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5.6: Drug Therapy

  • Page ID
    15596
  • There are a number of antimusarinic agents in contemporary use. Oxybutynin chloride is the most commonly prescribed anticholinergic for OAB worldwide. It has antimuscarinic activity acting primarily on the M1 and M3 receptor over the M2 receptor. Two oral formulations of this drug are now available on our market and include immediate – release (IR) and extended – release (ER) forms. More recently, a transdermal formulation has been introduced. Several randomised placebo controlled trials have shown oybutynin IR to be effective in producing subjective improvement in patients (at least 50% improvement in incontinence episodes) as well as objective parameters. Dose begins at 2.5mg bd, going up to a maximum of 5mg tds. Adverse effects include dry mouth, blurred vision, constipation, urinary retention, gastro – oesophageal reflux, dizziness and central nervous system (CNS) effects. The AEs, particularly dry mouth, can lead to a high (up to 80%) dropout rate within 6 months of commencing treatment.
    In an attempt to reduce the incidence of these AEs, a new formulation, allowing a more controlled release of the drug over a 24 – hour period (oxybutynin ER) was introduced. The sustained release produces a more sustained plasma concentration when compared with the IR preparations and, hence, a much more stable steady – state concentration for 24 hours. Tablet doses between 5 and 10 mg are available, and several randomized controlled studies have shown that oxybutynin ER is as effective as IR preparations with the additional benefit of a reduction in dry mouth. Other modes of oxybutynin delivery include intravesical and transdermal administration. Intravesical therapy was developed to increase the balance in favour of efficacy over AEs in those patients routinely using intermittent self – catheterisation. Oxybutynin (typically 5mg) is mixed with normal saline and administered twice a day via a urethral catheter. Several small open – label studies have shown that intravesical administration of oxybutynin can reduce subjective and objective detrusor overactivity. Clearly, the main limitation of this route of administration, associated with the use of intermittent self – catheterisation, is the increased risk of developing cystitis due to an irritant effect of the solution, and a higher risk of developing urinary tract infections with subsequent high dropout rates.
    Following the hypothesis that oxybutynin metabolites are the principal cause of AEs, alternative delivery routes have been sought that would avoid oral administration and first pass metabolism. Consequently, a transdermal preparation of oxybutynin has been developed. At the present time, this agent has not yet been licensed for use in SA. An initial short – term study of transdermal verus oral oxybutynin IR in adults with urinary urge incontinence reported that both treatment options had similar efficacy, but the transdermal route produced significantly less dry mouth. A double – blinded randomised controlled trial (RCT) of transdermal oxybutynin at 3.9 mg administered twice weekly versus placebo, reduced the number of weekly incontinence episodes, reduced average daily urinary frequency increased average voided volume and significantly improved quality of life (QOL) compared with placebo. The incidence of dry mouth was similar in both the groups, and the main AEs associated with transdermal delivery were erythema and pruritis at the site of application.

    TABLE

    Propiverine hydrochloride is a tertiary amine with a half – life of approximately 20 hours, showing peak levels in serum after approximately 2.3 hours after ingestion. Like oxybutynin it exhibits a mixed action, exhibiting both anticholinergic and musculotropic effects (calcium channel blocking activity). Doses vary between 15 and 30 mg daily. The clinical trials and data with this agent are limited to a month’s duration or less. In a double – blinded randomized placebo – controlled trial of people with OAB, propiverine 15 mg three times daily was compared with oxybutynin 5 mg twice daily and placebo. Both drugs produced objective and subjective improvements compared with placebo at 4 weeks compared with baseline. Propiverine was as effective as oxybutynin in reducing urgency and urge incontinence, but was associated with a lower incidence of dry mouth.

    Tolterodine was launched in 1998 and was the first modern anticholinergic on the market. The ER formulation was released as a once – daily preparation aimed at producing a stable serum concentration over 24 hours. ER has peak serum concentration at 2 – 6 hours post administration. Therapy with tolterodine ER 4mg appears to be efficacious in both older and younger people with OAB; it is useful for at least up to 12 months with improvement in voiding diary parameters including urgency, and patient perception of their condition with a benefit of HRQL based on the King’s health questionnaire. The ER formulation is more effective than placebo in different degrees of incontinence severity. It has been shown to be effective in treating women with mixed urinary incontinence with a predominance of urge symptoms over stress.

    Trospium chloride, a quaternary amine, is purported to lack CNS effects as it does not cross the blood – brain barrier. Its half – life is between 12 – 18 hours and reached peak plasma concentrations between 4 and 6 hours. The usual dose is 20mg twice daily. Trospium 20 mg twice daily has shown similar results when compared with oxybutynin 5 mg twice daily, with significant reduction in urodynamic and voiding diary parameters (frequency, urgency and urge incontinence) for up to 52 weeks after trospium 20 mg twice – daily treatment.

    Two new anticholinergic agents have been released in recent years, namely solifenacin and darifenacin. Solifenacin has a mean time to maximum plasma concentration of 3 – 8 hours and long elimination half – life of >45 – 68 hours. Solifenacin produces a significant reduction in voiding frequency and a significant increase in volume voided/void in people with OAB and urodynamic evidence of detrusor overactivity. The recommendation is for an initial 5 mg dose with the possibility of dose flexibility by increasing the dose to 10 mg as required. The long term efficacy of solifenacin has been reported in an open – label extension of randomised placebo – controlled trials. The efficacy seen in the initial trials was maintained for up to 52 weeks. About 85% of the study population was satisfied after 24 weeks of flexible dosing, and with regard to efficacy, 74% of the population were satisfied after 24 weeks of flexible dosing.

    Darifenacin is a tertiary amine derivative and is the most selective M3 receptor antagonist. It has been shown to have a higher degree of selectivity for the M3 over the M2 receptor compared with other anticholinergics, with marginal selectivity for the M1 receptor. In healthy volunteers after oral administration of darifenacin, peak plasma concentrations are reached after approximately 7 hours with multiple dosing, and steady – state plasma concentrations are achieved by the sixth day of dosing. In a double – blind, radomised, crossover study comparing darifenacin with oxybutynin in people with proven detrusor overactivity and associated symptoms of OAB, darifenacin was as effective as oxybutynin in terms of the ambulatory urodynamic variables tested but darifenacin 15 and 30 mg controlled release was significantly better in salivary flow compared with oxybutynin 5 mg three times daily.
    The introduction of darifenacin has fuelled debate over the potential importance of pharmacological selectivity as related to the AE profile. M1 and M3 receptor have been attributed to dry mouth, M1 to cognitive impairment, M2 to cardiac effects and M3 and M5 to visual effects. Certainly, in this population, this would be of greater significance due to the existence of comorbidity and the susceptibility to impaired cognitive function and nervous system effects. Definitive comment on this subject will inevitably await adequately powered head – to – head comparative studies. Dose flexibility has been explored with darifenacin and clearly showed that some people who do not respond to a lower dose of drug (7.5mg) will do so at higher doses (15mg), but will develop more pronounced AEs inevitably, however, they may accept this as part of the ‘trade – off’ for the greater efficacy experienced.
    It is clear that among the many drugs tried for the treatment of OAB, acceptable efficacy, documented in RCT’s of good quality, has only been shown for a limited number. The anitmuscarinics tolterodine, trospium, solifenacin and darifenacin, the drugs mixed actions, oxybutynin and propiverine, and the vasopressin analogue, demopressin, were found to fulfill the criteria for level1 evidence according to the Oxford assessment system and were given grade A recommendations by the International Consultation on Incontinence. All antimuscarinics apart from oxybutynin IR were found to be well tolerated. Dry mouth was the most commonly reported adverse event and no drug was associated with an increase in any serious adverse event.
    Generally there is little or no good evidence to choose between the anticholinergics.

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