Sage Journals: Discover world-class research

Abstract

It has long been accepted that antimuscarinic agents are the backbone of the pharmacological treatment of overactive bladder. Oxybutynin has been the gold standard of these medications for years due to its efficacy, but suffers from a lack of selectivity for the bladder, and extensive metabolism and lipophilicity result in significant side-effect issues. The transdermal delivery of oxybutynin turns this disadvantage of lipophilicity into an advantage. This, in turn, bypasses gastrointestinal absorption and metabolism by the cytochrome P450 system and reduces the breakdown into metabolites responsible for many of the side effects, while providing equivalent efficacy to the immediate-release oral formulation.

Keywords

overactive bladder oxybutynin transdermal oxybutynin urinary urge incontinence

The functions of the lower urinary tract, to store and periodically release urine, are dependent on the activity of smooth and striated muscles in the urinary bladder, urethra, external urethral sphincter and pelvic floor. The bladder and urethra constitute a functional unit, which is controlled by a complex interplay between the central and peripheral nervous systems and local regulatory factors [1 –3]. Bladder emptying and urine storage involve a complex pattern of efferent and afferent signaling in parasympathetic, sympathetic and somatic nerves. These nerves are parts of reflex pathways that either maintain the bladder in a relaxed state, enabling urine storage at low intravesical pressure, or initiate micturition by relaxing the outflow region and contracting the bladder smooth muscle. The postganglionic neurons in the pelvic nerve mediate the excitatory input to the human detrusor smooth muscle by releasing acetylcholine (ACh), which acts upon muscarinic receptors. Most of the sensory innervation of the bladder and urethra reaches the spinal cord via the pelvic nerve and dorsal-root ganglia. The most important afferents for the micturition process are myelinated Aδ-fibers and unmyelinated C-fibers travelling in the pelvic nerve to the sacral spinal cord, conveying information from receptors in the bladder wall to the spinal cord. The Aδ-fibers respond to passive distension and active contraction, thus conveying information regarding bladder filling [4]. C-fibers have a high mechanical threshold and respond primarily to chemical irritation of the bladder mucosa [5] or cold [6].

Malfunction at various levels may result in bladder-control disorders, which can be roughly classified as disturbances of filling or storage, or disturbances of emptying. Failure to store urine may lead to various forms of incontinence (mainly urge and stress incontinence), and failure to empty can lead to urinary retention, which may result in overflow incontinence. A disturbed filling or storage function can, at least theoretically, be improved by agents that decrease detrusor activity, increase bladder capacity and/or increase outlet resistance [7].

As previously discussed, bladder-control disorders can be divided into two general categories: disorders of filling or storage and disorders of voiding [7]. Storage problems can occur as a result of weakness or anatomical defects in the urethral outlet, causing stress urinary incontinence, which may account for a third of cases. Overactive bladder (OAB) is a phrase invented by the International Continence Society (ICS) for those patients with urinary urgency and frequency (with or without urge incontinence) that is idiopathic in nature. However, the same symptoms can occur as a result of sensitization of afferent nerve terminals in the bladder or outlet region, changes of the bladder smooth muscle secondary to denervation, or damage to CNS inhibitory pathways as can be seen in various neurological disorders, such as multiple sclerosis, cerebrovascular disease, Parkinson's disease, brain tumors and spinal cord injury. These symptoms can therefore be neurogenic in origin, so that when OAB is used in this report, it will refer to the syndrome and not just the ICS definition. OAB and/or detrusor overactivity (DO) may also occur in elderly patients due to changes in the brain and/or bladder during aging [8].

As stated previously, normal bladder contraction in humans is mediated mainly through stimulation of muscarinic receptors in the detrusor muscle via the neurotransmitter ACh, hence the attempts to treat overactivity via pharmacological agents that block the effects of ACh at the detrusor muscarinic receptor level. In the human bladder, where the mRNAs for all five pharmacologically defined muscarinic receptors, (M_1–5), are found [9], there is a predominance of mRNAs encoding the M₂ and M₃ receptors [9,10]. Both M₂ and M₃ receptors can be found on detrusor muscle cells, where M₂ receptors predominate in a ratio of at least 3:1 over M₃ receptors, but also in other bladder structures, which may be of importance for detrusor activation. Muscarinic receptors can be found on urothelial cells, suburothelial nerves and other suburothelial structures, and possibly on interstitial cells [11,12]. However, in human as well as animal detrusor muscle, the M₃ receptors are believed to be the most important for contraction [11,13]. No differences between genders can be demonstrated in rat or human bladders [14]. The functional role of the M₂ receptor has not been clarified. Thus, one can comprehend the emphasis on attempting to use pharmacological agents that preferentially block the M₃ muscarinic receptor. While the muscarinic receptor functions may be changed in different urological disorders, such as outflow obstruction, neurogenic bladders, OAB without overt neurogenic cause and diabetes [15], it is not always clear what these changes mean in terms of changes in detrusor function. It appears that OAB may be the result of several different mechanisms, both myogenic [16] and neurological [17], but most probably both factors contribute to the genesis of the disease.

Antimuscarinic (anticholinergic) drugs

Many drugs have been used to treat OAB, but the results are often disappointing, partly due to poor treatment efficacy and/or side effects. The development of pharmacological treatments for the different forms of urinary incontinence has been slow, and the use of some of the currently prescribed agents is based more on tradition than on evidence from controlled clinical trials [3]. Pharmacological and/or physiological efficacy evidence means that a drug has been shown to have its desired effects in relevant preclinical experiments or healthy volunteers, or in experimental situations in patients.

Antimuscarinics block, more or less selectively, muscarinic receptors. The common view is that in OAB/DO, the drugs act by blocking the muscarinic receptors on the detrusor muscle, which are stimulated by ACh released from activated cholinergic (parasympathetic) nerves. This then results in a decrease in the ability of the bladder to contract. However, antimuscarinic drugs act mainly during the storage phase, decreasing urge and increasing bladder capacity, and during this phase there is normally no parasympathetic input to the lower urinary tract [18]. Furthermore, antimuscarinics are usually competitive antagonists. This implies that when there is a massive release of ACh, as during micturition, the effects of the drugs should be decreased; otherwise, the reduced ability of the detrusor to contract would eventually lead to urinary retention. Undeniably, high doses of antimuscarinics can produce urinary retention in humans, but in the dose range needed for beneficial effects in OAB/DO, there is little evidence for a significant reduction of the voiding contraction. The question is whether there are other effects of antimuscarinics that can contribute to their beneficial effects in the treatment of OAB/DO [19]. Muscarinic receptor functions may change in bladder disorders associated with OAB/DO, implying that mechanisms that normally have little clinical importance may be upregulated and contribute to the pathophysiology of OAB/DO [20].

Muscarinic receptors are found on bladder urothelial cells, where their density can be even higher than in detrusor muscle. The role of the urothelium in bladder activation has attracted much interest [21], but whether the muscarinic receptors on urothelial cells can influence micturition has not yet been established. ACh may be released from both neuronal and non-neuronal sources (e.g., the urothelium) and directly or indirectly excite afferent nerves in the suburothelium and within the detrusor muscle (by increasing detrusor smooth muscle tone). This mechanism may be important in the pathophysiology of OAB and is a possible target for antimuscarinic drugs.

Several studies have supported the theory that antimuscarinics can depress involuntary bladder contractions [22 –25]. On the other hand, there are several reports of insufficient efficacy of antimuscarinics given orally to patients with DO [26 –29]. It is unclear to what extent this can be attributed to the low bioavailability of the drugs used, side effects limiting the dose that can be given, or a resistance phenomenon.

Generally, antimuscarinics can be divided into tertiary and quaternary amines [30]. They differ with regard to lipophilicity, molecular charge and even molecular size (tertiary compounds generally having higher lipophilicity and molecular charge than quaternary agents). Atropine, tolterodine, oxybutynin, propiverine, darifenacin and solifenacin are tertiary amines. They are generally well absorbed from the gastrointestinal tract and should theoretically be able to pass into the CNS, dependent on their individual physicochemical properties. High lipophilicity, small molecular size and low charge will increase the possibility of passing the blood–brain barrier. Quaternary ammonium compounds, such as propantheline and trospium, are not well absorbed, pass into the CNS to a limited extent and have a low incidence of CNS side effects [31]. They still produce well-known peripheral antimuscarinic side effects, such as blurred vision, constipation, tachycardia and dryness of mouth. Many antimuscarinics (all currently used tertiary amines) are metabolized by the cytochrome P450 (CYP) enzyme system to active and/or inactive metabolites [30]. The most commonly involved CYP 450 enzymes are CYP 2D6 and CYP 3A4. The metabolic conversion creates a risk for drug–drug interactions, resulting in either reduced (enzyme induction) or increased (enzyme inhibition, substrate competition) plasma concentration/effect of either the antimuscarinic and/or interacting drug.

Antimuscarinics are still the most widely used treatment for urinary urge and urge incontinence [20]. However, currently used drugs lack selectivity for the bladder [32], and effects on other organ systems may result in side effects, which limit their usefulness. For example, all antimuscarinic drugs are contraindicated in untreated narrow-angle glaucoma.

Theoretically, drugs with selectivity for the bladder could be obtained if the subtype(s) mediating bladder contraction and those producing the main side effects of antimuscarinic drugs were different. Unfortunately, this does not seem to be the case. One way of avoiding many of the antimuscarinic side effects is to administer the drugs intravesically. However, this is only practical in a limited number of patients.

Oxybutynin

Clinical practice and the literature support the efficacy of antimuscarinic medications for the treatment of OAB, beginning with oxybutynin. In fact, oxybutynin immediate-release (IR) is recognized for its efficacy and the newer antimuscarinic agents are all compared with it once efficacy over placebo has been determined. Although most patients respond favorably to antimuscarinic medication, smaller percentages achieve total dryness. In general, the new formulations of oxybutynin and other antimuscarinic agents offer patients efficacy roughly equivalent to that of oxybutynin IR, and the advantage of the newer formulations lies in improved dosing schedules and side-effect profiles [33 –35].

With respect to oxybutynin, an extended-release (ER), once-daily oral formulation gained approval by the US FDA in 1999. More recently, an oxybutynin transdermal delivery system (TDS) was approved by the US FDA in 2003. Oxybutynin TDS offers a twice-weekly dosing regimen and the potential for improved patient compliance and tolerability. Again, however, the data demonstrate these newer formulations of oxybutynin to be effective in the treatment of OAB, with significant reductions in urge incontinence, but only a small number of patients reach total dryness. For this reason, in addition to side effects and cost, very few patients remain on the medications for a full year after they have been prescribed.

Oxybutynin is a tertiary amine antimuscarinic agent with combined local anesthetic and muscle-relaxant properties [36]. As a muscarinic receptor antagonist, it has a higher affinity for M₁ and M₃ receptors than for other muscarinic subtypes and its effects may be primarily attributed to the R-enantiomer [37]. It is well absorbed but undergoes extensive upper gastrointestinal and first-pass hepatic metabolism via the CYP3A4 enzyme into multiple metabolites. However, the primary metabolite, N-desethyloxybutynin (DEO), has pharmacological properties similar to the parent compound and has been implicated as the major cause of the troublesome side effect of dry mouth associated with the administration of oxybutynin [38]. Oxybutynin IR results in a reduction of urinary frequency by 50% and urge incontinence episodes by up to 70%, but the prevalence of dry mouth varies at 12–70% depending on the dosage [39]. Oxybutynin and DEO are highly lipophilic, which aids in absorption, but also have a higher penetration into the CNS by allowing crossing of the blood–brain barrier more readily than other tertiary amines. Electroencephalogram (EEG) studies have demonstrated an enhanced ability for oxybutynin to gain access to the CNS via the blood–brain barrier [31,40–41], where oxybutynin is associated with changed power density in the α ranges and qEEG bands.

Transdermal oxybutynin

The lipophilic quality of oxybutynin allows for it to be adequately absorbed transdermally. A skin-permeation enhancer, triacetin, temporarily changes the characteristics of the stratum corneum, allowing oxybutynin to diffuse from the TDS through the skin. This is enhanced by the fact that oxybutynin is lipophilic. The hydrophilic treatments for OAB, such as tolterodine and tropsium, do not have this option of transdermal delivery. Transdermal delivery also has the positive attribute of altering the metabolism of oxybutynin, reducing DEO production substantially. Only small amounts of CYP3A4 are found in the skin, limiting presystemic metabolism during the transdermal absorption. It was hoped that this reduction in metabolism would improve the rates of dry mouth complaints when compared with oxybutynin IR. DEO is still formed during first-pass metabolism by the hepatic CYP 450 enzymes, but clinical trials have demonstrated improved dry-mouth rates compared with oxybutynin IR [42]. A recent study comparing oxybutynin TDS with oxybutynin IR demonstrated a statistically equivalent reduction in daily incontinence episodes (66% for oxybutynin TDS and 72% for oxybutynin IR), but a much lower incidence of dry mouth (38% for oxybutynin TDS and 94% for oxybutynin IR) [43]. In another study, the 3.9 mg/day dose patch significantly reduced the number of weekly incontinence episodes while reducing average daily urinary frequency, confirmed by an increased average voided volume [35]. Furthermore, the dry mouth rate was similar to placebo (7 vs 8.3%). In a third study, oxybutynin TDS was compared not only with placebo but with tolterodine ER [44]. Both drugs equivalently and significantly reduced daily incontinence episodes and increased the average voided volume, but tolterodine ER was associated with a significantly higher rate of antimuscarinic adverse events. The primary adverse events for oxybutynin TDS were application-site reaction pruritis in 14% and erythema in 8.3% of patients, with nearly 9% feeling that the reactions were severe enough to withdraw from the study despite the lack of systemic problems, as once the system is removed, the application site quickly reverts to its normal barrier function.

The pharmacokinetics and adverse-effect dynamics of oxybutynin TDS (3.9 mg/day) and oxybutynin ER (10 mg/day) were compared in healthy subjects in a randomized, two-way crossover study [42]. Multiple blood and saliva samples were collected and pharmacokinetic parameters and total salivary output assessed. Oxybutynin TDS administration resulted in greater systemic availability and minimal metabolism to DEO compared with oxybutynin ER. This resulted in greater salivary output in oxybutynin TDS patients and less dry mouth symptomatology than those patients receiving oxybutynin ER.

Currently, the only patch commercially available is the 3.9 mg/day patch. There is currently a size restriction based upon the fact that approximately 1 mg of oxybutynin, to be delivered daily for up to 4 days, requires nearly 1 cm² of patch (0.92 mg/cm²). The patch may be cut and remain intact, such that other patch doses have been studied up to 5.2 mg/day, and a dose-escalation study with patients wearing up to two patches for a total of 7.8 mg/day has been undertaken; however, there have been no reports on the correlation between efficacy or adverse events upon increasing the dose of oxybutynin TDS. In a laboratory analysis, cutting the oxybutynin TDS patches did not significantly affect drug content, triacetin content, adhesion or drug release [45]. Furthermore, there has not been a rigorously established conversion factor between oral and transdermal dosing of oxybutynin.

Conclusion

At present, antimuscarinic therapy is the backbone of pharmacological therapy for OAB. The gold standard drug to which everything else has been compared is oxybutynin, a nonselective antimuscarinic agent with additional antispasmodic and local anesthetic attributes. Since the primary problem with the agent has been side effects (due to the nonselective nature of the chemical and its metabolism) of dry mouth, constipation, blurred vision and heat intolerance, and the transdermal delivery of oxybutynin markedly reduces this antimuscarinic side-effect problem, while providing equivalent efficacy to the standard IR oral formulation of the drug, it would seem clear that oxybutynin TDS has improved the utilization of this effective agent for OAB.

Future perspective

More selective antimuscarinic agents for the bladder will be sought in order to both improve efficacy and reduce side effects, and thereby improve patient compliance with taking medication for the chronic disorder of OAB. Transdermal application of drugs has gained increasing popularity with patients, whether as a patch or a gel, to further reduce side-effect issues. Other drug types, such as those that act on membrane channels (e.g., calcium antagonists and potassium channel openers) may have the potential to further slow detrusor muscle activity; however, it would appear that the real future lies in the ability to control the sensory side of the reflex arc, especially when one considers that two-thirds of OAB patients have no incontinence, just incessant urgency and frequency of urination. Currently, this has been approached (due to our lack of knowledge to do otherwise) via intravesical instillations of vanilloids or toxins such as botulinum toxin. Empirically, these can be helpful but are not sustained. Thus, our efforts need to move away from detrusor muscle contraction and towards bladder sensation in order to find agents that can be delivered safely in a more conventional manner, either orally or transdermally.

Executive summary

Mechanisms of action

Oxybutynin is an antimuscarinic agent with combined local anesthetic and muscle-relaxant properties.

As a muscarinic receptor antagonist, it has a higher affinity for M₁ and M₃ receptor subtypes.

The matrix-type transdermal formulation reduces antimuscarinic side effects without a loss of efficacy.

Pharmacokinetic properties

Oxybutynin is a racemic mixture (50:50) of R- and S-isomers.

Oxybutynin is transported across intact skin and into the systemic circulation by passive diffusion across the stratum corneum.

Following application, 3.9 mg of oxybutynin is delivered continuously for up to 4 days. It increases for the first 24–48h; thereafter, steady concentrations are maintained for up to 96 h.

Following removal of the patch, plasma concentrations of oxybutynin decline, with an apparent half-life of approximately 7–8h.

Oxybutynin is extensively metabolized by the liver, with less than 0.1% excreted unchanged in the urine.

The transdermal system alters the metabolism of oxybutynin, which improves ratios of antimuscarinic side effects by reducing the effects of the cytochrome P450 system.

No adjustments are required for renal or hepatic impairment.

Clinical efficacy

Transdermal oxybutynin demonstrates a statistically equivalent reduction in daily incontinence episodes to immediate-release oral oxybutynin and extended-release tolterodine.

Safety & tolerability

Antimuscarinic side effects occur less frequently with transdermal systems than with oral antimuscarninics.

Dry mouth occurs at rates similar to placebo (approximately 7–8%).

The primary adverse event is application-site pruritus in up to 14% of patients.

Drug interactions

No specific drug-drug interaction studies have been performed with transdermal oxybutynin.

Dosage & administration

Each 3.9 mg patch should be applied to dry, intact skin on the abdomen, hip or buttock. Eight systems are supplied in calendar box/month.

A new application site should be selected with each new system to avoid re-application to the same site within 7 days.

References

Papers of special note have been highlighted as either of interest (•) or of considerable interest (••) to readers.

Andersson

K-E

: Pharmacology of lower urinary tract smooth muscles and penile erectile tissues. Pharmacol. Rev. 45, 253–269 (1993).

de Groat

Yoshimura

: Pharmacology of the lower urinary tract. Annu. Rev. Pharmacol. Toxicol. 41, 691–721 (2001).

Andersson

K-E

Wein

: Pharmacology of the lower urinary tract – basis for current and future treatments of urinary incontinence. Pharmacol. Rev. (2005) (In press).

Janig

Morrison

: Functional properties of spinal visceral afferents supplying abdominal and pelvic organs, with special emphasis on visceral nociception. Prog. Brain Res. 67, 87–114 (1986).

Habler

Janig

Koltaenburg

: Activation of unmyelinated afferent fibres by mechanical stimuli and inflammation of the urinary bladder in the cat. J. Physiol. 425, 545–562 (1990).

Fall

Lindstrom

Mazieres

: A bladder-to-bladder cooling reflex in the cat. J. Physiol. 427, 281–300 (1990).

Wein

: Neuromuscular dysfunction of the lower urinary tract and it treatment. In: Campbell's Urology (7th Edition). Walsh

Retik

Vaugn

Darricott E

Jr Wein

(Eds). WB Saunders Company, PA, USA, 953–1006 (1998).

Abrams

Cardozo

Fall

: The standardization of terminology of lower urinary tract function. Neurourol. Urodyn. 21, 167–178 (2002).

10.

Sigala

Mirabella

Peroni

: Differential gene expression of cholinergic muscarinic receptor subtypes in male and female normal human urinary bladder. Urology 60, 719–725 (2002).

11.

Yamaguchi

Shisda

Tamura

: Evaluation of mRNAs encoding muscarinic receptor subtypes in human detrusor muscle. J. Urol. 156, 1208–1213 (1996).

12.

Chess-Williams

Chapple

Yamanishi

: The minor population of M3-receptors mediate contraction of human detrusor muscle in vitro. J. Auton. Pharmacol. 21, 243–248 (2001).

13.

Gillespie

Harvey

Drake

: Agonist and nerve induced phasic activity in the isolated whole bladder of the guinea-pig: evidence for two types of bladder activity. Exp. Physiol. 88, 343–357 (2003).

14.

Andersson

K-E

Arner

: Urinary bladder contraction and relaxation: physiology and pathophysiology. Physiol. Rev. 84, 935–986 (2004).

15.

Excellent review of the current understanding of bladder function and dysfunction

16.

Kories

Czborra

Fletcher

: Gender comparison of muscarinic receptor expression and function in rat and human urinary bladder: differential regulation of M2 and M3 receptors? Naunyn Schmiedebergs Arch. Pharmacol. 367, 524–531 (2003).

17.

Andersson

K-E

: New roles for muscarinic receptors in the pathophysiology of lower urinary tract symptoms. BJU Int. 86(Suppl. 2), 36–42; discussion 42–43 (2000).

18.

Brading

: A myogenic basis for the overactive bladder. Urology 50(Suppl. 6A), 57–67; discussion 68–73 (1997).

19.

de Groat

: A neurological basis for the overactive bladder. Urology 50(Suppl. 6A), 36–52; discussion 53–56 (1997).

20.

Morrison

Steers

Brading

: Neurophysiology and neuropharmacology. In: Incontinence, 2nd International Consultation on Incontinence. Abrams

Khoury

Wein

(Eds). Plymbridge Distributors Ltd, Plymouth, UK, 85–164 (2002).

21.

Andersson

K-E

Yoshida

: Antimuscarinics and the overactive detrusor – which is the main mechanism of action? Eur. Urol. 43, 1–5 (2003).

22.

Andersson

K-E

: Antimuscarinics for treatment of overactive bladder. Lancet Neurol. 3, 46–53 (2004).

23.

Andersson

K-E

: Bladder activation: afferent mechanisms. Urology 59(5 Suppl. 1), 43–50 (2002).

24.

Low

: Urethral behavior during the involuntary detrusor contraction. Am. J. Obstet. Gynecol. 128, 32–42 (1977).

25.

Cardozo

Stanton

: An objective comparison of the effects of parenterally administered drug in patients suffering from detrusor instability. J. Urol. 122, 58–59 (1979).

26.

Blaivas

Labib

Michalik

: Cystometric response to propantheline in detrusor hyperreflexia: therapeutic implications. J. Urol. 124, 259–262 (1980).

27.

Naglo

Nergardh

Boreus

: Influence of atropine and isoprenaline on detrusor hyperactivity in children with neurogenic bladder. Scand. J. Urol. Nephrol. 15, 97–102 (1981).

28.

Ritch

Castleden

George

: A second look at emepronium bromide in urinary incontinence. Lancet 1, 504–506 (1977).

29.

Walther

Hansen

: Urinary incontinence in old age. A controlled trial of emepronium bromide. Br. J. Urol. 41, 249–253 (1982).

30.

Bonnesen

Tikjob

Kamper

: Effect of emepronium bromide on sumptoms and urinary bladder function after transurethral resection of the prostate. A double-blind randomized trial. Urol. Int. 39, 318–320 (1984).

31.

Zorzitto

Jewett

Fernie

: Effectiveness of propantheline bromide in the treatment of geriatric patients with detrusor instability. Neurourol. Urodyn. 5, 133–141 (1986).

32.

Guay

: Clinical pharmacokinetics of drugs used to treat urge incontinence. Clin. Pharmacokinet. 42, 1243–1285 (2003).

33.

Pietzko

Dimpfel

Schwantes

: Influence of trospium chloride and oxybutynin on quantitative EEG in healthy volunteers. Eur. J. Clin. Pharmacol. 47, 337–343 (1994).

34.

Eglen

Hegde

Watson

: Muscarinic receptor subtypes and smooth muscle function. Pharmacol. Rev. 48, 531–565 (1996).

35.

Appell

Sand

Dmochowski

: Prospective randomized, controlled trial of extended-release oxybutynin chloride and tolterodine tartrate in the treatment of overactive bladder: results of the OBJECT study. Mayo Clin. Proc. 76(4), 358–363 (2001).

36.

First of the head-to-head studies of overactive bladder drugs

37.

Diokno

Appell

Sand

: Prospective, randomized, double-blind study of the efficacy and tolerability of the extended-release formulations of oxybutynin and tolterodine for overative bladder; result of the OPERA trial. Mayo Clin. Proc. 78(6), 687–695 (2003).

38.

Head-to-head evaluation of fixed dosages of oxybutynin extended-release (ER) and tolterodine ER

39.

Dmochowski

Davila

Zinner

: Efficacy and safety of transdermal oxybutynin in patients with urge and mixed urinary incontinence. J. Urol. 168, 580–586 (2002).

40.

Yarker

Goa

Fitton

: Oxybutynin. A review of its pharmacodynamic and pharmacokinetic properties, and its therapeutic use in detrusor instability. Drugs Aging 6(3), 243–262 (1995).

41.

Norona-Blob

Kachur

: Enantiomers of oxybutynin: in vitro pharmacological characterization at M1, M2 and M3 muscarinic receptors and in vivo effects on urinary bladder contraction, mydriasis and salivary secretion in guinea-pigs. J. Pharmacol. Exp. Ther. 256, 562–567 (1991).

42.

Waldeck

Larsson

Andersson

: Comparison of oxybutynin and it active metabolite, N-desethyl-oxybutynin, in the human detrusor and parotid gland. J. Urol. 157(3), 1093–1097 (1997).

43.

Explains how and why salivary effects are so troublesome with oxybutynin

44.

Douchamps

Derenne

Stockis

: The pharmacokinetics of oxybutynin in man. Eur. J. Clin. Pharmacol. 35(5), 515–520 (1988).

45.

Pak

Petrou

Staskin

: Trospium chloride: aquaternary amine with unique phamacologic properties. Curr. Urol. Rep. 4(6), 436–440 (2003).

46.

Todorova

Vonderheid-Guth

Dimpfel

: Effects of tolterodine, trospium chloride, and oxybutynin on the central nervous system. J. Clin. Pharmacol. 41(6), 636–644 (2001).

47.

Appell

Chancellor

Zobrist

: Pharmacokinetics, metabolism, and saliva output during transdermal and extended-release oral oxybutynin administration in healthy subjects. Mayo Clin. Proc. 78(6), 696–702 (2003).

48.

Clinical experience of decreased effects on salivation by the oxybutynin transdermal system (TDS)

49.

Davila

Daugherty

Sanders

: A short-term, multicenter, randomized double-blind dose titration study of the efficacy and anticholinergic side effects of transdermal compared to immediate release oral oxybutynin treatment of patients with urge urinary incontinence. J. Urol. 166(1), 140–145 (2001).

50.

Comparison of oxybutynin immediate-release and oxybutynin TDS on efficacy and side effects

51.

Dmochowski

Sand

Zinner

: Comparative efficacy and safety of transdermal oxybutynin and oral tolterodine versus placebo in previously treated patients with urge and mixed urinary incontinence. Urology 62(2), 237–242 (2003).

52.

Comparison of tolterodine ER and oxybutynin TDS on efficacy and side effects

53.

Zinner

Davila

Anderson

: Dose modulation using oxybutynin transdermal system for overactive bladder in older adults. Presentation: American Geriatrics Society Annual Meeting. Las Vegas, NV, USA, May 17–21 (2004).

Oxybutynin and its New Transdermal Application for the Treatment of Overactive Bladder

Abstract

Keywords

Antimuscarinic (anticholinergic) drugs

Oxybutynin

Transdermal oxybutynin

Conclusion

Future perspective

References