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Fatimah Aljohani, Pharm.D, BCACP

Internal Medicine Clinical Pharmacist

13/10/2021
 ▪ Introduction
▪ Etiology
▪ Pathophysiology

OUTLINES ▪ Risk factors

▪ Clinical presentation
▪ Diagnoses
▪ Treatment

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▪ Progressive, chronic disorder of central nervous system (CNS) resulting from loss of
dopamine from the nigrostriatal tracts in the brain characterized by impaired muscular
coordination and tremor
▪ The disorder was first described by James Parkinson in his 1817
▪ Affects 0.5% of people in their sixties and 2.5% of those older than age 80
▪ Usual age at diagnosis is 55–65 years
▪ Parkinson disease is twice as common in men than in women in most populations

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Parkinsonism comprises four cardinal motor features
▪ Bradykinesia (slow and small movements). Reduced blink, face expression, difficulty getting
out of chair, shuffling steps, reduced arm swing, freezing
▪ Tremor (usually resting) most common, unilateral
▪ Rigidity (different from spasticity) resistance during passive range of motion
▪ Postural changes is the most debilitating = Imbalance, falls

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▪ Idiopathic
▪ Heavy metal intoxication
▪ Destruction of dopaminergic neurons
- Free radical formation
▪ Increase activity of inhibitory GABAergic neurons
▪ Drugs: antipsychotics, metoclopramide, valproic acid

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Normal physiology:
▪ Dopamine activity = Acetylcholine activity
Parkinson Disease:
▪ DA< Ach activity
▪ Loss of neurons and presence of Lewy bodies in substantia nigra
pars compacta.
▪ Degree of nigrostriatal dopamine loss correlates directly with
severity of motor symptoms.
▪ Reduced activation of dopamine-1 and dopamine-2 receptors
results in greater inhibition of thalamus
▪ Loss of presynaptic nigrostriatal dopamine neurons inhibits
thalamic activity and reduces activation of motor cortex
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How to correct this balance?
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▪ Increasing age
▪ Male sex
▪ Heredity (close relative with disease)
▪ Toxin exposure (eg, herbicides, pesticides)

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SIGNS AND SYMPTOMS
Autonomic and sensory symptoms.
General features. ▪ Bladder and anal sphincter disturbances.
▪ Resting tremor.
▪ Constipation.
▪ Muscular rigidity.
▪ Bradykinesia (usually asymmetric)
▪ Diaphoresis.
▪ Postural instability in advanced disease. ▪ Fatigue.
▪ Olfactory impairment.
Motor symptoms. ▪ Pain.
▪ Decreased manual dexterity. ▪ Paresthesias.
▪ Difficulty arising from seated position. Mental status changes.
▪ Diminished arm swing during ambulation. ▪ Anxiety.
▪ Dysarthria. ▪ Apathy.
▪ Dysphagia. ▪ Cognitive impairment.
▪ Flexed posture. ▪ Depression.
▪ “Freezing” at initiation of movement. ▪ Hallucinosis/psychosis (typically drug-induced) 9
▪ Hypophonia. ▪ Sleep disorders.
▪ 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:

▪ Asymmetry of motor signs/symptoms

▪ Unilateral onset

▪ Progressive disorder

▪ Resting tremor

▪ Excellent response to carbidopa/L-dopa

▪ L-dopa response for 5 years or longer

▪ Presence of L-dopa dyskinesias 11

▪ LABORATORY TESTS
None available to diagnose Parkinson disease
▪ IMAGING
Neuroimaging may be useful for excluding other diagnoses

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▪ Improve motor and non-motor symptoms
▪ Maintain the best possible quality of life
▪ Preservation of the ability to perform activities of daily living and employment
▪ Improvement of mobility and minimization of adverse effects and treatment complications

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▪ Levodopa: precursor to dopamine (gets converted to dopamine in the brain by L-amino acid
decarboxylase since carbidopa dose not cross BBB)
▪ Carbidopa: peripherally acting L-amino acid decarboxylase inhibitor.
- Block peripheral conversion of L-dopa to dopamine, thus decrease side effect and
increase delivery to the brain.
▪ Most effective overall for motor symptoms ( bradykinesia and rigidity, but less on tremor)

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Dose: 25mg/100 mg initial. Titrate to 25/100mg TID, increase by half-tab q5-7 days
▪ 75 mg dose of (Carbidopa) required for maximal inhibition of L-AAD
▪ Best if taken on empty stomach. May need to decrease amount of protein as high amount
can decrease efficacy b/c of competition in the BBB
▪ Avoid use vitamin B6 supplementation unless medically necessary

Side effects:
▪ From peripheral metabolism of L-dopa: nausea, hypotension, tachycardia
▪ Confusion, delusion, delirium, nightmares, hallucinations (greater with SR formulation)
▪ Motor side effect: dyskinesias

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 Drug Interaction Mechanism
Anticholinergics ↓ Levodopa effect ↓ Gastric emptying,
thus ↑ degradation of
levodopa in gut, and ↓ amount
absorbed
Ferrous sulfate Levodopa oral Formation of
absorption by 50% chelation complex
Food ↓ Levodopa effect Large, neutral amino
acids compete with
levodopa for
intestinal absorption
Comments
Watch for ↓ levodopa effect when
anticholinergics cause ↓ GI motility. When
anticholinergic therapy is discontinued in
apatient on levodopa, watch for signs of
levodopa toxicity. Theoretic interaction
with
minor clinical significance
Avoid concomitant administration or
separate administration by at least 2 hours
Although levodopa is usually taken with
meals to slow absorption and ↓ central
emetic effect, high-protein diets should be
avoided
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 Drug Interaction Mechanism Comments

MAOI (e.g., Hypertensive crisis Peripheral dopamine Avoid combination use; monoamine oxidase
phenelzine, and norepinephrine type B (MAO-B) inhibitors such as
tranylcypromine) selegiline can be used, but the dose of
levodopa should be reduced after 2–3 days
of therapy; carbidopa might minimize
hypertensive reaction to levodopa in
patients receiving an MAOI.
Methyldopa ↑ or ↓ levodopa Acts as central and Observe for response; may need to switch
effect peripheral to another antihypertensive.
decarboxylase
inhibitor
Metoclopramide ↓ Levodopa effect Central dopamine Avoid combination use
blockade
Neuroleptics (e.g., ↓ Levodopa effect Central blockade of Avoid combination use; important
butyrophenones, dopamine interaction
phenothiazines) neurotransmission

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 Drug Interaction Mechanism Comments

Phenytoin ↓ Levodopa effect Mechanism Avoid combination use

unknown
Pyridoxine (vitamin ↓ Levodopa effect Peripheral Not observed when levodopa given with
B6) decarboxylation of carbidopa; avoid levodopa monotherapy
levodopa with vitamin B6 supplementation
Tricyclic ↓ Levodopa effect Levodopa Use with caution
antidepressants degradation in gut
because of delayed
emptying

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▪ Can be monotherapy in early disease; need l-dopa in mid to late disease
▪ Can add to l-dopa to reduce OFF time
▪ Advantages:
- Dopamine agonists have a longer half-life than levodopa formulations, reducing the
need for multiple daily dosing
▪ As a class, dopamine agonists provide adequate control of symptoms when given as
monotherapy in up to 80% of patients with early stage disease
▪ Frequent side effects! Nausea, sleep attacks, hypotension, compulsive behaviors, Leg
edema 
▪ More prone than l-dopa to causing hallucinations and confusion. Caution in older or
demented patients! 

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▪ Dopamine agonists should always be initiated at a low dosage and gradually titrated to the
maximal effective dose, as tolerated. This approach minimizes adverse effects that may
result in nonadherence or discontinuation of the drug

▪ The most common reasons for discontinuing these agents are mental disturbances (e.g.,
nightmares, confusion, hallucinations, insomnia) and orthostatic hypotension

▪ Sudden, excessive daytime somnolence, including while driving, has been reported with
dopamine agonists and has resulted in accidents.

▪ Labeling for these drugs includes a warning that patients should be alerted to the possibility
of falling asleep while engaged in daily activities.
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▪ Selegiline:
▪ The usual dosage is 10 mg/day administered as 5 mg in the morning and early afternoon.
▪ It is not given in the evening because excess stimulation from metabolites (l-methamphetamine and
lamphetamine) can cause insomnia and other psychiatric side effect
▪ Selegiline should be used with caution in patients with severe hepatic impairment or with creatinine
clearance less than 30 ml/minute

▪ Rasagiline:
▪ Second-generation, irreversible selective inhibitor of MAO-B
▪ More potent inhibitor of MAO-B than selegline
▪ Rasagiline lacks the amphetamine-like metabolites of selegiline
▪ Lacks The time-specific dosing constraints.
▪ Avoid with: tramadol, meperidine, TCAs, tyramine containing products
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▪ Safinamide
▪ Approved by the FDA in may 2017 as an adjunct to carbidopa/levodopa for patients experiencing
“off” episodes
▪ The side effect profile is similar to rasagiline
▪ Patients should additionally be monitored for visual changes as retinal detachment and loss of
photoreceptor cells were noted in animal studies
▪ Safinamide has a half–life of 20-26 hours, reaches steady state in 5-6 days, and can be taken without
regard to meals
▪ It requires hepatic dose adjustment but no renal dose adjustments

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▪ Mechanism of action:
Inhibits COMT (in periphery and GUT) and extend levodopa bioavailability delivery to the CNS

▪ Used mainly as Adjunct to Levodopa: reduce the development of levodopa induced motor
complications (wearing off)

▪ Side effects:
Orthostasis, diarrhea, hallucination, discolored urine (Brownish), hepatotoxicity (tolcapone only)

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▪ Effective against Tremor
▪ Little effect on bradykinesia
▪ ADR:
- Dry mouth
- Blurred vision
- Constipation
- Urinary retention

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FOR TREATING DYSKINESIAS (MOTOR COMPLICATIONS)

▪ Mechanism of Action:
- May augment DA release & delay uptake
- May act as dopamine agonist
- Anticholinergic effects
▪ Dose:
- 200-300 mg/d given BID or TID *Adjust for renal
▪ ADR:
- Periphral edema, sedation, vivid dreams, livido reticularis (reversible), hyponatremia
▪ Has little use on tremors and tolerance may develop
▪ Not drug of choice in elderly

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 ▪ 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
MONITORING
▪ Liver function monitoring required for patients
taking tolcapone
▪ Discontinue therapy if liver function tests above
upper limit of normal or if signs/symptoms suggest
hepatic injury

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 Monitoring of Potential Adverse Reactions to Drug Therapy for Parkinson 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; Reversible upon drug

ankle edema discontinuation

Benztropine Anticholinergic effects, Dry mouth, mental status, Reduce dosage; avoid in
Trihexyphenidyl confusion, drowsiness constipation, urinary elderly and in those with a
retention, vision history of constipation,
memory impairment, urinary
retention
Carbidopa/L-dopa Drowsiness Mental status Reduce dose
Dyskinesias Abnormal involuntary Reduce dose; add amantadine
Nausea movements Take with food
Nausea
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 Monitoring of Potential Adverse Reactions to Drug Therapy for Parkinson Disease
COMT Inhibitors

Generic Name Adverse Drug Reaction Monitoring Parameter Comments

Entacapone Augmentation of L-dopa side See carbidopa/L-dopa; also Reduce dose of L-dopa; antidiarrheal
effects; also diarrhea bowel movements agents

Tolcapone See entacapone; also liver See carbidopa/L-dopa; also See carbidopa/L-dopa; also at start of
toxicity ALT/AST 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.

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 Monitoring of Potential Adverse Reactions to Drug Therapy for Parkinson Disease
Dopamine Agonist
Generic Name Adverse Drug Reaction Monitoring Parameter Comments

Apomorphine Drowsiness Mental status Reduce dosage; adjust dReduce dose

Nausea Nausea Premedicate with trimethobenzamide
Orthostatic hypotension Blood pressure, dizziness upon Reduce dose
standing dose for renal impairment
Bromocriptine See pramipexole; also Mental status; also chest Reduce dose; chest radiograph at baseline
pulmonary fibrosis radiograph and once yearly
Pramipexole Confusion Mental status Reduce dose
Ropinirole Drowsiness Mental status Reduce dose
Edema Lower extremity swelling Reduce dose or discontinue medication
Hallucinations/delusions Behavior, mental status Reduce dose or discontinue medication
Impulsivity Behavior Discontinue medication
Nausea Nausea Titrate dose upward slowly; take with food
Orthostatic hypotension Blood pressure, dizziness upon Reduce dose
standing

Rotigotine See pramipexole; also skin ee pramipexole; also skin See pramipexole; rotate patch application
irritation at site of patch examination site
application 31
 Monitoring of Potential Adverse Reactions to Drug Therapy for Parkinson Disease
MAO-B Inhibitors
Generic Name Adverse Drug Reaction Monitoring Parameter Comments

Rasagiline Nausea Nausea Take with food

Selegiline Agitation/confusion Mental status Reduce dose

Insomnia Sleep Administer dose earlier in day
Hallucinations Behavior, mental status Reduce dose
Orthostatic hypotension Blood pressure, dizziness Reduce dose
upon standing

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 Which treatment to start?
▪ Monoamine oxidase-B (MAO-B) inhibitor (eg, rasagiline) as monotherapy typically first treatment

▪ Either rasagiline or dopamine agonist can be used first in physiologically young patients

▪ Levodopa is preferred initial therapy for older patients

▪ Consider adding catechol-O-methyltransferase (COMT) inhibitor to extend levodopa duration of

activity when motor fluctuations develop. Alternatively, consider adding MAO-B inhibitor or dopamine
agonist
▪ Amantadine may be added to manage levodopa-induced peak-dose dyskinesias

▪ Despite advances in pharmacologic treatment options for PD, no therapy has been proven to be
disease-modifying or neuroprotective

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Parkinson’s disease: summary of updated NICE guidance, BMJ 2017
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Parkinson’s disease: summary of updated NICE guidance, BMJ 2017
▪ Wearing-off effect
▪ Dyskinesias
▪ Dystonias
▪ Psychosis

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 ▪ End of dose deterioration
▪ Believed to be from decrease presynaptic storage
capacity for dopamine following long term therapy
WEARING-OFF
▪ Can be reduced by smaller doses more frequently
EFFECT
- Sinemet CR is useful
- Dopamine agonist, COMTi, or MAOi can be added

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 ▪ Abnormal involuntary movement involving the neck,
trunk and upper extremities
▪ Solutions:
• Reduce levodopa/carbidopa dose
DYSKINESIAS
• Use dopamine agonist as major agent
• Switch to CR formulation
• Amantadine

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 ▪ Sustained muscle contractions or abnormal postures
▪ Common in distal lower extremities
▪ Solution:
DYSTONIAS - Bedtime dosing
- Dopamine agonists
- Baclofen, clonazepam

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 ▪ Parkinson Disease associated Psychosis:
- Usually delirium (altered consciousness or awareness,
disorganized thinking, hallucinations, or atypical
behavior)
- Evaluate and treat other underling causes including
PSYCHOSIS infections
▪ Treatment:
✓ Pimavanserin:
- Atypical antipsychoyic approved for PD associated
psychosis)
- Dose: 34 mg OD (17 mg if taking 3A4 INHIBITOR)
- Avoid if CrCl < 30 ml/min

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▪ Physical therapy (regular exercise)

▪ Occupational therapy (orthoses, adaptive equipment, home and workplace modification)

▪ Speech training (if appropriate)

▪ Increased fluid and fiber intake to reduce constipation.

▪ Discontinue concomitant medications that may worsen motor symptoms, memory, falls, or behavioral
symptoms.
▪ Surgery (deep brain stimulation)

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2 MIN BREAK
&
MCQs

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1- A 68-year-old woman with PD has taken levodopa/carbidopa 100/25 mg four times daily for 2 weeks. Previously
she took levodopa/carbidopa 100/25 mg three times daily. She calls your clinic to ask about her symptoms, which
include nausea, light-headedness, and involuntary movements that she describes similarly to dyskinesias. Her PD
symptoms were fairly well controlled on her dose schedule of three times daily, but her physician increased the dose
to four times daily for additional benefit.
Which is the best recommendation to address this patient’s symptoms?

A. Continue levodopa/carbidopa; add rasagiline.

B. Decrease levodopa/carbidopa dose to 100/25 mg three times daily.
C. Continue levodopa/carbidopa; add ropinirole.
D. Change levodopa/carbidopa dose to 100/10 mg four times daily.

ANSWER: B
This patient’s symptoms are consistent
with excessive dopaminergic
treatment, particularly in the context
of dyskinesias
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2- A 63-year-old man received a diagnosis of early PD about 6 months ago but is otherwise healthy. He did not
receive treatment with any medications when his PD was first diagnosed; however, on his physician’s advice, 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; on most days he feels tired but cannot fall asleep. He notes that his wife has
a prescription for lorazepam 0.5 mg and that he has taken 1 tablet when he has had difficulty sleeping. He asks for a
prescription for lorazepam to help him sleep. Which is the best recommendation for this patient?

A. Continue selegiline; add lorazepam 0.5 mg at bedtime.

B. Continue selegiline; add diphenhydramine 50 mg at bedtime.
C. Continue selegiline, but change the twice-daily dose timing to morning and noon.
D. Continue selegiline; add levodopa/carbidopa.

ANSWER: C
Selegiline is metabolized to an
amphetamine metabolite, and
administering the second daily dose late in
the day can been associated with insomnia
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3- L.S. takes carbidopa/levodopa 25 mg/100 mg orally four times daily and trihexyphenidyl 2 mg orally three times
daily for Parkinson disease. L.S.’s wife reports that his movements are very slow and that he is having trouble
walking.
Given these symptoms, which change seems most reasonable?

A. Increase carbidopa/levodopa, discontinue trihexyphenidyl.

B. Continue carbidopa/levodopa, increase trihexyphenidyl.
C. Decrease carbidopa/levodopa, continue trihexyphenidyl.
D. Decrease carbidopa/levodopa, increase trihexyphenidyl. ANSWER: A

4- Six months later, L.S. returns to the clinic concerned that his carbidopa/levodopa dose is wearing off before
his next dose is due, because his tremor and slow movements are worse before the next dose of carbidopa/
levodopa. Which recommendation is best?

A. Increase the carbidopa/levodopa dose.

B. Decrease the carbidopa/levodopa dose. ANSWER: D
C. Increase the dosing interval. This problem can be resolved by giving doses more
often, administering the controlled-release
D. Decrease the dosing interval. formulation of carbidopa/levodopa, or adding a
catechol-O-methyl transferase inhibitor 45
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5- P.J. is a 57-year-old man with an 8-year history of Parkinson disease. His current drugs include carbidopa/
levodopa 50 mg/200 mg orally four times daily, entacapone 200 mg orally four times daily, and amantadine
100 mg three times daily. He presents to the clinic with a reddish blue discoloration on his lower arms and legs.
Which, if any, of his drugs most likely caused this condition?

A. Carbidopa/levodopa.
B. Entacapone.
C. Amantadine.
D. None; probably represents venous stasis.

ANSWER: C

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6- 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.

ANSWER: D
Decreasing carbidopa/levodopa
dose will improve the dyskinesia

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7- C.A. is a 70-year-old white man with tremors in his right hand that have progressively worsened for the past
6 months. He has difficulty walking. He also has backaches and no longer plays golf. In addition, he is losing
his sense of taste. His wife notes that he is moving more slowly and that his handwriting has deteriorated.
He is given a diagnosis of Parkinson disease.
Which is the best treatment for this man?

A. Trihexyphenidyl.
B. Entacapone.
C. Carbidopa/levodopa.
D. Ropinirole.

ANSWER: C
Carbidopa/levodopa is the preferred
initial treatment for Parkinson disease in
individuals older than 65.

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 . . .THE END. . .

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Ph.f.aljohani@gmail.com
@phalsydalani