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56

CHAPTER
Parkinson’s disease (PD) has highly characteristic neuropathologic findings and a clin-
ical presentation, including motor deficits and, in some cases, mental deterioration.

PATHOPHYSIOLOGY
Two hallmark features in the substantia nigra pars compacta are loss of
neurons and presence of Lewy bodies. The degree of nigrostriatal dopamine
loss correlates posi-tively with severity of motor symptoms.
Reduced activation of dopamine1 and dopamine2 receptors results in greater
inhibi-tion of the thalamus and reduced activation of the motor cortex. Clinical
improve-ment may be tied to restoring activity more at the dopamine2 receptor
than at the dopamine 1 receptor.

CLINICAL PRESENTATION
PD develops insidiously and progresses slowly. It is relatively asymptomatic until pro-
found depletion (70%–80%) of substantia nigra pars compacta neurons has occurred.
Initial symptoms may be sensory, but as the disease progresses, one or more
classic primary features presents (eg, resting tremor, rigidity, bradykinesia,
and postural instability that may lead to falls).
Resting tremor is often the sole presenting complaint. However, only two thirds of
PD patients have tremor on diagnosis, and some never develop this sign. Tremor
is present most commonly in the hands, often begins unilaterally, and sometimes
has a characteristic “pill-rolling” quality. Resting tremor is usually abolished by
volitional movement and is absent during sleep.
Muscular rigidity involves increased muscular resistance to passive range of
motion and can be cogwheel in nature. It commonly affects both upper and
lower extremi-ties, and facial muscles may be affected.
Intellectual deterioration is not inevitable, but some patients deteriorate in a
manner indistinguishable from Alzheimer’s disease.

DIAGNOSIS
A diagnosis of PD can be made with a high level of confidence when there is
bra-dykinesia (along with resting tremor and/or rigidity), prominent
asymmetry, and a positive response to dopaminergic medication.
Other symptoms may include: decreased dexterity, difficulty arising from a chair,
postural instability, festinating gait, dysarthria, difficulty swallowing, reduced facial
expression, freezing at initiation of movement, hypophonia, micrographia, bladder
disturbances, constipation, blood pressure changes, dementia, anxiety,
depression, sleepiness, insomnia, obstructive sleep apnea.
Several other conditions must be excluded, such as medication-induced
Parkinsonism (eg, induced by antipsychotics, phenothiazine antiemetics, or
metoclopramide), essential tremor, corticobasal ganglionic degeneration,
multiple system atrophy, and progressive supranuclear palsy.

TREATMENT
Goals of Treatment: The goals of treatment are to minimize symptoms,
disability, and side effects while maintaining quality of life. Education of
patients and caregivers, exercise, and proper nutrition are essential.

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Parkinson’s Disease | CHAPTER 56

Diagnosis of
Parkinson’s disease

Nonpharmacologic: Pharmacologic
Education
Exercise
Nutrition
Consider rasagiline
Psychosocial support

<65 yearsa Need for additional >65 yearsa


symptomatic control
Consider
Consider
anticholinergic Tremor
amantadine
or amantadine

Add amantadine, Add amantadine,


dopamine agonist, or Bradykinesia, rigidity, dopamine agonist, or
carbidopa/levodopa tremor carbidopa/levodopa

Management of motor fluctuations: Management of peak-dose dyskinesia


Increase dosing frequency of levodopa Reduce dopaminergic drug dose
Add MAO-B inhibitor or COMT inhibitor Add amantadine
Add a dopamine agonist

Need for more symptomatic control of


motor complications (despite optimized
pharmacotherapy): Consider surgery

aAge is not the sole determinant for drug choice. Other factors such as cognitive function and
overall safety and tolerability of drug (especially in the elderly) should be considered.

FIGURE 56–1. General approach to the management of early to advanced


Parkinson’s disease.

PHARMACOLOGIC THERAPY
General Approach
An algorithm for management of early to advanced PD is shown in Fig. 56–1.
Table 56–1 is a summary of available antiparkinson medications and their
dosing, and Table 56–2 shows side effect monitoring.
Monotherapy usually begins with a monoamine oxidase-B (MAO-B) inhibitor.
Consider addition of a catechol-O-methyltransferase (COMT) inhibitor if motor
fluctuations develop to extend l-dopa duration of activity. Alternatively,
consider addition of an MAO-B inhibitor or dopamine agonist.
For management of l-dopa-induced peak-dose dyskinesias, consider
addition of amantadine.
Anticholinergic Medications
Anticholinergic drugs can improve tremor and sometimes dystonic features in some
patients, but they rarely substantially improve bradykinesia or other disabilities. They can
be used as monotherapy or in conjunction with other antiparkinson drugs.
Anticholinergic side effects include dry mouth, blurred vision, constipation, and urinary
retention. More serious reactions include forgetfulness, confusion, sedation,
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Table 56–1 Dosing of Drugs Used in Parkinson’s Diseasea


Starting Maintenance
Generic Trade Doseb Doseb Dosage
Name Name (mg/day) (mg/day) Forms (mg)
Anticholinergic Drugs
Benztropine Cogentin 0.5–1 1–6 0.5, 1, 2
Trihexyphenidyl Artane 1–2 6–15 2, 5, 2/5 mL
Carbidopa/Levodopa Products
Carbidopa/l-dopa Sinemet 100–300c 300–1,000c 10/100, 25/100, 25/250
Carbidopa/l-dopa ODT Parcopa 100–300c 300–1,000c 10/100, 25/100, 25/250
Carbidopa/l-dopa CR Sinemet CR 200–400c 400–1,000c 25/100, 50/200
Carbidopa/l-dopa/ Stalevo 200–600d 600–1,600d 12.5/50/200,
entacapone 18.75/75/200,
25/100/200,
31.25/125/200,
37.5/150/200,
50/200/200
Carbidopa Lodosyn 25 25–75 25
Dopamine Agonists
Apomorphine Apokyn 1–3 3–12 30/3 mL
Bromocriptine Parlodel 2.5–5 15–40 2.5, 5
Pramipexole Mirapex 0.125 1.5–4.5 0.125, 0.25, 0.5, 1, 1.5
Pramipexole ER Mirapex ER 0.375 1.5–4.5 0.375, 0.75, 1.5, 3, 4.5
Ropinirole Requip 0.75 9–24 0.25, 0.5; 1, 2, 3, 4, 5
Ropinirole XL Requip XL 2 8–24 2, 4, 6, 8, 12
Rotigotine Neupro 2 2–8 1, 2, 3, 4, 6, 8
COMT Inhibitors
Entacapone Comtan 200–600 200–1,600 200
Tolcapone Tasmar 300 300–600 100, 200
MAO-B Inhibitors
Rasagiline Azilect 0.5–1 0.5–1 0.5, 1
Selegiline Eldepryl 5–10 5–10 5
Selegiline ODT Zelapar 1.25 1.25–2.5 1.25, 2.5
Miscellaneous
Amantadine Symmetrel 100 200–300 100, 50/5 mL

COMT, catechol-O-methyltransferase; CR, controlled release; MAO, monoamine


oxidase; ODT, orally disintegrating tablet.
aMarketed in the United States for Parkinson’s disease.
bDosages may vary beyond stated range.
cDosages expressed as l-dopa component.
dDosages expressed as entacapone component.

580
Table 56–2 Monitoring of Potential Adverse Reactions to Drug Therapy for Parkinson’s Disease
Generic Name Adverse Drug Reaction Monitoring Parameter Comments
Amantadine Confusion Mental status; renal function Reduce dosage; adjust dose for renal impairment
Livedo reticularis Lower extremity examination; ankle Reversible upon drug discontinuation
edema
Benztropine Anticholinergic effects, confusion, Dry mouth, mental status, constipation, Reduce dosage; avoid in elderly; history of constipation,
sedation urinary retention memory impairment, urinary retention
Trihexyphenidyl See benztropine See benztropine See benztropine
Carbidopa/l-dopa Drowsiness Daytime drowsiness Reduce dose
Dyskinesias Abnormal involuntary movements Reduce dose; add amantadine
Nausea Nausea Take with food
COMT Inhibitors

Parkinson’s Disease
Entacapone Augmentation of l-dopa side effects; See carbidopa/l-dopa; also bowel Reduce dose of l-dopa; antidiarrheal agents
also diarrhea movements
Tolcapone See entacapone; also liver toxicity See carbidopa/l-dopa; also ALT/AST See carbidopa/l-dopa; also at start of therapy and for every dose
increase, ALT and AST levels at baseline and every 2–4 weeks
for the first 6 months of therapy; afterward monitor based on
clinical judgment.

|
Dopamine agonists

CHAPTER 56
Apomorphine Drowsiness Mental status Reduce dose
Nausea Nausea Premedicate with trimethobenzamide
Orthostatic hypotension Blood pressure, dizziness upon standing Reduce dose
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Bromocriptine Confusion Mental status Reduce dose


Drowsiness Mental status Reduce dose
(continued )
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Table 56–2 Monitoring of Potential Adverse Reactions to Drug Therapy for Parkinson’s Disease (Continued )

Generic Name Adverse Drug Reaction Monitoring Parameter Comments


Hallucinations/delusions Mental status Reduce dose
Nausea Nausea Titrate dose upward slowly; take with food

|
Neurologic Disorders
Orthostatic hypotension Blood pressure, dizziness upon standing Reduce dose
Pulmonary fibrosis Chest radiograph Chest radiograph at baseline and once yearly
Pramipexole Confusion Mental status Reduce dose
Drowsiness Mental status Reduce dose
Hallucinations/delusions Mental status Reduce dose
Impulsivity Behavior Reduce dose
Nausea Nausea Titrate dose upward slowly; take with food
Orthostatic hypotension Blood pressure, dizziness upon standing Reduce dose
Ropinirole See pramipexole See pramipexole See pramipexole
Rotigotine See pramipexole; also skin irritation See pramipexole; also skin examination See pramipexole; rotate patch application site
at site of patch application
MAO-B inhibitors
Rasagiline Nausea Nausea Take with food
Selegiline Confusion Mental status Reduce dose
Insomnia Mental status Administer dose earlier in day
Hallucinations Mental status Reduce dose
Orthostatic hypotension Blood pressure, dizziness upon standing Reduce dose
ALT, alanine aminotransferase; AST, aspartate aminotransferase; COMT, catechol-O-methyltransferase; MAO, monoamine oxidase.
Parkinson’s Disease | CHAPTER 56

depression, and anxiety. Patients with preexisting cognitive deficits and the
elderly are at greater risk for central anticholinergic side effects.
Amantadine
Amantadine often provides modest benefit for tremor, rigidity, and
bradykinesia. It may also decrease dyskinesia.
Adverse effects include sedation, dry mouth, hallucinations, dizziness, and
confu-sion. Livedo reticularis (a diffuse mottling of the skin in the upper or
lower extremi-ties) is a common but reversible side effect.
Doses should be reduced in patients with renal dysfunction (100 mg/day with creati-nine
clearances of 30–50 mL/min [0.50–0.84 mL/s], 100 mg every other day for cre-atinine
clearances of 15–29 mL/min [0.25–0.49 mL/s], and 200 mg every 7 days for creatinine
clearances less than 15 mL/min [0.25 mL/s]) and those on hemodialysis.
Levodopa and Carbidopa/Levodopa
l-dopa, the most effective drug available, is a precursor of dopamine. Unlike
dopa-mine, carbidopa, and benserazide, it crosses the blood-brain barrier.
Ultimately, all PD patients will require l-dopa.
When to start l-dopa (eg, right after diagnosis or when symptoms compromise
social, occupational, or psychological well-being) is controversial.
In the central nervous system (CNS) and peripherally, l-dopa is converted by
l-amino acid decarboxylase (l-AAD) to dopamine. In the periphery, carbidopa
or benserazide can block l-AAD, thus increasing CNS penetration of
administered l-dopa and decreasing dopamine adverse effects (eg, nausea,
cardiac arrhythmias, postural hypotension, and vivid dreams). Benserazide is
unavailable in the United States.
Initially l-dopa 300 mg/day (in divided doses) combined with carbidopa often achieves
adequate relief. The usual maximal dose of l-dopa is 800 to 1000 mg/day.
About 75 mg of carbidopa is required to effectively block peripheral l-AAD, but some
patients need more. Carbidopa/l-dopa is most widely used in a 25/100 mg tablet, but
25/250 mg and 10/100 mg dosage forms are available. Controlled-release prepara-tions
of carbidopa/l-dopa are available in 50/200 mg and 25/100 mg strengths. For patients
with difficulty swallowing, an orally disintegrating tablet is available.
After oral l-dopa, time to peak plasma concentrations varies intra- and inter-subject.
Meals delay gastric emptying, but antacids promote gastric emptying. l-dopa is absorbed
primarily in the proximal duodenum via a saturable large neutral amino acid transport
system, thus high-protein meals can interfere with bioavailability.
l-dopa is not bound to plasma proteins, and the elimination half-life is
approximately 1 hour. Adding carbidopa or benserazide can extend the half-
life to 1.5 hours, and adding a COMT inhibitor (eg, entacapone) can extend it
to approximately 2 to 2.5 hours.
Long-term, l-dopa-associated motor complications can be disabling. The most com-mon
of these are “end-of-dose wearing off ” and “peak-dose dyskinesias.” The risk of
developing motor fluctuations or dyskinesias is approximately 10% per year of l-dopa
therapy. However, motor complications can occur 5 to 6 months after start-ing l-dopa,
especially when excessive doses are used initially. Table 56–3 shows these motor
complications and suggests management strategies.
“End-of-dose wearing off ” is related to the increasing loss of neuronal dopamine
storage capability and the short half-life of l-dopa. Bedtime administration of a
dopa-mine agonist or a sustained-release formulation product (eg, carbidopa/l-
dopa CR, ropinirole XL, rotigotine transdermal patch, or pramipexole ER) may help
reduce nighttime off episodes and improve morning functioning.
“Delayed-on” or “no-on” can result from delayed gastric emptying or decreased
absorption in the duodenum. Crushing carbidopa/l-dopa tablets and taking with a
glass of water or using the orally disintegrating tablet on an empty stomach may
help. Subcutaneous apomorphine may be used as rescue therapy.

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Table 56–3 Common Motor Complications and Possible Initial Treatments


Effect Possible Treatments
End-of-dose “wearing off” Increase frequency of carbidopa/l-dopa doses; add either COMT
(motor fluctuation) inhibitor or MAO-B inhibitor or dopamine agonist
“Delayed on” or “no on” Give carbidopa/l-dopa on empty stomach; use carbidopa/
response l-dopa ODT; avoid carbidopa/l-dopa CR; use apomorphine
subcutaneous
Start hesitation (“freezing”) Increase carbidopa/l-dopa dose; add a dopamine agonist or
MAO-B inhibitor; utilize physical therapy along with assistive
walking devices or sensory cues (e.g., rhythmic commands,
stepping over objects)
Peak-dose dyskinesia Provide smaller doses of carbidopa/l-dopa; add amantadine

COMT, catechol-O-methyltransferase; CR, controlled release; MAO, monoamine


oxidase; ODT, orally disintegrating tablet.

“Freezing,” episodic inhibition of lower extremity motor function, may be


worsened by anxiety and may increase falls.
Dyskinesias, involuntary choreiform movements usually involving the neck, trunk,
and extremities, are usually associated with peak striatal dopamine levels. Less
commonly, dyskinesias can develop during the rise and fall of l-dopa effects (the
dyskinesias-improvement-dyskinesias or diphasic pattern of response).
“Off-period dystonia,” muscle contractions most commonly in distal lower
extremi-ties (eg, feet or toes) occurs often in the early morning. Consider
bedtime adminis-tration of sustained-release products, use of baclofen, or
selective denervation with botulinum toxin.
Monoamine Oxidase B Inhibitors
At therapeutic doses, selegiline and rasagiline, selective, irreversible inhibitors of
MAO-B, are unlikely to induce a “cheese reaction” (hypertension, headache)
unless excessive amounts of dietary tyramine are ingested. However, combining
MAO-B inhibitors with meperidine and other opioid analgesics is contraindicated
because of a small risk of serotonin syndrome.
Selegiline blocks dopamine breakdown and can extend the duration of action
of l-dopa up to 1 hour. It often permits reduction of the l-dopa dose by as
much as one half.
Selegiline also increases the peak effects of l-dopa and can worsen preexisting dys-
kinesias or psychiatric symptoms, such as delusions. Metabolites of selegiline are l-
methamphetamine and l-amphetamine. The oral disintegrating tablet may provide
improved response and fewer side effects than the conventional formulation.
Rasagiline also enhances l-dopa effects and is modestly beneficial as
monotherapy. Early initiation may be associated with better long-term outcomes.
Rasagiline may provide 1 hour of extra “on” time during the day. It is considered a
first-line agent (as is entacapone) for managing motor fluctuations of l-dopa.
There is no firm evidence that selegiline or rasagiline slow neurodegeneration.
Catechol-O-Methyltransferase Inhibitors
Tolcapone and entacapone are used in conjunction with carbidopa/l-dopa to
pre-vent the peripheral conversion of l-dopa to dopamine (increasing the area
under the curve of l-dopa by approximately 35%). Thus, “on” time is increased
by approxi-mately 1 to 2 hours, and dosage requirements of l-dopa are
decreased. Avoid con-comitant use of nonselective MAO inhibitors to prevent
inhibition of the pathways for normal catecholamine metabolism.
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Parkinson’s Disease | CHAPTER 56

COMT inhibition is more effective than controlled-release carbidopa/l-dopa


in pro-viding consistent extension of effect.
Tolcapone’s use is limited by the potential for fatal liver toxicity. Strict
monitoring of liver function is required. Reserve tolcapone for patients with
fluctuations unrespon-sive to other therapies.
Because entacapone has a shorter half-life, 200 mg is given with each dose
of carbidopa/l-dopa up to eight times a day. Dopaminergic adverse effects
may occur and are managed by reducing the carbidopa/l-dopa dose.
Brownish orange urine discoloration may occur (as with tolcapone), but
hepatotoxicity is not reported with entacapone.
Dopamine Agonists
The ergot derivative bromocriptine and the nonergots pramipexole, rotigotine,
and ropinirole are beneficial adjuncts in patients experiencing fluctuation in
response to l-dopa. They decrease the frequency of “off ” periods and provide
an l-dopa-sparing effect.
Titrate the dose of dopamine agonists slowly to enhance tolerance and find
the least dose that provides optimal benefit (see Table 56–1).
The nonergots are safer and are effective as monotherapy in mild to
moderate PD and as adjuncts to l-dopa in patients with motor fluctuations.
There is less risk of developing motor complications from monotherapy with dopa-mine
agonists than from l-dopa. Because younger patients are more likely to develop motor
fluctuations, dopamine agonists are preferred in this population. Older patients are more
likely to experience psychosis and orthostatic hypotension from dopamine agonists;
therefore, carbidopa/l-dopa may be the best initial medication in elderly patients,
particularly if cognitive problems or dementia is present.
Common side effects of dopamine agonists are shown in Table 56–2. Other side
effects include vivid dreams, sleep attacks, and impulsive behaviors.
Hallucinations and delusions can be managed using a stepwise approach (Table
56–4). When added to l-dopa, dopamine agonists may worsen dyskinesias.

Table 56–4 Stepwise Approach to Management of Drug-Induced


Hallucinosis and Psychosis in Parkinson’s Disease
General measures such as evaluating for electrolyte disturbance
(especially hypercalcemia or hyponatremia), hypoxemia, or infection
(especially encephalitis, sepsis, or urinary tract infection)
Simplify the antiparkinsonian regimen as much as possible by discontinuing or
reducing the dosage of medications with the highest risk-to-benefit ratio firsta
Discontinue anticholinergics, including other nonparkinsonian medications with
anticholinergic activity such as antihistamines or tricyclic antidepressants
Taper and discontinue amantadine
Discontinue monoamine oxidase-B inhibitor
Taper and discontinue dopamine agonist
Consider reduction of l-dopa (especially evening doses) and
discontinuation of catechol-O-methyltransferase inhibitors
Consider atypical antipsychotic medication if disruptive hallucinosis or psychosis persists
Quetiapine 12.5–25 mg at bedtime; gradually increase by 25 mg
each week if necessary, until hallucinosis or psychosis improved or
Clozapine 12.5–50 mg at bedtime; gradually increase by 25 mg
each week if necessary until hallucinosis or psychosis improved
(requires frequent monitoring for leukopenia)
If dosage reduction or medication discontinuation is either infeasible or undesirable, go to step 3.
a

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Bromocriptine is not commonly used because of a risk of pulmonary fibrosis and less efficacy than the other agonists.
Pramipexole is primarily renally excreted, and the initial dose must be adjusted in renal insufficiency. A once-daily extended-release
formulation is available.
Ropinirole is metabolized by cytochrome P4501A2; fluoroquinolones and smoking may alter ropinirole clearance. A once-daily
formulation is available.
Rotigotine patch provides continuous release over 24 hours, and disposition is not affected by hepatic or renal impairment.
Apomorphine is a nonergot dopamine agonist given as a subcutaneous “rescue” injection. For patients with advanced PD with
intermittent “off ” episodes despite optimized therapy, subcutaneous apomorphine triggers an “on” response within 20 minutes,
and duration of effect is up to 100 minutes. Most patients require 0.06 mg/kg. Prior to injection, patients should be premedicated
with the antiemetic trimethobenzamide. It is contraindicated with the serotonin-3-receptor blockers (eg, ondansetron).

EVALUATION OF THERAPEUTIC OUTCOMES


Educate patients and caregivers about recording medication doses and administra-tion times and duration of “on” and “off ”
periods.
Monitor symptoms, side effects, and activities of daily living, and individualize therapy. Concomitant medications that may worsen motor
symptoms, memory, falls, or behavioral symptoms should be discontinued if possible.