1
Q
Parkinson’s Disease is _______, ___________, and ___________________
A
chronic, progressive, neurodegenerative
2
Q
Why is dopamine important in terms of movement? (3)
A
- Important for smooth, coordinated, controlled movements
- Death of dopaminergic neurons -> messages telling the body how and when to move are delivered slowly or incompletely
- Individual is unable to initiate and control movements in a normal way
3
Q
What is the pathophysiology of PD?
A
Progressive death of dopamine-producing neurons in the substantia nigra (part of the basal ganglia)
4
Q
What are the 2 components that make up the substantia nigra? What does each component produce?
A
- Pars compacta - dopamine producing
- Pars reticulata - GABA neurons
4
Q
What are 2 subtypes of PD?
A
- Tremor-predominant subtype
- Often younger PD patients
- Typically have a slower, more benign course of progression - Akinetic/rigid subtype
- Often have a more rapid rate of progression of motor symptoms
- Particularly in older patients – more likely to develop dementia
4
Q
What are 3 protective factors against PD?
A
- Cigarette smoking
- High coffee consumption
- Intensive exercise
4
Q
What are 3 risk factors for PD?
A
- Family history -> genetic component
- Pesticide exposure (rural, farmer, drink well water)
- Repeated head injuries
5
Q
For the hallmark movement symptoms of PD, remember TRAP. What is that?
A
Tremor
Rigidity
Akinesia/Bradykinesia
Postural instability
5
Q
What antinauseant/prokinetic agent can cause secondary Parkinsonism? What is a safer alternative?
A
- Metoclopramide
Safer alternative = domperidone
5
Q
The key motor features of PD can be remembered as the 3S’s. What are they?
A
Slow
Stiff
Shaky
5
Q
What are 3 typical APs that can cause secondary Parkinsonism?
A
- Chlorpromazine
- Haloperidol
- Prochlorperazine
5
Q
What is the Movement Disorder Society Clinical Diagnostic Criteria for PD?
(What must be present? Need at least 1 of what? What are the supportive criteria?)
A
- Must be present - bradykinesia
- At least 1 of - rest tremor or rigidity
- Supportive criteria:
- Clear response to dopaminergic treatment
- Levodopa-induced dyskinesias
- Olfactory loss
5
Q
What are the non-motor symptoms of PD that often precede motor symptoms? (5)
A
Hyposmia – loss of sense of smell
Constipation
Depression
Fatigue
REM Sleep Behaviour Disorder
6
Q
What are some of the later non-motor PD symptoms? (5)
A
- Psychiatric disturbances – delusions and hallucinations
- Sialorrhea (drooling)
- Sexual dysfunction
- Autonomic dysfunction
- Orthostatic hypotension
- Urinary and fecal incontinence - Cognitive impairment and dementia
6
Q
What are 3 alternative atypical APs that are less likely to cause secondary Parkinsonism?
A
- Quetiapine
- Clozapine
- Pimavanserin
6
Q
Which PD med is the effective cornerstone of therapy?
A
Levodopa
6
Q
What does PD pharmacotherapy primarily focus on?
A
Increasing dopamine levels (directly or indirectly)
6
Q
What are some medications classes that cause secondary Parkinsonism? (4)
A
- Typical APs
- Atypical APs
- Antinauseants/prokinetics
- Miscellaneous
- Lithium
- DVP
6
Q
What are the 6 pharmacological classes of medications for PD management?
A
- Levodopa
- Dopamine Agonists
- MAO-B Inhibitors (MAOIs)
- Amantadine
- COMT Inhibitors
- Anticholinergics
6
Q
What are 4 atypical APs that can cause secondary Parkinsonism?
A
- Risperidone
- Olanzapine
- Aripiprazole
- Ziprasidone
6
Q
True or False? PD treatment modifies disease progression
A
False - no PD treatment modifies disease progression - symptomatic treatment only
6
Q
What are the non-pharm treatment options for PD? (6)
A
- Physical Therapy: Help maintain motor function
- Occupational Therapy: Adaptive equipment, home safety
- Speech Therapy:
- Assist with soft speech
- Assess swallowing safety - Hearing, vision, and dental care
- Psychological Support
- Surgery
6
Q
Initially, levodopa treatment is universally effective for: (2 - symtpoms)
A
- Bradykinesia
- Usually start seeing response within days - Rigidity
- Maximal improvement in ~2 weeks
6
Q
What are the goals of therapy for PD? (4)
A
- Reduce signs and symptoms of PD (both motor and non-motor)
- Minimize complications of drug therapy
- Maintain independence
- Improve/maintain quality of life
6
What are the non-motor symptoms of PD that are seen early in the disease course? (4)
“Flat affect”
Micrographia
Hypophonia – soft speech
Dry eyes
6
Why is levodopa given in combination with a peripheral decarboxylase inhibitor? (2)
1. Prevents conversion of levodopa to dopamine outside of the brain
- Enhances efficacy
- Reduces adverse effects
2. Both carbidopa and benserazide cannot cross BBB
- Levodopa → crosses BBB → converted to dopamine via decarboxylase
6
Levodopa is always used in combination with?
A peripheral decarboxylase inhibitor (carbidopa or benserazide)
6
The most common adverse reactions of Vyalev SQ infusion are? (3)
1. Injection-site reactions
2. Dyskinesias
3. Psychosis
6
What 3 things decrease bioavailability of levodopa?
1. Protein
2. Iron
3. Antacids
6
After ~5 years of treatment, complications of levodopa therapy develop. What are they? (4)
1. Wearing off - meds not lasting as long as they used to
2. On-off phenomena
3. Freezing - inability to move
4. Dyskinesias - abnormal, uncontrollable, involuntary movements
7
Levodopa has variable effect on which PD symptom?
Tremor
7
What is on-off phenomena?
Fine one minute, drug effect has totally worn off the next
7
Which symptoms of PD is levodopa less likely to help with? (2)
1. Poor balance
2. Non-motor symptoms
7
What are the adverse effects of levodopa? (5)
1. Nausea, stomach upset
2. Dizziness
3. Fatigue
4. Vivid dreams
5. Confusion/hallucinations --> usually not until later stages
7
How is duodopa gel infusion administered?
Via enteral PEG-J tube
- Connected to a pump, which delivers low and constant doses of Duodopa
7
What are the 3 non-ergot derivative dopamine agonist drugs? (3)
1. Pramipexole (Mirapex)
2. Ropinirole (Requip)
3. Rotigotine (Neupro) - transdermal patch
7
New formulations of levodopa have been developed to address some of the limitations with oral administration. What are they?
1. Duodopa - levo/carbidopa intestinal gel
2. Vyalev - foslevodopa/foscarbidopa SQ infusion
3. Levodopa inhaled capsules (not in Canada, don't worry about this one)
7
What is the MOA of dopamine agonists?
Mimic the effect of dopamine by stimulating post-synaptic dopamine receptors
7
How is Vyalev SQ infusion administered?
Administered via continuous subcutaneous infusion
- Connected to a pump, which delivers low and constant doses of Vyalev
- Does NOT require surgery to initiate (i.e. insertion of PEJ tube)
7
What is the benefit of Duodopa gel infusion?
Reduces off-time by ~2 hours/day without increasing dyskinesias
7
What are the 2 subclasses of dopamine agonists?
1. Ergot derivatives
2. Non-ergot derivatives
7
When are dopamine agonists typically used for PD? (1)
Why is it done that way? (4)
1. May be used as initial therapy in young PD patients (< 60y)
- “Save” levodopa for later
- Less effective for motor symptoms than levodopa
- More side effects
- Less risk of motor complications seen with levodopa (on-off, freezing, dyskinesias)
7
What are the adverse effects of dopamine agonist drugs? (7)
1. Nausea and GI upset
2. Orthostatic hypotension
3. Hallucinations
4. Confusion
5. Drowsiness, sudden sleep attacks
6. Leg swelling
7. Impulse control disorders (ICDs) – up to 15% of patients!
7
What are the 2 ergot derivative dopamine agonist drugs? What is there to note with this class?
1. Bromocriptine
2. Cabergoline
- Basically never used due to pulmonary and cardiac valve toxicities
7
Dopamine agonists are not preferred agents for _____ ______ due to poor tolerability
older adults
- may be used for add-on therapy once motor complications develop if refractory/intolerant to other options
7
Dopamine agonists may also be used for ________ ___ syndrome
restless leg
7
True or False? Dopamine agonists can be abruptly stopped
False - need to be tapered off SLOWLY if discontinuing - risk of neuroleptic malignant syndrome
7
Aside from the ergots, there is another dopamine agonist medication. What is it called?
Apomorphine
7
What impulse control disorders (ICDs) might we see in patients taking dopamine agonists? (4)
1. Hypersexual behavior
2. Pathological gambling
- Important to educate families on this
3. Compulsive shopping
4. Dopamine dysregulation syndrome
7
What is the MOA of MAO-B inhibitors?
Increase dopamine by preventing the breakdown of it via MAO-B
7
When is apomorphine used?
A very potent dopamine agonist used for rescue therapy (freezing)
7
What are the two forms of apomorphine?
Injectable (Movapo) and sublingual (Kynmobi)
7
What does the enzyme MAO-B do?
Breaks down dopamine and other amines preferentially
7
Talk about Movapo (injectable apomorphine)
- How injected (2)?
- ADEs?
1. Administered via SC injection in advanced Parkinson’s
2. May not be possible to administer without the help of others
3. High incidence of nausea and vomiting – concurrent antiemetic recommended
7
What are the 2 selective MAO-B inhibitors?
1. Rasagiline
2. Selegiline
8
What are 2 non-selective MAO inhibitors?
1. Phenylzine
2. Tranylcypramine
9
MAO-B inhibitors lose selectivity at _-_x the recommended therapeutic dose
2-5
9
What difference do non-selective and selective MAO-B inhibitors have in terms of diet?
Non-selective MAO-B inhibitors require STRICT dietary tyramine restriction because irreversible, non-selective inhibition of MAO means the body is unable to break down dietary tyramine -> hypertensive crisis, cardiac arrhythmias
9
When might MAO-B inhibitors be used in PD? (3)
1. Can be used for PD monotherapy for mild symptoms
2. Less effective than levodopa
- Fewer adverse effects and less frequent dosing
3. May be used later in the disease course to manage motor complications with levodopa therapy (rasagiline)
- Wearing off, freezing
9
Name the COMT inhibitor drug
Entacapone (Comtan)
9
MAO-B inhibitors and serotonin syndrome. How do we feel about this interaction?
1. Combination of MAO-B inhibitor and serotonergic medications (SSRIs, SNRIs) unlikely to cause serotonin syndrome at recommended doses
- May still warrant a conversation with patient and prescriber
2. Lowest effective dose should be used
9
What medication should be avoided in patients taking MAO-B inhibitors?
Dextromethorphan
10
How MUST entacapone be taken?
MUST be given with levodopa (has no effect on its own)
10
Although generally well tolerated, what are some potential ADEs of MAO-B inhibitors? (3)
1. Nausea
2. Headaches
3. Insomnia
10
When starting entacapone, how does levodopa dosing need to be adjusted accordingly?
Decrease levodopa dosing by ~30% when starting entacapone to minimize dyskinesias
10
What are the ADEs of amantadine? (4)
1. Nausea
2. Confusion
3. Hallucinations
4. Peripheral edema
10
Name 3 anticholinergic agents that can be used in PD treatment
1. Benztropine
2. Trihexyphenidyl
3. Procyclidine
10
What is the MOA of COMT inhibitors?
By inhibiting the enzyme COMT, they prevent peripheral degradation of levodopa, allowing higher concs. to cross the BBB
10
What formal antiviral drug is now used in PD treatment?
Amantadine
10
What is the surgical treatment of PD?
Deep Brain Stimulation
- Electrodes are placed in movement centres in brain – function almost like “electronic levodopa” 24/7
- For advanced PD in patients with extreme motor fluctuations or dyskinesias
10
What are the ADEs of COMT inhibitors? (3)
1. Nausea
2. Diarrhea
3. **May turn urine and sweat an orangey-brown color**
11
What is the ADE of anticholinergics?
It being anticholinergic lol
11
What role does amantadine have in PD treatment?
Role in PD treatment generally limited to treating bothersome dyskinesias later in the disease course
11
What is the MOA of anticholinergics (in PD specifically I guess) (2)
- ↓ the amount of acetylcholine in the brain, which restores the dopamine/acetylcholine balance in the striatum
- Effective mainly for tremor - not effective for other motor symptoms
11
True or False? Non-motor symptoms of PD aren't substantial enough to worry about treating
False - often under-treated and they can have a substantial impact on QoL
11
Levovdopa is starting to fail and we decide to add another agent. What would we add for bothersome dyskinesias?
What would we add for levodopa wearing off?
1. For bothersome dyskinesias: Amantadine (may also need to consider decreasing/stopping concurrent dopamine agonist or MAO-B inhibitor)
2. For wearing off:
- COMT inhibitor (↓levocarb dose when adding), MAO-B inhibitor -> both ↓ off-time ~1-1.5 h/d
- Dopamine agonist – ↓ off-time by ~2h per day
11
Levodopa is starting to fail. What are some things we can do? (5)
1. Take on an empty stomach as much as possible
2. Increase dosing frequency for wearing-off
3. Smaller, more frequent doses for dyskinesias
4. Add a dose of levocarb CR @ HS
5. Add another agent
11
Which antidepressants are safe and effective in depression treatment in PD pts? (4)
1. Citalopram
2. Sertraline
3. Venlafaxine
4. Duloxetine
11
How do we manage constipation in PD? (4)
1. Usual recommendations for constipation apply – increase fiber, fluids, exercise
2. Avoid constipating medications/OTC products
3. Domperidone can be considered to ↑ GI motility
4. Polyethylene glycol considered first-line agent for preventing and managing constipation
- If insufficient, may require ongoing stimulant laxative use to keep on top of PD-constipation
-- Titrate to effect
12
Generally, depression in PD can be managed similarly to depression in pts without PD. What is NOT a drug of choice?
Bupropion not drug of choice due to additive dopaminergic effect -> may ↑ restlessness, insomnia, and dyskinesias
13
It is important to frequently re-evaluate the necessity of antidepressant use in patients with PD and deprescribe if possible. Why? (2)
1. ↑ fall risk
2. Contribute to orthostatic hypotension
14
What is the treatment of orthostatic hypotension in PD pts? (7)
1. Ensure adequate hydration
2. Avoid eating large meals -> eat smaller meals more frequently
3. ↑ Salt intake
4. Stand slowly
5. Taper/stop antihypertensives
6. Re-evaluate other medications that can contribute
- Antidepressants, antipsychotics
7. Wear compression stockings
15
Non-pharmacological management of urinary incontinence is preferred. What are some options? (5)
1. Regular toileting
2. ↓ Caffeine intake
3. ↓ Fluid intake in the evening to ↓ nocturia
4. Assistive devices to ease access
- Bedside commode or urinal
5. If refractory -> consider pharmacotherapy
15
How might erectile dysfunction in PD be treated? (2)
1. Phosphodiesterase-5 inhibitors used first-line
- Sildenafil, tadalafil, vardenafil
2. Apomorphine injections may be helpful
15
Which of the following is TRUE regarding the pharmacological treatment of Parkinson's disease?
A. MAO-B inhibitors can be used as initial drug therapy for PD
B. Dopamine agonists can be used as a "therapeutic trial": If the pt's motor symptoms respond to therapy, the diagnosis of PD is likely
C. COMT inhibitors can be administered prn for freezing or "off" episodes
D. Levodopa is most helpful for the tremor associated with PD
E. None of the above
A.
15
Which of the following is TRUE of Parkinson's disease?
A. it results from the progressive loss of dopamine-producing neurons in the frontal lobe of the brain
B. Postural instability is typically seen later on in the disease progression
C. Dopaminergic medications are important to help slow the progression of the disease
D. Increased arm swing and step length are commonly seen when walking
E. None of the above
B.
16
How can we help manage drooling in PD? (4)
1. Chewing gum or sucking on soft candy can help trigger swallowing reflex
2. Ipratropium spray to mouth
3. Atropine eye drops can also be administered sublingually to dry up extra secretions
- Atropine 1% gtts
- 1 drop SL Q2h prn
4. If refractory or side effects with atropine – Botox may be considered
16
What may worsen REM sleep behaviour disorder?
HS dosing of antidepressants - avoid
16
What is REM Sleep Behaviour Disorder? (3)
1. Loss of normal muscle atony during REM sleep
2. Individuals act out dreams – can get violent and result in injuries
3. Often predates diagnosis of PD
16
Insomnia is common in PD. How do we treat/manage? (4)
1. Usual sleep hygiene measures
2. Ensure adequate control of PD motor symptoms at night (freezing, etc.)
3. Melatonin has some evidence of benefit
4. Low-dose doxepin or trazodone may be tried if refractory
- Trazodone may worsen orthostatic hypotension (dose-dependent)
16
If treatment of REM sleep behaviour is necessary, what can we try? (2)
1. Melatonin 3-12 mg at bedtime may be tried; less evidence of efficacy but few adverse effects
2. Clonazepam 0.125 -0.5 mg hs
17
How can we help manage restless legs syndrome in PD? (3)
1. Screen for iron deficiency
2. Optimize dopaminergic therapy – consider hs dopamine agonist
3. Second-line therapies include gabapentin or pregabalin
18
What is the treatment for excessive daytime somnolence in PD?
Modafinil
- Stimulant indicated for narcolepsy
19
How might hallucinations be treated in PD pts? (6)
1. Slowly discontinue medications that may be contributing
- Anticholinergics, amantadine, dopamine agonists, sedative/hypnotics
2. Avoid typical antipsychotics, olanzapine, risperidone, aripiprazole
3. Clozapine has demonstrated efficacy but not often used due to risk for agranulocytosis
4. Quetiapine – less consistent efficacy, but has not been shown to worsen PD symptoms
5. *Pimavanserin – FDA-approved for PD psychosis
- NOT available in Canada yet ?special access
6. Cholinesterase inhibitors may improve psychosis in patients with PD dementia
- May worsen movement symptoms
20
True or False? All hallucinations require treatment
False - apparently not - as long as insight is preserved, they are relatively infrequent and not bothersome, then pharmacotherapy is not required
