine, and fesoterodine is superior to it. However, the incidence of adverse effects increases with increasing dose.

How safe are antimuscarinic drugs?

Antimuscarinic drugs are associated with the common
anticholinergic adverse effects of dry mouth, constipation, blurred vision, and somnolence. Although these are not life threatening, they may be associated with poor compliance or persistence with treatment. A recent systematic review of 149 papers found discontinuation rates of 43–83% in the first 30
days of treatment, and more than half of patients never refill the initial prescription.

More serious adverse effects include cognitive and cardiac effects, specifically prolongation of the
QT interval, though all the safety data suggest that routine electrocardiography is not required. A recent meta-analysis of prospective randomised trials investigating the effect of antimuscarinic drugs on the central nervous system found the incidence of adverse effects was poorly reported overall, and
77% of studies neither measured nor reported central nervous system outcomes.


In those that did, dizziness was the most common adverse effect (oxybutynin 3%, propiverine 3.2%,
tolterodine 1.8%, and placebo 1.6%), and confusion was found in <1% of cases. Small randomised studies have also shown no effect on cognition in elderly patients with solifenacin, darifenacin, and trospium chloride.

What are the precautions?

• Hepatic or renal impairment—As antimuscarinic drugs undergo both hepatic metabolism and renal excretion, the dose may need to be decreased in such patients
• Elderly patients—A lower dose should be considered because of the risk of postural hypotension and cognitive impairment
• Voiding dysfunction—In men there may be some concerns regarding the exacerbation of voiding difficulties, but this is only rarely reported in women, so post-void residual urine volumes need not be monitored routinely.

• Contraindications—Do not prescribe these drugs in patients

with angle closure glaucoma, myasthenia gravis, severe ulcerative colitis, toxic megacolon, or intestinal obstruction because of their anticholinergic effects
• Pregnancy—There is limited evidence for all
antimuscarinic agents. Oxybutynin is generally felt to be safe if essential, but avoid darifenacin, fesoterodine, propiverine, tolterodine, solifenacin, and trospium.
• Drug interactions—Box 3 summarises possible interactions

Antimuscarinics may interact with drugs that compete for hepatic metabolism via cytochrome P450 and renal excretion, especially in patients with mild hepatic and renal impairment and in elderly patients, who may be receiving polypharmac .Concomitant use of other drugs that have antimuscarinic effects may increase the risk of adverse effects.

How cost effective are antimuscarinic drugs?

In a recent assessment of cost effectiveness of all antimuscarinic therapies within the UK National Health Service, solifenacin was associated with the highest quality adjusted life year (QALY) gain in terms of urinary urgency, frequency, and incontinence. Solifenacin was found to be more cost effective than fesoterodine, tolterodine, and propiverine, though not oxybutynin. A cost utility analysis comparing solifenacin and
tolterodine found that solifenacin was less expensive and more effective than tolterodine.

How are antimuscarinic drugs taken and monitored

All antimuscarinic drugs can be taken orally, and oxybutynin is also available as a transdermal preparation (gel and patch).Counsel patients on the adverse effects associated with antimuscarinic treatment (see box of tips for patients) and always review concomitant medication before starting treatment. Some patients may have sufficient improvement in their symptoms with conservative measures and be reluctant to take drugs. In general start at a low dose and titrate against efficacy and adverse effects. It is not necessary to monitor liver and renal function in patients with hepatic and renal impairment.


How do antimuscarinic drugs compare with conservative therapy and other drugs?
Antimuscarinic drugs may be a useful addition to non-drug therapy in the management of overactive bladder. In a Cochrane review of 13 trials including 1770 patients, symptomatic improvement was more common among those taking antimuscarinic drugs compared with bladder retraining (relative
risk 0.73 (0.59 to 0.90)), and combination treatment was also associated with more improvement than bladder training alone (0.55 (0.32 to 0.93)).

Similarly there was a trend towards greater

improvement with a combination of antimuscarinic drugs with bladder retraining compared with antimuscarinics alone (relative risk 0.81 (0.61 to 1.06)), although this was not significant.
Many other drugs are used to treat overactive bladder, but evidence for their effectiveness is variable (see table⇓). Of these, only desmopressin, a synthetic vasopressin analogue used primarily to treat nocturia and nocturnal enuresis, has level evidence to support its use, although there are no comparative studies with antimuscarinic drugs.

Although the use of calcium blocking agents and potassium channel opening drugs showed initial promise, neither have proved to be useful in the clinical setting. The search for novel agents to treat overactive bladder continues and has
recently focused on the use of neurokinin antagonists, vitamin D analogues, and β adrenoceptor agonists.

Box 1: Antimuscarinic drugs used to treat overactive bladder

• Darifenacin
• Fesoterodine
• Oxybutynin
• Propiverine
• Solifenacin
• Tolterodine
• Trospium
Based on level I evidence for all these drugs, the International Consultation on Incontinence has made grade A recommendations for their use in overactive bladder syndrome. (See box 2 for definitions of levels of evidence and recommendations)


Box 2: Categories of clinical evidence and recommendations
Levels of evidence
I—Systematic review of all relevant randomised controlled trials
IIA—One randomised controlled trial, with low probability of bias and high probability of causal relationship
IIB—One randomised controlled trial
IIIA—Well designed controlled trials (no randomisation)
IIIB—Cohort or case-control studies
IIIC—Multiple time series or dramatic results in uncontrolled experiments
IV—Expert opinion (traditional use)

Grades of recommendations

A—A systematic review of randomised controlled trials or a body of evidence consisting principally of studies rated as level I directly
applicable to the target population and showing overall consistency of results
B—A body of evidence including studies rated as level IIA directly applicable to the target population and showing overall consistency
of results, or extrapolated evidence from studies rated as level I
C—A body of evidence including studies rated as IIB directly applicable to the target population and showing overall consistency of
results, or extrapolated evidence from studies rated as level II
D—Evidence level III or IV, or extrapolated evidence from studies rated as II

Box 3: Antimuscarinic drug interactions

Antiarrythmics—Darifenacin and tolterodine may increase risk of arrythmias when given with antiarrythmics
Antifungals—Solifenacin and fesoterodine levels increased by itraconazole and ketoconazole. Avoid use of darifenacin and tolterodine
with itraconazole and ketoconazole


Antipsychotics—Reduce the effect of haloperidol and phenothiazines
Antiretrovirals—Fesoterodine and solifenacin levels increased with antiretrovirals. Avoid darifenacin with antiretroviral agents
Domperidone—Antimuscarinics may antagonise the effects on gastric motility
Levodopa—Antimuscarinics may reduce absorption
Metoclopramide—Antimuscarinics may antagonise the effects on gastric motility
Phenothiazines—Antimuscarinics may increase risk of antimuscarinic side effects
Tricyclic antidepressants—May increase risk of antimuscarinic effects

Tips for patients

Overactive bladder is a common and distressing condition.
Bladder retraining, lifestyle advice, and pelvic floor exercises should help to improve the symptoms of overactive bladder
Think about fluid intake and try to avoid caffeinated drinks, artificially sweetened carbonated drinks, and alcohol. Try not to drink too
much (generally no more than 1.5 litres a day), and limit your fluid intake before bed.

Your local continence advisory service will be able to provide you with tips for coping strategies and advice about containment products such as continence pads
Antimuscarinic drugs may be useful in addition to conservative measures when trying to control your bladder symptoms; these may be required long term as overactive bladder is a chronic condition
Antimuscarinic drugs may be associated with a dry mouth. Try sucking a sweet or chewing gum to increase salivation .Constipation may also be associated with taking antimuscarinic drugs: it may be necessary to alter your diet or consider laxatives