Original Articles
Muscarinic receptor antagonists in the treatment of overactive bladder

https://doi.org/10.1016/S0090-4295(99)00492-6Get rights and content

Abstract

A wealth of clinical evidence supports the view that muscarinic receptor antagonists are effective in the treatment of overactive bladder. However, treatment-limiting adverse effects such as dry mouth, constipation, and blurred vision have restricted the usefulness of previously available agents, such as oxybutynin. A real need therefore existed for effective and well-tolerated agents for the long-term management of the troublesome symptoms of overactive bladder. This review outlines the various approaches that have been used in attempts to overcome the tolerability problems of oxybutynin. It also describes how advances in our understanding of muscarinic receptors and bladder function has led to the potential development of either tissue- or subtype-selective antimuscarinic agents with improved tolerability. Drugs that have been developed in this way include tolterodine and darifenacin, each of which shows some bladder selectivity in animal models. Unlike darifenacin, however, the bladder selectivity of tolterodine has been confirmed by numerous clinical studies. Tolterodine’s improved tolerability compared with oxybutynin, along with its equivalent therapeutic efficacy at recommended dosages, permits patients to experience the beneficial effects of long-term treatment. Tolterodine therefore represents a real alternative for the long-term management of overactive bladder. The results of ongoing clinical studies with darifenacin are awaited before it can be concluded that selective antagonism of M3 receptors leads to improved tolerability over existing agents in the treatment of overactive bladder. Similarly, the potential improvements in tolerability associated with different dosage formulations of oxybutynin, and the clinical utility of S-oxybutynin, are yet to be conclusively demonstrated.

Section snippets

Rationale for the use of antimuscarinic agents in overactive bladder

The etiology of overactive bladder remains unknown, and may involve both neurologic and myogenic causes.7, 8 It is well established, however, that acetylcholine-induced stimulation of post-ganglionic muscarinic receptors on detrusor smooth muscle is involved in both normal and involuntary bladder contraction.9 This profile explains the therapeutic efficacy of muscarinic receptor antagonists in overactive bladder.

Muscarinic receptors are heterogeneous in nature and widely distributed throughout

Oxybutynin

Oxybutynin was originally identified in the 1960s as a potential treatment for gastrointestinal hypermotility.23, 24 Further investigation showed that it was effective in inhibiting uncontrolled bladder contractions.25 Subsequently, oxybutynin became the most widely used pharmacologic agent for the treatment of overactive bladder.

New approaches to improve tolerability

New approaches to improving the tolerability of oxybutynin include alternative routes of administration, use of extended-release oral formulation technology, and stimulation of salivation. Clinical development of the S-enantiomer of oxybutynin has also been advocated.

Tolterodine

Tolterodine is the first drug to have been specifically developed for the treatment of patients with overactive bladder presenting with frequency, urgency, and urge incontinence. Given the complexity of the role of muscarinic receptors in bladder function, this agent was developed using a functional approach to achieve bladder selectivity, rather than relying on muscarinic receptor subtype selectivity.

Darifenacin

Given the major involvement of M3 receptors in bladder contraction,12 compounds selective for this subtype may prove effective in the treatment of overactive bladder without the systemic adverse effects caused by blockade of M1 and M2 receptors.104 Darifenacin is a new agent, currently undergoing clinical trials, that was identified for development by using this subtype-selectivity rationale.

Conclusions

There is little doubt that compounds with antimuscarinic properties are effective in the treatment of overactive bladder, and so form the mainstay of treatment for this common and distressing condition. However, the usefulness of previously available agents, such as oxybutynin, has been limited by the occurrence of treatment-limiting adverse events, principally dry mouth. Intravesical instillation of oxybutynin overcomes many of the tolerability problems associated with oral therapy, but this

References (119)

  • K Waldeck et al.

    Comparison of oxybutynin and its active metabolite, N-desethyl-oxybutynin, in the human detrusor and parotid gland

    J Urol

    (1997)
  • M Yono et al.

    Pharmacological effects of tolterodine on human isolated urinary bladder

    Eur J Pharmacol

    (1999)
  • C.M Fredericks et al.

    Comparative in vitro effects of imipramine, oxybutynin, and flavoxate on rabbit detrusor

    Urology

    (1978)
  • J.B Gajewski et al.

    Oxybutynin versus propantheline in patients with multiple sclerosis and detrusor hyperreflexia

    J Urol

    (1986)
  • S.P Greenfield et al.

    The use of intravesical oxybutynin chloride in children with neurogenic bladder

    J Urol

    (1991)
  • C.A Massad et al.

    The pharmacokinetics of intravesical and oral oxybutynin chloride

    J Urol

    (1992)
  • G Buyse et al.

    Intravesical oxybutynin for neurogenic bladder dysfunctionless systemic side effects due to reduced first pass metabolism

    J Urol

    (1998)
  • R.U Anderson et al.

    Once daily controlled versus immediate release oxybutynin chloride for urge urinary incontinence

    J Urol

    (1999)
  • L Nilvebrant et al.

    Tolterodine—a new bladder selective muscarinic receptor antagonistpreclinical pharmacological and clinical data

    Life Sci

    (1997)
  • R.M Eglen et al.

    Muscarinic acetylcholine receptor subtypes in smooth muscle

    Trends Pharmacol Sci

    (1994)
  • G Larsson et al.

    Tolterodine in the treatment of overactive bladderanalysis of the pooled phase II efficacy and safety data

    Urology

    (1999)
  • R.A Appell

    Clinical efficacy and safety of tolterodine in the treatment of overactive bladdera pooled analysis

    Urology

    (1997)
  • W.R Lenderking et al.

    A review of the quality-of-life aspects of urinary urge incontinence

    Pharmacoeconomics

    (1996)
  • G Kobelt et al.

    Quality-of-life aspects of the overactive bladder and the effect of treatment with tolterodine (review)

    Br J Urol

    (1999)
  • Fantl JA, Newman DK, Colling J, et al: Managing Acute and Chronic Urinary Incontinence. Clinical Practice Guidelines....
  • Abrams P, Khoury S, Wein A (eds): First International Consultation on Incontinence. Plymouth, UK: Health Publications,...
  • Y Yarker et al.

    Oxybutynina review of its pharmacodynamic and pharmacokinetic properties, and its therapeutic use in detrusor instability

    Drugs Aging

    (1995)
  • C.J Kelleher et al.

    A medium term analysis of the subjective efficacy of treatment for women with detrusor instability and low bladder compliance

    Br J Obstet Gynaecol

    (1997)
  • K.-E Andersson

    The pharmacology of lower urinary tract smooth muscles and penile erectile tissues

    Pharmacol Rev

    (1993)
  • M.P Caulfield et al.

    International Union of PharmacologyXVII. Classification of muscarinic acetylcholine receptors

    Pharmacol Rev

    (1998)
  • P Wang et al.

    Muscarinic acetylcholine receptor subtypes mediating urinary bladder contractility and coupling to GTP binding proteins

    J Pharmacol Exp Ther

    (1995)
  • S.S Hegde et al.

    Functional role of M2 and M3 muscarinic receptors in the urinary bladder of rats in vitro and in vivo

    Br J Pharmacol

    (1997)
  • G.T Somogyi et al.

    Evidence for inhibitory nicotinic and facilitatory muscarinic receptors in cholinergic nerve terminals of the rat urinary bladder

    J Auton Nerv Syst

    (1992)
  • Flood HD, Somogyi GT, Bellinger MF, et al: Muscarinic facilitation of acetylcholine release in the human bladder: a...
  • G.T Somogyi et al.

    M1 muscarinic receptor-mediated facilitation of acetylcholine release in the rat urinary bladder

    J Physiol

    (1994)
  • P Alberts

    Classification of the presynaptic muscarinic receptor subtype that regulates 3H-acetylcholine secretion in the guinea pig urinary bladder in vitro

    J Pharmacol Exp Ther

    (1995)
  • G D’Agostino et al.

    M4 muscarinic autoreceptor-mediated inhibition of [3H]acetylcholine release in the rat isolated urinary bladder

    J Pharmacol Exp Ther

    (1997)
  • G.T Somogyi et al.

    Function, signal transduction mechanisms and plasticity of presynaptic muscarinic receptors in the urinary bladder

    Life Sci

    (1999)
  • M.E Rossman et al.

    A clinical evaluation of oxybutynin chloride in the treatment of gastro-intestinal disease

    Curr Ther Res

    (1964)
  • C.W Hock

    Clinical evaluation of oxybutynin chloride

    Curr Ther Res

    (1967)
  • L Nilvebrant

    On the muscarinic receptors in the urinary bladder and the putative subclassification of muscarinic receptors

    Acta Pharmacol Toxicol

    (1986)
  • L Noronha-Blob et al.

    Enantiomers of oxybutyninin vitro pharmacological characterization at M1, M2 and M3 receptors and in vivo effects on urinary bladder contraction, mydriasis and salivary secretion in guinea pigs

    J Pharmacol Exp Ther

    (1991)
  • M Tonini et al.

    Depressant action of oxybutynin on the contractility or intestinal and urinary tract smooth muscle

    J Pharm Pharmacol

    (1987)
  • J.F Kachur et al.

    R and S enantiomers of oxybutyninpharmacological effects in guinea pig bladder and intestine

    J Pharmacol Exp Ther

    (1988)
  • J.S Peterson et al.

    Mini-pig urinary bladder functioncomparisons of in vitro anticholinergic responses and in vivo cystometry with drugs indicated for urinary incontinence

    J Auton Pharmacol

    (1990)
  • F Nagy et al.

    Idiopathic bladder hyperactivity treated with Ditropan (oxybutynin chloride)

    Int Urol Nephrol

    (1990)
  • C.M Fredericks et al.

    A study of the anticholinergic and antispasmodic activity of oxybutynin (Ditropan) on rabbit detrusor

    Invest Urol

    (1975)
  • G.F Anderson et al.

    Characterization of the oxybutynin antagonism of drug-induced spasms in detrusor

    Pharmacology

    (1977)
  • Smith ER, Wright SE, Aberg G, et al: Comparison of the antimuscarinic and antispasmodic actions of racemic oxybutynin...
  • P.M Lish et al.

    Oxybutynina musculotropic antispasmodic drug with moderate anticholinergic action

    Arch Int Pharmacodyn Ther

    (1965)
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