Cardozo_A4_template_04 17/03/2010 15:20 Page 44
Overactive Bladder and Incontinence
Figure 1: The Chemical Structure of Trospium Chloride drugs. As expected, trospium chloride is poorly absorbed from the
Distinguishes It from All Other Anticholinergics
gastrointestinal tract and displays a rather low bioavailability; this
can easily be overcome by increasing the administered dose
(without risk of increasing adverse events) and by not taking the
+
Other
N N
Trospium chloride =
drug together with food. Because of its hydrophilicity trospium
anticholinergics = quaternary
chloride is unlikely to cross the blood–brain barrier.
20
This may lead
tertiary amine ammonium
compounds
R
compound
to a number of clinical advantages of particular importance when
1
R
1
managing elderly patients, including the expected lack of associated
cognitive dysfunction.
21
While there have been no studies aimed at
directly showing whether trospium chloride causes cognitive
Table 1: Muscarinic-receptor-binding Affinities of
Trospium Chloride and Selected Drugs Used for the
adverse effects, this assumption is supported not only by
Treatment of Overactive Bladder Syndrome
experimental studies in healthy volunteers but also by clinical
studies monitoring lack of incidence of cognitive adverse events and
Drug Muscarinic Receptor Subtype
showing complete absence of treatment-induced sleepiness.
22
Binding Affinity (pKi)
M2 M3 Trospium Chloride Has High Affinity to Both
Trospium chloride 9.2 9.3 M2 and M3 Muscarinic Receptor Subtypes
Darifenacin 7.4 9.1
Trospium chloride is a concentration-dependent competitor of
Oxybutynin 7.8 8.9
acetylcholine for post-synaptic binding sites
23,24
and binds selectively in
Tolterodine 8.0 8.5
vitro to all five muscarinic receptor subtypes without marked
Solifenacin 6.9 8.0
differences between them. However, the hydrophilic nature of trospium
prevents any significant interaction with the M1 subtype, which is
Trospium chloride has been available for many years as a mostly distributed in the CNS. While the physiological significance of M4
twice-daily antimuscarinic drug for the treatment of OAB. Of all oral and M5 receptor subtypes appears to be limited, the particularly high
antimuscarinics available for the same indication, trospium chloride affinity to both M2 and M3 receptors is certainly noteworthy, since both
is characterised by the lowest CNS penetration, which may explain receptors are of particular significance for the control of bladder
the lack of CNS adverse events reported in clinical trials.
14,15
The contraction (see Table 1).
25–27
The proportion of receptors in the bladder
clinical development of the once-daily extended-release (ER) probably varies in relation to age and to pathophysiological changes,
formulation of trospium chloride has further improved the with studies indicating that the proportion of the M2 subtype increases
therapeutic index of this drug: clinical efficacy against placebo with age.
10
The theoretical therapeutic advantage of subtype-specific
reaches the upper range not only compared with the immediate- anticholinergics with increased affinity for M3 receptors may be
release formulation but also among all reported clinical trials of important in view of these recent findings.
antimuscarinic drugs, whereas the adverse event profile is
significantly reduced, with the lowest reported incidence of dry Trospium Chloride Is Not Metabolised by the
mouth across the whole oral antimuscarinic class.
16,17
The ER Cytochrome Systems in the Liver
trospium chloride formulation seems to provide a meaningful Once absorbed in the gastrointestinal tract, trospium chloride is
balance between efficacy and tolerability, which may be the basis metabolised only to a very slight extent by enzymes of the
for good patient compliance in clinical practice. The aim of this mitochondrial P450 system. Studies of the most important enzymes
article is to highlight the individual properties of trospium chloride have shown that it is not metabolised via isoenzymes CYP1A2,
that may relate to some of the parameters of efficacy and CYP2A6, CYP3A4, CYP2C9, CYP2C19, CYP2D6 or CYP2E1, and that
tolerability reported in clinical trials. only enzyme CYP2D6 is inhibited at high, clinically irrelevant
concentrations. Active metabolites, such as those seen with all
Trospium Chloride – other anticholinergics that are metabolised by isoenzymes CYP3A4
Distinct Among Anticholinergics and CYP2D6, are not formed after the administration of trospium
Molecular characteristics clearly distinguish trospium chloride from chloride. Only about 10% is hydrolysed in the liver to inactive
other anticholinergics used for the treatment of OAB.
18
In general, four spiroalcohol.
20,28
The potential for interaction (inhibition or induction)
specific properties can be highlighted. with concomitantly administered drugs is thus minimal for trospium
chloride, in contrast to all other anticholinergics used for the
Trospium Chloride Is a Positively Charged same indication; this is particularly significant for elderly patients
Quaternary Ammonium Compound with with co-morbidity and consequent polypharmacy.
Low Central Nervous System Impact
Unlike other anticholinergics, which are tertiary amines, trospium Trospium Chloride Is Mainly Excreted in Urine
chloride is a quaternary ammonium compound and is markedly Systemically absorbed trospium chloride does not undergo a
hydrophilic, being positively charged at physiological pH (see Figure first-pass effect and is very largely (up to 80%) excreted through the
1). Moreover, in previous experiments in Caco-2 cells as well as in kidneys
29,30
in an unchanged form: urinary excretion as an unmodified
recent experiments in knock-out mice, it has been found that active compound is of interest to both researchers and clinicians. It
active transporters (PgP or MDR1) induce efflux from cells and has been observed that the recent shift in understanding of the
therefore possibly extrude trospium chloride molecules entered in pathophysiology of OAB, with implication of the afferent nerves from
central nervous tissue.
19
This has major consequences for its the bladder and input from the urothelium, may be clinically
pharmacokinetics, metabolism and potential interaction with other beneficial. In particular, accumulation of the active compound in the
44
EUROPEAN UROLOGICAL REVIEW
Page 1 |
Page 2 |
Page 3 |
Page 4 |
Page 5 |
Page 6 |
Page 7 |
Page 8 |
Page 9 |
Page 10 |
Page 11 |
Page 12 |
Page 13 |
Page 14 |
Page 15 |
Page 16 |
Page 17 |
Page 18 |
Page 19 |
Page 20 |
Page 21 |
Page 22 |
Page 23 |
Page 24 |
Page 25 |
Page 26 |
Page 27 |
Page 28 |
Page 29 |
Page 30 |
Page 31 |
Page 32 |
Page 33 |
Page 34 |
Page 35 |
Page 36 |
Page 37 |
Page 38 |
Page 39 |
Page 40 |
Page 41 |
Page 42 |
Page 43 |
Page 44 |
Page 45 |
Page 46 |
Page 47 |
Page 48 |
Page 49 |
Page 50 |
Page 51 |
Page 52 |
Page 53 |
Page 54 |
Page 55 |
Page 56 |
Page 57 |
Page 58 |
Page 59 |
Page 60 |
Page 61 |
Page 62 |
Page 63 |
Page 64 |
Page 65 |
Page 66 |
Page 67 |
Page 68 |
Page 69 |
Page 70 |
Page 71 |
Page 72 |
Page 73 |
Page 74 |
Page 75 |
Page 76 |
Page 77 |
Page 78 |
Page 79 |
Page 80 |
Page 81 |
Page 82 |
Page 83 |
Page 84 |
Page 85 |
Page 86 |
Page 87 |
Page 88 |
Page 89 |
Page 90 |
Page 91 |
Page 92 |
Page 93 |
Page 94 |
Page 95 |
Page 96 |
Page 97 |
Page 98 |
Page 99 |
Page 100