Parkinson disease- Pharmacotherapy 3 (semester 5) 2017

Capaian pembelajaran
• Mampu mengenali gejala motor dan non-
motor pada Parkinson Disease (PD),
• Mampu membuat rencana terapi untuk pasien
PD,
• Mampu merekomendasikan penggantian
terapi jika terjadi efek samping,
• Mampu memberikan edukasi terkait PD dan
terapinya.
 Kasus
• C.P. is a 69-year-old man given a diagnosis of Parkinson disease 7 years
ago. He states that he is most bothered by his bradykinesia symptoms. On
examination, he also has a pronounced tremor, postural instability, and
masked facial expression. He currently takes carbidopa/
levodopa/entacapone 25 mg/100 mg/200 mg orally four times daily,
ropinirole 1 mg orally three times daily, and selegiline 5 mg orally twice
daily. He has no drug aller- gies. He also describes a worsening of his
Parkinson disease symptoms, which fluctuate randomly during the day. He
has developed a charting system for his symptoms during the day, and no
relationship seems to exist with the time he is scheduled to take his carbi-
dopa/levodopa/entacapone doses.
1. Which condition best describes C.P.’s fluctuating Parkinson disease
symptoms?
AWearing-off.
BOn-off.
CDyskinesia.
DDystonia.
 Kasus
2. For his symptoms, C.P. is given a prescription for
apomorphine. Which statement about this drug is most
accurate?
A. He must be trained on self-injection techniques with
saline, but he can administer his first dose of
apomorphine at home when he needs it.
B. He should not take apomorphine if he is allergic to
penicillin.
C. If he does not take a dose for more than 1 week, he
should begin with a loading dose with his next injection.
D. It may cause severe nausea and vomiting.
 Kasus
3. W.S. is a 57-year-old man initiated on
rasagiline for treatment of his newly diagnosed
Parkinson disease. He develops a cough, body
aches, and nasal congestion. Which medication
is best to treat W.S.’s symptoms?
A. Guaifenesin.
B. Dextromethorphan.
A. Tramadol.
B. Pseudoephedrine.
 Kasus
4. L.L. is a 47-year-old man with Parkinson disease.
He takes carbidopa/levodopa 50 mg/200 mg
orally four times daily. He recently noticed an
involuntary twitching movement of his left foot.
Which is the best therapy for L.L.’s dyskinesia?
A.Add ropinirole.
B.Add selegiline.
C.Increase the carbidopa/levodopa dose.
D. Decrease the carbidopa/levodopa dose.
 Parkinson Disease
• Gangguan sistem ekstrapiramidal pada otak yang melibatkan
ganglia basalis yang berperan menjaga postur tubuh dan tonus
otot, dan meregulasi otot polos.
• Pada Parkinson Disease (PD) , dopamin (neurotransmiter
inhibitorik) secara progresif berkurang pada traktus nigrostriatal,
dan asetilkolin (neurotransmiter eksitasi) relatif meningkat.
• Pada pemeriksaan patologis ganglia basalis postmortem, terdapat
badan Lewy (agregat protein intraneuronal abnormal, sferik) pada
sel-sel dopaminergik yang tersisa pada substantia nigra.
• The presence of Lewy bodies is considered pathognomic for the
disease.
 Epidemiology
1. Third most common neurologic disorder, behind AD and
stroke
a. Average age at onset is 60 years (40-70yo).
b. More common in men, approaching a 2:1 ratio
2. Incidence
a. Age-dependent, increased with age
b. Annual incidence of 20/100,000 in adults older than 50 years
3. Prevalence
a. Between 2% and 3% of adults older than 65 years
b. Affects around 1 million people in the United States, 4 million
worldwide
 Caused by
(Etiology and Risk Factors)
• 1. Idiopathic disease
a. Genetic factors (several possible genetic links and mutations)
b. Aging-related factors (oxidative stress, mitochondrial dysfunction)
c. Environmental factors (heavy metals, pesticides)
Viral encephalitis
Cerebrovascular disease
Hydrocephalus

• 2. Drug-induced effects on dopamine

a. Antipsychotics – Phenothiazines, butyrophenones, atypical agents
b. Antiemetics – Metoclopramide, prochlorperazine
c. Toxic substances – Manganese dust, carbon monoxide poisoning, MPTP (1-
methyl-4-phenyl- 1,2,5,6-tetrahydropyridine)
 Drug-induced PD
• Drugs with strong antidopaminergic
activity  Parkinsonism
• Neuroleptics, prochlorperazine,
metoclopramide
• Valproate, amiodarone, phenytoin,
lithium
• Reversible, may persist for weeks/
months after discontinuation
 4 characteristics
(no need to be present
all at once)
• Tremor (unilateral,
bilateral)
• Rigidity, Ratchet (catch-
release)
• Slow movement
(bradykinesia)
• Postural disturbance
 Clinical Presentation
1. Cardinal features
a. Resting tremor – Unilateral or bilateral; reduced/absent with
movement and sleep
b. Rigidity – Limb muscles, cogwheeling
c. Bradykinesia – Slowed movement
2. Motor symptoms
a. Gait abnormalities, stooped posture, shuffling, festinations, lack of
arm swing
b. Impaired fine movements (buttoning shirt)
c. Micrographia (small handwriting)
d. Masked face, dysarthric hypophonic speech
e. Decreased blinking, dysphagia, drooling
3. Autonomic symptoms
a. Orthostatic hypotension – Can be problematic because both the
disease and the drugs used to treat it can cause orthostatic changes
b. Impaired GI motility, constipation
c. Bladder dysfunction, sexual dysfunction
4. Cognitive and psychiatric symptoms
a. Cognitive decline
b. Hallucinations – Can also be disease related or treatment related
(dopaminergic medications)
c. Anxiety, depression, sleep disorders
d. Behavioral symptoms, agitation
5. Similar features in other neurologic diseases
a. Benign essential tremor
b. Wilson disease
c. Huntington disease
d. Lewy body dementia
e. Progressive supranuclear palsy
f. Creutzfeldt-Jacob disease
 Clinical Management

• 1. Treatment goals
– a. Minimize motor and nonmotor symptoms.
– b. Maximize functional status and quality of life.
– c. Minimize medication-related adverse effects.
– d. Maximize safety (reduce fall risk).
• 2. Nonpharmacologic Therapy
– a. Physical therapy
– b. Balance and gait training
 Overview of drug therapy
• Because the salient pathophysiologic feature of PD is the progressive loss of dopamine
from the nigrostriatal tracts in the brain, drug therapy for the disease is aimed primarily
at replenishing the supply of dopamine (Table1 ).

This is accomplished through one, or a combination, of the following methods:

(a) administering exogenous dopamine in the form of a precursor, levodopa;
(b) stimulating dopamine receptors within the corpus striatum through the use of
dopamine agonists (e.g., pramipexole, ropinirole); or
(c) inhibiting the major metabolic pathways within the brain that are responsible for the
degradation of levodopa and its metabolites.
This latter effect is achieved through the use of
• aromatic L-amino acid decarboxylase (AAD) inhibitors (e.g., carbidopa),
• Catechol-O-methyltransferase (COMT)-inhibitors (e.g., entacapone), or
• monoamine oxidase type B (MAO-B) inhibitor (e.g. selegiline, rasagiline)

Anticholinergic agents may occasionally be used to counterbalance the negative effects of

the relative increase in acetylcholine activity and improve tremor symptoms.
 Pharmacologic Therapy
a. Anticholinergics (benztropine, diphenhydramine)
i. Help correct imbalance between dopamine and acetylcholine
ii. Mainly beneficial for tremors; can be used as initial therapy if tremors are predominant
iii. Limited utility because of adverse effects, particularly among older patients (confusion,
urinary retention, constipation)
b. Dopamine precursor
i. Levodopa is the most clinically effective therapy for PD symptoms.
ii. Effective for all three cardinal features.
iii. Dopa decarboxylase inhibitor (carbidopa) added to prevent peripheral conversion of
levodopa to dopamine
(a) Reduces levodopa dose requirement
(b) Improves tolerability (nausea, orthostasis, cardiac adverse effects)
(c) Need 75–100 mg of carbidopa daily to saturate dopa decarboxylase enzyme
peripherally
iv. Most patients eventually develop motor complications (wearing off, dyskinesias, on-off
phenomenon, freezing) with this drug after several years of use; some clinicians advocate
delaying use of levodopa until symptoms become quite bothersome or more severe because
of the high likelihood of developing motor complications with long-term use of levodopa.
This practice may be more relevant to younger patients with longer life expectancy.
 Motor complications (wearing off, dyskinesias,
on-off phenomenon, freezing) with levodopa
(a) Wearing off describes loss of the clinical effect toward the end
of the dosing interval; as the disease progresses, the wearing-
off effect occurs earlier, necessitating shorter dosing intervals.
(b) Dyskinesias are involuntary choreiform movements involving
the neck, trunk, and upper extremities; usually associated with
peak drug effects
(c) On-off phenomenon or fluctuations describe rapid transitions
from normal or controlled motor activity to bradykinetic or
uncontrolled motor activity.
(d) Freezing describes a drug-resistant off period or inability to
initiate motor function; start hesitations
 Initial therapy
i. Therapy generally initiated when symptoms become sufficiently
bothersome to patient functioning
ii. Dopaminergic agents (levodopa, dopamine agonists) are generally
preferred as initial therapy because of their superior control of motor
symptoms.
iii. MAO-B inhibitors (selegiline, rasagiline) can be considered in patients
with mild symptoms before initiating dopaminergic treatments.
iv. Motor control: Levodopa > dopamine agonist > MAO-B
v. Risk of dyskinesias or motor complications: Levodopa > dopamine
agonists
vi. Hallucinations: Dopamine agonists > levodopa
vii. No clear evidence that using sustained-release levodopa provides
advantages relative to immediate-release levodopa
 Add-on therapy
i. If treatment is initiated with a dopamine agonist and
unable to control motor symptoms, levodopa should be
considered.
ii. If treatment is initiated with levodopa, can consider
adding agents if total daily levodopa dose is 800–1000 mg;
choice of agent depends on patient characteristics.
iii. If adding on therapy, need to watch closely for
complications of excess dopaminergic response (e.g.,
dyskinesias, nausea and vomiting, hallucinations); adding
therapy to levodopa may necessitate a decrease in the
levodopa dose
 Motor complications
(wearing off, on-off phenomenon, freezing)

i. To reduce off time, a MAO-B inhibitor, COMT inhibitor,

or dopamine agonist can be considered.
ii. End-of-dose wearing off occurs because of shorter
duration of individual doses of levodopa; can consider
increasing frequency of levodopa dosing; if not
helpful, consider adding MAO-B inhibitor, COMT
inhibitor, or dopamine agonist.
iii. Freezing episodes: Add a dopamine agonist or MAO-B
inhibitor; intermittent apomorphine; physiotherapy
and assistive walking devices and sensory cues.
Selected PD Pharmacotherapy guidelines
Sialorrhea=excessive drooling, hypersalivation,
obatnya: hiosiamin; hiosin, scopolamin, oscimin,
atropin, glikopirolat
Simplified treatment algorithm for PD
Generic (trade Unit dosis Jadwal titrasi Dosis lazim Efek samping
name)
Amantadine
Antikolinegik
Benztropin
Trihexyphenidyl 2, 5 mg tab; 1-2 mg/hari 6-15 mg dibagi Konstipasi,
(Arkine, 2mg/5mL ditingkatkan 1-2 2-3 dosis xerostomia
Hexymer) mg tiap 3-5 hari (BID/TID) (mulut kering),
kulit kering,
disfagia,
bingung,
gangguan
ingatan
Kombinasi
Carbidopa- 12,5/50/200; Titrasi dengan Bervariasi Spt tiap
levodopa 25/100/200; dan bentuk tunggal kandungannya
(immediate 37,5/150/200 terlebih dahulu,
release)/entecap mg tab kemudian ganti
one (Stalevo) ke kombinasi
Agonis
dopamin
Bromokriptin 2,5 mg tab; 5 1,25 HS; titrasi 10-40 mg dibagi Hipotensi
(Parlodel) mg kap perlahan dalam dalam 3 dosis ortostatik, bingung,
4-6 minggu (TID) pusing, halusinasi,
mual, kram kaki,
fibrosis perikardiak,
penebalan katup
jantung
Pramipexole 0,125; 0,25; 0,125 dibagi 3 1,5-4,5 mg dibagi Hipotensi
(Sifrol) 0,50; 1; 1.5 mg dosis (TID), 3 dosis (TID) ortostatik, bingung,
tab titrasi pusing, halusinasi,
mingguan mual, somnolence
0,125-0,25 (ngantuk sekali)
mg/dosis
Ropinirole 0,25; 0,5; 1; 2; Titrasi 3-12 mg dibagi 3 sda
(Requip PD 24 4;5 mg tab mingguan 0,25 dosis (TID)
hour) mg/dosis
Apomorfin
Rotigotine
COMT (catechol-O-methyltransferase) inhibitor
Entecapone 200 mg tab 1 tab setiap 3-8 tab/hari Diare diskinesia,
(Stalevo) pemberian nyeri abdomen,
levodopa/carbid pewarnaan urin
opa, sampai 8
tab/hari
MAO (monoamine oxydase) inhibitor
Selegiline 5 mg pagi;dapat 5-10 mg (5 mg Insomnia,
ditingkatkan bersama pusing,
sampai 5 mg sarapan; 5 mg mual,muntah,
BID bersama makan xerostomia,
siang) diskinesia,
perubahan
mood, hindari
makanan mgd
tiramin, hati-
hati
peemberian
bersama
simpatimimetik
Rasagiline
 Levodopa

i. Improvement in disability and possibly

mortality
ii. Greatest effect on bradykinesia and rigidity;
less effect on tremor and postural instability
 Carbidopa

i. Combined in fixed ratios with levodopa

ii. Prevents some of the peripheral conversion of
levodopa to dopamine by inhibiting peripheral
dopamine decarboxylase; therefore, levodopa
is available to cross the blood-brain barrier
iii. 75 mg/day is usually needed to inhibit
peripheral decarboxylase activity.
 Carbidopa/levodopa (Sinemet)
i. Pharmacokinetic considerations
(a) High-protein diets decrease absorption.
(b) Immediate-release half-life 60–90 minutes
(c) Orally disintegrating tablet available; not absorbed sublingually
ii. Acute adverse effects: Nausea and vomiting, orthostatic hypotension, cardiac
arrhythmias, confusion, agitation, hallucinations
iii. Long-term adverse effects: Wearing-off and on-off phenomena, involuntary
movements (dyskinesias)
(a) Wearing-off phenomenon is the return of Parkinson disease symptoms before the
next dose. Treatment of wearing-off includes adding a dopamine agonist, adding a
MAO-B inhibitor, adding a catechol-O-methyl transferase (COMT) inhibitor, or
increasing the frequency or dose of levodopa.
(b) On-off phenomenon is a profound, unpredictable return of Parkinson disease
symptoms without respect to the dosing interval. Treatment of on-off includes
adding entacapone, rasagiline, pramipexole, ropinirole, apomorphine, and
selegiline or redistributing dietary protein.
(c) Dyskinesias are drug-induced involuntary movements including chorea and
dystonia. Treatment of dyskinesias includes decreasing the levodopa dose or
adding amantadine as an antidyskinetic drug.
Therapy initiation carbidopa/levodopa
a. Standard formulation: 25 mg/100 mg 1 tablet orally
three times daily; also available as orally
disintegrating tablet
b. Controlled-release formulation: 1 tablet orally two or
three times daily
c. Titration always necessary
d. A combination of formulations may be needed (e.g.,
½ tablet of Sinemet 25 mg/100 mg on awakening and
1 tablet of Sinemet CR 25/100 three times daily).
Levodopa Interactions
 Direct dopamine agonists
Drugs: Apomorphine (Apokyn), bromocriptine (Parlodel), pramipexole
(Mirapex), ropinirole (Requip), rotigotine (Neupro)

Rotigotine is a transdermal system. With the initial formulation, problems

occurred with crystallization of the medication. The product was withdrawn
from the market and has since been reformulated.

Adverse effects: Nausea, vomiting, postural hypotension, hallucinations,

hypersexuality, compulsive behaviors, falling asleep during activities of daily
living.

Pramipexole and ropinirole also have FDA indications for restless legs syndrome.
Ropinirole and pramipexole are available as extended-release formulations.
 Pharmacologic and Pharmacokinetics
Dopamin Agonists
Bromocriptine Pramipexole Ropinirole Apomorphine Rasagiline
Type of Ergot Non-ergoline Non-ergoline Non-ergoline Non-ergoline
compound derivative
Receptor D2, D1,*1, D2,D3,D4, 2 D2, D3, D4 D1,D2,D3,D4D D1,D2,D3,5-
specificity
2, 5-HT 5, 1, 2, 5- HT1
HT1;5-HT2
Bioavailability 8% >90% 55% (first pass <5% orally; <1% orally
metabolism) 100%subcutan
eous
Tmax (min) 70-100 60-180 90 10-60 15-18 (hr), no
characteristic
peak observed
Protein 90-96% 15% 40% >99.9% 89.5%
binding
Elimination Hepatic Renal Hepatic Hepatic and Hepatic
route extrahepatic
Half-life (hr) 3-8 8-12 6 0.5-1 3
* Antagonist
 Bromocriptine
• Ergot dopamine agonists such as bromocriptine have fallen out
of favor in the treatment of PD. Concern for rare but serious
cardiac valve regurgitation has prompted providers to use
safer choices with similar efficacy (Schade 2007). Other serious
adverse effects include reversible pleural effusions and
irreversible pulmonary and cardiac valvular fibrosis (Sprenger
2013). Although ergot dopamine agonists may be used at
lower dosages in other indications (e.g., hyperprolactinemia),
the doses needed to treat PD are more likely to lead to the
rare but serious adverse effects (Medical Letter 2013). Regular
monitoring of the electrocardiogram is recommended.
 Apomorphine
• Apomorphine is a high-potency rescue non-ergot nonselective dopamine
agonist for off periods, including wearing-off episodes or unpredictable
on/off episodes.
• The drug must be administered subcutaneously and initiated in an office
setting so that close monitoring of orthostasis can occur. Onset of effect is
rapid and precluded by yawning (Goren 1998).
• It is NOT to be used in conjunction with serotonin receptor antagonists such
as the antiemetic ONDANSETRON because the combination may lead to
severe hypotension.
• As with other dopamine agonists, a common adverse effect of apomorphine
is nausea. Nausea may respond best to trimethobenzamide, with
pretreatment to start 3 days before apomorphine initiation. Nausea often
subsides within 2–4 months of apomorphine treatment, allowing for
elimination of antiemetic use (Chen 2011).
 For hypomobility/off episodes in PD
• Apomorphine: use with antiemetic
trimethobenzamide 3 days before initiating
apomorphine and continued for 2 months of
treatment.
• NOT with ondansentron (serotonin antagonist)
 may cause severe hypotension
• NOT with prochlorperazine and
metoclopramide (dopamine antagonists) 
decrease effectiveness of apomorphine
 Anticholinergics
Drugs: Trihexyphenidyl (Artane), benztropine
(Cogentin)
Most useful for tremor
Initial dosing:
• Trihexyphenidyl 0.5 mg 1 tablet orally twice daily
• Benztropine 0.5 mg 1 tablet orally twice daily
Adverse effects: Dry mouth, urinary retention, dry
eyes, constipation, confusion
 Special situations
Hallucinations or psychosis may be caused by
either Parkinson disease or treatment.
i. Discontinue or reduce Parkinson disease
medications as tolerated.
ii. If an antipsychotic is needed, use quetiapine or
clozapine as the first choice.
iii. Avoid typical antipsychotics, risperidone, and
olanzapine because they may worsen Parkinson
symptoms.
 Special situations
Cognitive disorders
i. Discontinue or reduce Parkinson disease
medications as tolerated.
ii. Rivastigmine has an FDA indication for treatment;
other cholinesterase inhibitors may have efficacy.
Sleep disorders, depression, agitation, anxiety,
constipation, orthostatic hypotension,
seborrhea, and blepharitis can be seen in
Parkinson disease; treat as usual.
 #1
• A 56-year-old man with advanced PD continues to have severe
unpredictable “off” periods that cause significant impairment. His home
drugs include carbidopa/ levodopa/entacapone 18.75/75/200 mg 1
tablet four times daily, rasagiline 1 mg by mouth daily, ropinirole 1 mg
by mouth three times daily, ondansetron 4 mg by mouth every 8 hours
as needed for nausea, and atropine eyedrops 2 drops by mouth at
bedtime for drooling. Which one of the following would be best to
discontinue when initiating the rescue medication apomorphine
subcutaneous injection for this patient?
A. Rasagiline.
B. Ropinirole.
C. Atropine.
D. Ondansetron.
 Time Course of Response

• Treatment for motor symptoms with PD agents should

be initiated at a low dose and titrated to response
according to efficacy and tolerability.
• Improvements in motor symptoms usually occur within
the first few days of achieving a therapeutic dose.
• Dyskinesias that result from treatment with carbidopa/
levodopa may require treatment modifications.
• Progression of disease also requires treatment
modifications.
 Assessment of Response/Scales
• Patients should be assessed at least every 3 months during
treatment for motor and nonmotor symptoms as well as
quality of life. However, making assessments at more
frequent intervals (e.g., every 2 weeks) may be needed in
the initial treatment stages for appropriate dose titration.
• Assessments should include symptom severity, nonmotor
symptoms, comorbid mental disorders, functioning and
quality of life, treatment adherence, and adverse effects.
• Despite their limited use in clinical practice, scales may be
used to determine the progression of both motor and
nonmotor symptoms of PD.
 Staging of Disability in PD
Stage Signs/symptoms
I Unilateral involvement only; minimal or no functionl impairment
II Bilateral involvement, without impairment of balance
III Evidence of postural imbalance; some restriction in activities; capable of
leading independent life; mild to moderate disability
IV Severely disabled, canno twalk and stand unassisted; significantly
incapacitated
V Restricted to bed or wheelchair unless aided

I-II : mild;
III daily activities are restricted; III-IV: advanced stage  levodopa and combination with
COMT inh (carbidopa, Sinemet) or dopamin agonist (pramipexole, ropinirole) or
selegiline or rasagiline or amantadine.
V: do not respond well to drug therapy.
Pharmacotherapy for Essential
Tremor
 #2
• A 45-year-old man presents to your outpatient clinic with
bilateral tremor in his hands. The tremor is of low
amplitude and rapid frequency. This has become
impairing to his career as an electrician. Other neurologic
symptoms are absent. Which one of the following is most
helpful in confirming this patient’s essential tremor (ET)?
A. Improvement with smoking cigarettes.
B. Worsening with smoking cigarettes.
C. Improvement with alcohol intake.
D. Worsening with alcohol intake.
 #3
• A 67-year-old man has symptoms of bilateral upper
extremity resting tremor and moderate rigidity of limbs.
His current drugs include metformin 1000 mg twice
daily and metoclopramide 5 mg with meals. Which one
of the following would most likely indicate PD rather
than ET or pseudoparkinsonism in this patient?
A. Olfactory dysfunction.
B. Metoclopramide treatment.
C. Improvement with primidone.
D. Advanced age of onset.
 Patient education
• Patients with a diagnosis of PD must be educated about treatment options and
realistic expectations with respect to symptom management (SIGN 2010).
• Possibly the most important issue to convey is the relationship between
symptomatology and medication timing. Small adjustments in time of dosing
throughout the day may allow for fewer movement difficulties.
• Understanding how to manage the common adverse effects may improve
adherence. Patients who experience nausea with drug therapy may benefit from
taking the medication with food or adding an antiemetic. Dizziness and blood
pressure changes must be managed by instructing that patients use care when
rising and minimize sudden movements. If a patient has hypertension, blood
pressure drugs may need to be lowered once the patient is prescribed PD agents.
• Participation in support groups often helps patients (and their caregivers) feel less
isolated by their illnesses. In fact, some providers perform group encounters for
both the assessment of symptoms and the opportunity for encouragement from
peers.
• For optimization of care, patients should be encouraged to complete movement
diaries, including instances of falling as well as dyskinesias.
 Pharmacoeconomics
• In 2010, treatment of PD in the United States cost almost $22,800
per patient (totaling $14 billion), a daunting number as the older
adult population continues to grow (Kowal 2013).
• A review of privately insured patients determined that patients with
newly diagnosed PD incur a lower annual cost of treatment (about
$4000). Cost increases as the illness progresses (upper range
nearing $37,400), with the highest factors being hospitalization and
presence of motor fluctuations (Johnson 2013, Scheife 2000). With
this information, it seems that delaying motor fluctuations, which
result from carbidopa/levodopa, may slow the escalation of
treatment costs.
• The availability of generic formulation of most classes of PD drugs
allows for patient options in treatment choice.
 4
A patient presents with an onset of rigidity and
bradykinesia over 48 hours. Her home drugs include
lisinopril 20 mg daily, simvastatin 40 mg every night at
bedtime, and risperidone 3 mg twice daily. Which one
of the following is this patient most likely
experiencing?
A. PD.
B. ET.
C. Pseudoparkinsonism.
D. Tardive dyskinesia (TD).
 5
A patient presents with the following regimen:
carbidopa/levodopa 25/100 mg 2 tablets three times
daily, amantadine 100 mg daily, and pramipexole 1 mg
daily. Which one of this patient’s nonmotor symptoms
is least likely to respond to dopaminergic medications?
A. Muscle pain.
B. Micrographia.
C. Constipation.
D. Depression.
 6
A 68-year-old woman has PD managed with the following drugs:
carbidopa/levodopa 25/100 mg four times daily, rasagiline 1 mg daily,
atorvastatin 10 mg daily, polyethylene glycol 17 g daily, and chlorthalidone
50 mg daily. Her most prominent PD symptoms/complications include
wearing off nearing the time of her next dose of carbidopa/levodopa and
bilateral resting tremor of her upper extremities. She has no edema or
hypertensive blood pressure readings. She is currently experiencing
orthostasis and has fallen a few times in the past week. Which one of the
following would best treat this patient’s postural instability?
A. Decrease the dose of carbidopa/levodopa.
B. Decrease the dose of rasagiline.
C. Add fludrocortisone.
D. Decrease the dose of chlorthalidone.
 6a
A 72-year-old female patient is in the clinic for assessment after a fall 1 week ago. She
was seen in the emergency department at that time, but no significant injuries
were noted. She states that she was dizzy before her fall. She has a history of
hypertension, PD, and osteoarthritis. Her current medications include
hydrochlorothiazide 25 mg/day, metoprolol XL (extended release) 50 mg/day,
lisinopril 10 mg/day, tramadol 50 mg three times daily as needed for pain,
levodopa/carbidopa CR (controlled release) 200/50 mg twice daily, and
pramipexole 0.125 mg twice daily. She states that her PD symptoms are much
better controlled since adding pramipexole and decreasing levodopa/carbidopa 1
month ago. On physical examination, blood pressure is 136/72 mm Hg, with a
heart rate of 60 beats/minute sitting, and 118/60 mm Hg, with a heart rate of 62
beats/minute standing. Her gait looks good, and her strength is good. Which is the
most appropriate recommendation to reduce her risk of future falls?
A. Discontinue pramipexole.
B. Decrease metoprolol dose.
C. Add midodrine.
D. Add fludrocortisone.
 7
R.M. is a 55-year-old man who has received a diagnosis of PD.
At this time, his symptoms are mild but slightly
embarrassing, consisting primarily of mild bradykinesia and
impaired dexterity, most notably with micrographia. Minimal
tremor is present. R.M. asks to be initiated on treatment.
Which one of the following is best to recommend for R.M.?
A. Carbidopa/levodopa 25/100 mg three times daily.
B. Bromocriptine 1.25 mg daily.
C. Benztropine 1 mg twice daily.
D. Rasagiline 1 mg daily.
 8
Four years later, R.M. has continued to receive treatment by
the movement disorder clinic, but his illness has progressed.
He now has worsened bradykinesia and muscle stiffness. He
is currently taking ropinirole 6 mg three times daily. Which
one of the following is best to recommend for R.M.?
A. Add amantadine 100 mg daily and continue ropinirole.
B. Switch to carbidopa/levodopa 25/100 mg three times daily.
C. Switch to apomorphine 2 mg daily.
D. Add entacapone 200 mg daily and decrease ropinirole.
 9
A 58-year-old man is referred to you after a new
diagnosis of early-onset PD. His symptoms are still
mild and consist of right hand tremor, bradykinesia,
and muscle stiffness. Which one of the following
education points is the best to provide this patient?
A. He should start carbidopa/levodopa.
B. Long-acting medications prevent adverse effects.
C. Consumption of coffee will delay progression.
D. Delaying the start of carbidopa/levodopa is prudent.
 10
An 86-year-old woman with PD arrives for her yearly checkup. She is currently
treated with carbidopa/levodopa 25/100 mg 2 tablets three times daily. Her
symptoms are well enough controlled that she can function independently,
and she has had no falls. However, she has postural instability because of her
dyskinesias. Reducing her carbidopa/levodopa dose was previously
unsuccessful because her rigidity and bradykinesia increased. At this visit,
the physician adds pramipexole 0.125 mg three times daily to optimize
symptom improvement. Which one of the following factors would best
optimize this patient’s treatment when pramipexole is added?
A. Increase carbidopa/levodopa.
B. Stop carbidopa/levodopa.
C. Decrease carbidopa/levodopa.
D. Add rasagiline.
 11
A 56-year-old man with advanced PD continues to have severe
unpredictable “off” periods that cause significant impairment. His home
drugs include carbidopa/levodopa/entacapone 18.75/75/200 mg 1
tablet four times daily, rasagiline 1 mg by mouth daily, ropinirole 1 mg
by mouth three times daily, ondansetron 4 mg by mouth every 8 hours
as needed for nausea, and atropine eye drops 2 drops by mouth at
bedtime for drooling. Which one of the following would be best to
discontinue when initiating the rescue medication apomorphine
subcutaneous injection for this patient?
A. Rasagiline.
B. Ropinirole.
C. Atropine.
D. Ondansetron.
 12
Q.T. is a 70-year-old man with a 9-year history of Parkinson disease (PD).
He comes to the clinic today with impairing “on-and-off” periods that
occur at least once per day, often at unpredictable times. Q.T.’s drug
regimen is as follows: carbidopa/levodopa 25/250 mg CR 1 tablet four
times daily (3 years), pramipexole 1 mg three times daily (1 year), and
entacapone 200 mg four times daily (2 years).
Which one of the following would best improve Q.T.’s on-and-off periods?
A. Add apomorphine 2 mg as needed during “off” period.
B. Increase entacapone to 200 mg five times daily.
C. Increase carbidopa/levodopa to 25/250 mg 4 tablets four times daily.
D. Change from pramipexole to ropinirole.
 13
Two years later, Q.T.’s illness has progressed as expected.
He is now experiencing dyskinesias of the upper
extremities and significant postural instability, which
impair his ability to complete activities of daily living
independently. Which one of the following is most likely
to prevent Q.T. from undergoing deep brain stimulation?
A. Advanced age.
B. Length of carbidopa/levodopa treatment.
C. Apomorphine treatment.
D. Onset of PD dementia.
14, 15
16,18
19,20
21,22
23,24
25,26
 27
A 66-year-old man with a diagnosis of PD is being examined today in the clinic. He has
been taking levodopa/ carbidopa for 6 years. His current levodopa/carbidopa dose is
100/25 mg, 1½ tablets in the morning, 1 tablet at 11 a.m., 1 tablet at 2 p.m., 1 tablet at
5 p.m., and ½ tablet at 8 p.m. He has been experiencing motor complications for about
3 months, including on-off symptoms and freezing episodes. On physical examination,
he has some weakness, gait and balance abnormalities, and rigidity. His ability to
ambulate and perform self-care activities during the past 3 months has continued to
decline. Which is the most appropriate recommendation for this man’s symptoms?
A. Add benztropine to levodopa/carbidopa.
B. Decrease the levodopa/carbidopa dose to 4 tablets daily.
C. Switch to levodopa/carbidopa CR.
D. Add entacapone to levodopa/carbidopa.
 28

The 66-year-old patient in the previous question returns to the clinic 2 weeks after
your recommendation above. He states that, overall, he thinks he is doing better,
but that he often feels nauseated and occasionally feels light-headed or dizzy. He
also describes some abnormal movements, which are identified as dyskinesias
on physical examination. He also states that he has experienced hallucinations
on two occasions, which was rather disturbing to him. Which is the most
appropriate recommendation for this man?
A. Add prochlorperazine for nausea.
B. Decrease the daily dose of levodopa/carbidopa.
C. Initiate rasagiline therapy.
D. Initiate ropinirole therapy.
 29
T.B. is a 63-year-old man who received a diagnosis of early PD about 6 months ago but who
is otherwise healthy. He did not receive treatment with any medications when his PD was
first diagnosed, but on the advice of his physician he started therapy with selegiline 5 mg
twice daily about 4 weeks ago. He is in the clinic today because of difficulty sleeping and
difficulty with his memory. He states that, on most days, he feels tired but just cannot fall
asleep. He states that his wife has a prescription for lorazepam 0.5 mg and that he has
taken one tablet when he has had difficulty sleeping. He is asking for a prescription for
lorazepam to help him sleep. Which is the best recommendation for this patient?
A. Give him a prescription for lorazepam 0.5 mg at bedtime.
B. Have him take diphenhydramine 50 mg at bedtime.
C. Change the selegiline dosing from twice daily to morning and noon.
D. Add levodopa/carbidopa to selegiline.
 30

A 68-year-old woman with PD has been taking levodopa/carbidopa 100/25 mg four

times daily for 2 weeks. Previously, she was taking levodopa/carbidopa 100/25 mg
three times daily. She is calling your clinic to see what she can do about the
symptoms she describes, which include nausea, light-headedness, and involuntary
movements, which sound like dyskinesias. Her PD symptoms were fairly well
controlled on the three-times-daily schedule, but her physician increased the dose to
four times daily to achieve additional benefit. Which is the best recommendation to
address this woman’s symptoms?
A. Add rasagiline.
B. Decrease the levodopa/carbidopa dose to 100/25 mg three times daily.
C. Add ropinirole.
D. Change the levodopa/carbidopa dose to 100/10 mg four times daily.
 Case presentation
• L.M., a 55-year-old, right-handed male artist, presents to the neurology clinic complaining of difficulty painting
because of unsteadiness in his right hand. He also complains of increasing difficulty getting out of chairs and
tightness in his arms and legs.
• His wife claims that he has become more "forgetful" lately, and L.M. admits that his memory does not seem to be
as sharp.
• His medical history is significant for depression for the past year, gout (currently requiring no treatment),
constipation, benign prostatic hypertrophy, and aortic stenosis.
• On physical examination, L.M. is noted to be a well-developed, well-nourished man who displays a notable lack of
normal changes in facial expression and speaks in a soft, monotone voice. A strong body odor is noted.
Examination of his extremities was slight "ratchetlike" rigidity in both arms and legs, and a mild resting tremor is
present in his right hand. His gait is slow, but otherwise normal, with a slightly bent posture. His balance is
determined to be normal , with no retropulsionor loss of righting reflexesafter physical threat. His genitourinary is
only remarkable for enlargement of prostate. The remainder physical examination of LM and laboratory findings
are normal.
• What signs and symptomssuggestive of PD present in LM?
• Which of symptoms are of classic symptoms for diagnosing PD and which are considered “associated”symptoms?
• How should LM be treated for PD and associated symptoms?
• In what stage of the disease is LM?
• Should therapy be initited with a dopamine agonist or levodopa?
• LM is to be started on dopamine agonist. Which agent should be
selected?
• What is the most effective way to dose pramipexole or ropinirole?
• What are the adverse effects of pramipexole and ropinirole? How
can these be managed?
• When to begin levodopa?
• What are the advantages and disadvantages of Sinemet over
levodopa alone?
• How is Sinemet dosed? Before, with or after meals?
• When should entacapone (COMT inhibitor) be initiated? How is it
dosed?
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