Aims of Study:
Tolterodine, oxybutynin and trospium chloride are antimuscarinic agents
commonly
used in
the treatment
of the overactive
bladder.
These agents
differ in
terms of
their lipid
solubility
and, therefore,
may cross
the blood-brain
barrier
to different
extent.
However,
comparative
data regarding
their influence
on the central
nervous
system (CNS)
are limited. The objective of
this study
was to evaluate
the effects
of these
antimuscarinic
agents on
the CNS
by using
quantitative-topographical
EEG (qEEG).
Methods:
In a single-blind, placebo-controlled,
parallel-group,
multiple-dose
study, 64
healthy
male volunteers
(aged 18–35 years)
were randomised
to receive
tolterodine
2 mg
twice daily,
oxybutynin
5 mg
three times
daily (tid)
or trospium
chloride
15 mg
tid. Changes
from baseline
in spectral
EEG-power
(mV2) were evaluated in 6 frequency bands at 17 electrode positions
(qEEG) during
rest and
under mental
demand over
a period
of 14 hours.
Safety assessments
included
monitoring
of adverse
events,
vital signs
and 12-lead
ECG recordings.
Results:
Oxybutynin caused statistically significant power reduction in theta,
alpha1,
alpha2 and
beta1 EEG
frequency
bands, consistent
with a probable
direct CNS
effect.
Maximum
effects
were seen
1‑2 hours
after dosing.
Cumulative
effects
from multiple
dosing were
noted.
Tolterodine and trospium chloride induced only a marginal effect on the
CNS, as
shown by
a slight
theta power
reduction.
Such effects
were assumed
to be of
secondary
origin,
reflecting
the feedback
control
from the
periphery
to Barrington’s
nucleus
(the pontine
micturition
centre).
Oxybutynin
differed
significantly
from tolterodine
and trospium
chloride
in terms
of effects
on theta,
alpha1,
alpha2 and
beta1 power.
No significant
difference
was found
between
trospium
chloride
and tolterodine.
A total of 57 adverse events were reported (4 placebo; 14 tolterodine;
15 trospium
chloride;
and 24 by
oxybutynin
recipients),
of which
36 were
CNS-related.
Only 19
of the CNS-related
adverse
events were
classified
as drug-related
(3 tolterodine;
5 trospium
chloride;
and 11 oxybutynin).
Conclusions:
Oxybutynin (a tertiary amine) has significant effects on the CNS as measured
with qEEG,
while tolterodine
and trospium
chloride
show marginal
effects.
These differences
are explained
by the fact
that tolterodine
(a tertiary
amine) and
its active
metabolite
have a lipophilicity
30 and >350
times lower
than oxybutynin,
respectively,
while trospium
chloride
is a quaternary
amine that
barely crosses
the blood-brain
barrier.
This study was supported by Pharmacia & Upjohn GmbH, Erlangen, Germany.
