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Pathophysiology: Parkinson's Disease (PD) Has Highly Characteristic Neuropathologic Findings and A Clin
Pathophysiology: Parkinson's Disease (PD) Has Highly Characteristic Neuropathologic Findings and A Clin
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
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.
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 56–2 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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Table 56–2 Monitoring of Potential Adverse Reactions to Drug Therapy for Parkinson’s Disease (Continued )
|
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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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).