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A New Once-daily Medication for the Treatment of Overactive Bladder Syndrome
bladder may account for its rapid onset of action and relatively Figure 2: Theoretical Representation of the
greater effect on the bladder compared with the salivary glands, as
Local Action of Trospium in Urine
shown by the comparatively low incidence of cholinergic adverse
effects such as dry mouth.
21
Trospium
Interaction of Trospium Chloride
with the Urothelium
The long-held assumption that antimuscarinic drugs were clinically
effective by acting solely via muscarinic receptors located on
detrusor smooth muscle has recently been questioned, and it is
Urothelium
thought that these drugs could work by also affecting muscarinic
receptors within the urothelium and on bladder afferent nerve
branches.
31
The role of the urothelium in the physiology of the
micturition process and its potential implications in the
pathophysiology and pharmacological treatment of OAB have been
the subject of several reviews.
32–36
The muscarinic receptor density
on bladder urothelium has been found to be 40% higher in pig’s
bladders than in detrusor muscle, although it has not been
demonstrated that these receptors actually play a role in
micturition. On the basis of several experimental findings it has
been suggested that a release of acetylcholine of non-neuronal
Afferent nerves
origin, possibly generated by the urothelium, may interact with
these receptors and excite the afferent nerves in the suburothelium
and within the detrusor. This may be a mechanism by which the
detrusor muscle tone is controlled during the storage phase.
Andersson speculated that such a mechanism could prove to be
important in the pathophysiology of OAB and a possible target for
antimuscarinic drugs.
37
Further evidence supporting an active role for the urothelium points
Detrusor muscle
to involvement of muscarinic mechanisms in urothelial sensory
function.
32
It has been reported that activation of the muscarinic
receptors in the urothelium releases substances that modulate
afferent nerves and smooth-muscle activity: such functions could be
Interaction with the muscarinic receptors of the urothelium may influence the afferent-
involved under conditions of stretch and in age-related changes in pathway-mediated feeling of urgency to the central nervous system.
bladder function. Basal acetylcholine released from the urothelium
of patients >65 years of age is significantly higher than that obtained bladder overactivity. The authors speculated that antimuscarinic
in younger patients, and the same is true with the percentage of agents present in urine may have a local effect on bladder function
acetylcholine release induced by stretch. The afferent innervation during the storage phase, in addition to the smooth-muscle-
from the bladder includes both myelinated and unmyelinated C mediated voiding phase.
42,43
This study not only confirmed the
fibres, the latter terminating in the suburothelial layer, with some pharmacokinetic findings regarding the excretion of metabolically
nerve endings even penetrating the urothelium. It has also been unmodified trospium in urine, but also demonstrated that it retains
suggested that such a proximity of sensory terminals to the bladder its pharmacological action – most likely mediated by the muscarinic
inner surface makes the bladder potentially responsive to in situ receptors present in the urothelium – at the concentrations reached
pharmacological challenges and, in general, potentially sensitive to in urine after a standard therapeutic regimen. Therefore, the overall
urine composition.
32
clinical efficacy of trospium chloride in OAB may be ascribed to a
dual mode of action: systemic and local, with the former targeting
The potential in situ pharmacological action of unmetabolised the muscarinic receptors mediating contraction of the detrusor
trospium that is excreted in urine has been described,
38,39
and is muscle and the latter potentially mediated by the muscarinic
supported by experiments in which human urine from volunteers receptors of the urothelium (see Figure 2). The extent to which and
treated with trospium, tolterodine or oxybutynin was tested in an mechanisms by which afferent muscarinic receptor pathways may
animal model of OAB.
40,41
These human urine samples were contribute to normal or pathological bladder sensation are still not
administered intravesically in female rats with carbachol-induced fully understood, with contrasting evidence being shown in a murine
bladder overactivity; cystometric variables were monitored during ex vivo bladder model where potentially confounding evidence from
infusion of saline or urine samples from the different experimental the CNS is avoided.
44
groups in the presence and absence of carbachol. Bladder capacity
and intercontraction intervals were significantly decreased when Clinical Significance of the Dual Mode of
carbachol was instilled with urine taken from untreated subjects or Action of Trospium Chloride
those treated with tolterodine or oxybutynin. By contrast, urine from Since urgency is the defining symptom of OAB, pharmacological
subjects treated with trospium prevented carbachol-induced control of the afferent stimuli from the bladder may be important in
EUROPEAN UROLOGICAL REVIEW
45
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