Drug Therapy for Parkinson’s Disease

Neal Hermanowicz, M.D.1

ABSTRACT

The fundamental concepts of the medical treatment of Parkinson’s disease are

simple, and remain based on the enhancement of dopaminergic transmission by means of
levodopa and dopamine agonists. Recently published practice parameters from the
American Academy of Neurology and an evidence-based review under the auspices of
the Movement Disorder Society provide guidance on motor complications and also
cognitive and psychiatric issues associated with Parkinson’s disease. The choices of
medications are increasing as are the routes of administration, with the arrival of injectable
and transdermal dopamine agonists and a monoamine inhibitor absorbed via the buccal
mucosa. Although simple conceptually, the actual care of patients with Parkinson’s disease
is often complex, requiring consideration of potential future complications and individu-
alized medication regimens, and minimizing the adverse effects of medications that range
from unpleasant to seriously disturbing.

KEYWORDS: Parkinson’s disease, levodopa, dopamine agonists, COMT inhibition,

MAO inhibition, dyskinesias, impulse control disorder

T he fundamental concepts of the pharmacolog-
ical treatment of Parkinson’s disease (PD) are simple and
are almost entirely based on the deficiency of dopamine
identified in 1959. Although the number of drugs has
increased and our sophistication in using them has
improved, levodopa and dopamine agonists, first ap-
proved by the U.S. Food and Drug Administration
(FDA) in 1973 and 1974, respectively, remain the
principal choices.
Although the concepts are simple and some
clarity has been provided by the recent publication of
Practice Parameters by the American Academy of Neu-
rology,1–3 the treatment of Parkinson’s disease continues
to be a daunting challenge even for clinicians with
considerable experience. Individual patient variability
of symptoms and responses to medications preclude a
formulaic approach to therapy.
Some issues of therapy have been addressed by
careful analyses of evidence-based medical practice,
although the method of achieving optimal quality of
life, our primary goal for all our patients, has not been
addressed by most clinical trials to date. We know
unequivocally, for example, that use of dopamine
agonists in conjunction with levodopa will reduce the
appearance of some motor complications compared
with levodopa monotherapy. We do not know, how-
ever, which approach best serves our patients’ quality of
life. Optimizing outcome from the patient’s perspec-
tive guides therapy in the clinic, and in recent trials
more extensive quality-of-life measures have been
incorporated. In this article, the medical treatments
for Parkinson’s disease are reviewed.
ACETYLCHOLINE RECEPTOR
ANTAGONISTS
Before the arrival of levodopa, medications that block
postsynaptic acetylcholine receptors served as the

1
Department of Neurology, Movement Disorders Program, University
of California–Irvine; Phillip and Carol Traub Center for Parkinson’s
Disease, Eisenhower Medical Center, Rancho Mirage, California.
Address for correspondence and reprint requests: Neal Hermano-
wicz, M.D., Department of Neurology, 105 Irvine Hall, University of
California–Irvine, Irvine, CA 92697-4275.
Movement Disorders; Guest Editor, Robert L. Rodnitzky, M.D.
Semin Neurol 2007;27:97–105. Copyright # 2007 by Thieme
Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001,
USA. Tel: +1(212) 584-4662.
DOI 10.1055/s-2007-971177. ISSN 0271-8235.
97
98 SEMINARS IN NEUROLOGY/VOLUME 27, NUMBER 2 2007
mainstay for the treatment of PD. Whether catego-
rized as belladonna alkaloids (e.g., atropine) or as
synthetic drugs (trihexyphenidyl, benztropine, biper-
iden), the putative pharmacology was the same; central
cholinergic antagonism and the side effects mediated
by central or peripheral blockade of acetylcholine are
similar among them.4
Although long used for treatment of PD, and
probably because of their long use, the anticholinergic
drugs have not been subjected to the same scrutiny in
terms of efficacy and adverse events as more recent
arrivals. Among them, benztropine was described as
particularly beneficial for tremor, a quality later ascribed
by some clinicians to this category in general. This
notion of tremor specificity, however, seems to be largely
propagated as folk medicine rather than based on rig-
orous assessment. A recent, careful literature review
failed to locate data from clinical trials to substantiate
this belief.5 The same review was not able to identify by
comparison study the also widely held belief that these
medications are more poorly tolerated than later, ex-
pressly dopaminergic drugs. One study examining anti-
cholinergic medications described an alarming increase
in neuritic plaques and tangles correlating with chronic
use.6 Although to date this has been an isolated report, it
does cause concern and warrants investigation by others.
Side effects of anticholinergic medications may
include mental confusion, mydriasis with decreased
visual acuity, dry eyes, dry mouth, constipation, and
urinary retention. They are contraindicated in patients
with acute angle glaucoma and should be used cautiously
in patients with peptic ulcer disease. Anticholinergic
medications do remain in use for PD despite the lack
of modern methods to assess their efficacy and adverse
effects.
LEVODOPA
The identification of dopamine deficiency in the brains
of people with PD and the reduction of symptoms by
oral supplementation of its chemical precursor, levodopa,
not only remains one of the triumphs of clinical neuro-
science, but also the cornerstone of PD medical treat-
ment and the basis of comparison for other medications.
Because dopamine itself does not efficiently pass through
the blood-brain barrier, levodopa instead is provided.
Although in PD the numbers of nigral neurons produc-
ing dopamine are diminished by half or more, those that
remain have an increased rate of dopamine synthesis.
Levodopa supplementation is used by these overdriven
neurons to increase dopamine production and thereby
reduce symptoms.7
Early reports of the treatment of parkinsonism
with levodopa and DOPA (a racemic mixture of D and
L types was used for cost reasons) described marked
improvement in symptoms, in some cases unresponsive
to other therapies of the day, and also improvement in
symptoms such as dysphagia and mental confusion now
regarded as poorly responsive to dopaminergic medica-
tion.8,9 Additionally, both short and longer responses to
levodopa were reported long ago, the former after a
single dose and with a duration of a few hours, and the
latter occurring after accumulated doses and lasting for
days.9
Of interest also was the observation of the emer-
gence of dyskinesias with relatively brief DOPA treat-
ment in some patients. Although the time course for
development of these movements was not specified in
detail, duration of treatment before their emergence
ranged from 16 to 347 days. These movements were
noted to be evident only when the clinical improvement
with DOPA was marked.9
Modern data on the effectiveness of levodopa was
obtained in the ELLDOPA (Early versus Late Levodopa
Therapy of Parkinson’s) trial.10 This was a multicenter
study organized by the Parkinson Study Group and
funded by the National Institutes of Health, with the
intent of determining whether levodopa treatment con-
tributed to a more rapid decline in PD. Subjects recently
diagnosed and untreated were enrolled and randomly
assigned to placebo or to 150 mg, 300 mg, or 600 mg
of levodopa divided into a regimen of three times per day
for 9 months. The primary outcome measure was the
score on the Unified Parkinson Disease Rating Scale
(UPDRS). A secondary outcome was employed using
imaging by means of single-photon emission computed
tomography (SPECT) using 2-beta-carboxymethoxy-3-
beta-(4-iodophenyl)tropane (b-CIT), a ligand for the
presynaptic dopamine transporter and a presumed
method for quantitative assessment of dopaminergic
neurons. Subjects were clinically assessed during the
treatment period and again at the conclusion after a 2-
week medication washout. The ELLDOPA study re-
ported for the first time in the long use of this drug a
dose-response relationship between dosage and clinical
effect. The impact of levodopa on individual symptoms,
such as tremor, rigidity, and bradykinesia, was not re-
ported in the data analysis.
The ELLDOPA study showed that compared
with placebo, levodopa improved scores of activities of
daily living and motor assessment but not in the rela-
tively superficial analysis of mental function. Moreover,
after the washout period, a significant and positive
difference between those who received treatment and
the placebo group remained. One interpretation of this
result proposed by the authors of the study was that
levodopa may in fact have a protective effect and actually
delay disease progression. Alternatively, others have
pointed out that the washout period of 2 weeks may
not have been sufficient. Predictably, subjects receiving
levodopa had more side effects than those on placebo,
notably dyskinesias and nausea.

A subgroup analysis of the subjects undergoing
SPECT imaging with b-CIT showed that the group
receiving the highest dosage of levodopa showed a
significant reduction in binding compared with the
placebo group, suggesting a greater decline in neurons.
The authors of ELLDOPA noted that this clinical/
imaging mismatch has been observed in other studies
involving dopamine agonist drugs and posited another
possible explanation, that the treatment medication
might alter ligand binding. This is currently under
investigation, but to date the issue has not been
resolved.
The motor complications of levodopa therapy
have been well documented, starting with early trials
and more recently in large, multicenter therapeutic
studies. These studies report the appearance of choreic
dyskinesias, end-of-dose wearing off in the range of 17
to 45% and 37 to 57% of patients, respectively, after

2 to 5 years of levodopa therapy.11–13 The pharma-
cokinetic profile of levodopa is often blamed as the
source of these complications, and studies of animal
models of PD using dopamine agonists support this
notion.14,15
It is likely that the half life of levodopa is not the
sole contributing factor to the development of dyskine-
sias. Although a substantial fraction of patients will
develop dyskinesias after treatment with levodopa for
2 years, the majority do not. The percentage apparently
increases with duration of therapy, but it remains that
some people are more likely to develop dyskinesias than
others.16,17 Patients under age 50 years, for example, are
recognized as being at increased risk. Why it is that some
people are more likely to develop dyskinesias has not
been identified.
Despite its inherent problems, it is unlikely that
levodopa will be supplanted by another medical therapy
soon. Efforts to enhance the delivery of this drug and
possibly reduce the complications attributed to its rela-
tively short half life are underway.
The effective half life and duration of clinical
benefit of levodopa are augmented when used in
combination with an inhibitor of catechol-O-methyl-
transferase (COMT), the secondary pathway, after
decarboxylase, of levodopa degradation in the periph-
ery. Currently underway is an international, multicen-
ter study to examine whether introduction of levodopa
with a COMT inhibitor, specifically entacapone, will
have an impact on the appearance of levodopa-associ-
ated dyskinesia.
A patch with transdermal delivery of levodopa has
long been discussed but so far has not been deemed
realistic because of the instability of the levodopa mol-
ecule with sunlight exposure and also difficulty with its
permeability through the dermis. This is being reex-
amined in conjunction with stabilizers and other meth-
ods to enhance absorption through the skin.
DRUG THERAPY FOR PARKINSON’S DISEASE/HERMANOWICZ 99
Currently levodopa is available in three prepara-
tions: (1) combined with carbidopa, (2) combined with
carbidopa in an extended-release tablet, and (3) com-
bined with carbidopa and entacapone. The concept of an
extended-release formulation of levodopa remains at-
tractive, but the present formulation does not achieve its
intended result of reducing end-of-dose wearing off, nor
has it been found to reduce the appearance of other
motor complications such as dyskinesias.18
DOPAMINE AGONISTS
Dopamine agonists alleviate symptoms of Parkinson’s
disease by simulating the action of dopamine at post-
synaptic receptors. Dopamine agonists have been avail-
able since 1974 when bromocriptine, the first such
drug, was approved.19 Since then the number of such
drugs available has increased to a total of four with
pergolide, ropinirole, and pramipexole in the United
States with a fifth, rotigotine, anticipated shortly.
Cabergoline, a long-acting, once-daily medication
widely used in Europe, is unavailable in the United
States for the treatment of PD.
Dopamine agonists have some prominent advan-
tages when compared with levodopa. First, they are not
dependent on conversion to an active form by the
presynaptic neurons that are being depleted by PD.
Second, as a group these medications have plasma half
lives of several hours and are thus less likely to create the
motor complications of medical therapy attributed to the
shorter half life of levodopa, namely, end-of-dose wear-
ing off and dyskinesias.
Dopamine agonists are useful agents for both
monotherapy and as adjuncts combined with levodopa.
Both ropinirole and pramipexole, when used as mono-
therapy for mild PD, have been reported to be equivalent
to levodopa as assessed by limited quality-of-life meas-
ures and patient and examiner impressions in mild PD,
but they are inferior in terms of motor improvement.13,20
Patients treated with levodopa who experience
end-of-dose wearing off will have reduced off time and
may be able to reduce the levodopa dosage with the
addition of a dopamine agonist. The reduction of off
time by adding a dopamine agonist has been reported to
be from 8 to 32%.1 It is important to emphasize that the
percentages of change in off and on time were derived
largely from different studies and, with the exception of
ropinirole and bromocriptine,21 not head-to-head com-
parisons among the dopamine agonists.
Two large, industry-sponsored clinical trials
reached the same conclusion that initial therapy with a
dopamine agonist with levodopa added later forestalls
the appearance of dyskinesias and also diminishes end-
of-dose wearing off.13,20 An independent, rigorous ex-
amination of the literature established unequivocally that
initial treatment with a dopamine agonist in conjunction
100 SEMINARS IN NEUROLOGY/VOLUME 27, NUMBER 2 2007
with levodopa added later compared with levodopa
monotherapy does indeed reduce the appearance of these
problems.22 However, this analysis drew no conclusions
as to which line of therapy is best as assessed by patient
quality-of-life measures. Preventing or forestalling the
appearance of dyskinesias has been advocated as a goal
of therapy, sometimes leading to extreme avoidance of
levodopa, coined ‘‘levodopa phobia.’’23 One analysis of
this problem of dyskinesias indicates that severe dyski-
nesias are an uncommon problem, more typically are not
disruptive, and can be successfully addressed by medi-
cation adjustment.24
Prescription of dopamine agonists as well as
sophistication in their use has increased in the past
10 years. Now, methods of agonist administration are
also increasing. The potent but short-acting agonist
apomorphine has long been used by episodic intramus-
cular injection and subcutaneous infusion in Europe, and
is also available as an intramuscular injection rescue
medication in the United States. Transdermal delivery
of a dopamine agonist has been tested for several years.25
At the time of this writing, rotigotine, a nonergot
dopamine agonist, is available in some European coun-
tries under the trade name Neupro as a once-daily patch
used as monotherapy in early PD, and has been sub-
mitted for consideration to the U.S. FDA. Ropinirole
has been formulated into a prolonged release tablet
administered once per 24 hours, and has been reported
to be beneficial as both monotherapy and as an adjunct
for patients not optimally treated with levodopa alone.26
Pramipexole is under investigation in a twice-daily
rather than three-times-a-day dosing regimen and at a
lower total daily dosage.
The modification of disease progression, or neu-
roprotection, has long been a goal in developing ther-
apeutics for PD. In vitro experiments point to several
areas where dopamine agonists may have a favorable
effect on reducing neuronal injury incurred by the
processes of PD.27,28 Functional imaging using markers
of dopamine metabolism both by positron emission
tomography (PET) and SPECT, using fluorodopa and
b-CIT, respectively, have stimulated discussion of mod-
ification of neuronal survival in subjects treated with a
dopamine agonist in comparison to those treated with
levodopa.12,13 Both of these studies concluded that
agonist treatment had a favorable effect on altering
disease progression as measured by imaging, although
both studies also have been criticized on methodology
and interpretation of results. To date no medication,
including a dopamine agonist, has been definitively
identified to slow the progression of PD.
A collection of case reports of sudden sleepiness in
a small number of patients treated with either ropinirole
or pramipexole invigorated examination of sleep disorders
in PD.29 Although this first report of ‘‘sleep attacks’’ and
associated car crashes suggested a role for ropinirole
and pramipexole in sudden, irresistible drowsiness, later
and more extensive examination of sleepiness in PD
indicates that this problem is more complex than a simple
medication side effect.30,31 Sleep disorders are pervasive
and diverse in PD, and, consequently, separating an effect
from a drug from the disease itself can be challenging or
impossible.
Another unpleasant phenomenon associated with
agonist medications that has recently received increased
attention is the emergence of behaviors associated with
abnormal reward regulation, described as compulsions,
impulse control disorders, or hedonistic homeostatic
dysregulation.32–34 This has been manifested as compul-
sive gambling; hypersexuality; and excessive eating, shop-
ping, and hobbyism. The reports to date indicate these
problems arise in association with dopamine agonists
more so when they are used in conjunction with levo-
dopa, and affect somewhere in the range of a few to 14%
of patients who use these medications.35 Although pra-
mipexole has in some reports most often been associated
with this phenomenon, this likely simply reflects the fact
that it is more widely used in the United States than other
agonist medications. The scope of this problem is not yet
clear, but it does warrant discussion with patients receiv-
ing dopaminergic medications. Patients may be unwilling
to discuss these behaviors or fail to recognize them as
possibly associated with their diagnosis and treatment.
More conventional side effects of the agonist
medications as a class include nausea, orthostatic hypo-
tension, dizziness, somnolence, hallucinations, and pedal
edema.
MONOAMINE OXIDASE INHIBITORS
Dopamine is degraded centrally to dihydroxyphenyl-
acetic acid (DOPAC), a process facilitated by mono-
amine oxidase (MAO). Substances that inhibit MAO
and thus prolong the action of dopamine have been
proposed for the treatment of PD since shortly after the
appearance of levodopa.36
Two isoenzymes of MAO have been identified,
type A and type B, according to their inhibition by
clorgyline and selegiline, respectively.37 Both types A
and B are present in the brain and are associated with
dopaminergic and serotonergic neurons. The predom-
inant type of MAO in the gut is A, which metabolizes
tyramine. Inhibition of type A allows entry of tyramine
to the circulation, where it may produce a pressor effect
mediated through the generation of sympathomimetic
compounds. Selective inhibition of type B, however,
allows tyramine metabolism in the gut and thus avoids
the risk of a hypertensive crisis, the so-called ‘‘cheese
effect’’ of tyramine-containing foods.
The first such medication to come into clinical use
was selegiline, also known initially as deprenyl, which
was approved in the United States in 1989 by the FDA

as an adjunct for patients who have experienced a decline
in their response to levodopa. Recently, selegiline has
become available in a freeze-dried tablet preparation
(trade name Zelapar) that dissolves rapidly when placed
on the tongue. Intended initially for patients with
dysphagia, it was determined that when administered
in this fashion, selegiline is rapidly absorbed through the
buccal mucosa. By avoiding hepatic metabolism on first
entering the circulation, the dosage in this form is
reduced and may also be administered only once daily
rather than twice a day as with the swallowed tablets.
This administration method also reduces the production
of amphetamine metabolites, suspected by some to
contribute to adverse effects such as sleep disruption
and agitation. This selegiline preparation at a dose of 2.5
mg once daily has been reported to reduce off time by
2
hours each day in patients with motor fluctuations.38
Selegiline has not been demonstrated to be of value as a
monotherapy.
Rasagiline (trade name Azilect) has recently be-
come available and received approval by the FDA as both
monotherapy and an adjunct medication for PD. In a 26-
week, randomized, double-blind, placebo-controlled trial
in subjects with mild PD receiving no other antiparkinson
medication (anticholinergics were allowed), rasagiline
showed modest efficacy.39 A second study of rasagiline
as an adjunct medication for subjects treated with levo-
dopa and experiencing motor fluctuations showed a
reduction of off time of approximately 1 hour compared
with placebo with a similar increase in on time.40 Rasagi-
line does not produce amphetamine metabolites.
Both selegiline and rasagiline continue to be of
interest as agents that may modify the progression of
PD. Laboratory investigations of both drugs indicate a
protective effect in models of PD.41,42 Selegiline was
examined as a possible disease-slowing agent in the
large, multicenter DATATOP (Deprenyl And Toco-
pherol Antioxidative Therapy Of Parkinsonism) study,
which generated several publications and discussions but
was inconclusive regarding neuroprotection.11 Rasagi-
line is currently being examined for its potential benefit
in slowing the progression of PD in a multicenter,
multinational study.
CATECHOL-O-METHYLTRANSFERASE
INHIBITORS
COMT metabolizes levodopa to the clinically useless
3-O-methyldopa both in the periphery and central
nervous system (CNS). This pathway assumes greater
significance in the periphery when the primary route for
levodopa degradation, decarboxylation, is inhibited by
carbidopa or benserazide.
Tolcapone first became available in the United
States in 1997 and was soon followed by entacapone.
Both provide inhibition of COMT to enhance delivery of
DRUG THERAPY FOR PARKINSON’S DISEASE/HERMANOWICZ 101
levodopa to the CNS and thus prolong its clinical effect.
Of the two, tolcapone is the more potent inhibitor of
COMT. At 1 hour, tolcapone achieves red blood cell
COMT inhibition of 80% compared with 70% with
entacapone; at 4 hours, the red blood cell COMT
inhibition was 60% and 10% for tolcapone and entaca-
pone, respectively.43
The administration regimens reflect these proper-
ties of COMT inhibition. Entacapone is given at a fixed
dose of 200 mg with each dose of levodopa, whereas
tolcapone is administered at 100 mg or 200 mg three
times a day at 6-hour intervals.
Both tolcapone and entacapone reduce off time
and increase on time in patients with motor fluctuations.
In clinical trials of fluctuating patients, off time has been
decreased by approximately an hour per day with en-
tacapone and 2 to 3 hours with tolcapone in relation to
placebo.44,45 However, these numbers are not derived
from studies involving head to head comparison of
entacapone with tolcapone.
Dyskinesia may be enhanced by the addition of a
COMT inhibitor, although this can be addressed by
reducing the levodopa dosage. Urine and other bodily
fluids may be discolored to an orange or amber hue,
which is distressing to patients if they are not notified
beforehand but otherwise has no significance. Diarrhea
is induced in
5 to 10% of patients using either
entacapone or tolcapone. This sometimes sounds attrac-
tive to people who are chronically constipated, but when
it does occur it too is distressing. People who are
unaware of this potential side effect may be subjected
unnecessarily to tests, such as colonoscopy, to identify
the cause of the diarrhea.
The prescription of tolcapone dropped drastically
when three cases of fulminate liver toxicity
were associated with this drug.46 Tolcapone was re-
moved from some European countries, and in the
United States its prescription now requires use first of
other reasonable alternatives, a signed patient consent,
and discontinuation of the drug if there is no benefit
after 3 weeks of use. Monitoring of serum transaminase
levels monthly for 6 months is required and continued
thereafter according to the clinician’s judgment.
The suspicion that the short half life of levodopa
contributes to the appearance of motor complications
has lead to efforts to modify this by use of COMT
inhibition, and studies are currently underway to ascer-
tain whether this will be successful.
AMANTADINE
Amantadine has long been used to treat the primary
symptoms of PD,47 and it continues to be used despite
the lack of clarity of its pharmacological mechanism and
the arrival of levodopa and dopamine agonists. It re-
mains the choice of some clinicians for treating mild
102 SEMINARS IN NEUROLOGY/VOLUME 27, NUMBER 2 2007
symptoms when a dopaminergic medication is judged to
be not yet necessary. Early double-blind trials indicated
its efficacy in alleviating some of the primary symptoms
of PD.48
In recent years, amantadine has risen in prom-
inence as the only medication that both alleviates symp-
toms of PD and also reduces medication-induced
dyskinesia. Reported long ago as having a beneficial effect
on chorea associated with Huntington’s disease,49 this
antichorea effect was rediscovered in the choreic dyski-
nesias of treated PD.50 This was an important finding for
an old drug that eases management of an otherwise tricky
problem, reducing dyskinesias without reducing mobility.
Regarded by some as a relatively benign medica-
tion for mild PD, the side effects of amantadine can be
troubling or even harrowing. Livedo reticularis, a mot-
tled skin rash, may be induced by the drug, although this
is often of no clinical significance other than the cos-
metic effect. More problematic is the leg edema that may
be caused by amantadine, and the hallucinations some-
times created by this drug are as troubling as any other
PD therapy. Withdrawal of amantadine should be ac-
complished slowly and with caution because its abrupt
cessation has been associated with acute delirium.51
MEDICATIONS FOR COGNITIVE
IMPAIRMENT ASSOCIATED WITH
PARKINSON’S DISEASE
Dopaminergic medications often provide substantial
improvement in the motor symptoms of PD but do
not necessarily address many of the nonmotor problems,
such as autonomic dysfunction, sleep disturbance, and
cognitive impairment. These can be disabling and may
be the patient’s most prominent complaint. Some cog-
nitive functions are influenced by levodopa or other
dopaminergic medications,52–54 although the clinical
benefit, if any, may not be of significance to patients or
their family members.
No drugs have been developed to specifically
address cognitive dysfunction in PD, although in prac-
tice medications developed for Alzheimer’s disease have
often been prescribed in an off-label fashion. With the
exception of memantine, all of these medications are
cholinesterase inhibitors and, following the logic that
anticholinergic medications improve motor symptoms of
PD, it has been intuitively suspected these drugs may
produce motor worsening.
Rivastigmine and donepezil have both been
examined in well-organized studies as agents to treat
dementia in PD, although the number of subjects in the
donepezil study was relatively small.55,56 Both drugs
show modest benefit in some measures of cognitive
function. Donepezil was not found to worsen scores on
the UPDRS, although rivastigmine was associated with
increase in tremor in a relatively small percentage of
subjects compared with placebo. Nausea and vomiting
associated with rivastigmine were problematic in some
subjects. Rivastigmine has been approved by the U.S.
FDA for the treatment of mild to moderate PD
dementia. At this writing, no controlled studies have
been published on the use of galantamine for PD
dementia.
Memantine as a putative glutamate antagonist
would be more attractive as an agent to improve both
motor and cognitive symptoms in PD, but no such
supportive data have been published. Moreover, given
its antiglutamate activity, it might be thought to reduce
dyskinesias, along the lines of amantadine. Again, no
such data have been published.
MEDICATIONS FOR AUTONOMIC
DYSFUNCTION ASSOCIATED WITH
PARKINSON’S DISEASE
Another very troubling symptom group is attributed to
autonomic dysfunction in PD. This includes sialorrhea,
orthostatic hypotension, urinary urgency and frequency,
delayed gastric emptying and gastrointestinal transit,
constipation, and erectile and other sexual dysfunction.
All of these are common in PD, and all may and often do
occur in a single patient.
Large, placebo-controlled studies have not been
accomplished for many of these problems, but some data
are available and pharmacological methods for address-
ing these symptoms are often employed by practitioners.
Sialorrhea may be reduced by cautious use of
small quantities of sublingual atropine 1% solution57
or, failing this, by injection of the parotid glands with
botulinum toxin.58 Orthostatic hypotension can be
improved by use of increased salt intake and volume-
expanding drinks. A second step is to use medications
that promote volume retention, fludrocortisone and
midodrine.59 The former is a steroid and as such
should be used knowledgably in this osteoporosis-
prone group. A more recent method to stabilize pos-
tural fall in blood pressure has been with pyridostig-
mine, ostensibly to increase sympathetic output by
acting at the cholinergic, autonomic ganglion. This
has been reported to be successful with and without the
use of midodrine.60,61
Urinary urgency and frequency generally require
investigation by a urologist to characterize the mecha-
nism of the symptoms before initiating treatment, par-
ticularly in men in whom bladder outflow obstruction by
prostate enlargement may be a contributing factor.
Peripherally acting anticholinergic agents may be of
benefit in alleviating overactive bladder symptoms,62
but an undesired consequence mediated by the same
pharmacology may be exacerbation of problems with gut
motility and constipation and, as suggested in the
preceding paragraph, blood pressure volatility.

Erectile dysfunction occurs commonly among men
with PD and may respond to medications developed for
this problem such as sidenafil.63
Constipation is another common PD problem; it
was described in detail by James Parkinson in his 1817
monograph, and it still has relevance today. It is dis-
tressing to patients and difficult to satisfactorily treat.
Although the package inserts for dopaminergic medi-
cations cite constipation as a potential side effect, the
source of this in many patients may be primarily from
PD itself rather than from its treatment. Exercise, fiber,
and fluids, the usual recommendations to alleviate con-
stipation, usually do not work and more creative meth-
ods are necessary. Lactulose works but too often results
in unpleasant cramping, flatulence, and loose stools.
Polyethylene glycol, like lactulose, is an osmotic agent
effective for constipation but seems less likely to create
the unpleasantness of the latter.
CONCLUSION
The heterogeneity of the clinical manifestations, the
diversity of response to medications, and the potential
for adverse effects all contribute to the challenge of the
medical management of Parkinson’s disease. Successful
symptom management often is not a simple task that can
be taught or learned in a strictly formulaic manner; it
requires time, attention, and communication with our
patients. When done poorly, the outcome can be more
distressing to patients than the symptoms of the disease
the drugs are intended to alleviate. When done well, it
results in sustained enhancement of quality of life and
reassurance to the patients and their families that this
disease can be successfully treated and managed.
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