Download Pharmacologic treatment of Parkinson disease:

Pharmacologic treatment of
Parkinson disease:
Dr behnaz ansari
• The array of pharmacologic and surgical treatments
available for the treatment of idiopathic Parkinson
disease (PD) is broader than for any other degenerative
disease of the central nervous system.
• Management of individual patients requires careful
consideration of a number of factors, including the
patient's symptoms and signs, age, stage of disease,
degree of functional disability, and level of physical
activity and productivity. Treatment can be divided
into pharmacologic, nonpharmacologic, and surgical
therapy.
• nearly all of the available treatments are
symptomatic in nature and do not appear to
slow or reverse the natural course of the
disease. However, several potential
neuroprotective agents for PD have shown
some promise in animals and/or humans and
are undergoing further investigation.
SYMPTOMATIC THERAPY :
• The decision to initiate symptomatic medical therapy in
patients with PD is determined by the degree to which
the patient is functionally impaired. The timing of this
decision varies greatly among patients but is influenced
by a number of factors, including :
●The effect of disease on the dominant hand
●The degree to which the disease interferes with work,
activities of daily living, or social and leisure function
●The presence of significant bradykinesia or gait
disturbance
●Patient values and preferences regarding the use of
medications
• The major drugs available for the treatment of PD
motor symptoms include:
●Levodopa
●Dopamine agonists
●Monoamine oxidase (MAO) B inhibitors
●Anticholinergic agents
●Amantadine
●Catechol-O-methyl transferase (COMT) inhibitors
Parkinson’s Disease
Symptoms: (the 4 R’s) initially unilateral disease
1. Resting tremor and cogwheeling
2. Rigidity and flexed posture
3. Retarded movement (brady and hypokinesia)
4. Loss of postural Reflexes
Drug
Mechanism
Adverse effect
Levodopa-carbidopa
Dopamine
replacement
DOC for older
patients
1. Motor fluctuations:
dopamine agonist or
amantadine
2. Wearing off: inc dose or
frequency
Ropinirole, Pramipexole
Dopamine
receptor agonist
DOC for <65yo
Impulse control disordershypersexual and gambling
Amantadine
NMDA receptor
antagonist
Mild symptoms,
tremor
AMS and psychosis
Selegiline, Rasagiline
MAO-B inhibitor
May delay need
for L-dopa
Seratonin syndrome if with
SSRIs or tricyclics
**Acutely discontinuing dopa therapy may cause NMS. Treat with a dopamine agonist:
bromocriptine, amantadine or dantrolene
The following general principles can be used to
guide the choice of therapy in symptomatic PD:
• Levodopa is the most effective drug for the
symptomatic treatment of PD and is the drug
of first choice if symptoms, particularly those
related to bradykinesia, become intrusive or
troublesome. In addition, levodopa should be
introduced when akinetic symptoms become
disabling for patients receiving other
antiparkinsonian drugs.
• The dopamine agonists may be employed
either as monotherapy in early PD or in
combination with other antiparkinsonian
drugs for treatment of more advanced
disease. They are ineffective in patients who
show no response to levodopa. While
dopamine agonists possibly delay the need to
initiate levodopa therapy, their use is
associated with an increased risk of impulse
control disorders.
• Either levodopa or a dopamine agonist can be used initially
for patients who require symptomatic therapy for PD .
Given the potential that dopamine agonists may be
associated with fewer motor fluctuations than levodopa,
and the evidence that there is a higher incidence of
levodopa-related dyskinesia in young-onset PD, it is
reasonable to start therapy with a dopamine agonist in
younger patients (age <65 years), and with levodopa in
older patients (age ≥65 years). In practice, while symptoms
can be controlled initially with dopamine agonists, few
patients with progressive disease can be satisfactorily
maintained on dopamine agonist monotherapy for more
than a few years before levodopa is needed.
• The MAO B inhibitors selegiline and rasagiline may be
useful in patients with early PD but have only modest
symptomatic benefit as monotherapy.
• Anticholinergic drugs are most useful as monotherapy
in patients under 70 years of age with disturbing
tremor who do not have significant bradykinesia or gait
disturbance. They also may be useful in patients with
more advanced disease who have persistent tremor
despite treatment with levodopa or dopamine
agonists. Their use in older or demented individuals
and those without tremor is strongly discouraged.
• Amantadine is a relatively weak
antiparkinsonian drug with low toxicity that is
most useful in treating younger patients with
early or mild PD and perhaps later when
dyskinesia becomes problematic. However,
toxic side effects are more likely in older
patients.
• Low-dose estrogen may be helpful as
adjunctive therapy in postmenopausal women
Swallowing restrictions in Parkinson
disease:
• Most patients with PD can go without antiparkinson
medications for a brief period (ie, <24 hours) when oral
intake is temporarily restricted (eg, when perioperative
or periprocedural), or when seriously ill.
• In patients who are critically ill and bedbound, the
parkinsonian symptoms are typically overshadowed by
the burden of other medical problems, and
antiparkinson medications may not provide any clear
benefit.
• However, sudden withdrawal or dose reduction of
antiparkinson medications can rarely precipitate the
parkinsonism-hyperpyrexia syndrome.
• When treatment is still desired for patients who are
restricted to take nothing by mouth (nil per os; NPO),
options include:
transdermal rotigotine and apomorphine by injection
or continuous infusion. The use of apomorphine
requires a test dose prior to ongoing treatment
• For patients with a nasogastric feeding tube, levodopa
tablets can be crushed and given through the tube . For
patients with dysphagia, orally
disintegrating carbidopa-levodopa (Parcopa) is a
potential treatment option.
Parkinsonism-hyperpyrexia
syndrome :
• There have been reports of patients with PD who developed neuroleptic
malignant syndrome in the context of sudden withdrawal or dose
reductions of levodopa or dopamine agonists, and rarely amantadine, as
well as with switching from one agent to another. In this context, the
condition has been termed the parkinsonism-hyperpyrexia syndrome
.Prompt recognition and treatment are important, as severe cases and
even fatalities have been reported .
• Management of parkinsonism-hyperpyrexia syndrome involves replacing
antiparkinson medications at the dose that was used prior to the onset
of the syndrome . Levodopa and dopamine agonists can be given orally or
via nasogastric tube. Levodopa can also be given intravenously (50 to 100
mg infused over three hours, repeated four times daily) if both oral and
nasogastric feeding are contraindicated; options for dopamine agonists
include transdermal rotigotine and apomorphine by injection or
continuous infusion. The use of apomorphine requires a test dose prior to
ongoing treatment.
• In addition to replacing antiparkinson medications,
patients with significant hyperthermia and rigidity
should be admitted to an intensive care unit setting
and undergo aggressive supportive care as well as
monitoring for potential dysautonomia and other
complications .
• For patients with severe symptoms who do not
respond to restarting antiparkinson medications and
supportive care within the first day or two, additional
though unproven measures to consider include the use
of dantrolene, bromocriptine, and/or amantadine.
LEVODOPA:
• Levodopa (L-dopa) is well-established as the
most effective drug for the symptomatic
treatment of idiopathic or Lewy body PD . It is
particularly effective for the management of
bradykinetic symptoms and should be
introduced when these become intrusive or
troublesome or are uncontrolled by other
antiparkinsonian drugs. Tremor and rigidity
can also respond to levodopa therapy, but
postural instability is less likely to do so.
• As noted previously ,either levodopa or a dopamine
agonist can be used initially for patients who require
symptomatic therapy for PD. It is reasonable to initiate
therapy with a dopamine agonist in younger patients
(age <65 years), and with levodopa in older patients
(age >65 years).
• However, there are exceptions to these general rules,
and all treatments should be individualized. Levodopa
is the drug of choice if symptoms, particularly those
related to bradykinesia, seriously threaten the patient's
lifestyle.
• Levodopa is combined with a peripheral decarboxylase
inhibitor to block its conversion to dopamine in the
systemic circulation and liver (before it crosses the bloodbrain barrier) in order to prevent nausea, vomiting, and
orthostatic hypotension. In the United States, the
decarboxylase inhibitor is carbidopa. The combination
drug carbidopa-levodopa (immediate-release Sinemet) is
available in tablets of 10/100, 25/100, and 25/250 mg, with
the numerator referring to carbidopa and the denominator
referring to the levodopa dose.
• An immediate-release formulation of carbidopa-levodopa
(Parcopa) is available that dissolves on the tongue and can
be taken without water ; its time of onset of action is not
different from Sinemet.
Sinemet:
• In some countries, benserazide is the peripheral
decarboxylase inhibitor. The combination drug
benserazide-levodopa (Madopar or Prolopa) is
available in 25/100 and 50/200 mg tablets. In many
countries, both carbidopa-levodopa (eg, Sinemet) and
benserazide-levodopa (eg, Prolopa) are marketed.
• Controlled-release formulations of carbidopalevodopa and benserazide-levodopa are available as
Sinemet CR and Madopar HBS, respectively. Compared
with regular levodopa, the absorption of the
controlled-release formulations is approximately 70
percent.
Madopar:
• Treatment should begin with small doses, such
as carbidopa-levodopa (Sinemet) 25/100 mg, one-half
tablet two to three times daily with meals. Tolerance
for the appropriate starting dose must be assessed
individually. Once initiated without side effects, the
total daily dose of carbidopa-levodopa can be titrated
carefully upward over several weeks to a full tablet
of 25/100 mg three times daily as tolerated.
• Older adults or those with dementia should begin with
smaller doses and slower titration because of their
increased susceptibility to psychiatric side effects.
• The vast majority of patients with idiopathic PD
will enjoy a significant therapeutic response to
moderate doses of levodopa (300 to 600 mg
daily).
• Complete absence of response to a levodopa
dose of 1000 to 1500 mg/day suggests that the
original diagnosis of PD may be incorrect and that
one of the other parkinsonian syndromes, such as
multiple system atrophy, progressive
supranuclear palsy, or vascular parkinsonism
should be considered.
• Levodopa should not be stopped abruptly because
sudden withdrawal has been associated (rarely) with a
syndrome resembling neuroleptic malignant syndrome
or akinetic crisis.
• Patients taking levodopa for the first time should take
each dose with a meal or snack to avoid nausea, a
common early side effect. Patients with more
advanced disease, especially those with motor
fluctuations, often notice that a dose of levodopa is
more effective if taken on an empty stomach 30
minutes before or one hour after meals due to
reduced competition with other amino acids for
gastrointestinal absorption.
• Small starting doses of levodopa of less
than 25/100 mg three times daily combined with a
decarboxylase inhibitor (eg, Sinemet, Madopar, or
Prolopa) are more likely to cause nausea because of
inadequate amounts of carbidopa.
• this can be managed by administering supplemental
doses of carbidopa or by use of antiemetics such
as trimethobenzamide or domperidone (not available
in the United States) taken prior to Sinemet.
Phenothiazine antiemetics such
as prochlorperazine andmetoclopramide should be
avoided because they are dopamine receptor blockers
that can aggravate parkinsonian symptoms.
Adverse effects :
•
Nausea, somnolence, dizziness, and headache are among the more
common early side effects that may accompany treatment with
levodopa, but they are not likely to be serious in most patients.
More serious adverse reactions to levodopa (mainly in older
patients) may include confusion, hallucinations, delusions,
agitation, psychosis, and orthostatic hypotension.
• Levodopa may also induce a mild to moderate elevation in serum
homocysteine levels , which in turn may be associated with an
increased risk of hip fractures in older adults.
• In addition, there is some preliminary evidence suggesting that
levodopa exposure in patients with idiopathic PD is associated with
elevated methylmalonic acid levels and possibly a higher than
expected incidence of sensorimotor peripheral neuropathy
Motor fluctuations :
• These include motor fluctuations (the wearing-off
phenomenon), involuntary movements known as
dyskinesia, abnormal cramps and postures of the
extremities and trunk known as dystonia, and a variety
of complex fluctuations in motor function.
• It is estimated that such motor complications occur in
at least 50 percent of patients after 5 to 10 years of
treatment .
• The risk of motor complications increases with a
younger age at PD onset and with higher levodopa
doses
• The increase in motor fluctuations over time is
most likely due to progressive degeneration of
nigrostriatal dopamine terminals, which
increasingly limits the normal physiologic
uptake and release of dopamine, thereby
leading to reduced buffering of the natural
fluctuations in plasma levodopa levels that
occur due to its 90-minute pharmacologic
half-life.
Wearing "off" phenomenon:
•
•
•
•
•
•
•
Examine the effect of diet, and avoid taking levodopa with high protein meals.
A sustained-release levodopa formulation may be beneficial, but only in the early stages of
wearing "off" in patients with less advanced PD.
In patients with more advanced PD, reduce the levodopa dose interval by 30 to 60 minutes.
This may require the addition of an extra levodopa dose at the end of the day.
Consider adding the COMT inhibitors entacapone (Comtan) or tolcapone (Tasmar).
Entacapone should be given first because of the small risk that tolcapone can cause an
elevation of liver enzymes.
Consider adding an oral dopamine agonist such as pramipexole or ropinirole. Watch for
dopaminergic toxicity such as visual hallucinations and confusion, and be prepared to lower
the levodopa dose.
Consider parenteral apomorphine in patients with sudden and severe wearing "off" effects.
This rescue therapy is very effective.
Consider the MAO B inhibitors rasagiline and selegiline .Be aware that selegiline exerts only a
mild effect on the wearing "off" phenomenon, while rasagiline has an effect comparable to
entacapone. Rasagiline is now approved in the United States and in the European Union.
Dyskinesia and dystonia:
• Lower the levodopa dose when possible
• Replace a portion of the levodopa dose with a dopamine
agonist, if necessary
• Replace sustained-release levodopa with regular levodopa,
if dyskinesia is occurring in the late afternoon and evening
• Add amantadine to counteract dyskinesia
• Manage diphasic dyskinesia with more frequent levodopa
dosing
• Use middle-of-the-night levodopa or a dopamine agonist to
treat early morning "off" period dystonia
• Reduce the levodopa dose intervals or add a dopamine
agonist to treat "off" period dystonia during the day
DOPAMINE AGONISTS :
• The dopamine agonists (DAs) are a group of
synthetic agents that directly stimulate dopamine
receptors. The drugs currently approved by the
United States Food and Drug Administration
(FDA)
include bromocriptine, pramipexole, ropinirole, r
otigotine, and injectableapomorphine.
• Pergolide has been voluntarily withdrawn from
the United States market and is best avoided
because it is associated with a risk of cardiac
valve problems.
• Apomorphine and lisuride are additional DAs that
can be administered parenterally for "rescue
therapy" in patients experiencing sudden akinetic
episodes.
• Lisuride is not currently approved in the United
States, but is available in Europe.
• Injectable apomorphine has been approved by
the United States FDA for treatment of motor
fluctuations in PD . Apomorphine infusion pumps
may also be useful, but are not available in the
United States.
• Dopamine agonists (DAs) were initially introduced as
adjunctive treatment for advanced PD complicated by
reduced levodopa response, motor fluctuations,
dyskinesia, and other adverse effects of levodopa.
• DAs are associated with fewer motor fluctuations and
the evidence that there is a higher incidence of
levodopa-related dyskinesia in young-onset PD, some
experts suggest using DAs as initial treatment for PD in
patients younger than age 60, and using the more
effective agent levodopa in patients 60 and older
• Bromocriptine is usually started at 1.25 mg twice
a day; the dose is increased at two to four week
intervals by 2.5 mg a day. Most patients can be
managed on 20 to 40 mg daily in three to four
divided doses, although total daily doses as high
as 90 mg can be used.
• Pramipexole is usually started at 0.125 mg three
times a day. The dose should be increased
gradually by 0.125 mg per dose every five to
seven days. Most patients can be managed on
total daily doses of 1.5 to 4.5 mg.
Pramipexole:
• Ropinirole is usually started at 0.25 mg three
times a day. The dose should be increased
gradually by 0.25 mg per dose each week for
four weeks to a total daily dose of 3 mg. Most
patients can be managed on this dose. After
week four, the ropinirole dose may be
increased weekly by 1.5 mg a day up to a
maximum total daily dose of 24 mg. Benefit
most commonly occurs in the dosage range of
12 to 16 mg per day.
Ropirinole:
• Transdermal rotigotine is a once-daily patch
that is usually started at 2 mg/24 hours and
titrated weekly by increasing the patch size in
2 mg/24 hour increments to a dose of
6 mg/24 hours.
• Apomorphine may be administered either as
intermittent rescue injections or as continuous
infusions to treat "off" episodes or levodopainduced motor fluctuations.
• A challenge test dose must precede routine use.
This is usually done with a 2 mg subcutaneous
injection under medical supervision and
monitoring of standing and supine blood pressure
before the injection, and repeated at 20, 40, and
60 minutes after.
• Antiemetic therapy (eg, with trimethobenzamide) is initiated
three days prior to starting apomorphine and is usually
continued for two months before reassessing need.
• However, the use of apomorphine is contraindicated
with ondansetron and other serotonin receptor agonists
commonly used to treat nausea and vomiting, as the
combination may cause severe hypotension and loss of
consciousness .
• In addition, dopamine antagonists used to treat nausea and
vomiting such
as prochlorperazine and metoclopramideshould be avoided,
as they may reduce the effectiveness of apomorphine.
• The usual starting dose for intermittent
apomorphine use, if the patient tolerates and
responds to the test dose, is 2 mg. The dose
may be increased by 1 mg per dose every two
to four days to a maximum of 6 mg per dose.
The average dosing frequency is three times
daily and should not exceed five times a day
dosing or a total daily dose of 20 mg.
Adverse effects of dopamine
agonists :
• Adverse effects caused by dopamine agonists (DAs) are
similar to those of levodopa, including nausea, vomiting,
sleepiness, orthostatic hypotension, confusion, and
hallucinations. Peripheral edema is common with the
chronic use of DAs but is rare in patients using levodopa
alone.
• These adverse effects of DAs can usually be avoided by
initiating treatment with very small doses and titrating to
therapeutic levels slowly over several weeks. Patients
intolerant of one DA may tolerate another.
• Accumulating evidence suggests that the use of DAs as a
class may lead to compulsive use of dopaminergic
drugs and/or impulse control disorders in up to 15 percent
of patients taking these drugs.
• Ergot-related side effects such as Raynaud phenomenon,
erythromelalgia, and retroperitoneal or pulmonary fibrosis are
uncommon with bromocriptine and pergolide, and they do not
occur at all with the nonergot agonists ropinirole, pramipexole,
and rotigotine.
• Dopamine receptor agonists decrease prolactin concentration .
Thus, there is a potential for decreased milk production in
postpartum women taking these agents, which are contraindicated
in women who are breast feeding.
• The manufacturer of pramipexole has issued a warning regarding
somnolence that can occur abruptly and without premonition,
particularly at a dose above 1.5 mg/day. Patients with PD who drive
are at particular risk of developing these "sleep attacks" .
Dopaminergic dysregulation
syndrome :
• DDS typically involves male patients with early onset
PD who take increasing quantities of dopaminergic
drugs despite increasingly severe drug-induced
dyskinesia .
• DDS can be associated with a cyclical mood disorder
characterized by hypomania or manic psychosis.
Tolerance (or frank dysphoria) to the mood elevating
effects of dopaminergic therapy develops, and a
withdrawal state occurs with dose reduction or
withdrawal. Impulse control disorders including
hypersexuality and pathologic gambling may
accompany DDS.
• Management of DDS is not well studied.
Practitioners should limit dopaminergic dose
increases when possible, particularly in
patients who may have increased
susceptibility to DDS. Continuous
subcutaneous apomorphine infusions may be
useful to suppress off-period dysphoria, and
low doses ofclozapine or quetiapine may be
helpful for some patients.
Impulse control disorders :
• Dopamine (DA) agonist therapy is associated
with an increased risk of impulse control
disorders including pathologic gambling,
compulsive sexual behavior, or compulsive buying
• A randomized crossover trial of 17 patients found
that amantadine (target dose 100 mg twice
daily), administered as add-on to baseline
antiparkinsonian medications, was effective for
reducing or abolishing pathologic gambling in all
treated patients.
MAO B INHIBITORS :
• Selegiline, a selective monoamine oxidase (MAO) type
B inhibitor , is modestly effective as symptomatic
treatment for PD and may have neuroprotective
properties.
• In many individuals, selegiline monotherapy does not
produce a functionally significant benefit. However, the
use of selegiline in early PD is a reasonable option as
long as the patient understands its limitations.
• The selective MAO B inhibitor rasagiline has
neuroprotective properties in animal models and
appears modestly effective as symptomatic treatment
for PD in human clinical trials.
• The dose of selegiline used was 5 mg twice daily,
with the second dose given at noon to avoid
insomnia. However, lower doses are sufficient to
induce MAO B inhibition, and 5 mg once daily in
the morning is currently recommended. Doses
higher than 10 mg daily are of no additional
benefit and may result in nonselective MAO
inhibition, thereby placing the patient at risk of
hypertensive crisis due to dietary interactions
with tyramine-containing foods.
Selegiline:
• Rasagiline as monotherapy for PD is usually
started at 1 mg daily. When used as adjunctive
therapy with levodopa, rasagiline is started at
0.5 mg once daily and can be increased to 1
mg daily based upon response and tolerability
Rasagiline:
Adverse effects :
• Selegiline often causes confusion in older adults, thereby
limiting its use in patients with late-onset disease. As
previously mentioned, selegiline enhances the effect of
levodopa by slowing its oxidative metabolism. Thus, it may
increase levodopa-induced side effects such as dyskinesia
and psychiatric toxicity.
• Serious adverse reactions have rarely occurred following
the concomitant use of selegiline with tricyclic
antidepressants or selective serotonin reuptake inhibitors
(SSRIs). In practice, the vast majority of patients on these
combinations are able to tolerate them for years without
problems. However, the Physicians' Desk Reference (PDR)
warns not to use selegiline with either tricyclics or SSRIs.
ANTICHOLINERGICS:
• Dopamine and acetylcholine are normally in a state of
electrochemical balance in the basal ganglia. In PD,
dopamine depletion produces a state of cholinergic
sensitivity so that cholinergic drugs exacerbate and
anticholinergic drugs improve parkinsonian symptoms .
• Centrally acting anticholinergic drugs such
as trihexyphenidyl and benztropine have been used for
many years in PD and continue to have a useful role .
Other anticholinergic agents such as
biperiden,orphenadrine, and procyclidine produce
similar effects and are more commonly used in Europe
than the United States.
• Anticholinergic drugs are most useful as
monotherapy for patients with PD who are
<70 years of age and have disturbing tremor
but do not have significant bradykinesia or
gait disturbance. They also may be useful in
patients with more advanced disease who
have persistent tremor despite treatment with
levodopa or dopamine agonists.
Adverse effects :
• Older adults and cognitively impaired patients are
particularly susceptible to memory impairment,
confusion, and hallucinations and should not
receive these drugs.
• Peripheral antimuscarinic side effects include dry
mouth, blurred vision, constipation, nausea,
urinary retention, impaired sweating, and
tachycardia. Caution is advised in patients with
known prostatic hypertrophy or closed-angle
glaucoma.
AMANTADINE :
• Amantadine is an antiviral agent that has mild
antiparkinsonian activity . Its mechanism of action is
uncertain; it is known to increase dopamine release,
inhibit dopamine reuptake, stimulate dopamine
receptors, and it may possibly exert central
anticholinergic effects . Amantadine has N-methyl-Daspartate (NMDA) receptor antagonist.
• Amantadine in divided doses of 200 to 400 mg a day
may reduce the intensity of levodopa-induced
dyskinesia and motor fluctuations in patients with PD.
Amantadine:
Dosing:
• The dose of amantadine in early PD is 200 to
300 mg daily; there is no evidence that larger
doses are of additional benefit. The main
advantage of this agent is a low incidence of
side effects. It is excreted unchanged in the
urine and should be used with caution in the
presence of renal failure.
Adverse effects :
• Peripheral side effects include livedo
reticularis and ankle edema, which are rarely
severe enough to limit treatment.
• Confusion, hallucinations, and nightmares
occur infrequently, but unpredictably, even
after long periods of use without side effects.
These effects are more likely when
amantadine is used together with other
antiparkinsonian drugs in older patients.
COMT INHIBITORS :
• The catechol-O-methyl transferase (COMT)
inhibitors tolcapone andentacapone are ineffective when
given alone, but they may prolong and potentiate the
levodopa effect when given with a dose of levodopa, and
thus are useful as levodopa extenders.
• Inhibition of COMT reduces the peripheral (entacapone)
and central (tolcapone) methylation of levodopa and
dopamine, which in turn increases the plasma half-life of
levodopa, produces more stable plasma levodopa
concentrations, and prolongs the therapeutic effect of each
dose.
• These medications are mainly used to treat patients with
motor fluctuations who are experiencing end-of-dose
wearing "off" periods, as discussed separately.
Entacapone(200 mg):
Stalevo(50,100,150):
Dosing :
• The starting dose of tolcapone is 100 mg three
times daily; the clinical effect is evident
immediately. The dose of entacapone is one
200 mg tablet with each dose of levodopa, up
to a maximum of eight doses per day.
Adverse effects :
• The most common side effects of tolcapone are due to
increased dopaminergic stimulation and include dyskinesia,
hallucinations, confusion, nausea, and orthostatic
hypotension.
• The adverse effects are managed by lowering the dose of
levodopa either before or after the addition of tolcapone.
Diarrhea that is poorly responsive to antidiarrheal
medications appears in approximately 5 percent of
patients. An orange discoloration of the urine is a common
but benign adverse event. Elevations in liver enzymes may
rarely occur.
• Side effects of entacapone are similar to tolcapone,
although entacapone has thus far not been associated with
hepatotoxicity.
ESTROGEN:
• Low-dose estrogen may be helpful as
adjunctive therapy in postmenopausal women
with motor fluctuations on antiparkinsonian
medication .
• Furthermore, concerns about adverse effects
associated with longterm estrogen/progestin therapy may limit its
use in PD.