Parkinson’s Disease
Ibrahim Sales, Pharm.D.
Assistant Professor of Clinical Pharmacy
King Saud University
isales@ksu.edu.sa
Learning Objectives
• Describe Parkinson’s Disease
• List drugs used in the treatment of Parkinson’s
Disease
• Describe the pharmacological management of
each drug used in the treatment of
Parkinson’s Disease
• Describe the mechanism of action, toxicities,
and pharmacokinetics of drugs used to treat
Parkinson’s Disease
Parkinson’s Disease (PD)
• Second most common neurodegenerative
disease
• Clinical symptoms are motor and nonmotor
• Diagnosis based on motor symptoms
• Etiology is unknown
• No treatment can stop the progression of PD
Epidemiology
• Gender non-specific
• Average onset is approximately 60 years old
• Risk increases with age
Clinical Presentation
• d
Pharmacological Management
• There is no treatment that can stop or reverse
the loss of dopaminergic neurons
• Symptomatic relief
• Strategies
– Increase the amount of dopamine activity in the
brain
– Decrease the amount of cholinergic brain activity
– Both (dopamine and acetylcholine need to be in
balance for normal, balanced movement)
Therapeutic Goals
• Reduce the incidence and severity of motor
and nonmotor symptoms
• Maintain quality of life
• Improve activities of daily living
• Minimize complications of drug therapy
Levodopa
• First introduced in the 1960s
• Gold standard
• Dopamine cannot cross the blood-brain
barrier
• Levodopa (amino acid) precursor of dopamine
• Carbidopa – decarboxylase inhibitor in
peripheral body tissues
Levodopa
• Ameliorates the motor symptoms
• Improves QOL, lengthens independence and
decreases mortality rate
• Effects last for several hours initially
• Therapeutic response nears t½ eventually
Levodopa
• Rapidly absorbed from the small intestines
• High-protein meals will delay absorption and
decrease peak plasma concentration
• Peak plasma concentration: 0.5 to 2 hours
• t ½ : 1 to 3 hours
Levodopa
• Contraindications:
– Psychotic patients, closed-angle glaucoma, active
peptic ulcer (monitor closely), MAO inhibitor if
taken within 14 days, undiagnosed skin lesion or
history of melanoma
• Pregnancy risk factor C
• Adverse effects:
– Nausea, vomiting, anorexia; postural hypotension;
nightmares, agitation, confusion insomnia,
depression, somnolence, anxiety
Levodopa
• Patients may develop myoclonus or dystonia
when medication is at its peak concentration
• Dyskinesia is not disabling if mild; only severe
• “On-off phenomenon”
– Initial responders
• Decreased absorption/effect:
– Oral iron salts (except iron sucrose, ferumoxytol, iron
dextran complex and ferric gluconate); sapropterin,
metoclopramide, phenytoin, pyridoxine, kava kava;
methylphenidate can increase levodopa toxicity
Levodopa
• Usually prescribed with carbidopa
• IR tablet: carbidopa 25mg/levodopa 100mg
TID
– Increase dose by one tab every other day
• Carbidopa 25mg/levodopa 250mg
– Increase dose by ½ tab every 1 to 2 days
• Max number of tablets is 8 or 200mg
carbidopa and 2000mg levodopa
Levodopa
• Sustained release
• Carbidopa 50mg/levodopa 200mg BID at least
6 hours apart
– Increase dose every 3 days
• Max number of tablets per day is 8
• Initial dose for elderly is carbidopa
25mg/levodopa 100mg two tablets daily
Dopamine Agonists
• Directly stimulate dopamine receptors
• Ergot dopamine agonists (bromocriptine)
• Non-ergot dopamine agonists (pramipexole and ropinirole)
– Stimulate the D3 and D2 receptors
• Ineffective in patients that do not respond to levodopa
• Monotherapy or in combination with carbidopa/levodopa
– Can postpone levodopa use
• Improves tremor, bradykinesia, and rigidity
• Dopamine agonists last therapeutically longer than
levodopa
• Minimize fluctuations in dopamine blood concentrations,
allow for levodopa dose reduction, improve ADLs
Bromocriptine
• Partial dopamine agonist
• Ergot derived
• Ergot derived side effects:
Pulmonary/cardiofibrosis infiltrates
• Dosing: 1.25 mg BID
– Increase at 2 to 4 weeks by 2.5mg/day
– Average dose: 20-40mg daily in TID or QID doses
– Max dose: 90mg/day
Rotigotine
• Transdermal Patch
– Daily patch formulation
– Start at 2mg/24 hours; max 6mg/24 hours
– Do not discontinue abruptly
• Neuroleptic malignant syndrome like
• Akinetic crisis
Pramipexole
• Stimulates the D3 receptors
• May be prescribed for mild cases of PD;
especially effective for treating patients
experiencing the “on-off phenonmenon”
– Reduces the “off” time
Pramipexole
• Rapidly absorbed from the GI tract
• Plasma concentration peaks in 2 hours for the
IR form; peaks in 6 hours for the extended
release form
• t ½ is 8.5 hours; 12 hours for the elderly
• Excreted in the urine, 90% unchanged
Pramipexole
• Initial dose for the IR form is 0.375mg daily divided into 3
doses
– Titrate dose every 5 to 7 days to minimize adverse effects
– Maximum dose 4.5mg daily
CrCl (mL/min)
>60
35 to 59
15 to 34
Initial dose
0.125mg TID
0.125mg BID
0.125mg daily
Maximum
dose
1.5mg TID
1.5mg BID
1.5mg daily
• Initial dose for the ER for is also 0.375mg daily
– Titrate dose by 0.75mg a day every 5 to 7 days
– Maximum dose is 4.5mg a day
– CrCl 30 – 50 mL/min, dose every other day up to 2.25mg daily
Pramipexole
• If discontinuing, taper over one week
– Risk of developing a disorder resembling
neuroleptic malignant syndrome
• Pregnancy risk factor C
Ropinirole
• Stimulates the D2 receptor and is effective in mild
cases
• Effective in patients in an advanced stage who
have “on-off phenomenon”
• Absorbed in the GI tract; unaffected by food
• Plasma concentration peaks at 1 to 2 hours for IR
form; 6 to 10 hours for ER form
• t ½ 6 hours
• Excreted in the urine; clearance is decreased from
15 to 30% in patients over 65 years old
Ropinirole
• Initial dose for the IR tablet for the first week is
0.25mg TID
–
–
–
–
–
Titrate slowly to avoid toxic effects
Week 2: 0.5mg TID
Week 3: 0.75mg TID
Week 4: 1mg TID
Can increase by 1.5mg a day on a weekly basis up to a
total dose of 9mg a day
– Can raise dose by 3mg a day on a weekly basis up to a
total of 24mg a day
Ropinirole
• If discontinuing, gradually taper over a 7 day
period
– Frequency should be decreased to BID for the first
4 days then lowered to once daily for the
remaining 3 days
Ropinirole
• The initial dose for the ER tablet is 2 mg once
daily for the first 1 or 2 weeks
• The dose can be increased by 2 mg a day on a
weekly basis with the maximum dosage as
24mg daily
• Taper in the same manner as the IR tablet
Apomorphine
• Stimulates D2, D3, D4, and D5 receptors
• “Rescue therapy” for a patient who has severe
“off” period and is not responding to other
medication
• Subcutaneously injected
• Therapeutic benefit begins in 10 minutes and
lasts for 2 hours
• Plasma concentration peak in 20 minutes
• t ½ is 40 minutes
Apomorphine
• Contraindications
– Hypersensitivity to apomorphine or ingredients;
administration IV; concomitant use with serotinin
antagonists (loss of consciousness and extreme
hypotension)
– Toxic effects include hypotension, chest pain, dyskinesia,
sweating, drowsiness, falls, abnormal EKG (QT
prolongation), nausea and vomiting (pre and post antiemetics )
• Trimethobenzamide at 300mg TID should be started 3 days before
the patient receives the first dose and continued at least for the
first 2 months
• Ondansetron is a serotonin antagonist and should not be used
Apomorphine
• Three days before initial dose, administer
trimethobenzamide 300mg TID; continue for 2
months then assess
• Initial dose is a test dose of 2mg given during
an “off” period
• If patient tolerates the test dose, start at 2mg
– May increase dose by 1mg every few days
• Max dose is 6mg
Apomorphine
• Patients tolerating the test dose, but not
therapeutically responding
– 2nd test dose of 4mg administered
– If responds, starting dose is 3mg
– Increase dose every few days; max is 6mg
• Patients who don’t tolerate the test dose of 4mg
– 3rd test dose of 3mg can be given
– If tolerated, the start dosage is 2mg
– 2mg dose may be increased by 1mg to a max of 3mg
Apomorphine
• If not administered for more than 1 week, the
start dose is 2mg; the dosage must gradually
be increased
• Standing and supine BP must be checked
before administering a test dose
– Both pressures must be checked 20, 40, and 60
minutes after the test dose
– If additional test dosed are needed, there must be
a 2-hour wait before the next test dose which
should be only given during an “off” period
Apomorphine
• Use cautiously in patients with mild to
moderate impairment of the liver
• The test dose and starting dose should be 1mg
for patients with mild to moderate renal
impairment
• Pregnancy risk factor C
Dopamine Agonists ADEs
• Nausea, vomiting, dyskinesias, somnolence,
sedation, hallucinations, nightmares,
confusion, and postural hypotension
• Obsessive-compulsive disorder and impulsecontrol disorder
• Excessive daytime sleepiness
– Modafinil 200 – 400mg daily
MAO-B Inhibitors
• Monoamine oxidase type B is an enzyme
which metabolizes dopamine to homovanillic
acid in the striatum
• Selegiline and rasagiline interfere with
dopamine metabolism, thereby increasing the
concentration of dopamine at the neuronal
synapse
MAO-B Inhibitors
• They provide some therapeutic benefit when
used as monotherapy in early or mild
symptomatic PD
• May decrease the effects of the “off” period
when administered with levodopa and
prolong its effects, allowing the dosage of
levodopa to be reduced
Pharmacokinetics
• Selegiline
– Effects start within 1 hour and last for 24-72 h
– T ½ is 10 h for the tablet, but 18 to 25 for the
transdermal form
• Rasagiline
– Effects start within 1 hour and last for 1 week
– T ½ is 1.3 to 3 h
Selegiline and Rasagiline
• Dyskinesias may increase if administered with
levodopa, but can be controlled by lowering the
levodopa dose
• Potential for serotonin syndrome
• Pregnancy risk factor C
• Adverse effects
– Selegiline: nausea, confusion, hallucinations,
insomnia, headache, jitteriness, orthostatic
hypotension, dyskinesias
– Rasagilinie: diarrhea, weight loss, hallucinations, rash
– Tyramine – hypertensive crisis
Dosing
• Selegiline
– 5mg BID at breakfast and lunch (insomnia)
– Initial dose for ODT is 1.25mg daily x 6 weeks
• May increase to max dose of 2.5mg daily
• Rasagiline
– 1mg daily if needed and tolerated
– Lower levodopa dose 9 to 13% (dyskinesias)
– Mild hepatic impairment dose: 0.5mg daily
• Avoid in moderate to severe hepatic impairment
COMT Inhibitors
• The enzyme catechol-o-methyltransferase
(COMT) metabolizes dopamine to
homovanillic acid
• Levodopa is mainly metabolized by COMT
• COMT inhibitors increase the levodopa halflife and allow more levodopa to cross the BBB
• COMT administered with levodopa decreases
the “off” period and increases the “on” period
• Possible lowering of the levodopa dosage
COMT Inhibitors
• Entacapone
– Quickly absorbed; quick onset of action
– Peak effect at 1 hour
– T ½ is 2 hours
• Tolcapone
– Rapidly absorbed
– T ½ is 2-3 hours
– Peak plasma concentration in 2 hours
Adverse Reactions
• Entacapone
– Diarrhea, brown-orange colored urine from the
accumulation of metabolites, dyskinesia, nausea
and vomiting
• Dyskinesia and nausea can be decreased or avoided by
lowering the dose of levodopa by 20 to 30% in the first
48 hours of administering entacapone
Adverse Reactions
• Tolcapone
– Same as entacapone
– Dyskinesia and nausea can be decreased by
lowering the levodopa dose, but the diarrhea can
be so severe that 5 to 10% of patients d/c
– Dizziness, hallucinations, somnolence, postural
hypotension; hepatic toxicity (some fatal cases)
• Administer if no other treatment is available or
responsive; patients must sign a consent form; liver
enzymes must be monitored every two weeks for the
first year
Dosing
• Entacapone
– With every dose of levodopa/carbidopa, 200mg is
prescribed
– Max frequency is 8x daily; max dose is 1600mg daily
• Tolcapone
–
–
–
–
More potent; advanced patients
100mg TID; can be increased to 200mg TID
If no improvement in 3 weeks, d/c
If hepatic impairment develops, d/c
• Both medications are pregnancy risk factor C
Anticholinergics
• Antimuscarinic anticholinergic medications
lower the actions of the cholinergic neurons in
the striatum; basis for therapeutic effects is
not understood
• Due to the toxicity of the other PD
medications, if the patient is in early stages of
PD, not elderly and the main symptom is
tremor, may prescribe
Anticholinergics
• Benefits:
– Rest tremor
– Urinary frequency
– Excess sweating
– Drooling
• Less effective for bradykinesia, rigidity, or gait
problems
Anticholinergics
• Elderly concerns
– Increased risk of confusion, cognitive problems,
hallucinations
– Dementia
• 2.5-fold increase in amyloid plaque and neurofibrillary tangle
densities
• Baseline cognition evaluation, psychiatric history,
and blood pressure
• Monitor for typical symptoms; decreased gastric
acid secretion; decreased gastric emptying
Anticholinergics
• Trihexyphenidyl
– t ½ or 33 hours
– Plasma concentration peaks in 1.3 hours
• Benztropine
– Effects start in 1 hour and lasts for 6 to 48 hours
Adverse Reactions
• Constipation, urinary retention, mydriasis,
blurred vision, tachycardia, confusion,
hallucinations, nausea, vomiting,
hyperthermia
• Use with caution in CV disease, renal
impairment, hepatic impairment, glaucoma,
and prostatic hyperplasia
• KCl can interact and lead to ulcers
Dosing
• Trihexyphenidyl
– Initial dose is 1mg daily
•
•
•
•
Increase by 2 mg every 3-5 days
Usual dose is 6-10mg daily in 3-4 doses
Some patients need 12-15mg daily
If prescribed with levodopa, dose is 3-6mg daily in divided doses
• Benztropine
– Initial dose is 1 to 2 mg daily in 2-4 doses
• May increase dose by 0.5mg each week; max 6mg/daily
• Avoid in patients > 60 years of age
• Pregnancy risk factor C
Amantadine
• Releases stored dopamine and inhibits the
NMDA glutamate receptor (excitatory)
• Prescribed in early PD; primarily prescribed to
decrease the dyskinesia, tremor and rigidity of
the advanced stage
• May only be beneficial for a few weeks or
months
Amantadine
• Well absorbed and takes effect within 48 hrs
• t ½ from 9 to 31 hrs
• Plasma concentration peak of 2 to 4 hrs
• Adverse effects
– Nausea, dizziness, insomnia, livedo reticularis (benign
purple mottling of the skin of dependent extremities),
peripheral edema, orthostatic hypotension,
hallucinations, and confusion
– Its stimulant action may worsen insomnia and
restlessness
Dosing
• Standard dose for monotherapy is 100mg BID
– May be increased to 400mg daily in divided doses
• Patients taking high doses of other
medications for PD
– Initial dose is 100mg daily
• Dose can be increased after 1 week or more to 100mg
BID
• Pregnancy risk factor C
Treatment Algorithm
Treatment Algorithm
Treatment Algorithm
Wearing off therapy
• If monotherapy with levodopa
– Increase frequency of levodopa
• Change to SR/CR formulation
– Increase dose of levodopa
– Add a dopamine agonist
– Add COMT-I
• If monotherapy with dopamine agonists
– Add carbidopa/levodopa
• Apomorphine – rescue therapy
• Diet – Avoid high protein
On-Off Phenomena
• Rapid fluctuations from “on” to “off” motor
states
• Freezing gate
• Occurs in patients with advanced disease
– Have motor fluctuations
– Dyskinesia
– On chronic levodopa
• Increase the frequency of levodopa
• Add dopamine agonist
• Add COMT-I