9. • Diagnostic features
§ Tremor
§ Rigidity
§ Akinesia/Bradykinesia
§ Postural instabilty
• Diagnosis
§ Bradykinesia with any one element (T, R, P)
§ Higher confidence with B, R, P, and good response to
dopaminergic therapy
Source: Chen JJ, Nelson MV, Swope DM. Parkinson’s Disease. In: DiPiro JT, Talbert RL, Yee GC,
Matzke GR, Wells BG, Posey LM, eds. Pharmacotherapy: A Pathophysiologic Approach. 9th ed. 9
Diagnostic
Clinical Presentation
10. Table
43-1.
— Step 1: Presence of bradykinesia and at least one of the
following: resting tremor, rigidity, or postural instability
— Step 2: Exclude other types of parkinsonism or tremor
disorders (see Differential diagnosis)
— Step 3: Presence of at least three supportive positive
criteria:
Source: Chen JJ, Nelson MV, Swope DM. Parkinson’s Disease. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR,
Wells BG, Posey LM, eds. Pharmacotherapy: A Pathophysiologic Approach. 9th ed. 10
Diagnostic Criteria for PD and Differential
Diagnosis
— Asymmetry of motor signs/
symptoms
— Unilateral onset
— Progressive disorder
— Resting tremor
— Excellent response to
carbidopa/L-dopa
— L-dopa response for 5 yrs or longer
— Presence of L-dopa dyskinesias
14. Differential Diagnosis:
Essential Tremor cause
• Medication
• Corticosteroids
• Metoclopramide (S#11)
• Valproate
• Sympathomimetics
• SSRIs, TCAs, theophylline
• Thyroid preparations
• Caffeine
• Tobacco
• Chronic alcohol
Source: Michael EE, Mildred DG, Parkinson’s Disease and other movement disorders. In: Brian KA, Robin
LC, Michael EE, Joseph BG, Pamala AJ, Wayne AK, Bradley RW, eds. KODA-KIMBLE & YOUNG’S Applied
Therapeutics: The Clinical Use of Drugs. 10th ed.
14
S#4
15. Essential tremor and PD
— Table 57-9
Source: Michael EE, Mildred DG, Parkinson’s Disease and other movement disorders. In: Brian KA,
Robin LC, Michael EE, Joseph BG, Pamala AJ, Wayne AK, Bradley RW, eds. KODA-KIMBLE &
YOUNG’S Applied Therapeutics: The Clinical Use of Drugs. 10th ed. 15
16. Source:
http://www.cmecorner.com/programs.asp?audience=&ProductID=1144&partner=medpage
16
Prodromal
Enteric (Gut)
Nervous System
Olfactory Bulb Cortical Pathology
Lewy body pathology in the
myenteric plexus results in
colonic denervation
Olfactory loss occurs bilaterally
despite the fact that motor signs are
generally asymmetric or unilateral
Cognitive impairment and
dementaia eventually affect
80% of patients with PD
Constipation is reported in
60% to 80% patients and
may predate motor
symptoms by years
Olfactory dysfunction ultimately
affects up to 90% of PD patients
Neuropsychiatric symptoms
(visual and auditory
hallucinations) may present
in PD
Table 3. Non-motor symptoms in early PD
• Non-specific symptoms may precede motor symptoms and
Tremor by 20 years
• Non-specific symptoms
o Hyposmia
o Constipation
o Fatigue
17. TREATMENT
Source: Chen JJ, Nelson MV, Swope DM. Parkinson’s Disease. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR,
Wells BG, Posey LM, eds. Pharmacotherapy: A Pathophysiologic Approach. 9th ed. 17
— Goal
1. Improve motor and motor symptoms
2. Preserve ability to perform activities of daily living (ADL)
§ Improve mobility
§ Minimize adverse effect and treatment complication
§ Positive disease modification
§ Improve nonmotor features
19. Source: Chen JJ, Nelson MV, Swope DM. Parkinson’s Disease. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR,
Wells BG, Posey LM, eds. Pharmacotherapy: A Pathophysiologic Approach. 9th ed. 19
Fig. 43-4. General approach to the management of early to advanced PD
- AGE
- DISEASE SEVERITY
- TREMOR CAUSE
- SURGERY
23. Treatment: General Approach
• Algorithm for management of early and late disease Figure 43-4:
Monoamine oxidase-B (MAO-B) inhibitor (e.g., rasagiline) as monotherapy
typically first treatment.
• Either rasagiline or DA agonist can be used first in physiologically young
patients.
• Levodopa (e.g., carbidopa/levodopa) is preferred initial therapy for patients
older, cognitively impaired, or who have moderately severe functional
impairment.
• Consider adding catechol-O-methyltransferase (COMT) inhibitor to extend
levodopa duration of activity when motor fluctuations develop. Alternatively,
consider adding MAO-B inhibitor or DA agonist.
• Amantadine may be added to manage levodopa-induced peak-dose
dyskinesias.
Source: Chen JJ, Nelson MV, Swope DM. Parkinson’s Disease. In: DiPiro JT, Talbert RL, Yee GC, Matzke
GR, Wells BG, Posey LM, eds. Pharmacotherapy: A Pathophysiologic Approach. 9th ed. 23
26. Table 43-3 Monitoring of Potential Adverse Reactions to Drug
Therapy
Source: Chen JJ, Nelson MV, Swope DM. Parkinson’s Disease. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds.
Pharmacotherapy: A Pathophysiologic Approach. 9th ed.
26
Generic Name Adverse Drug Reaction Monitoring Parameter Comments
Anticholinergic
Benztropine
Anticholinergic effects,
confusion, sedation
Dry mouth, mental status,
constipation, urinary
retention
Reduce dosage; avoid in
elderly; history of
constipation, memory
impairment, urinary
retention
Trihexyphenidyl See benztropine See benztropine See benztropine
Anti-Parkinson’s / Antiviral / Dopamine Agonist (Lexicomp)
Amantadine
Confusion
Livedo reticularis
Mental status; renal function
Lower extremity
examination; ankle edema
Reduce dosage; adjust dose
for renal impairment
Reversible upon drug
discontinuation
L-dopa
Carbidopa/L-dopa
Drowsiness
Dyskinesias
Nausea
Daytime drowsiness
Abnormal involuntary
movements
Nausea
Reduce dose
Reduce dose; add
amantadine
Take with food
27. Source: Chen JJ, Nelson MV, Swope DM. Parkinson’s Disease. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds.
Pharmacotherapy: A Pathophysiologic Approach. 9th ed.
27
Generic
Name
Adverse Drug
Reaction
Monitoring
Parameter
Comments
COMT inhibitors
Entacapone
Augmenta*on
of
L-‐dopa
side
effects;
also
diarrhea
See carbidopa/L-dopa; also
bowel movements
Reduce
dose
of
L-‐dopa;
an*diarrheal
agents
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
wks
for
the
first
6
months
of
therapy;
aHerward
monitor
based
on
clinical
judgment
Table 43-3. cont’d
28. Source: Chen JJ, Nelson MV, Swope DM. Parkinson’s Disease. In: DiPiro JT, Talbert RL, Yee GC,
Matzke GR, Wells BG, Posey LM, eds. Pharmacotherapy: A Pathophysiologic Approach. 9th ed. 28
Generic
Name
Adverse Drug Reaction Monitoring Parameter Comments
Dopamine agonists
Apomorphine
Drowsiness
Nausea
Orthostatic hypotension
Mental status
Nausea
Blood pressure, dizziness upon standing
Reduce dose
Premedicate with trimethobenzamide
Reduce dose
Bromocriptine
Confusion
Drowsiness
Hallucinations/delusions
Nausea
Orthostatic hypotension
Pulmonary fibrosis
Mental status
Mental status
Mental status
Nausea
Blood pressure, dizziness upon standing
Chest radiograph
Reduce dose
Reduce dose
Reduce dose
Titrate dose upward slowly; take with food
Reduce dose
Chest radiograph at baseline and once yearly
Pramipexole
Confusion
Drowsiness
Hallucinations/delusions
Impulsivity
Nausea
Orthostatic hypotension
Mental status
Mental status
Mental status
Behavior
Nausea
Blood pressure, dizziness upon standing
Reduce dose
Reduce dose
Reduce dose
Reduce dose
Titrate dose upward slowly; take with food
Reduce dose
Ropinirole
See pramipexole
See pramipexole
See pramipexole
Table 43-3. cont’d
29. Source: Chen JJ, Nelson MV, Swope DM. Parkinson’s Disease. In: DiPiro JT, Talbert RL, Yee GC,
Matzke GR, Wells BG, Posey LM, eds. Pharmacotherapy: A Pathophysiologic Approach. 9th ed. 29
Generic
Name
Adverse Drug Reaction Monitoring Parameter Comments
MAO-B inhibitors
Rasagiline
Nausea
Nausea
Take with food
Selegiline
Confusion
Insomnia
Hallucinations
Orthostatic hypotension
Mental status
Mental status
Mental status
Blood pressure, dizziness upon standing
Reduce dose
Administer dose earlier in day
Reduce dose
Reduce dose
Table 43-3. cont’d
30. Anticholinergics
o Can be used as monotherapy or in combination with other drugs.
o May improve tremor and dystonia but rarely have substantial benefit for
bradykinesia or other symptoms.
Side effects More serious reactions
• Dry mouth
• Blurred vision
• Constipation
• Urinary retention
• Forgetfulness
• Confusion
• Sedation
• Depression
• Anxiety
o Use with caution in patients with preexisting cognitive deficits and in elderly.
Source: Chen JJ, Nelson MV, Swope DM. Parkinson’s Disease. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR,
Wells BG, Posey LM, eds. Pharmacotherapy: A Pathophysiologic Approach. 8th ed. 30
31. Amantadine
o Modest benefit for tremor, rigidity, and bradykinesia; may also decrease
dyskinesia at high doses (400 mg/day).
Adverse effects Renal dysfunction
• Sedation
• Vivid dreams
• Dry mouth
• Depression
• Hallucinations
• Anxiety
• Dizziness
• Psychosis
• Confusion
• Livedo reticularis common but
reversible
• 100 mg/day with CLcr 30–50 mL/min (0.5–0.84 mL/s)
• 100 mg every other day for CLcr 15–29 mL/min
(0.25–0.49 mL/s)
• 200 mg every 7 days for CLcr <15 mL/min(0.25 mL/s)
and patients on hemodialysis
Source: Chen JJ, Nelson MV, Swope DM. Parkinson’s Disease. In: DiPiro JT, Talbert RL, Yee GC, Matzke
GR, Wells BG, Posey LM, eds. Pharmacotherapy: A Pathophysiologic Approach. 8th ed. 31
32. Carbidopa and carbidopa/levodopa
o Levodopa is most effective drug and ultimately required by all
patients.
o May be started at diagnosis or withheld until symptoms compromise
social, occupational, or psychological well-being.
o Carbidopa increases CNS penetration of levodopa and decreases
adverse effects from peripheral levodopa metabolism to DA:
Ø Nausea, Vomiting,
Cardiac arrhythmias,
Postural hypotension,
Vivid dreams
o Initially, levodopa 300 mg/day (in divided doses) plus carbidopa
(75 mg/day in divided doses) often provides adequate benefit.
o Sweat, urine, saliva appears in dark in color (i.e., red, brown, or
balck) => not a harmful side effect
o Contraindication; concurrent use with nonselective MAOIs or use
within the last 14 days
Sources: Chen JJ, Nelson MV, Swope DM. Parkinson’s Disease. In: DiPiro JT, Talbert RL, Yee GC, Matzke
GR, Wells BG, Posey LM, eds. Pharmacotherapy: A Pathophysiologic Approach. 8th ed.
Lexicomp: http://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/7167
32
33. Catechol-O-Methyltransferase Inhibitors
o Use only in combination with carbidopa/levodopa to prevent peripheral
conversion of levodopa to DA
o Increase “on” time by 1–2 hrs and decrease levodopa dosage requirements.
o Avoid concomitant use of nonselective MAO inhibitors to prevent inhibition of
normal catecholamine metabolism.
o May cause brown-orange urine discoloration.
Source: Chen JJ, Nelson MV, Swope DM. Parkinson’s Disease. In: DiPiro JT, Talbert RL, Yee GC, Matzke
GR, Wells BG, Posey LM, eds. Pharmacotherapy: A Pathophysiologic Approach. 8th ed. 33
Entacapone
Tolcapone
Give 200 mg with each dose of
carbidopa/l-dopa up to 8 times
a day.
Manage dopaminergic adverse
effects by reducing carbidopa/
levodopa dose.
No evidence of hepatotoxicity.
100 mg 3 times daily starting
and recommended dose as
adjunct to carbidopa/levodopa.
Reserve for patients with
fluctuations unresponsive to
other therapies because of
potential for fatal liver toxicity.
34. DA Agonists
o Adjunctive therapy in patients with deteriorating, fluctuating, or limited response to
levodopa due to inability to tolerate higher doses.
o Decrease frequency of “off” periods and provide levodopa sparing effect.
o Preferred in younger patients because of less risk of developing motor complications
with monotherapy than from levodopa.
o More likely to cause psychosis and orthostatic hypotension in older patients than
carbidopa/levodopa.
Side effects: Less common side effects:
§ Nausea
§ Confusion
§ Hallucinations
§ Lightheadedness
§ Lower extremity edema
§ Postural hypotension
§ Sedation
§ Vivid dreams
§ Compulsive behaviors
§ Psychosis
§ Sleep attacks
§ May worsen dyskinesias when
added to levodopa.
Source: Chen JJ, Nelson MV, Swope DM. Parkinson’s Disease. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR,
Wells BG, Posey LM, eds. Pharmacotherapy: A Pathophysiologic Approach. 8th ed. 34
35. o Pramipexole 0.125 mg 3 times daily initial dose, increased every
5–7 days as tolerated to maximum of 1.5 mg 3 times a day.
o Ropinirole 0.25 mg 3 times daily initial dose, increased by 0.25 mg
3 times daily every week to maximum of 24 mg/day.
o Apomorphine given as SC “rescue” injection for patients with
advanced disease and intermittent “off” episodes despite optimized
therapy.
§ Triggers “on” response within 20 minutes.
§ Duration of effect: up to 100 minutes.
§ Most patients require 0.06 mg/kg SC.
§ Premedicate with antiemetic trimethobenzamide
§ Contraindicated with serotonin-3-receptor blockers (e.g.,
ondansetron).
o Bromocriptine not commonly used because of increased risk of
pulmonary fibrosis and reduced efficacy.
Source: Chen JJ, Nelson MV, Swope DM. Parkinson’s Disease. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR,
Wells BG, Posey LM, eds. Pharmacotherapy: A Pathophysiologic Approach. 8th ed. 35
36. Monoamine Oxidase B Inhibitors
Selegiline Rasagiline
Blocks DA breakdown and can extend
levodopa duration up to 1 hr; may permit
reduction of levodopa dose by as much as
one half.
Increases peak levodopa effects and can
worsen dyskinesias or psychiatric
symptoms.
Adverse effects:
• Insomnia
• Jitteriness
Oral disintegrating tablet may provide
improved response and fewer side effects.
Also enhances levodopa effects.
Modest beneficial effect as monotherapy.
Early initiation associated with better long-
term outcomes.
First-line agent for motor fluctuations; may
provide 1 hr of extra “on” time during the
day.
Source: Chen JJ, Nelson MV, Swope DM. Parkinson’s Disease. In: DiPiro JT, Talbert RL, Yee GC, Matzke
GR, Wells BG, Posey LM, eds. Pharmacotherapy: A Pathophysiologic Approach. 8th ed. 36
37. Personalized pharmacotherapy
• No pharmacogenomics parameters utilized to guide PD
pharmacotherapy
• Mild functional impairment
• Dopamine agonist monotherapy
• Required therapy in time
• Consider in motor fluctuations
• Management of L-dopa induced peak dose dyskinesias
• Surgery
• Treatment plan
Source: Chen JJ, Nelson MV, Swope DM. Parkinson’s Disease. In: DiPiro JT, Talbert RL, Yee GC, Matzke
GR, Wells BG, Posey LM, eds. Pharmacotherapy: A Pathophysiologic Approach. 9th ed. 37
39. 1. Monitor medication administration times.
2. Monitor to ensure that the patient and/or caregivers understand the
prescribed medication regimen.
3. Monitor and inquire specifically about dose-by-dose effects of
medication, including response to doses of medication and the
presence of dyskinesias, wearing-off effects, dizziness, nausea, or
visual hallucinations.
4. Monitor and inquire about concerns that caregivers may have about the
patient, such as presence of abnormal behaviors, dyskinesias, falls,
hallucinations, memory problems, mood changes, and sleep disorders
5. Monitor for nonadherence and, if present, inquire for possible reasons
(e.g., dosing convenience, financial issues, and adverse effects) and
offer suggestions
6. Monitor for presence of drugs that can exacerbate idiopathic
Parkinson’s disease motor features (e.g., D2 receptor blockers), and
evaluate whether the presence of anticholinergic agent is causing
cognitive impairment
Source: Chen JJ, Nelson MV, Swope DM. Parkinson’s Disease. In: DiPiro JT, Talbert RL, Yee GC, Matzke
GR, Wells BG, Posey LM, eds. Pharmacotherapy: A Pathophysiologic Approach. 9th ed. 39
Table 43-6. Monitoring PD Therapy
40. Periodic Review of Medication
— STARTing and STOPPing Medications in the Elderly
— STOPP/START criteria for potentially inappropriate
prescribing in older people: version 2
— START - Screening tool to alert to right treatment
— STOPP - Screening tool of older people's prescriptions
40
Sources: http://www.ngna.org/_resources/documentation/chapter/carolina_mountain/
STARTandSTOPP.pdf
http://ageing.oxfordjournals.org/content/early/2014/10/16/ageing.afu145.full
41. Monitoring
• Ask patients and caregivers to record medication
administration times and duration of “on” and “off”
periods.
• Monitor symptoms, side effects, and activities of daily
living.
• Liver function monitoring required for patients taking
tolcapone.
o Discontinue therapy if liver function tests above
upper limit of normal or if signs/symptoms
suggest hepatic injury.
Source: Chen JJ, Nelson MV, Swope DM. Parkinson’s Disease. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR,
Wells BG, Posey LM, eds. Pharmacotherapy: A Pathophysiologic Approach. 8th ed. 41
42. Source: Chen JJ, Nelson MV, Swope DM. Parkinson’s Disease. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR,
Wells BG, Posey LM, eds. Pharmacotherapy: A Pathophysiologic Approach. 9th ed. 42
Effect
Possible Treatments
End-of-dose “wearing off”
(motor fluctuation)
Increase frequency of carbidopa/L-dopa doses;
add either COMT inhibitor or MAO-B inhibitor or DA agonist
“Delayed on” or “no on” response
Give carbidopa/L-dopa on empty stomach;
use carbidopa/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
Table 43-4 Common Motor Complications and Possible Initial Treatments
43. Source: Chen JJ, Nelson MV, Swope DM. Parkinson’s Disease. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds.
Pharmacotherapy: A Pathophysiologic Approach. 9th ed.
43
1. General measures such as evaluating for electrolyte disturbance (especially
hypercalcemia or hyponatremia), hypoxemia, or infection (especially encephalitis,
sepsis, or urinary tract infection)
2. Simplify the antiparkinsonian regimen as much as possible by discontinuing or
reducing the dosage of medications with the highest risk-to-benefit ratio firsta
a. Discontinue anticholinergics, including other nonparkinsonian medications
with anticholinergic activity such as antihistamines or tricyclic
antidepressants
b. Taper and discontinue amantadine
c. Discontinue monoamine oxidase-B inhibitor
d. Taper and discontinue dopamine agonist
e. Consider reduction of L-dopa (especially evening doses) and
discontinuation of catechol-O-methyltransferase inhibitors
3. Consider atypical antipsychotic medication if disruptive hallucinosis or psychosis
persists
a. Quetiapine 12.5–25 mg at bedtime; gradually increase by 25 mg each
week if necessary, until hallucinosis or psychosis improved or
b. 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)
Table 43-5 Stepwise Approach to Management of Drug-Induced
Hallucinosis and Psychosis in PD
44. • Course unpredictable but disease progresses over
time.
• Secondary complications (e.g., pneumonia, fall-related
injuries, choking) can be fatal.
• With appropriate treatment, most patients have long,
productive lives for years after diagnosis.
Source: Chen JJ, Nelson MV, Swope DM. Parkinson’s Disease. In: DiPiro JT, Talbert RL, Yee GC, Matzke
GR, Wells BG, Posey LM, eds. Pharmacotherapy: A Pathophysiologic Approach. 8th ed. 44
Prognosis
45. Clinical Pearl
• As PD progress, the timing of medication needs to
coincide with symptoms
• Evaluate the onset and duration of each dose and
make modification accordingly
• Symptoms may worsen when patients are forced to
receive medications at predetermined dosing times
such as those used in hospitals and nursing homes
=>Let the patient’s symptoms guide the dosing
times
Source: Chen JJ, Nelson MV, Swope DM. Parkinson’s Disease. In: DiPiro JT, Talbert RL, Yee GC, Matzke
GR, Wells BG, Posey LM, eds. Pharmacotherapy: A Pathophysiologic Approach. 9th ed. 45
46. Summary
• Clinical Presentation
• Diagnostic criteria
• Pharmacotherapy goals, drug therapy,
nondrug therapy, and monitoring
parameters
• Based on patient’s perception of the
severity of symptoms and effect on quality
of life, recommendation should be given
Source: Chen JJ, Nelson MV, Swope DM. Parkinson’s Disease. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR,
Wells BG, Posey LM, eds. Pharmacotherapy: A Pathophysiologic Approach. 9th ed. 46
48. Case Study
• After completing this case study, the reader should
be able to:
• Recognize motor and non-motor symptoms of PD
• Develop an optimal pharmacotherapeutic plan for a patient
with PD as he or she progress through different stages of the
disease
• Recommend alterations in therapy for a patient experiencing
adverse drug effects, drug-drug interactions, and drug-food
interactions.
• Educate patients with PD about the disease, its drug therapy
and non-pharmacologic treatments.
48
49. 1. DiPiro CV, Schwinghammer TL. DiPiro C.V., Schwinghammer T.L. DiPiro, Cecily V., and Terry L.
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49
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