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Published on 1 January 2005

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Drug treatment of overactive bladder

teaser

Mohammed Belal
MA MB BChir MRCS
Research Registrar
E:mobelal@doctors.org.uk

Paul Abrams
MD FRCS
Professor
Bristol Urological Institute
Southmead Hospital
Bristol
UK
E:paul_abrams@bui.ac.uk

Overactive bladder (OAB) was defined by the International Continence Society (ICS) in 2002 as a symptom complex of urgency, with or without urge incontinence, usually with frequency and nocturia.(1) Absence of infection or of other pathology to explain the symptoms is an important criterion. The symptoms are thought to be caused by involuntary contractions of the bladder muscle. A definition of the different terms used in OAB is presented in Table 1.

[[HPE18_table1_49]]

The prevalence of OAB has been studied in population- based surveys. In Europe, a six-country survey (including the UK) on 16,776 patients showed the prevalence of OAB to be 15.6% and 17.4% for men and women, respectively. (2) The authors of this study estimated that over five million people may suffer from OAB. A recent study, the National Overactive Bladder Evaluation (NOBLE), showed a similar prevalence in the USA.(3) Both studies demonstrated that OAB increased with age.

Treatment
The management of OAB includes conservative measures and drug treatment.(4) Conservative management includes lifestyle advice (reducing caffeine or tea) and bladder retraining and pelvic floor exercises. The aim of bladder retraining is to increase the interval between voids and volume voided. Bladder retraining in combination with drug therapy is synergistic.(5)

Antimuscarinics
Normal bladder contraction is caused by the release of acetylcholine from the nerves, which stimulates the muscarinic receptors present on bladder smooth muscle. There are five muscarinic receptor subtypes in the human body, termed M(1) to M(5). The predominant receptor in the bladder is the M(2)-receptor. The role of this receptor, however, is not well understood. The M(3)-receptor appears to be responsible for detrusor contraction.(6) Blocking the M(3)-receptor would seem a reasonable approach to treating OAB. Unfortunately, the presence of M(3)-receptors in salivary glands, smooth muscle, eyes and the brain explains the side-effects associated with the use of antimuscarinics – dry mouth, constipation, blurred vision and drowsiness.(7)

In the 1970s, oxybutynin was the first licensed antimuscarinic. This tertiary amine undergoes extensive first-pass hepatic metabolism, transforming the compound into N-desethyloxybutynin, which is thought to be responsible for the side-effects. The original formulation was a three-times daily dose starting from 2.5mg to 5mg. To limit the side-effect profile, once-a-day formulations have appeared on the market in 5, 10 and 15mg doses. The extended- release formulations appear to be as effective and better tolerated.(8) An additional mode of delivery of oxybutynin has been investigated in the form of the transdermal route. The transdermal route appears to offer the advantage of missing the hepatic metabolism and, hence, lower doses may be used with a reduction in side-effects such as dry mouth.(9) The efficacy of the licensed transdermal patch (3.9mg/day) is comparable to that of long-acting tolterodine in patients with urge and mixed urinary incontinence.(10) The patch is applied twice a week, and skin irritation can be a problem.

The liver metabolism of tolterodine, another tertiary amine, leads to a 5-hydroxymethyl metabolite, the action of which is similar to that of its parent compound. Initial formulations were 1mg or 2mg twice daily, but an extended once-daily dose of 4mg has since been released. The efficacy of tolterodine 2mg twice-daily dose is similar to that of oxybutynin, and the treatment is better tolerated.(11) Extended once-daily dosing shows a better side-effect profile.(12) Trials comparing different preparations of tolterodine and oxybutynin are summarised in Table 2.

[[HPE18_table2_50]]

Trospium chloride is a quaternary ammonium derivative that is not metabolised but is excreted in the urine. Use of this compound leads to minimal blood–brain barrier crossover and probably less central nervous system effects; however, food consumption reduces oral drug bioavailability. The usual dosage regimen is 20mg twice daily. Trospium has been shown to be effective in reducing urinary frequency and incontinent episodes, compared with oxybutynin and tolterodine.(16) Trospium has been used in Europe for some years and has recently undergone phase III trials in the USA.(17)

Propiverine is a tertiary amine with extensive first-pass metabolism resulting in three metabolites. The doses are given as 15mg three times a day, up to a maximum of four times a day. Efficacy, change in urodynamics parameters and side-effects profile are similar to those of oxybutynin and tolterodine.(18)

The antimuscarinic drug solifenacin succinate (Vesicare) was recently licensed. Solifenacin succinate is a competitive, predominantly M(3)-receptor antagonist that is extensively metabolised in the liver. The dosage formulations are 5mg and 10mg once daily. Animal studies in vitro and in vivo have suggested a greater selectivity for the bladder than for salivary glands, compared with oxybutynin and tolterodine.(19) Clinical trials have suggested better efficacy and side-effect profile than tolterodine.(20)

The other antimuscarinics currently in development are darifenacin and fesoterodine. Darifenacin is a selective M(3)-receptor antagonist with high functional selectivity for the bladder.(21) A phase III trial demonstrated that darifenacin (7.5mg and 15mg once daily) reduced OAB symptoms with a reasonable side-effect profile.(22) The drug is expected to be launched on the market within a year at most. Fesoterodine is a bladder-selective antimuscarinic metabolised mainly by the liver into its active metabolite.(23) Fesoterodine is currently being evaluated in phase III trials.

Other treatments
Recent systemic drug approaches have led to the study of beta(3)-adrenergic receptor agonists, which have been shown to reduce contractions in human detrusor in vitro.(24) Further studies are being carried out, and it may be some time before this new class of drugs is launched on the market for the treatment of OAB. ATP-sensitive K(+)-channel openers may have a role in the future, with animal studies in pigs showing efficacy in treating OAB.(25)

Intravesical drug treatments, including botulinum toxin A and resiniferatoxin, have recently attracted the attention of urologists. Botulinum toxin A is a potent neurotoxin that irreversibly blocks acetylcholine from nerve ending, resulting in muscle paralysis. Nonrandomised trials consisted of injecting botulinum toxin A into the bladder at 20–30 sites in a specific group of OAB patients (neurogenic patients). Results of these studies showed promise, as a reduction in OAB symptoms was observed.(26) Large clinical trials are required to assess this therapy before it can be applied to all OAB patients.

Resiniferatoxin, a potent analogue of capsaicin, is one of a family of compounds called vanilloids. This drug acts on vanilloid receptors to desensitise afferent C-fibres. Resiniferatoxin instilled into the bladder for 30 minutes has been shown to be helpful in reducing OAB symptoms in a specific group of patients with neurogenic bladder.(27) A recent study suggested that botulinum toxin A had greater duration of efficacy than resiniferatoxin in neurogenic bladder patients.(28)

Conclusion
Antimuscarinics are the main class of drugs used in the treatment of OAB, although their use is limited by side-effects such as dry mouth and constipation. Several attempts have been made to reduce these adverse effects, such as using older drugs in extended-release preparations and with novel delivery systems. This strategy has implications in terms of costs, especially in the case of oxybutynin. The latest generation of antimuscarinics, with drugs such as solifenacin, darifenacin and fesoterodine, has a better side-effect profile as these compounds are bladder- and muscarinic subtype-selective. In terms of the choice of an antimuscarinic drug, there is currently no clear answer, although cost has to be taken into consideration.

Future developments include new classes of drugs such as beta(3)-agonists and ATP-sensitive K(+)-channel openers. Intravesical treatment with botulinum toxin A and resiniferatoxin may constitute second-line drug treatments for OAB.

References

  1. Abrams P, Cardozo L, Fall M, et al. Urology 2003;61:37-49.
  2. Milsom I, Abrams P, Cardozo L, et al. BJU Int 2001;87:760-6.
  3. Stewart WF, Van Rooyen JB, Cundiff GW, et al. World J Urol 2003;20:327-36.
  4. Hashim H, Abrams P. Drugs 2004;64:1643-56.
  5. Mattiasson A, Blaakaer J, Hoye K, Wein AJ. BJU Int 2003;91:54-60.
  6. Chapple CR, Yamanishi T, Chess-Williams R. Urology 2002;60:82-8.
  7. Scarpero HM, Dmochowski RR. Curr Urol Rep 2003;4:421-8.
  8. Andersson KE, Chapple CR. World J Urol 2001;19:319-23.
  9. Appell RA, Chancellor MB, Zobrist RH, et al. Mayo Clin Proc 2003;78:696-702.
  10. Dmochowski RR, Davila GW, Zinner NR, et al. J Urol 2002;168:580-6.
  11. Abrams P, Freeman R, Anderstrom C, Mattiasson A. Br J Urol 1998;81:801-10.
  12. Abrams P. Expert Opin Pharmacother 2001;2:1685-701.
  13. Appell RA, Sand P, Dmochowski R, et al. Mayo Clin Proc 2001;76:358-63.
  14. Diokno AC, Appell RA, Sand PK, et al. Mayo Clin Proc 2003;78:687-95.
  15. Sussman D, Garely A. Curr Med Res Opin 2002;18:177-84.
  16. Frohlich G, Bulitta M, Strosser W. Int J Clin Pharmacol Ther 2002;40:295-303.
  17. Zinner N, Gittelman M, Harris R, et al. J Urol 2004;171:2311-5.
  18. Madersbacher H, Murtz G. World J Urol 2001;19:324-35.
  19. Ikeda K, Kobayashi S, Suzuki M, et al. Naunyn Schmiedebergs Arch Pharmacol 2002;366:97-103.
  20. Chapple CR, Rechberger T, Al-Shukri S, et al. BJU Int 2004;93:303-10.
  21. Miyamae K, Yoshida M, Murakami S, et al. Pharmacology 2003;69:205-11.
  22. Haab F, Stewart L, Dwyer P. Eur Urol 2004;45:420-9.
  23. Sachse R, Cawello W, Horstmann R. Neurourol Urodyn 2004;34:Abs 586.
  24. Yamaguchi O. Urology 2002;59:25-9.
  25. Fey TA, Gopalakrishnan M, Strake JG, et al. Neurourol Urodyn 2003;22:147-55.
  26. Schurch B, Stohrer M, Kramer G, et al. J Urol 2000;164:692-7.
  27. Chancellor MB, de Groat WC. J Urol 1999;162:3-11.
  28. Giannantoni A, Di Stasi SM, Stephen RL, et al. J Urol 2004;172:240-3.


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