Tài liệu CLINICAL PHARMACOLOGY 2003 (PART 22) pdf

20
Epilepsy,
parkinsonism
and
allied
conditions
SYNOPSIS
•
Antiepilepsy drugs: principles
of
management;
withdrawal
of
therapy;
pregnancy;
teratogenic
effects; epilepsy
in
children;
status
epilepticus
•
Individual drugs: carbamazepine,
phenytoin,
sodium valproate,
lamotrigine,
vigabatrin,
gabapentin, clonazepam,
topiramate,
levetiracetam.
•

Parkinsonism
Objectives
of
therapy
Drug
therapy;
problems
of
long-term
treatment
•
Other
disorders
of
movement
•
Tetanus
cortical
neurons simultaneously (primary generalised
seizure).
Bromide
(1857)
was the
first
drug
to be
used
for
the
treatment

of
epilepsy,
but it is now
obsolete.
Phenobarbital, introduced
in
1912, controlled
patients resistant
to
bromides.
The
next success
was
the
discovery
in
1938
of
phenytoin
(a
hydantoin)
which
is
structurally related
to the
barbiturates.
Since
then many other drugs have been discovered,
but
phenytoin still remains

a
drug
of
choice
in the
treatment
of
major
epilepsy. Over
the
past
ten
years
there
has
been
a
dramatic increase
in the
number
of
new
anticonvulsant drugs (vigabatrin, gabapentin,
lamotrigine,
topiramate,
oxcarbazepine, levetira-
cetam),
but
none
has

been shown
to be
superior
to
the
major
standard anticonvulsants (phenytoin,
carbamazepine
and
sodium valproate).
Antiepilepsy
drugs
Epilepsy
affects
5-10
per
1000
of the
general
population.
1
It is due to
sudden, excessive depolar-
isation
of
some
or all
cerebral neurons. This
may
remain localised

(focal
seizure)
or may
spread
to
cause
a
secondary generalised seizure,
or
affect
all
1
Some people with epilepsy make pilgrimages
to
Terni
(Italy)
to
seek intercession
from
Saint Valentine
to
relieve
their
condition. There
was
more than
one
Saint Valentine
and
it

is
unclear
if he was
also
the
patron saint
of
lovers.
MODE
OF
ACTION
Antiepilepsy (anticonvulsant) drugs inhibit
the
neuronal discharge
or its
spread,
and do so in one
or
more
of
three ways:
1.
Reducing cell membrane permeability
to
ions,
particularly
the
voltage-dependent
sodium
channels which

are
responsible
for the
inward
current
that generates
an
action potential. Cells
that
are
firing
repetitively
at
high
frequency
are
blocked preferentially, which
permits
discrimination between epileptic
and
physiological activity.
2.
Enhancing
the
activity
of
gamma-aminobutyric
413
20
EPILEPSY,

PARKINSONISM
AND
ALLIED
CONDITIONS
acid
(GABA)
the
principal inhibitory transmitter
of
the
brain;
the
result
is
increased membrane
permeability
to
chloride
ion,
which reduces cell
excitability.
3.
Inhibiting excitatory neurotransmitters, e.g.
glutamate.
CLASSIFICATION
OF
EPILEPSIES
A
generally accepted
classification

is
given
in
Table
20.2
(p.
418), together with drugs
of
choice
for the
various seizure disorders.
Principles
of
management
These
call
for
attention
to
nondrug
as
well
as
drug
measures,
as set out
below:
• Any
causative
factor

must,
of
course,
be
treated,
e.g. cerebral neoplasm.
•
Educate
the
patient about
the
disease, duration
of
treatment
and
need
for
compliance.
•
Avoid precipitating
factors,
e.g.
alcohol, sleep
deprivation, emotional stress.
•
Anticipate natural variation, e.g.
fits
may
occur
particularly

or
exclusively around periods
in
women (catamenial
2
epilepsy).
•
Give
antiepilepsy
drugs only
if
seizure type
and
frequency
require
it,
i.e.
more than
one fit
every
6-12 months.
GENERAL
GUIDETO
ANTIEPILEPSY
DRUG
THERAPY
The
decision whether
or not to
initiate drug therapy

after
a
single seizure remains controversial since
approximately
25% of
patients
may not
have
another
seizure. Some advocate treatment
on the
basis that early initiation
may
improve prognosis
but the
matter
has not yet
been resolved.
1.
Therapy should start with
a
single
well-tried
and
safe
drug.
The
majority
of
patients (70%)

can be
controlled
on one
drug (monotherapy).
2.
Anticonvulsant drug treatment should
be
2
Greek katamenios,
monthly
appropriate
to the
type
of
seizure disorder.
Although
some drugs have
a
wide spectrum
of
action
against
different
seizure types, some
are
more
specific
and may
even aggravate certain
seizure

types. Carbamazepine
is a
drug
of
first
choice
for
focal
and
secondary generalised
epilepsy
but
aggravates myoclonic
and
absence
seizures.
Sodium valproate
and
lamotrigine
have
a
wide spectrum
of
action
and are
active
against both primary
and
secondary generalised
epilepsy.

3.
Choice
of
drug
is
also determined
by the
patient's
age and
sex. This
is
particularly true
for
women
who
prefer
to
avoid drugs associated
with teratogenesis
or
that have adverse
effects
on
their appearance,
e.g.
hirsutism
from
phenytoin.
4.
If the

attempt
to
control
a
patient's epilepsy
by
use of a
single drug
is
unsuccessful,
it
should
be
withdrawn
and
replaced
by a
second
line
drug,
though these
are
effective
in
only about
10% of
patients.
There
is
little

evidence
that
three
drugs
are
better than two,
and not
much that
two are
better
than one. More drugs
often
mean more
adverse
effects.
5.
Abrupt
withdrawal.
Effective
therapy must never
be
stopped suddenly either
by the
doctor
(carelessness)
or by the
patient (carelessness,
intercurrent illness
or
ignorance),

or
status
epilepticus
may
occur.
But if
rapid withdrawal
is
required
by the
occurrence
of
toxicity,
a
substantial dose
of
another antiepilepsy drug
should
be
given
at
once.
6.
In
cases where
fits
are
liable
to
occur

at a
particular
time,
e.g.
the
menstrual
period,
dosage should
be
adjusted
to
achieve maximal
drug
effect
at
that time
or
drug treatment
can be
confined
to
this time.
For
example,
in
catamenial
epilepsy, clobazam
can be
useful
given only

at
period time.
Dosage
and
administration
Generally
drugs
are
best given
as a
single
or
twice
daily
dose
to
increase compliance. Many patients
dislike taking medication
to
work
or
school
and
being seen
to
take
it
but,
necessarily, drugs with
short

duration
of
action
may
require
to be
taken
three
or
even
four
times
a
day.
414
PRINCIPLES
OF
MANAGEMENT
20
Regimens
for
initial
dosing
tend
to
vary with
different
drugs.
In
general, drugs

are
started
in a
small dose
and
increased
at
two-weekly intervals
to
the
minimum
effective
dose.
The
patient's seizures
are
then monitored
and
further
increases
in
dose
only made
if
seizures continue.
The
time interval
for
dosage increases should
therefore

be
sufficiently
wide apart
to
allow changes
in the
seizure
frequency
due to
changes
in
drug therapy
to be
accurately
determined. These issues
are
particularly important
for
a
doctor,
e.g.
in an
emergency department,
who
has
never seen
the
patient with
a fit or
series

of
fits.
It
is
important then
to
consider
the
cause, whether
it
is
noncompliance (which
can be due to
intercurrent
disease),
an
inadequate drug regimen
or an
increase
in the
severity
of the
disease.
MONITORING BLOOD
CONCENTRATIONS
OF
ANTICONVULSANTS
Many
biochemistry laboratories
no

longer under-
take routine measurement
of the
plasma concentra-
tion
for
most anticonvulsant drugs because plasma
concentrations
are
insufficiently
stable
to
serve
as a
useful
guide
to
change
of
dose.
The
exception
is
phenytoin, where
a
small increase
in
dose
may
lead

to a
disproportionate rise
in the
plasma drug
concentration
(see
zero-order pharmacokinetics,
p. 99) and
plasma monitoring
is
essential. With
other drugs
the
dose
is
increased
to the
maximum
tolerated level
and,
if
seizures continue,
it is
replaced
by
another.
DRUG
WITHDRAWAL
After
a

period
of at
least
2-3
years
free
from
seizures, withdrawal
of
antiepilepsy drug therapy
can be
considered.
The
prognosis
of a
seizure
dis-
order
is
determined
by a
number
of
factors.
Some
are
known
to
remit spontaneously
e.g.

benign
rolandic
epilepsy
and
petit
mal,
whereas others
never
remit
e.g.
juvenile myoclonic epilepsy.
In
many types
of
epilepsy
the
outlook
is
less
certain
and
only general indicators
are
available.
The
following
factors
can be
important:
• The

type
of
seizure disorder
—
major
seizures
are
more
easily controlled.
• The
time
to
remission
—
early remission carries
a
better
outlook.
• The
number
of
drugs required
to
induce
remission
—
rapid remission
on a
single drug
is

a
favourable
indicator
for
successful
withdrawal.
• The
presence
of an
underlying
lesion
—
control
is
often
difficult.
• The
presence
of an
associated
neurological
deficit
or
learning
difficulty
—
control
is
often
difficult.

In
general,
if a
patient with
a
major
epilepsy
has
no
neurological
deficit
or
structural lesion
and is of
normal intelligence, there
is a
reasonable chance
of
continued remission, particularly
if
this
is
rapidly
achieved with
a
single drug.
In
general,
in
adult

epilepsy,
discontinuing
the
antiepilepsy drug
is
asso-
ciated with about
20%
relapse during withdrawal
and a
further
20%
relapse over
the
following
5
years;
after
this period relapse
is
unusual.
It is
generally
recommended that
the
antiepilepsy drug
be
withdrawn over
a
period

of 6
months.
If a fit
occurs
during this time,
full
therapy must
be
resumed again until
the
patient
has
been
free
from
seizures
for a
further
2-3
years.
DRIVING
REGULATIONS
AND
EPILEPSY
The UK
allows patients
to
drive
a car
(but

not a
truck
or
bus)
if
they have
not had a
daytime
fit for
1
year
(or
after
3
years
if
they continue
to be
subject
to
fits
only whilst asleep).
Any fit
that occurs during
or
after
drug
withdrawal
incurs
loss

of the
driving
licence
for a
year.
Because
losing
the
right
to
drive
is
perceived
to be a
significant
social disability, most
patients
prefer
to
remain
on
medication.
PREGNANCY
AND
EPILEPSY
Pregnancy
can
affect
seizure disorder which worsens
in

about
a
third, improves
in a
third,
and
remains
unchanged
in the
remainder.
Ideally,
patients should
have their seizure disorder properly investigated
and
treated
before
pregnancy with
the
best control
achieved
on the
lowest dose
of the
least teratogenic
drug.
Major
seizures
are
harmful
to the

developing
fetus
because
of the
possibility
of
anoxia
and
meta-
bolic disorder.
Minor
seizures
are
probably harm-
less
and
therefore
need
not be
eradicated. Patients
415
20
EPILEPSY,
PARKINSONISM
AND
ALLIED
CONDITIONS
should
be
advised

of the
necessity
of
taking
folic
acid
supplements,
since some antiepilepsy drugs
affect
folic
acid metabolism
and
folic
acid
deficiency
is a
risk
factor
for
neural tube
defects.
Hepatic
enzyme inducing antiepilepsy drugs lower
the
mother's
concentration
of
vitamin
K,
which

can
aggravate
any
postpartum haemorrhage. Pregnant
mothers
should
therefore
be
given
an
oral vitamin
K
for the
last
two
weeks
of
pregnancy.
Pharmacokinetics
in
pregnancy
The
total plasma concentration
of
drug
falls,
especially towards
the end of
pregnancy,
due to

haemodilution,
but the
therapeutically important
free
(unbound)
fraction in
plasma
is
less
affected.
In
practice,
the
patient's
clinical state
is
observed
closely
and the
dose
of
drug
is
increased
if
seizures
occur
more
often
than expected. Hepatic drug

metabolism
tends
to
increase during pregnancy.
After
delivery,
the
pharmacokinetics revert
to the
prepregnancy state over
a few
days.
Breast
feeding
Antiepilepsy drugs pass into breast milk (see
p.
116),
phenobarbital, primidone
and
ethosuximide
in
significant
quantities, phenytoin
and
sodium
valproate less
so.
There
is a
risk that

the
baby will
become
sedated
or
suckle poorly
but,
provided
a
watch
is
maintained
for
these
effects,
the
balance
of
advantage
favours
breast feeding whilst taking
antiepilepsy drugs.
Teratogenic
effects
Children
of
mothers taking antiepilepsy drugs
have
an
approximately

2-3 x
increased
frequency
of
malformations
at
birth.
In a
case-control study
of
pregnant women,
the
frequency
of
malformation
was
20.6%
in
infants
whose mothers took
one
anticonvulsant drug
and
28.0% with
two or
more
such drugs, compared
to
8.5%
in

matched controls.
3
Infants
of
mothers
who
gave
a
history
of
epilepsy
but did not
take antiepilepsy drugs
did not
have
a
higher
frequency
than
the
controls, indicating that
malformations
are
largely
due to the
antiepilepsy
3
Holmes
LB et al
2001

New
England Journal
of
Medicine
344:1132-1138.
drugs themselves (rather than
to
factors
related
to
the
mother
or her
epilepsy).
The
features
of
what
has
collectively become
known
as
anticonvulsant
embryopathy
comprise:
major
malformations
(often
cardiac),
microcephaly,

growth retardation,
and
hypoplasia
of the
midface
and
fingers.
The
frequency
of
most malformations
was
increased
in
infants exposed
to
phenytoin alone
or
phenobarbital alone. Carbamazepine
was
asso-
ciated
with
major
malformations, microcephaly
and
growth retardation
but not
hypoplasia
of the

mid-
face
and
fingers.
In
general,
the
major
malforma-
tions were
not
distinct
from
those occurring among
infants
whose mothers
had not
taken antiepilepsy
drugs, with
two
exceptions: marked hypoplasia
of
the
nails
and
stiff
joints were strongly associated
with phenytoin with
or
without phenobarbitone,

and
lumbosacral
spina
bifida
was
commoner
in
infants
exposed
to
carbamazepine
or
sodium
valproate.
With
current information,
carbamazepine
seems
to
be the
safest
drug
for use
during pregnancy. Data
on
lamotrigine (more recently introduced)
are
increasing
but it has not
been

shown
to be
strongly
associated with malformations.
When counselling whether
or not to
treat,
and
with
which drug,
factors
such
as the
severity
and
type
of
seizure disorder also need
to be
taken
in
to
account since control
of
major
seizures
is of
fundamental
importance.
EPILEPSY

AND
ORAL
CONTRACEPTIVES
Some
antiepilepsy drugs (carbamazepine, phenytoin,
barbituates, topiramate, oxcarbazepine) induce
steroid metabolising enzymes
and can
cause
hormonal contraception
to
fail.
Patients
who are
taking
these drugs need
a
higher
dose
of
oestrogen
(least
50
micrograms/day)
if
they
wish
to
continue
on

the
pill, although this does
not
guarantee
complete protection
from
pregnancy with
the
asso-
ciated
risks
to the
fetus.
Lamotrigine
and
sodium
valproate
are not
enzyme inducers
and
their
use is
not
reason
to
alter
the
dose
of
oral contraceptive.

EPILEPSY
IN
CHILDREN
Fits
in
children
are
treated
as in
adults,
but
children
416
PHARMACOLOGY
OF
INDIVIDUAL
DRUGS
20
may
respond
differently
and
become irritable, e.g.
with
sodium
valproate
or
phenobarbitone.
Whether
antiepilepsy drugs

interfere
with later mental
and
physical
development
remains
uncertain,
and it is
unwise
to
assume they
do
not.
The
sensible course
is
to
control
the
epilepsy with monotherapy
in
minimal doses
and
with special attention
to
preci-
pitating
factors,
and to
attempt drug withdrawal

when
it is
deemed
safe
(see above).
When
a
child
has,
febrile
convulsions
the
decision
to
embark
on
continuous prophylaxis
is
serious
for
the
child,
and
depends
on an
assessment
of
risk
factors,
e.g. age, nature

and
duration
of the
fits.
Most
children
who
have
febrile
convulsions
do not
develop epilepsy. Prolonged drug therapy, e.g.
with
phenytoin
or
phenobarbitone,
has
been shown
to
interfere
with cognitive
4
development,
the
effect
persisting
for
months
after
the

drug
is
withdrawn.
Parents
may be
supplied with
a
specially
formu-
lated solution
of
diazepam
for
rectal administration
(absorption
from
a
suppository
is too
slow)
for
easy
and
early administration,
and
advised
on
managing
fever,
e.g.

use
paracetamol
at the
first
hint
of
fever,
and
tepid sponging.
STATUS
EPILEPTICUS
Status
epilepticus
is a
medical emergency.
Loraze-
pam
i.v.
is now the
preferred
initial choice.
Clona-
zepam
is an
alternative.
Diazepam
i.v.
was
widely
used

as the
first
line drug,
but it is
more likely
to
cause
hypotension
and
respiratory depression,
and
its
antiepilepsy
effect
wears
off
after
about
20
minutes,
so
that phenytoin
i.v
must also
be
given
at
the
same time
to

suppress
further
fitting
(with
ECG
and
blood pressure monitoring, since cardiac
arrhythmias
and
further
hypotension
may
result).
For
this reason some consider
phenobarbitone
to be
safer.
If
resuscitation
facilities
are not
immediately
available, diazepam
can be
given
by
rectal solution.
Midazolam
(nasally)

may be
preferred
in
institu-
tions, e.g. mental hospitals, rather than diazepam
rectally
because patient
and
carer compliance
are
better.
Clomethiazole
is
often
given
in
status
epilepticus since
it is
easy
to
administer,
but it has
no
prolonged anticonvulsant
effect
and is
prone
TABLE
20.1

Treatment
of
status epilepticus
in
adults
Early
status Lorazepam
4 mg
i.v.;
repeat
once
after
10
minutes
if
necessary
or
Clonazepam
I mg
i.v.
over
30
seconds,
repeat
if
necessary
or
Diazepam 10-20
mg
over

2-4
min;
repeat
once
after
30
minutes
if
necessary.
Established status
Phenytoin
15-18
mg/kg
i.v.
at a
rate
of
50
mg/minute
and/or
Phenobarbitone
10-20
mg/kg
i.v.
at a
rate
of 100
mg/minute
or
Refractory

status
Thiopental
or
Propofol
or
Midazolam
with
full
intensive care
support
to
cause respiratory depression
and
hypotension.
Details
of
further
management appear
in
Table
20.1.
Once
the
emergency
is
over, exploration
of the
reason
for the
episode

and
reinstitution
of
normal
therapy
are
essential. Magnesium sulphate
may be
better than phenytoin
for the
treatment
of the
seizure disorder
of
eclampsia (see also
p.
493).
5
Paraldehyde
is now
rarely used.
It
smells
and
tastes unpleasant
and is
partly excreted unchanged
via
the
lungs (75%

is
metabolised; t
1
/
2
5 h); it is an
irritant (avoid
in
peptic ulcer)
and
causes
painful
muscle necrosis when
injected
i.m.
It
dissolves
plastic syringes.
Pharmacology
of
individual
drugs
The
drugs used
in the
treatment
of
epilepsy
are
given

in
Table 20.2.
CARBAMAZEPINE
Carbamazepine
(Tegretol)
has a
range
of
actions,
of
which
the
most important probably
is
blockade
of
voltage-dependent sodium
ion
channels, reducing
membrane excitability.
Activities
associated with thinking, learning
and
memory.
5
Eclampsia
Trial
Collaborative Group 1995 Lancet 345:
1455-1463.
417

20
EPILEPSY,
PARKINSONISM
AND
ALLIED
CONDITIONS
TABLE
20.2 Drugs
of
choice
for the
treatment
of
epilepsy
Seizure
disorder
Generalised
seizures
Primary generalised
tonic-clonic (grand mal)
Absence
(petit
mal)
Atypical
absence,
myotonic, atonic
Myoclonic
Partial
and/or
secondary

generalised
seizures
Drug
Drugs
of
choice
Sodium
valproate
Lamotrigine
Alternatives
Clonazepam
To
pi ram ate
Carbamazepine
(b)
Phenytoin
Drugs
of
choice
Ethosuximide
Sodium
valproate
Alternatives
Clonazepam
Lamotrigine
Drugs
of
choice
Sodium
valproate

Clonazepam
Lamotrigine
(c)
Phenytoin
Ethosuximide
Phenobarbital
Drug
of
choice
Sodium
valproate
(d)
Clonazepam
Alternatives
Lamotrigine
Drugs
of
choice
Carbamazepine
Sodium
valproate
Alternatives
Phenytoin
Lamotrigine
Gabapentin
Vigabatrin
(e)
Topiramate
Oxcarbazepine
Levetiracetam

Usual
daily
oral
dose
Adult
Child
1-2 g
(a)
2-6 mg
200-400
mg
0.8-
1.2
g
200-400
mg
1-1.5
g
(as
above)
(as
above)
(a)
(as
above)
(as
above)
(a)
(as
above)

(as
above)
60-90
mg
(as
above)
(as
above)
(a)
(as
above)
(as
above)
(as
above)
(a)
0.9-
1.2
g
2-3 g
(as
above)
0.6-2.4
g
1-3 g
1
5-40 mg/kg
(a)
< 1 y
0.5-1

mg
1
-5 y 1 -3 mg
5-12
y 3-6 mg
5-9
mg/kg (2-16
y)
< 1 y
100-200
mg
l-5y 200-400
mg
5-10
y
400-600
mg
10-15
y
0.6-1
g
4-8
mg/kg
>6yl-l.5g
(as
above)
(as
above)
(a)
(as

above)
(as
above)
(a)
(as
above)
(as
above)
5-8
mg/kg
(as
above)
(as
above)
(as
above)
(as
above)
(as
above)
(a)
0.9
g
(26-36
kg
b.wt.)
1.2
g
(37-50
kg

b.wt.)
0.5-1
g
(10-15
kg
b.wt.)
1-1.5
g
(15-30
kg
b.wt.)
1.5-3
g
(30-50
kg
b.wt.)
2-3 g (> 50 kg b.
wt.)
(as
above)
(a)
Varies
with
mono-
or
adjunctive therapy;
see
manufacturer's recommendations.
(b)
Avoid

if
major
seizures
are
accompanied
by
absence
seizures
or
myoclonic jerks.
(c)
Lamotrigine
may be
effective, particularly
if
used
with
sodium valproate.
(d)
Alone
or in
combination
with
clonazepam, which
may be
synergistic.
(e) In
adults,
used
as a

last
resort;
in
children,
used
for
infantile
spasms
(West's syndrome).
Regular
visual
field
monitoring
is
mandatory.
418
PHARMACOLOGY
OF
INDIVIDUAL
DRUGS
20
Pharmacokinetics.
Carbamazepine
is
extensively
metabolised;
one of the
main products,
an
epoxide

(a
chemically reactive
form),
has
anticonvulsant
activity
similar
to
that
of the
parent drug
but may
also cause some
of its
adverse
effects.
The
t
1
/
2
of
carbamazepine
falls
from
35 h to 20 h
over
the
first
few

weeks
of
therapy
due to
induction
of
hepatic
enzymes that metabolise
it as
well
as
other drugs,
including corticosteroids (adrenal
and
contracep-
tive),
theophylline
and
warfarin.
Cimetidine
and
valproate
inhibit
its
metabolism. There
are
complex
interactions with other antiepilepsy
drugs,
which

constitute
a
reason
for
monodrug therapy.
Standard tablets
are
taken twice
a
day,
but
with
higher
doses
a
three
or
four
times
a day
regimen
may be
necessary.
Rectal
and
liquid formulations
are
available,
but
there

is no
i.v. preparation.
Uses.
Carbamazepine
is
used
for
secondary gen-
eralised
and
partial seizures,
and
primary genera-
lised seizures. Because another antiepilepsy drug
(phenytoin)
was
sometimes
beneficial
in
trigeminal
neuralgia,
carbamazepine
was
tried
in
this
con-
dition,
for
which

it is now the
drug
of
choice
Adverse
effects
include
CNS
symptoms (revers-
ible
blurring
of
vision, diplopia, dizziness
and
ataxia)
and
depression
of
cardiac
AV
conduction.
Alimentary symptoms, skin
rashes,
blood disorders
and
liver
and
kidney dysfunction also occur. Osteo-
malacia
by

enhanced metabolism
of
vitamin
D
(enzyme
induction) occurs over years;
so
also does
folate
deficiency.
Enzyme induction reduces
the
efficacy
of
combined
and
progestogen-only contra-
ceptives. Carbamazepine impairs cognitive
function
less than phenytoin.
Oxcarbazepine,
like
its
analogue carbamazepine,
acts
by
blocking voltage-sensitive sodium channels.
It
is
rapidly

and
extensively metabolised
in the
liver;
the
t
1
/
2
of the
parent drug
is 2 h but
that
of its
principal metabolite (which also
has
therapeutic
activity)
is 11 h.
Unlike carbamazepine,
it
does
not
form
an
epoxide which
may
explain
why
oxcarba-

zepine
has
fewer
unwanted
effects.
Oxcarbazepine
is a
selective inducer
of a
cytochrome isoenzyme
that metabolises
the
oral contraceptive
and a 50
microgram
oestrogen preparation
is
necessary
for
contraception.
It
does
not
induce hepatic enzymes
in
general.
Oxcarbazepine
is as
effective
as

carbamazepine,
sodium valproate
and
phenytoin
in the
treatment
of
partial
and
secondary generalised seizures,
for
which
it is
used either
as
monotherapy
or add on
therapy.
The
most common chronic adverse
effect
is
hyponatraemia,
but
this
is
usually mild, asympto-
matic
and of no
clinical

significance.
Routine serum
monitoring
of the
plasma sodium
is
indicated
only where there
is
special risk, e.g. patients taking
diuretics
or the
elderly.
PHENYTOIN
Phenytoin (diphenylhydantoin, Epanutin, Dilantin)
alters
ionic
fluxes
but
principally
the
voltage-
dependent sodium
ion
channels
in the
neuronal
membrane;
this
action

is
described
as
membrane
stabilising,
and
discourages
the
spread (rather than
the
initiation)
of
seizure discharges.
Pharmacokinetics.
Phenytoin provides
a
good
example
of the
application
of
pharmacokinetics
for
successful
prescribing.
The
important aspects are:
•
Saturation (zero-order) kinetics
•

Hepatic enzyme induction
and
enzyme
inhibition
•
Opportunities
for
clinically important unwanted
interactions
are
extensive.
Saturation
kinetics.
Phenytoin
is
extensively hyd-
roxylated
in the
liver
and
this process becomes
saturated
at
about
the
doses
needed
for
therapeutic
effect.

Thus phenytoin
at low
doses exhibits
first-
order kinetics
but
saturation
or
zero-order kinetics
develop
as the
therapeutic plasma concentration
range
(10-20 mg/1)
is
approached, i.e.
the
dose
increments
of
equal size produce
disproportional
rise
in
steady-state
plasma
concentration.
A
clinically meaningful single
half-life

can be
quoted where
a
drug
is
subject
only
to
first-order
kinetics.
At low
doses, giving subtherapeutic plasma
concentrations,
the
t
l
/
2
of
phenytoin
is
6-24
h. But at
doses giving therapeutic plasma concentrations,
when metabolism
is
becoming saturated, elimina-
tion
of the
drug

is
relatively slower. This
has
signi-
419
20
EPILEPSY,
PARKINSONISM
AND
ALLIED
CONDITIONS
ficant
implications
for
patient care,
e.g.
the
time
taken
to
reach
a
steady-state plasma concentration
after
a
dose increment (about
5 x
t
1
/

2
)
is 2-3
days
at
low
dose
and
about
2
weeks
at
high
doses.
Thus
dose
increments should become smaller
as the
dose
increases (which
is why
there
is a
25-mg capsule).
Plainly,
monitoring serial plasma concentration
measurement will help.
Enzyme
induction
and

inhibition. Phenytoin
is a
potent
inducer
of
hepatic
metabolising
enzymes
affecting
itself,
other drugs
and
dietary
and
endo-
genous substances (including vitamin
D and
folate).
The
consequences
of
this
are:
a
slight
fall
of
steady
state phenytoin level over
the

first
few
weeks
of
therapy,
though this
may not be
noticeable
if
dose
increments
are
being given; enhanced metabolism
of
other drugs,
e.g.
carbamazepine,
warfarin,
steroids
(adrenal
and
gonadal), thyroxine, tricyclic anti-
depressants, doxycycline. Naturally
this
can
also
work
in
reverse,
and

other enzyme inducers,
e.g.
rifampicin,
ethanol,
may
lower phenytoin concen-
trations when there
is
capacity
for
increase
in
enzyme induction.
Drugs that inhibit phenytoin metabolism (causing
its
plasma concentration
to
rise)
include: sodium
valproate, cimetidine, co-trimoxazole, isoniazid,
chloramphenicol, some NSAIDs, disulfiram. There
is a
considerable body
of
mediocre
and
contra-
dictory
data,
the

lesson
of
which
is
that
possible
interaction should
be
borne
in
mind wherever
other drugs
are
prescribed
to a
patient taking
phenytoin.
Phenytoin
is 90%
bound
to
plasma albumin
so
that quite small changes
in
binding,
e.g.
a
drop
to

80%,
will result
in a
higher concentration
of
free,
active, drug. Since
free
drug
is
also available
to be
metabolised,
the
effect
of
such changes
is
probably
short-lived. Phenytoin orally
is
well absorbed
but
there have been pharmaceutical bioavailability
problems
in
relation
to the
nature
of the

diluent
in
the
capsule; patients should always
use the
same
formulation.
Phenytoin
should
not be
given
i.m.
since
it
precipitates
and is
poorly absorbed.
It may
be
diluted
and
given
by
i.v.
infusion
over
1
hour
but
care

should
be
taken
to
follow
the
manufacturer's
instructions including
the use of an
in-line
filter,
because
phenytoin
may
also precipitate
in
infusion
fluids,
particularly dextrose.
Uses.
Phenytoin
is
used
to
prevent
all
types
of
partial
epilepsy, whether

or not the
seizures there-
after
become generalised,
and to
treat generalised
seizures
and
status epiepticus.
It is not
used
for
absence
attacks.
Other
uses.
The
membrane-stabilising
effect
of
phenytoin
has
been used
in
cardiac arrhythmias
and, rarely,
in
cases
of
resistant

pain,
e.g.
trigeminal
neuralgia.
Adverse
effects
of
phenytoin, many
of
which
can
be
very slow
to
develop, include impairment
of
cognitive
function,
which
has led
many physicians
to
prefer
carbamazepine
and
valproate. Other
nervous system
effects
range
from

sedation
to
deli-
rium
to
acute cerebellar disorder
to
convulsions.
Peripheral neuropathy also occurs. Cutaneous
reactions
include rashes (dose related), coarsening
of
facial
features
and
hirsutism.
Gum
hyperplasia
(due
to
inhibition
of
collagen catabolism)
may
develop
and is
more marked
in
children
and

when
there
is
poor
gum
hygiene.
Other
effects
include Dupuytren's contracture
and
pseudolymphoma. Some degree
of
macrocyto-
sis is
common
but
anaemia probably occurs only
when dietary
folate
is
inadequate. This responds
to
folate
supplement
(the
requirement
for
folate
is
increased,

as it is a
cofactor
in
some hydroxylation
reactions
that
are
accelerated
by
enzyme induction
by
phenytoin). Osteomalacia
due to
increased meta-
bolism
of
vitamin
D
occurs
after
years
of
therapy.
Overdose
(causing cerebellar symptoms
and
signs, coma, apnoea)
is
treated according
to

general
principles.
The
patient
may
remain unconscious
for
a
long time because
of
saturation kinetics,
but
will
recover
if
respiration
and
circulation
are
sustained.
Fosphenytoin,
a
prodrug
of
phenytoin,
is
soluble
in
water, easier
and

safer
to
administer;
its
conver-
tion
in the
blood
to
phenytoin
is
rapid
and it may be
used
as an
alternative
to
phenytoin
for
status
epilepticus
(Table
20.1).
SODIUM
VALPROATE
Sodium valproate (valproic
acid)
(Epilim)
acts
by

inhibiting
GABA
transaminase,
the
enzyme
responsible
for the
breakdown
of the
inhibitory
420
PHARMACOLOGY
OF
INDIVIDUAL
DRUGS
20
neurotransmitter,
GABA,
so
increasing
its
concen-
tration
at
GABA
receptors.
Sodium valproate
is
extensively metabolised
in

the
liver
and has a t
1
/
2
of 13 h. It is 90%
bound
to
plasma albumin. Sodium valproate
is a
nonspecific
inhibitor
of
metabolism,
and
indeed inhibits
its own
metabolism,
and
that
of
lamotrigine, phenobarbitone,
phenytoin
and
carbamazepine. Sodium valproate
does
not
induce drug metabolising enzymes
but its

metabolism
is
enhanced
by
induction
due to
other
drugs, including antiepileptics.
Sodium valproate
is
effective
for a
wide range
of
seizure disorders, including generalised
and
partial
epilepsy,
and the
prophylaxis
of
febrile
convulsions
and
post-traumatic epilepsy.
Adverse
effects
can be
troublesome.
The

main
ones
of
concern, particularly
to
women,
are
weight
gain,
teratogenicity (see
p.
416), polycystic ovary
syndrome,
and
loss
of
hair which grows back
curly.
6
Nausea
may be a
problem. Some patients exhibit
a
rise
in
liver enzymes
which
is
usually
transient

and
without sinister import,
but
they should
be
closely
monitored until
the
biochemical tests return
to
normal
as,
rarely, liver
failure
occurs (risk maximal
at
2-12 weeks); this
is
often
indicated
by
anorexia,
malaise
and a
recurrence
of
seizures. Other reactions
include pancreatitis,
and
coagulation

disorder
due
to
inhibition
of
platelet aggregation (coagulation
should
be
assessed
before
surgery).
Ketone metabolites
may
cause confusion
in
uring testing
in
diabetes.
Metabolic
inhibition
by
valproate prolongs
the
action
of
co-administered
antiepilepsy
drugs (see
above).
The

effect
is
significant
and the
dose
of
lamotrigine,
for
example, should
be
halved
in
patients
who are
also taking
sodium
valproate.
BARBITURATES
Antiepilepsy members include
phenobarbital
(pheno-
barbitone)
(t
l
/
2
100 h),
methylphenobarbital
and
primidone

(Mysoline), which
is
largely metabolised
to
phenobarbital, i.e.
it is a
prodrug. They
are
still
used
for
generalised seizures; sedation
is
usual.
CLONAZEPAM
Clonazepam
(Rivotril)
(t
1
/
2
25 h) is a
benzodiazepine
used
as a
second line drug
for
treatment
of
primary

generalised epilepsy
and for
status epilepticus (see
Table
20.1).
Vigabatrin
(Sabril)
(t
1
/
2
6 h) is
structurally related
to
the
inhibitory
CNS
neurotransmitter
GABA
and it
acts
by
irreversibly inhibiting GABA-transaminase
so
that
GABA
accumulates. GABA-transaminase
is
resynthesised over
6

days. Vigabatrin
is not
meta-
bolised
and
does
not
induce hepatic drug meta-
bolising enzymes.
Vigabatrin
is
effective
in
partial, secondary
generalised seizures which
are not
satisfactorily
controlled
by
other anticonvulsants,
and in
infantile
spasms,
as
monotherapy.
It
worsens absence
and
myoclonic
seizures

Unwanted
effects
from
drugs sometimes become
apparant only
following
prolonged use,
and
viga-
batrin
is a
case
in
point. Vigabatrin
had
been
licenced
for a
number
of
years,
before
it was
found
to
cause visual
field
constriction
in up to 40% of
patients,

an
effect
that
is
insidious
and
leads
to
irreversible tunnel vision.
7
Its
discovery emphasises
the
value
of
postmarketing drug surveillance
programmes.
8
Vigabatrin
is now
indicated only
for
patients with
the
specific
seizure disorders
responsive
to the
drug (above),
and no

other.
Patients should undergo visual
field
monitoring
at
six-monthly intervals whilst taking
the
drug. Other
adverse
effects
on the CNS are
similar
to
those
of
antiepilepsy drugs
in
general
but
include
confusion
and
psychosis. Increase
in
weight also occurs
in up
to 40% of
patients during
the
first

6
months
of
treatment.
Lamotrigine
acts
to
stabilise presynaptic neuronal
membranes
by
blocking voltage-dependent sodium
channels
(a
property
it
shares with carbamazepine
and
phenytoin)
and it
reduces
the
release
of
excita-
tory
amino acids, such
as
glutamate
and
aspartate.

The t
1
/
2
of 24 h
allows
for a
single daily dose.
6
'We
thought
the
change might
be
welcomed
by the
patients,
but
one
girl
prefered
her
hair
to be
long
and
straight,
and one
boy
was

mortified
by his
curls
and
insisted
on a
short
hair
cut.' Jeavons
P M
1977
Lancet
1:
359.
7
Eke T,
Talbot
J F et al.
1997 British Medical Journal 314:
180-181.
8
Wilton
L V,
Stephens
M D B,
Mann
R D
1999 British Medical
Journal
319:1165-1166.

421
20
EPILEPSY,
PARKINSONISM
AND
ALLIED
CONDITIONS
Lamotrigine
is
effective
as
monotherapy
and
adjunctive
therapy
for
partial
and
primary
and
secondarily
generalised tonic-clonic seizures.
It is
generally well tolerated
but may
cause serious
adverse
effects
on the
skin, including

Stevens-
Johnson syndrome
and
toxic
epidermal necrolysis
(fatally,
on
rare occasions).
The
risk
of
cutaneous
effects
can be
lessened
if
treatment
is
begun with
a
low
dose
and is
escalated slowly. Concomitant
use
of
valproate, which inhibits
the
metabolism
and

thus
the
inactivation
of
lamotrigine,
adds
to the
hazard.
Carbamazepine, phenytoin
or
primidone
accelerate
the
metabolic breakdown
of
lamotrigine
which must
be
given
in
higher dose when combined.
Gabapentin
is an
analogue
of
GABA
that
is
sufficiently
lipid

soluble
to
cross
the
blood-brain
barrier
but its
mode
of
action
is
uncertain.
It is
excreted
unchanged and, unlike other antiepilepsy
agents, does
not
induce
or
inhibit hepatic meta-
bolism
of
other drugs.
Gabapentin
is
effective
only
for
partial seizures
and

secondary generalised epilepsy (not absence
or
myoclonic
epilepsy),
in
combination with established
agents.
It is
also used
for
neuropathic pain.
Gaba-
pentin
may
cause somnolence, unsteadiness, dizz-
iness
and
fatigue.
Topiramate
possesses
a
range
of
actions that
include blockade
of
voltage-sensitive sodium
channels, enhancement
of
GABA

activity
and
possibly
weak blockade
of
glutamate
receptors.
The
t
1
/
2
of
21 h
allows once daily dosing;
it is
excreted
in
the
urine mainly
as
unchanged drug.
Topiramate
is
used
as
adjunctive
treatment
for
partial

seizures,
with
or
without
secondary
general-
isation.
It use is
limited
by its
unwanted
effects,
particularly
sedation, naming
difficulty
and
weight
loss. Acute myopia
and
raised intraocular pressure
may
occur.
Levetiracetam
acts
in a
manner
different
to
other
antiepilepsy drugs.

It has a
potentially broad spec-
trum
of use but is
currently indicated
for
adjunctive
treatment
in
partial seizures with
or
without
secondary generalisation.
It is
rapidly
and
com-
pletely
absorbed
after
oral administration,
and is
effective
with twice-daily dosing.
Its
therapeutic
index
appears
to be
high

and the
commonest
of the
adverse
effects
are
asthenia, dizziness
and
drowsiness.
Succinimides.
Ethosuximide
(Zarontin) (t
1
/
2
55 h)
differs
from
other antiepilepsy drugs
in
that
it
blocks
a
particular type
of
calcium channel that
is
active
in

absence seizures (petit mal),
and it is
used
specifically
for
this
condition.
Adverse
effects
include
gastric upset,
CNS
effects
and
allergic
reactions
including eosinophilia
and
other blood
disorders,
and
lupus erythematosus.
Parkinsonism
A
NOTE
ON
PATHOPHYSIOLOGY
Parkinson's disease
9
affects

about
1 in 200 of the
elderly
population.
In
broad
terms,
it is
caused
by
degeneration
of the
substantia nigra
10
in the
mid-
brain,
and
consequent loss
of
dopamine-containing
neurons
in the
nigrostriatal pathway (see Fig. 19.3,
p.
382). There
is no
known cure
but
drug treatment

can,
if
properly managed, dramatically improve
quality
of
life
in
this progressive disease.
Two
balanced
systems
are
important
in the
extrapyramidal
control
of
motor activity
at the
level
of
the
corpus striatum
and
substantia nigra:
in one
the
neurotransmitter
is
acetylcholine;

in the
other
it is
a
dopamine.
In
Parkinson's
disease
there
is
degen-
erative
loss
of
nigrostriatal dopaminergic neurons
and the
symptoms
and
signs
of the
disease
are due
to
dopamine depletion.
Certain
drugs
also
produce
the
features

of
Parkinson's disease (see below)
and the
general
term
'parkinsonism'
is
used
to
cover both
the
disease
and the
drug-induced states.
The
symptom
triad
of the
disease
is
bradykinesia, rigidity
and
tremor.
Patients
who
have received levodopa
for a
long
time
may

exhibit
the
'on-off'
phenomenon
in
which, abruptly
and
distressingly, dyskinesia (the
'on' phase) alternates with hypokinesia (the 'off
phase).
One
sufferer,
a
physician, wrote about
his
condition:
9
James
Parkinson (1755-1824), physician;
he
described
paralysis
agitans
in
1817.
10
Substantia nigra
is
(Latin) black substance.
A

coronal section
at
this point
in the
brain shows
the
distinctive
black
areas,
visible
with
the
naked
eye in the
normal brain,
but
absent
from
the
brains
of
patients with Parkinson's disease.
422
DRUGS
FOR
PARKINSON'S
DISEASE
20
'One
of its

most
trying
aspects
is the
extent
to
which
it
interferes
with
the
trivial
events
in
daily
life.
Nothing
is
easy
in
Parkinson's disease.
There
is
no
feature
of any
task
that
is not
potentially

out
of
control.
A
cuff-link
refuses
to
find
its way
into
a
tuxedo
shirt,
my
wife
is out of
town,
and I
miss
the
annual
dinner.
I am
unable
to
stuff
change
from
a
$5

bill
into
my
wallet,
and the
patrons
in
line
behind
the
cash register
fume.
Bow
ties won't
tie
and
shoelaces
won't
lace.
A
cube
of
beef
obstructs
the
glottis.
In
Parkinson's disease
one
must

expect
the
unexpected

About
five
years
ago,
my
disease
began
to
close
in on me,
becoming more
aggressive
and
difficult
to
handle.
I had
increasing
discomfort
from
hyperkinesias.
My
voice
was
almost
inaudible,

and
periods when
my
feet
felt
frozen
to the
floor
became
commonplace.
I
lost
the
advantage
I had
previously
enjoyed
of a
comfortable
margin between
the
effective
dose
and
the
dose with
intolerable
side
effects.
I had an

"off"
spell
in a
telephone
booth
.'
11
Objectives
of
therapy
The
dopaminergic/cholinergic balance
may be
restored
by the
following mechanisms.
1.
Enhancement
of
dopaminergic
activity
by
drugs which may:
(a)
replenish
neuronal dopamine
by
supplying
levodopa,
which

is its
natural precursor;
administration
of
dopamine
itself
is
ineffective
as it
does
not
cross
the
blood-brain
barrier
(b)
act as
dopamine
agonists
(bromocriptine,
pergolide, cabergoline, apomorphine);
(c)
prolong
the
action
of
dopamine through
selective inhibition
of its
metabolism

(selegiline).
(d)
release
dopamine
from
stores
and
inhibit
re-
uptake (amantadine)
or
2.
Reduction
of
cholinergic
activity
by
antimuscarinic
(anticholinergic
12
)
drugs;
this
11
Saltzman
E W
1996
Living
with Parkinson's
disease.

New
England
Journal
of
Medicine
334:114-116.
12
The
term
antimuscarinic
is now
preferred
(see
p.
435).
approach
is
most
effective
against tremor
and
rigidity,
and
less
effective
in the
treatment
of
bradykinesia (including iatrogenic, caused
by

dopamine receptor antagonists).
Both
approaches
are
effective
in
therapy
and
may
usefully
be
combined.
It
therefore
comes
as no
surprise that drugs which prolong
the
action
of
acetylcholine
(anticholinesterases)
or
drugs which
deplete dopamine stores (reserpine)
or
block dopa-
mine
receptors
(antipsychotics,

e.g. chlorpromazine)
will
exacerbate
the
symptoms
of
parkinsonism
or
induce
a
parkinson-like state.
Other parts
of the
brain
in
which dopaminergic
systems
are
involved include
the
medulla (induc-
tion
of
vomiting),
the
hypothalamus (suppression
of
prolactin secretion)
and
certain

paths
to the
cerebral
cortex.
Different
effects
of
dopaminergic
drugs
can be
explained
by
activation
of
these
systems, namely emesis, suppression
of
lactation
(mainly
direct dopamine agonists)
and
occasionally
psychotic illness. Classical antipsychotics (see
p.
381)
used
to
manage psychotic behaviour
act by
blockade

of
dopamine
D
2
receptors and,
as is to be
expected,
they
are
also antinauseant,
may
sometimes cause
galactorrhoea,
and can
induce parkinsonism. Drug-
induced parkinsonism
is
alleviated
by
anti-
muscarinics,
but not by
levodopa
or
dopamine
agonists, because
the
antipsychotics block dopamine
receptors
by

which these drugs act. Since many
antipsychotics also have some antimuscarinic
activity,
those with greatest
efficacy
in
this respect, e.g.
thioridazine,
are the
least likely
to
cause parkinsonism.
Drugs
for
Parkinson's
disease
DOPAMINERGIC
DRUGS
Levodopa
and
dopa-decarboxylase
inhibitors
Levodopa
('dopa'
stands
for
dihydroxyphenyl-
alanine)
is a
natural amino acid precursor

of
dopamine.
The
latter cannot
be
used because
it is
rapidly
metabolised
in the
gut, blood
and
liver
by
monoamine oxidase
and
catechol-O-methyltrans-
423
20
EPILEPSY,
PARKINSONISM
AND
ALLIED
CONDITIONS
ferase;
even intravenously administered dopamine,
or
dopamine
formed
in

peripheral
tissues,
is
insufficiently
lipid-soluble
to
penetrate
the
CNS.
But
levodopa
is
readily absorbed
from
the
upper
small intestine
by
active amino acid transport
and
has a t
1
/
2
of
1.5h.
It can
traverse
the
blood-brain

barrier
by a
similar active transport,
and
within
the
brain
it is
decarboxylated
(by
dopa decarboxylase)
to the
neurotransmitter
dopamine.
But
a
major
disadvantage
is
that levodopa
is
also
extensively
decarboxylated
to
dopamine
in
periph-
eral
tissues

so
that only
1-5%
of an
oral dose
of
levodopa reaches
the
brain. Thus large quantities
of
levodopa would have
to be
given. These inhibit
gastric
emptying,
delivery
to the
absorption
site
is
erratic
and
fluctuations
in
plasma concentration
occur.
The
drug
and its
metabolites cause

signifi-
cant
adverse
effects
by
peripheral actions, notably
nausea,
but
also cardiac arrhythmia
and
postural
hypotension. This problem
has
been largely circum-
vented
by the
development
of
decarboxylase
inhibi-
tors,
which
do not
enter
the
central nervous system,
so
that they prevent only
the
extracerebral

meta-
bolism
of
levodopa.
The
inhibitors
are
given
in
combination with levodopa
and
there
is a
range
of
formulations
comprising
a
decarboxylase inhibitor
with
levodopa:
•
co-careldopa
(carbidopa
+
levodopa
in
proportions 12.5/50
mg,
10/100, 25/100,

25/250)
(Sinemet)
•
co-beneldopa
(benserazide
+
levodopa
in
proportions
12.5
mg/50
mg,
25/100,50/200)
(Madopar).
The
combinations produce
the
same brain
con-
centrations
as
with levodopa alone,
but
only
25% of
the
dose
of
levodopa
is

required, which smooths
the
action
of
levodopa
and
reduces
the
incidence
of
adverse
effects,
especially nausea,
from
about
80%
to
less than 15%.
Dose
management
Levodopa alone
and in
combination
(see
above)
is
introduced
gradually
and
titrated

according
to
response,
the
dose being altered every
2
weeks.
The
dose
is
increased
to
provide
sufficient
benefit
for
each individual patient,
not to a
standard dose since
this
is
very variable.
Compliance
is
important. Abrupt discontinua-
tion
of
therapy
leads
to

dramatic relapse.
Adverse
effects.
Postural
hypotension
occurs.
Nausea
may
be a
limiting
factor
if the
dose
is
increased
too
rapidly;
it may be
helped
by
cyclizine
50 mg
taken
30
min
before
food
or by
domperidone
(little

of
which
enters
the
brain). Levodopa-induced
dyskine-
sias
take
the
form
of
involuntary limb jerking
or
head,
lip or
tongue movements
and
constitute
a
major
constraint
on how the
drug
is
used (see later).
Mental
changes
may be
seen: these include depres-
sion, which

is
common (best controlled with
a
tricyclic
antidepressant), dreams,
and
hallucina-
tions
and
delusions
(clozapine
may
help).
Agitation
and
confusion
occur
but it may be
difficult
to
decide
whether these
are due to
drug
or to
disease.
In
these
circumstances,
the

drugs most likely
to be the
cause
of
a
toxic confusional state (antimuscarinics
and
direct
dopamine agonists)
are
withdrawn.
Interactions. With nonselective monoamine
oxi-
dase inhibitors
(MAOI),
the
monoamine dopamine
formed
from
levodopa
is
protected
from
destruc-
tion;
it
accumulates
and
also
follows

the
normal
path
of
conversion
to
noradrenaline (norepineph-
rine),
by
dopamine 5-hydroxylase;
severe
hypertension
results.
The
interaction with
the
selective MAO-B
inhibitor, selegiline,
is
possibly therapeutic
(see
below).
Tricyclic
antidepressants
are
safe.
Levodopa
antagonises
the
effects

of
antipsychotics (dopamine
receptor blockers). Some
antihypertensives
enhance
hypotensive
effects
of
levodopa. Metabolites
of
dopamine
in the
urine
interfere
with some tests
for
phaeochromocytoma,
and in
such patients
it is
best
to
measure
the
plasma catecholamines directly.
Dopa-decarboxylase
is a
pyridoxine-dependent
enzyme
and

concomitant
use of
pyridoxine,
e.g.
in
self-medication
with
a
multivitamin preparation,
can
enhance peripheral conversion
of
levodopa
to
dopamine
so
that less
is
available
to
enter
the
CNS,
and
benefit
is
lost. This
effect
does
not

occur,
of
course,
with
the now
usual levodopa-decarboxylase
inhibitor combinations.
Dopamine
agonists
These
mimic
the
effects
of
dopamine,
the
endo-
genous
agonist,
which
stimulates
both
the
main
424
DRUGS
FOR
PARKINSON'S
DISEASE
20

two
types
of
dopamine receptor,
D
I
and D
2
(coupled
respectively
to
adenylyl cyclase stimulation
and
inhibition).
The
D
2
-receptor
is the
principal target
in
Parkinson's disease; chronic
D
l
stimulation appears
to
potentiate
the
response
to D

2
stimulation despite
acutely
having
an
inhibitory action
on
adenylyl
cyclase.
The
main problems with
dopamine
(i.e.
the
prodrug, levodopa)
are its
short
t
1
/
2
and, possibly,
the
consequences
of
delivering large amounts
of
substrate
to an
oxidative pathway,

MAO
(see
below).
On the
other
hand,
the
problems
of
developing
synthetic alternatives are:
•
reproducing
the
right balance
of
D
l
and D
2
stimulation (dopamine
itself
is
slightly
D
1
selective,
in
test systems,
but its net

effect
in
vivo
is
determined also by the relative amounts and
locations
of
receptors
—
which
differ
in
Parkinsonian patients
from
normal)
•
avoiding
the
undesired
effects
of
peripheral,
mainly
gastric, D
2
-receptors
•
synthesising
a
full,

not
partial, agonist.
Bromocriptine
(a
derivative
of
ergot)
is a D
2
-
receptor
agonist,
but
also
a
weak a-adrenoreceptor
antagonist.
It is
commonly used with levodopa.
The
drug
is
rapidly absorbed
after
administration
by
mouth;
the
t
l

/
2
is 5 h, so
that
its
action
is
smoother
than that
of
levodopa, which
can be an
advantage
in
patients
who
develop end-of-dose deterioration
with
levodopa. Dosing should start very
low
(1-1.25
mg
p.o.
at
night), increasing
at
approx-
imately
weekly intervals
and

according
to
clinical
response.
Nausea
and
vomiting
are the
commonest adverse
effects;
these
may
respond
to
domperidone
but
tend
to
become less marked
as
treatment continues.
Postural hypotension
may
cause dizziness
or
syncope.
In
high
dose confusion, delusions
or

hallucinations
may
occur and,
after
prolonged use,
pleural
effusion
and
retroperitoneal
fibrosis.
Lisuride
(t
l
/
2
2 h) and
pergolide
(t
l
/
2
6 h) are
similar
to
bromocriptine, though
the
latter also stimulates
Dj-receptors.
Cabergoline,
also

an
ergot derivative,
has a
t
l
/
2
of
more
than
80 h.
This long duration
of
action allows
it to be
used
in a
single daily
(or
even twice weekly)
dose,
which
is
appreciated
by
patients
who are
often
taking other drugs every
2-3

hours;
it is
also valuable
for
night-time problems
due to
lack
of
levodopa.
Pmmipexole
is a
non-ergot
dopamine D
2
-receptor agonist that
is
more
effective
against tremor than
the
others.
Ropinirole
is a
direct
D
2
-receptor agonist, which
is
also
a

non-ergot
derivate. There
are
insufficient
data
to
allow
an
informed
choice between these drugs.
Apomorphine
is a
derivative
of
morphine having
structural
similarities
to
dopamine;
it is a
full
agonist
at D
1
and
D
2
-receptors.
Its
main

use is in
young patients with severe motor
fluctuations
and
dyskinesias (the 'on-off phenomenon,
see
above)
when
it is
given
by
s.c.
injection
or
infusion
for
patients
with
levodopa resistant 'off.
The
rapid
onset
of
action
by the
s.c. route (self-administration
can
be
taught) enables
the

'off component
to be
aborted without
the
patient waiting
45-60
minutes
to
absorb another oral dose
of
levodopa. Apo-
morphine
may
need
to be
accompanied
by an
antiemetic, e.g. domperidone (which does
not
cross
the
blood-brain
barrier
as
does
metoclopramide),
to
prevent
its
characteristic emetic action. Overdose

causes
respiratory
depression;
it is
antagonised
by
naloxone. Apomorphine
can
induce penile erection
(without
causing sexual excitement)
and it
enhances
the
penile response
to
visual erotic stimulation.
Inhibition
of
dopamine metabolism
Monoamine
oxidase (MAO) enzymes have
an
important
function
in
modulating
the
intraneuronal
content

of
neurotransmitter.
The
enzymes exist
in
two
principal forms,
A and B,
defined
by
specific
substrates some
of
which cannot
be
metabolised
by
the
other
form
(Table
20.3).
The
therapeutic
importance
of
recognising these
two
forms
arises

because they
are to
some extent present
in
different
tissues,
and the
enzyme
at
these
different
locations
can
be
selectively
inhibited
by the
individual
inhibitors: moclobemide
for
MAO-A (used
for
depression,
p.
379)
and
selegiline
for
MAO-B
(Table

20.3).
Selegiline
is a
selective, irreversible inhibitor
of
MAO
type
B. The
problem with nonselective
MAO
inhibitors
is
that they prevent degradation
of
dietary amines, especially tyramine, which
is
then
able
to act
systemically
as a
sympathomimetic:
the
425
20
EPILEPSY,
PARKINSONISM
AND
ALLIED
CONDITIONS

TABLE
20.3 Isoforms
of
monoamine
oxidase:
MAO-A
and
MAO-B:
an
explanation
The
table
shows
the
definition
of the
isoforms
by
their
specific substrates,
and
then
their
selectivity
(or
nonselectivity)
towards
a
number
of

other
substrates
and
inhibitors.
Determination
of
therapeutic
and
adverse effects
is a
function
of
selectivity
of the
inhibitor
and
the
tissue
location
of the
enzyme.
Enzyme
MAO-A MAO-A
and B
MAO-B
Substrate
Inhibitors
Tissues
Serotonin
(see

below)
Moclobemide
Liver
CNS
(neurons)
Sympathetic neurons
Noradrenaline
(norepinephrine)
(see
below)
Phenylethylamine
Adrenaline (epinephrine)
Dopamine
Tyramine
Tranylcypromine
Selegiline
Phenelzine
Iproniazid
See
MAO-A,
Gut
MAO-B
CNS
(glial
cells)
Explanation:
the
specific substrate
for
MAO-A

is
serotonin,
whilst
for
MAO-B
it is the
nonendogenous amine, phenylethylamine (present
in
many brands
of
chocolate).
Noradrenaline,
tyramine
and
dopamine
can be
metabolised
by
both
isoforms
of
MAO.
MAO-A
is the
major
form
in
liver
and in
neurons

(both
CNS and
peripheral
sympathetic);
MAO-B
is the
major
form
in
gut,
but is
also present
in the
liver, lungs
and
glial
cells
of the
CNS.
hypertensive 'cheese reaction'.
As
will
be
apparent
from
Table
20.3, selegiline does
not
cause
the

cheese
reaction, because MAO-A
is
still present
in the
liver
to
metabolise tyramine. MAO-A also metabolises
tyramine
in the
sympathetic nerve endings,
so
providing
a
further
line
of
protection (tyramine
is
an
indirect acting amine which displaces noradre-
naline
from
the
nerve endings).
In the CNS
selegiline
protects dopamine
from
intraneuronal degradation.

It
has no
effect
on
synaptic
cleft
concentrations
of
those amines like serotonin
and
noradrenaline,
which
are
normally
potentiated
by the
MAOI
used
in
depression; therefore selegiline
has no
antidepressant action.
Selegiline
was
originally introduced
in the
belief
that
it
would delay end-of-dose deterioration

by
prolonging
the
action
of
levodopa; subsequently
it
was
held that this action might
be
protective
of
dopaminergic neurons
and so
allow later initiation
of
therapy with levodopa.
It
became
one of the
most
widely
prescribed drugs
for
Parkinson's disease.
Later
clinical trials, however,
failed
to
confirm

these
effects
and
indeed, combined treatment with
levodopa
and
selegiline
was
associated with excess
mortality;
13
many patients discontinued selegiline
without worsening
of
their condition.
A
minority
deteriorated acutely
and
they have continued
to
13
Ben-Sholomo
Y,
Churchyard
A,
Head
J,
Hurwitz
B,

Overstall
P,
Ockelford
J,
Lees
A J
1998 British Medical Journal
316:1191-1196.
receive
selegiline although
the
reason
for
this
benefit
is not
clear.
Entacapone
inhibits
catechol-O-methyltransferase
(COMT),
one of the
principal enzymes responsible
for
the
metabolism
of
dopamine;
the
action

of
levo-
dopa
is
thus prolonged.
It is
most
effective
for
patients with early end-of-dose
deterioration,
and
allows
them
to
take
levodopa
at 3- or
4-hourly inter-
vals,
giving
a
more predictable
and
useful
response.
Entacapone
is
preferred
to

long-acting preparations
of
levodopa whose main disadvantage
is
their slow
onset
of
action.
It can
increase
the
dyskinesias seen
in
the
late stages
of
Parkinson's disease.
Dopamine
release
Amantadine
antedates
the
discovery
of
dopamine
receptor
subtypes,
and its
discovery
as an

anti-
parkinsonian drug
was an
example
of
serendipity.
It
is
an
antivirus drug which, given
for
influenza
to a
parkinsonian patient,
was
noticed
to be
beneficial.
The
two
effects
are
probably unrelated.
It
appears
to
act
by
increasing synthesis
and

release
of
dopa-
mine,
and by
diminishing neuronal reuptake.
It
also
has
slight antimuscarinic
effect.
The
drug
is
much
less
effective
than levodopa, whose action
it
will
slightly
enhance.
It is
more
effective
than
the
standard antimuscarinic drugs, with which
it has
an

additive
effect.
Amantadine
is
relatively
free
from
adverse
effects,
which, however, include ankle
426
TREATMENT
OF
PARKINSON'S
DISEASE
20
oedema (probably
a
local
effect
on
blood vessels),
postural hypotension, livedo reticularis
and
central
nervous system disturbances: insomnia, hallucina-
tions and, rarely,
fits.
ANTIMUSCARINIC
(ANTICHOLINERGIC)

DRUGS
(see also
p.
441)
Antimuscarinic drugs benefit parkinsonism
by
blocking acetylcholine receptors
in the
central
nervous system, thereby partially redressing
the
imbalance created
by
decreased
dopaminergic
activity.
Their
use
originated when hyoscine
was
given
to
parkinsonian patients
in an
attempt
to
reduce
sialorrhoea
by
peripheral

effect,
and it
then
became apparent that they
had
other
beneficial
effects
in
this disease. Synthetic derivatives
are
now
used orally. These include benzhexol (tri-
hexyphenidyl),
orphenadrine,
benzatropine,
procy-
clidine, biperiden. There
is
little
to
choose between
these. Antimuscarinics produce modest improve-
ments
in
tremor, rigidity, sialorrhoea, muscular
stiffness
and leg
cramps,
but

little
in
bradykinesia,
the
most disabling symptom
of
Parkinson's disease.
They
are
also
effective
i.m.
or
i.v.
in
acute drug-
induced
dystonias.
Unwanted
effects
include
dry
mouth, blurred
vision,
constipation,
urine
retention,
glaucoma,
hallucinations, memory
defects,

toxic
confusional
states
and
psychoses (which should
be
dis-
tinguished
from
presenile dementia).
Treatment
of
Parkinson's
disease
The
main
features
that require alleviation
are
tremor,
rigidity
and
bradykinesia.
General measures
are
important
and
include
the
encouragement

of
regular physical activity
and
specific
help such
as
physiotherapy, speech therapy
and
occupational therapy.
DRUG
THERAPY
Drugs play
the
most important role
in
symptom
relief.
No
agent
has yet
been
found
to
alter
the
progressive course
of the
disease.
Initial
treatment

Treatment
should
begin
only
when
it is
judged
necessary
in
each individual case.
For
example,
a
young
man
with
a
physically demanding
job
will
require treatment
before
an
older retired person.
Two
conflicting objectives have
to be
balanced:
the
desire

for
satisfactory
relief
of
current symptoms
and the
avoidance
of
adverse
effects
as a
result
of
long-continued treatment. There
is
debate
as to
whether
the
treatment should commence with
levodopa
or a
synthetic
dopamine
agonist.
Levodopa
provides
the
biggest improvement
in

motor symp-
toms
but its use is
associated with
the
development
dyskinesias, which
are
inevitable
after
some 5-10
years,
and
sometimes sooner.
Dopamine
agonists
have
a
much less powerful motor
effect
but are
less
likely
to
produce dyskinesias. Some neurologists
therefore prefer
a
dopamine
agonist alone
as the

initial
choice. Unfortunately, only about
30% of
patients obtain
a
satisfactory motor response.
An
alternative, therefore,
is to
begin treatment with
levodopa
in low
dose
to get a
good motor response,
and to add a
dopamine agonist when
the
initial
benefit
begins
to
wane. With either approach,
it
seems
likely that
the
position
after
5

years treat-
ment
may
well
be the
same,
but
that
by
starting
with levodopa
the
patient will have
had the
benefit
of
a
earlier motor response.
Antimuscarinic
drugs
are
suitable only
for
younger
patients predominantly troubled with tremor
and
rigidity.
They
do not
benefit

bradykinesia,
the
main
disabling symptom.
The
unwanted
effects
of
acute
angle glaucoma, retention
of
urine, constipation
and
psychiatric disturbance
are
general contraindi-
cations
to the use of
antimuscarinics
in the
elderly.
Amantadine
or
selegiline
can
delay
the use of
either
levodopa
or a

synthetic dopamine agonist
in
the
early stages
of the
disease
if
mild symptomatic
benefit
is
required,
but
this
approach
is
seldom
necessary.
A
typical course
is
that
for
about
2-4
years
on
treatment
with levodopa
or a
dopamine agonist,

the
patient's disability
and
motor performance remains
near
normal despite progression
of the
underlying
disease.
After
some
5
years, about
50% of
patients
427
20
EPILEPSY,
PARKINSONISM
AND
ALLIED
CONDITIONS
exhibit
the
problems
of
long-term treatment, namely,
dyskinesia
and
end-of-dose

deterioration
with
the
'on-off phenomenon.
After
10
years virtually 100%
of
patients
are
affected.
Dyskinesia
comprises involuntary writhing move-
ment
of the
face
and
limbs that
may be
biphasic
(occurring
at the
start
and end of
motor response)
or
develop
at the
time
of the

maximum plasma
levodopa concentration. They respond initially
to
reducing
the
dose
of
levodopa
but at the
cost
of
bradykinesia
and as
time passes there
is
progres-
sively
less scope
to
obtain
benefit
without unwanted
effects.
End-of-dose
deterioration
is
managed
by
increasing
the

frequency
of
dosing with levodopa (e.g.
to
2-3-
hourly),
but
this tends
to
result
in the
appearance,
or
worsening
of the
dyskinesia.
The
motor
response
then becomes more brittle with abrupt swings
between hyper-
and
hypomobility (the
on-off
phenomenon). Despite their unpredicatable nature
over
the
course
of a
single

day,
these
changes
are in
fact
dose-related,
an
effect
that becomes apparent
only when
the
response
is
related
to
total medica-
tion taken over
a
week.
Various
strategies have been devised
to
over-
come
these problems. Controlled release preparations
of
levodopa tend
to be
associated with
an

inadequate
initial
response
and
disabling dyskinesia
at the end of
the
dose.
A
more
effective
approach appears
to be the
use of a
COMT
inhibitor,
e.g. entacapone, which
can
sometimes allay early end-of-dose deterioration
without causing dyskinesia. This
is now the
main
indication
for its
use.
In any
event, many patients
with Parkinson's
disease
take

at
least
two and
sometimes more drugs
at
frequent
intervals each day,
an
outcome that tends
to
rule their lives.
Continuous subcutaneous
infusion
of
apomorphine
can
transform
the
quality
of
life
of
younger patients
with severe motor
fluctuations
and
dyskinesia,
but
this
may

lead
to
neuropsychiatric
effects.
If
drug
treatment
fails
in
young non-demented patients,
stereotactic
subthalamotomy
or
bilateral stereotactic
subthalamic stimulation
can be
very
successful
with
only
a
small risk
of
surgical complications
in
experienced
hands. Some
20% of
patients with
Parkinson's disease, notable

the
older ones, develop
impairment
of
memory
and
speech
with
a
fluctuating
confusional
state
and
hallucinations.
As
these
symptoms
are
often
aggravated
by
medication,
it is
preferable
gradually
to
reduce
the
antiparkinsonian
treatment, even

at the
expense
of
lessened mobility.
DRUG-INDUCED
PARKINSONISM
The
classical antipsychotic (see
p.
380) drugs block
dopamine receptors
and
their antipsychotic activity
relates
closely
to
this action, which notably involves
the
D
2
-receptor,
the
principal target
in
Parkinson's
disease.
It
comes
as no
surprise, therefore, that

these drugs
can
induce
a
state whose clinical
features
are
very similar
to
those
of
idiopathic
Parkinson's disease.
The
piperazine phenothiazines,
e.g.
trifluoperazine,
and the
butyrophenones, e.g.
haloperidol,
are
most commonly involved.
In one
series
14
of 95 new
cases
of
parkinsonism
referred

to a
department
of
geriatric medicine,
51%
were
associated
with prescribed drugs
and
half
of
these
required hospital admission.
After
withdrawal
of
the
offending
drug most cases resolved completely
in 7
weeks.
But
One old
lady
who had
received
trifluoperazine
(for
a
minor

fright
and
anxiety)
for 5
weeks,
took
36
weeks
to
recover
from
the
drug-induced
parkinsonism
but
never
managed
to get
home
again.
When
drug-induced parkinsonism
is
troublesome,
an
antimuscarinic drug, e.g. benzhexol,
is
beneficial.
Atypical antipsychotics provoke
fewer

extrapyrimidal
effects
(see
p.
387).
Other
movement
disorders
Essential
tremor
is
often,
and
with
justice,
called
benign,
but a few
individuals
may be
incapacitated
by
it.
Alcohol, through
a
central action, helps about
50%
of
patients
but is

plainly
unsuitable
for
long-
term
use and a
nonselective 3-adrenoceptor blocker,
e.g. propranolol
120
mg/day, will benefit about
50%;
clonazepam
or
primidone
are
sometimes
beneficial.
14
Stephen
P J,
Williamson
J
1984 Lancet 2:1082.
428
TETAN
US
20
Drug-induced
dystonic
reactions

are
seen:
• as an
acute reaction,
often
of the
torsion type,
and
occur following administration
of
dopamine
receptor blocking antipsychotics, e.g.
haloperidol,
and
antiemetics, e.g.
metoclopramide.
An
antimuscarinic
drug,
e.g.
biperiden
or
benzatropine, given i.m.
or
i.v.
and
repeated
as
necessary, provides
relief

• in
some patients
who are
receiving levodopa
for
Parkinson's disease
• in
younger patients
on
long-term antipsychotic
treatment,
who
develop tardive dyskinesia (see
p.
387).
Hepatolenticular
degeneration (Wilson's disease)
is
caused
by a
genetic
failure
to
eliminate copper
absorbed
from
food
so
that
it

accumulates
in the
liver,
brain, cornea
and
kidneys. Chelating copper
in the gut
with penicillamine
(p.
293)
or
trientine
can
establish
a
negative copper balance (with some
clinical
improvement
if
treatment
is
started early).
The
patients
may
also develop cirrhosis,
and the
best treatment
for
both

may be
orthotopic liver
transplantation.
Chorea
of any
cause
may be
alleviated
by
dopa-
mine receptor blocking antipsychotics,
and
also
by
tetrabenazine, which inhibits neuronal storage
of
dopamine
and
serotonin.
Involuntary
muscle spasm: blepharospasm, hemi-
facial
spasm, spasmodic torticollis,
and
indeed
the
spasm
of
chronic anal fissure,
are

treated with
botulinum toxin. This irreversibly blocks release
of
acetylcholine
from
cholinergic nerve endings
and
is
injected
locally.
Its
effect
lasts about
3
months.
Botulinum
toxin
is at
least partially
effective
in up
to 90% of
patients
with
these
conditions. Mild
dysphagia occurs
in
-30%
of

patients receiving
injections
into their neck
for
torticollis
due to
spread
of the
toxin
in to the
pharyngeal muscles.
Spasticity
results
from
lesions
at
various sites within
the
central nervous system
and
spinal cord. Drugs
used include
the
GABA
agonist baclofen, diazepam
and
tizanidine
(an
2
-adrenoceptor agonist).

Myotonia
in
which
voluntary muscle
fails
to
relax
after
contraction
may be
symptomatically benefitted
by
drugs that increase muscle
refractory
period, e.g.
procainamide, phenytoin, quinidine.
Multiple
sclerosis
Drugs
are
used
to
alleviate chronic muscle spasm
or
spasticity (see above)
but
until recently, there
has
been
no

disease-modifying treatment
in
this relapsing
and
remitting condition, where
the
placebo
effect
of
most drugs
can
appear quite powerful. Although
its
cause
remains unknown,
it is now
held
to be an
autoimmune disorder. This
has led to the
testing
of
both
old and new
forms
of
drugs, which might
modify
the
immune response,

and
release
of
cytokines.
Interferon
beta
is set to
test
the
resilience
of
patients, doctors, health economists
and
adminis-
trators.
In
placebo-controlled trials,
it is the
first
treatment
to
show
a
reduction
in the
number
of
relapses. Interferon beta
may
also have

a
modest
effect
in
delaying disability
by
12-18 months
in
relapsing/remitting disease.
In a
clinical trial
372
patients with relapsing-remitting disease, able
to
walk
100
metres without
aid or
rest, were randomised
to
receive
8
million
IU or 1.6
million
IU of
interferon
beta
or
placebo

by
s.c.
injection
on
alternate days.
After
2
years there
was a
reduction
in the
relapse rate
from
1.27
per
year
in the
placebo group
to
0.84
per
year
in the
patients receiving
the
higher dose.
15
Interferon
beta
is not

indicated
in
patients with
progressive
forms
of
disease,
or in
severely disabled
patients.
The
high cost
per
patient treated
in
relation
to
the
benefit
gained
has
prevented widespread
access
to
this drug.
In the UK,
only designated
neurologists
can
prescribe interferon beta.

Motor-neuron
disease
The
cause
of the
progressive destruction
of
upper
and
lower motor neurons
is
unknown.
The
only
drug available,
riluzole,
may act by
inhibiting accu-
mulation
of the
neurotransmitter, glutamate.
In 959
patients, riluzole prolonged median survival time
from
13 to 16
months,
with
no
effect
on

motor
function.
16
It may
cause neutropenia.
15
The
IFNB
Multiple Sclerosis Study Group
and the
University
of
British Columbia MS/MRI Analysis Group
1995.
Neurology
45:1277-1285
16
Lacomblez
L et al
1996 Lancet 347:
1425-1431.
429
20
EPILEPSY,
PARKINSONISM
AND
ALLIED
CONDITIONS
Tetanus
Objectives

of
management
are to:
•
immediately
neutralise
with globulin
any
toxin
that
has not yet
become attached irreversibly
to
the
central nervous system
•
destroy tetanus bacteria
by
chemotherapy, thus
stopping toxin production
•
control convulsions
whilst
maintaining
respiratory
and
cardiovascular function, which
may
be
disordered

by the
toxin
•
prevent intercurrent infection (usually
pulmonary)
•
prevent electrolyte disturbances
and
maintain
nutrition.
TREATMENT
Human tetanus immunoglobulin
150
units/kg
should
be
given intramuscularly
at
multiple sites
to
neutralise unbound toxin. Where present, wounds
should
be
debrided. Metronidazole
is an
antibiotic
of
choice
for
Clostridium

tetani,
but
penicillin,
erythromycin, tetracycline, chloramphenicol
and
clindamycin
are
acceptable alternatives (see
p.
211).
Avoid
unnecessary stimulation, which
may
induce rigidity
and
spasms.
The
primary treatment
for
spasms
and
rigidity
is
sedation with
a
benzo-
diazepine, such
as
midazolam
or

diazepam. Addi-
tional sedation
may be
provided with propofol
or a
phenothiazine, usually chlorpromazine.
In
severe
disease
prolonged
spasms
and
respiratory dys-
function
will necessitate tracheal intubation
and
mechanical ventilation will
be
required.
If
the
patient
has
been intubated
and
sedation alone
is
inadequate
to
control spasms,

a
neuromuscular blocking drug,
e.g., intermittent doses
of
pancuronium
or a
continuous infusion
of
atracurium, will
be
required.
Tetanus
toxin
often
causes disturbances
in
auto-
nomic control, resulting
in
sympathetic overactivity
and
high
plasma catecholamine concentrations.
The
first-line
treatment
for
autonomic dysfunction
is by
sedation with

a
benzodiazepine
and
opioid.
Infu-
sion
of the
short-acting
fi-blocker
esmolol,
or the
a
2
-adrenergic agonist clonidine, helps
to
control
episodes
of
hypertension. Intravenous magnesium
sulphate
is
also used
to
reduce autonomic disturbance.
Severe
cases
of
tetanus generally require admis-
sion
to an

intensive care unit
for 3-5
weeks. Weight
loss
is
universal
in
tetanus
and
these patients
require
enteral nutrition. Other important measures
include:
close control
of
fluid balance, chest physio-
therapy
to
prevent pneumonia, prophylaxis
of
thromboembolism
and
intensive nursing care
to
prevent
pressure
sores.
GUIDETO
FURTHER
READING

Brodie
M J,
French
IA
2000
Management
of
epilepsy
in
adolescents
and
adults.
Lancet
356: 323-328
Browne
T R,
Holmes
G L
2001
Epilepsy.
New
England
Journal
of
Medicine 344:1145-1151
Cook
T M,
Protheroe
R T,
Handel

J M
2001 Tetanus:
a
review
of the
literature.
British
Journal
of
Anaesthesia
87:
477-487
Compston
A,
Coles
A
2002
Multiple
sclerosis.
Lancet
359:1221-1231
Delanty
N,
Vaughn
C J,
French
J
A1998
Medical
causes

of
seizures.
Lancet
532: 383-390
Harten
P N
van, Hoek
H W,
Kahn
R S
1999 Acute
dystonia
induced
by
drug treatment.
British
Medical
Journal 319: 623-626
Heafield
M T E
2000
Managing status epilepticus.
British
Medical
Journal
320: 953-954
Kapoor
W N
2000
Syncope.

New
England
Journal
of
Medicine
343:1856-1862
Kwan
P,
Brodie
M J
2001
Neuropsychological
effects
of
epilepsy
and
antiepileptic
drugs.
Lancet
357:216-222
Martin
J B
1999 Molecular basis
of the
neurodegenerative
disorders.
New
England
Journal
of

Medicine
340:1970-1980
Munchau
A,
Bhatia
K P
2000
Uses
of
botulinum
toxin
injection
in
medicine
today.
British
Medical
Journal
320:161-165
Polman
C H,
Uitdehaag
B M J
2000
Drug
treatment
of
multiple
sclerosis. British Medical Journal
2000:

490-494
Shaw
P J
1999
Motor
neuron
disease.
British
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