Oxybutynin

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Abstract
Oxybutynin possesses anticholinergic and spasmolytic properties, which together form the basis for its use as a therapeutic option in patients with overactive detrusor function — either idiopathic detrusor instability (DI) or detrusor hyperreflexia. Of the symptoms of detrusor overactivity, urge incontinence is often the most distressing to the patient. Urge incontinence and other subjective parameters (urinary frequency, urgency) improve in tandem with objective (cystometric) measures (maximum detrusor pressure during filling, volume at first desire to void, maximum bladder capacity) in ambulatory, including elderly, patients treated with oxybutynin. However, on the basis of results of limited investigations, the drug appears ineffective in elderly institutionalised individuals. Relative to other anticholinergic drugs, oxybutynin appears at least as effective as propantheline and similar in efficacy to propiverine in small trials, although these results are not definitive. Further investigation of intravesical oxybutynin may lead to this route becoming an option in patients with preexisting catheters. Adverse effects — dry mouth, constipation, blurred vision — related to the anticholinergic activity of oxybutynin occur frequently and can be sufficiently troublesome to necessitate treatment discontinuation in up to 25% of patients, depending on the dosage. Increases in residual urine volume suggesting urinary retention (undesirable in patients with idiopathic DI), also can develop in some oxybutynin recipients. In summary, oxybutynin is one of the few drugs proven to be beneficial in some patients with overactive detrusor function. Despite the occurrence of unwanted anticholinergic effects in many patients, and apparent lack of efficacy in the elderly institutionalised population, oxybutynin should be considered for the drug of first choice in patients with detrusor overactivity, including the elderly ambulatory population, when pharmacological therapy is indicated. The majority of the beneficial and unwanted effects of oxybutynin in patients with detrusor instability (DI) stem from its anticholinergic properties. Oxybutynin competitively binds to parasympathetic muscarinic receptors, with a higher affinity for brain (M1) than for cardiac (M2) or ileal⋉adder receptors (M3). In addition, it antagonises detrusor contractions in vitro and in vivo. Compared with atropine, its affinity for muscarinic receptors is 10 times less in the brain and between 5 and 27 times lower in the detrusor muscle. These anticholinergic effects of oxybutynin, together with its spasmolytic activity, are responsible for the relaxant effects of the drug on the detrusor muscle of the urinary bladder (thus reducing undesirable spontaneous contractions). The net result, as shown in both animals and humans (see Therapeutic Use, below) is a reduction in maximum detrusor pressure during filling and increases in bladder volume and capacity, but with a propensity for increases in residual urine volume. The contribution, if any, of local anaesthetic properties to the mechanism of action of the drug remains speculative. Wide interindividual variation in pharmacokinetic parameters is evident following oral administration of oxybutynin. The pharmacokinetic profile of the drug does not appear to be altered in healthy elderly individuals compared with young volunteers. However, the terminal plasma elimination half-life was prolonged from 2 to 3 hours in healthy elderly individuals to about 5 hours in ‘frail’ elderly individuals and its systemic bioavailability increased. The presence of food also increases the bioavailability of oxybutynin and slightly delays its rate of absorption. Hepatic biotransformation of oxybutynin yields the active metabolite N-desethyl-oxybutynin in addition to its most abundant but inactive metabolite, phenylcyclohexylglycolic acid. Active metabolites of oxybutynin may be responsible for much of the pharmacological activity of the drug. Oxybutynin alleviates subjective manifestations of idiopathic DI and detrusor hyperreflexia, including the distressing symptom of urge incontinence, and corrects abnormal objective measures. Subjective improvement in noncomparative trials was rated ‘excellent or good’ in 55 to 70% of patients receiving oxybutynin for up to 2 years. While this finding gives some preliminary indication of efficacy, placebo-controlled trials are vital to establish the benefit of a treatment in DI, as patients with this condition exhibit a high placebo response. As demonstrated by several such investigations in ambulatory patients, oxybutynin decreases urinary frequency, urgency and episodes of urge incontinence, in addition to increasing bladder volume at first desire to void, enhancing maximum bladder capacity and reducing maximum detrusor pressure during filling. However, oxybutynin appears to have varying degrees of success in alleviating nocturia, and potentially detrimental increases in residual urine volume have been documented with its use. Moreover, as with other pharmacotherapy, cure is elusive. Furthermore, in contrast to unselected populations, elderly institutionalised patients have generally failed to improve during oxybutynin therapy, although patient numbers have been small. Elderly but ambulatory individuals experienced a modest subjective improvement with oxybutynin in one placebo-controlled trial, but urge incontinence was relieved to a similar extent by placebo and oxybutynin. On the basis of limited comparisons with other anticholinergic drugs, oxybutynin appears at least as effective as propantheline and similar to propiverine in idiopathic DI. This benefit may be offset somewhat by the increases in residual urine volume which are associated with oxybutynin but apparently not with propantheline. However, urge incontinence was relieved in significantly more oxybutynin than propantheline recipients (58 vs 45%, p < 0.05) in the largest placebo-controlled trial, conducted in 154 patients. Some evidence suggests better results with oxybutynin than with propantheline in patients with detrusor hyperreflexia rather than idiopathic DI. Interestingly, intravesical administration of oxybutynin has shown promise in individuals with detrusor hyperreflexia: this route may become an option in individuals with pre-existing or intermittent catheters, and those unresponsive to or intolerant of oral therapy. Atropine-like symptoms are frequent during oral oxybutynin therapy. Dry mouth develops in at least 50% of oxybutynin recipients, constipation in about 15%, drowsiness in about 12% and blurred vision in approximately 5%. Discomfort has been severe enough to warrant treatment discontinuation in approximately 7 to 27% of patients given oxybutynin in clinical trials. Reflux oesophagitis has been reported infrequently during oxybutynin treatment and no serious cardiac effects have been linked to its use. Intravesical oxybutynin appears to cause few systemic adverse events. Oxybutynin may be less well tolerated than propantheline, as shown in the largest comparative trial, although smaller studies have demonstrated similar tolerability profiles for the 2 drugs, and in one study patients were more willing to tolerate the unwanted effects of oxybutynin than those of propantheline. Whether increasing age influences the severity and incidence of unwanted effects, particularly in institutionalised patients, has not been examined specifically. The recommended oral dosage of oxybutynin is 5mg 2 to 3 times daily, up to a maximum of 5mg 4 times daily. The dose should be titrated to maximise response and minimise adverse effects. However, a lower starting dose of 3 or 5mg twice daily is recommended in the elderly, titrated as necessary, and clinical experience has suggested that a dosage of 2.5mg 2 or 3 times daily may be a suitable starting dosage in elderly and nonelderly adults. The drug is contraindicated in patients with conditions which may be aggravated by its anticholinergic activity. Drowsiness or blurred vision may reduce patients’ ability to perform tasks requiring mental alertness.