Definition and Symptoms of Overactive Bladder Syndrome

Overactive bladder syndrome (OBS) is characterised by:-

  • urgency, with or without urge incontinence,
  • increased Frequency of micturition (>8 voids/day) and
  • nocturia (passing urine during the night) in the absence of another identifiable metabolic or pathological process affecting the lower urinary tract.

Prevalence of Overactive Bladder Syndrome

Overactive bladder symptoms in individuals aged >/= 40 years was 16.6% (one person in 6). Frequency (85%) was the most commonly reported symptom, followed by urgency (54%) and urge incontinence (36%). The prevalence of overactive bladder symptoms increased with advancing age. Overall, 60% of respondents with symptoms had consulted a doctor but only 27% were currently receiving treatment.0101

Problems associated with overactive bladder syndrome

Overactive bladder syndrome is a highly prevalent condition that can be extremely distressingto women.

It may be associated with co-morbidities such as

  • urinary tract infections
  • and sleep disturbances.

Women with urge urinaryincontinence are more likely to be depressed than those with stress urinary incontinence.9901

Shopping, travel, physical exercise and personal relationships are often avoided because of fear of embarrassment.

Many incontinent women develop coping mechanisms such as

  • ‘toilet mapping’,
  • frequent voiding
  • and fluid restriction.

The elderly are also at increased risk of falls and fractures from rushing to the toilet.

As Overactive bladder syndrome has a negative impact on quality of life, there is a necessity for increased awareness, early diagnosisand appropriate treatment for this condition.

normal bladder Function

The bladder wall has smooth (detrusor) muscle fibresinterspersed with connective tissue. The internal urinary sphincterconsists of the bladder neck and the proximal urethra itself. The bladder outlet consists of the internal sphincter and itssurrounding striated musculature and is supported by the pelvic floor muscles.

 The control of micturition includes the sympathetic and parasympathetic systems under the control of higher centres, including the brain stem (pons) and cerebral cortex.

When the bladder is full and it is socially convenient, the urethral sphincter and the pelvic floor relax and the bladder neck descends. This occurs early in the micturition phase. Simultaneously the intrinsic striated muscle of the urethra relaxes leading to a fall in intraurethral pressure. A few seconds later, the inhibitory input from the cerebral cortex on the sacral micturition centre is reduced allowing a rapid parasympathetic discharge. The detrusor muscle contracts as a response to this parasympathetic discharge. The intravesical pressure rises and when it is greater than the intraurethral pressure, voiding begins.

Treatment of Overactive Bladder Syndrome


Treatment options are

  • patient education

    Lifestyle Measures:

    • Do not cut back on fluid intake too much as the urine will concentrate and irritate the bladder making some symptoms worse - 1.5 to 2 litres is optimum.
    • Have easy access to the toilet. Occupational health departments can assist with installation of hand rails or a raised toilet seat. You may find it helpful to have a commode in the bedroom.
    • Avoid caffeine. It is found in tea and cola as well as coffee.
    • Avoid too much alcohol as it is a diuretic - increasing urine output.
  • bladder training - If you get into the habit of emptying the bladder frequently, it will not accept normal volumes of urine. You may have to steadily increase the bladder capacity by lengthening intervals between voiding.
  • pelvic floor exercises
  • medication.

Anticholinergic drugs remain the only commonly prescribed drugs.

Other drugs used include:

  • imipramine,9701
  • estrogens,0301 Estrogen therapy may be of benefit for the irritative symptoms of urinary urgency, Frequency, and urge UI, although this effect may result from reversal of urogenital atrophy rather than a direct action on the lower urinary tract. Low-dose, vaginally administered estrogens have a role in the treatment of urogenital atrophy in postmenopausal women and appear to be as effective as systemic preparations.
  • botulinum toxin0401
  • and intravesical vanilloids, such as capsaicin and resiniferatoxin.

Anticholinergic (antimuscarinic) drugs


Medication for Overactive bladder syndrome is based on inhibiting the action of acetylcholine, which stimulates detrusor contraction via muscarinic receptors.

Five subtypes of muscarinic receptors within the parasympathetic system have been identified.

Inhibition of these receptors in the brain disrupts cognitive functions such as learning and memory. This may be a particular problem when these drugs are used in the elderly who may already have a degree of confusion.

Non-selective anticholinergics also interfere with muscarinic function in other organ systems such as the eye and salivary glands resulting in dry eyes and a dry mouth.

Most anticholinergics relieve symptoms and have similar efficacy.0302

Adverse effects vary depending on receptor selectivity, peak serum levels and the route of delivery.

Selectivity of anticholinergics.

Oxybutynin


The highest affinity of oxybutynin is to M1 and M3 receptors. It reduces incontinence episodes by 55–83%. Adverse effects such as dry mouth, constipation and blurred vision are dose dependent and lead to discontinuation in up to 25% of patients.0001 Extended release (ER) preparations have fewer adverse effects but are of similar efficacy to immediate release preparations.0402 The transdermal route is comparable to immediate release preparations with a better adverse effect profile. The main adverse effect is pruritus at the site, which has been reported in 14% of patients.0201

Tolterodine - Detrusitol


Though non-selective, tolterodine appears to target bladder more than the salivary gland receptors.

Tolterodine is the first antimuscarinic agent to specifically developed for the treatment of overactive bladder. The functional selectivity of tolterodine for the bladder translates into good efficacy and tolerability in patients, including the elderly, with overactive bladder. Tolterodine is as effective as oxybutynin in improving micturition diary variables but is associated with a significantly lower incidence and intensity of dry mouth. This favourable tolerability profile, together with sustained clinical efficacy during long term treatment, places tolterodine as valuable treatment for the symptoms of overactive bladder.0102 Adverse effects, particularly dry mouth, were more common with oxybutynin compared with tolterodine (78% versus 40%). Although tolterodine was deemed more efficacious, the clinical differences in outcome measures may not be that significant.  Tolterodine extended release demonstrated an improved efficacy for reducing urge incontinence episodes and a lower Frequency of dry mouth compared with the existing IR twice-daily formulation.0104

The OPERA (Overactive bladder: Performance of Extended Release Agents)0303 trial was a randomized, double-blind, active-control study performed at 71 US study centers from November 21, 2000, to October 18,2001. Reductions in weekly urge urinary incontinence episodes and total incontinence episodes were similar with extended-release formulations of oxybutynin and tolterodine. In the oxybutynin group, micturition Frequency was significantly lower, and the percentage of women reporting no urinary incontinence episodes was significantly higher compared with the tolterodine group. Dry mouth was more common with oxybutynin, but tolerability was otherwise comparable, including adverse events involving the central nervous system.

Solifenacin (Vesicare)


In the study by Cardozo and her colleagues, treatment with Vesicare (solifenacin) 5 mg and 10 mg once daily significantly improved all the major symptoms of overactive bladder including Frequency, urgency and incontinence. Solifenacin 10 mg also decreased the Frequency of nocturia. Solifenacin therapy was associated with a favorable tolerability profile and a low incidence of dry mouth, especially at the 5 mg starting dose.0403 Solifenacin 5 and 10 mg once daily improved urgency and other symptoms of OAB, and was associated with an acceptable level of anticholinergic side-effects. Solifenacin demonstrated significantly favourable efficacy to side-effect ratio in treating symptomatic overactive bladder.0404

The STAR trial0702 was a prospective, double blind study comparing 5 mg of solifenacin with 4 mg of tolterodine ER. Within 4 weeks solifenacin 5mg was statistically significantly better than tolterodine ER 4 mg in improving incontinence and reducing incontinence pad use. Differences in efficacy in favour of solifenacin 5 mg were maintained from 4 weeks for the duration of the study for patients choosing to remain on their starting dose.

Darifenacin


A randomised controlled trial of darifenacin versus oxybutynin IR reported that both active agents significantly reduced incontinence episodes and urgency episodes compared with placebo, with dry mouth being less frequent in the darifenacin group.32

Adverse effects of anticholinergics


The most common adverse effect is dry mouth, with a prevalence of about 30%. oxybutynin IR is associated with more severe and frequent dry mouth episodes compared with other preparations, while tolterodine ER seems to have the best tolerability profile.

Other adverse effects include:

  • constipation,
  • blurred vision,
  • nausea and vomiting,
  • difficulty in micturition,
  • palpitations,
  • skin reactions,
  • angioedema,
  • arrhythmias and tachycardia.

Effects on the central nervous system (CNS) such as disorientation, hallucination and convulsion can also occur.

Anticholinergics may reduce sweating, leading to hyperthermia and fainting in hot environments.

Cautions

Antimuscarinic drugs require caution in women with autonomic neuropathy, hiatus hernia and hepatic and renal impairment.

They can worsen hyperthyroidism, coronary artery disease, congestive heart failure and arrhythmias.

Contraindications

Myasthenia gravis, glaucoma, significant bladder outflow obstruction or urinary retention, severe ulcerative colitis and gastrointestinal obstruction are contraindications to anticholinergic use.

The role of immediate release and extended release preparations

In a Cochrane Review, Hay-Smith, et al.0502 concluded that there were no statistically significant differences for cure/improvement, leakage episodes or micturition frequency in 24 hours between ER and IR regimens although the numbers in the study were low.

Overall, ER preparations are associated withfewer adverse effects, particularly dry mouth, and may thus be preferable, although the discontinuation rates caused by adverse events were similar between the two formulations. In the current economic climate cost may be a factor in deciding between ER and IR preparations.

The use of anticholinergics in nocturia

Nocturia is a common and troublesome symptom which can be caused by medical conditions such as renal failure, hypercalcaemia and diabetes. Desmopressin, an analogue of antidiuretic hormone, is effective. It can, however, cause fluid overload and hyponatraemia.Imipramine, a tricyclic antidepressant with anticholinergic effects, is beneficial.

Anticholinergic use in the elderly

It is worrying that up to 32% of the elderly use two or more drugs with anticholinergic effects. Those that spare M1 receptors have a lower impact on central nervous system function. The extent to which anticholinergics impair CNS function is proportional to their ability to cross the blood–brain barrier. Oxybutynin is the one most likely to cross the blood–brain barrier. Despite this, it is still widely used to treat overactive bladder syndrome in older patients because of the low cost.

Agents such as tolterodine and darifenacin have low lipophilicity and are thought to be more suitable for older patients. Tolterodine IR and oxybutynin IR have a similar efficacy but the former has fewer adverse effects in patients over 50 years of age. Trospium is the least likely to impair CNS function based on neuropsychological and coordination tests.When considering use of an antimuscarinic agent for the treatment of overactive bladder syndrome in elderly patients, prescribers should routinely consider the agent's receptor selectivity and ability to cross the BBB. The medical history should include all current medications that may contribute to the anticholinergic burden and cognitive impairment.0502

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