Tolterodine: a new drug for urinary incontinence
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THERAPY
-Dr Steve WinterUrinary incontinence is estimated to affect more than 30 million people in the developed world. However, while this disorder is treatable and often curable in most individuals, the efficacy and tolerability of currently available therapeutic agents is far from optimal. Tolterodine* is a new muscarinic antagonist specifically developed for the treatment of urinary urge incontinence and other symptoms of detrusor overactivity. In this week's issue, Inpharma® maps the progress of this interesting compound in preclinical studies and preliminary phase IT clinical trials. Urinary incontinence, or the 'involuntary' loss of urine which is objectively demonstrable and a social or hygienic problem, is both prevalent and costly. In the US alone, urinary incontinence occurs in up to 30% of individuals aged> 60 years l and the direct costs of treating this condition are estimated at $USI0.3 billion (1987 prices).2 Furthermore, numerous studies have shown that urinary incontinence has an adverse effect on quality of life. Urinary urge incontinence (UUI) is a type of urinary incontinence that is characterised by the involuntary loss of urine associated with a strong desire to void. While many individuals with UUlare candidates for drug treatment, few receive regular pharmacotherapy, partly because incontinence is often incorrectly dismissed by older patients as part of the normal aging process, while some patients are unwilling·to seek help because of psychosocial factors such as embarrassment and stigmatisation. For those patients who do seek treatment for UUI the utility of existing agents (e.g. oxybutynin) is often limited by . poor tolerability. Tolterodine [see figure] is anew muscarinic receptor antagonist specifically developed for the treatment of UUI and other symptoms of . detrusor overactivity.
limited by poor oral bioavailability and systemic anti muscarinic adverse effects (e.g. dry mouth). In vitro studies have shown that tolterodine has a high affinity and specificity for muscarinic receptors. In isolated strips of guinea pig and human detrusor muscle, for example, nanomolar concentrations of tolterodine competitively antagonised detrusor contractions elicited by carbachol3-s and greatly attenuated contractions induced by electrical stimulation.4 ,5
Radioligand binding and functional studies in vitro have confirmed that the affinity oftolterodine for muscarinic receptors of the urinary bladder is similar to that of the muscarinic receptor antagonist oxybutynin, the current 'gold standard' for the treatment of UUI. However, the affinity of tolterodine for muscarinic receptors of the salivary gland is 8-fold lower compared with oxybutynin [see tableV Selectivity of tolterodine for the bladder over the salivary gland has been demonstrated in vivo. 6
Urodynamic studies
Chemical structure of tolterodine
Muscarinic receptors and bladder selectivity During micturition, the normal human bladder contracts in response to parasympathetic nervereleased acetylcholine, which stimulates muscarinic re
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