12 - Parkinson's Flashcards
Second most common neurodegenerative disorder (after ______ disease)
Alzheimer’s
Prevalance of PD increases with ___ and higher among ____
age, males
True ethology of PD unknown but what are some factors?
Age
Genetics
Environment
Gender (males > females)
Briefly describe what’s going on/what causes parkinson’s disease
Overall, they have less dopamine present
What are the 4 cardinal motor features of PD?
1) Bradykinesia
2) Tremor at rest
3) Rigidity
4) Postural instability (instability of balance)
*PD is a slow, progressive, degenerative CNS disorder
Describe the diagnosis of PD
Bradykinesia PLUS either tremor at rest or rigidity
*postural instability of balance comes later
Describe the tremor at rest
- 70% of patients
- rhythmic, asymmetric -hands (pill rolling), feet, lip, jaw (not usually head or neck)
- may disappear with voluntary movement and sleep
- occurs in a body part that is relaxed and completely supported against gravity (ex. resting on a table or arm of chair)
- suppressed with voluntary movement
How do we induce resting tremor ?
ask patient to count down from 10 out loud (the tremor worsens with mental stress)
Describe the rigidity
- 90% of patients
- Lead pipe, cogwheel (‘catches’)
- neck, trunk, limbs
- resistance to passive movement of the limbs/joints
Describe bradykinesia
- 70% of patients
- slowness of all movements including walking
- difficulty initiating movement
*weakness, tremor, rigidity may contribute to but do not fully explain bradykinesia
Describe postural instability of balance
- often later presentation
- shuffling gait (becomes difficult to pick up feet)
- narrow base, festination
- freezing and falls
Is there muscle weakness in PD?
No; differentiates b/w motor cortex disorders
What are some other clinical features of PD?
- depression
- dementia
- sleep disturbances
- difficulty smelling
- micrographia
- dysphonia
- dysphagia
- hypomimia (lack of expression)
Describe the 4 dopaminergic pathways in the brain
1) Mesolimbic
- High DA = positive symptoms of schizophrenia
2) Mesocortical
- Low DA = negative symptoms of schizophrenia
3) Tuberinfudibular
- Low DA = hyperprolactinemia
4) Substantia nigra
- Extrapyramidal system (EPS)
- Low DA = Parkinson’s
- High DA = Dyskinesia
Describe how the substantial nivea is affected in parkinsons
- Substantia nigra (SN) is normally black
- SN controls movements and connects to the motor cortex
- In parkinson’s, the SN cells (black cells) start to die off
The _____ of neurotransmitters (ACh and DA) is what allows us to have smooth movements.
balance
______ = “no go” or inhibitory neurotransmitter
acetylcholine
______ = “go” or excitatory neurotransmitter
dopamine
How are ACh and DA affected in Parkinsonism?
When dopamine is blocked:
ACh > DA
Thus, movement becomes jerky and stiff because there is a relative excess of “no go” neurotransmitter
What drugs block all 4 dopaminergic pathways in the brain?
Typical antipsychotics block all 4 pathways
What drugs block dopamine in the mesolithic pathway (less frequent EPS) ?
Atypical antipsychotics
____ agents also affect dopaminergic pathways
GI agents (prochlorperazine, promethazine, metoclopramide)
What is EPS (extrapyramidal symptoms) ?
abnormal body movements due to a blockade of dopamine in the brain
What are the 4 main types of EPS (extrapyramidal symptoms) ?
- Dystonia
- Akathisia
- Pseudo-parkinsonism
- Tardive dyskinesia
EPS (extrapyramidal symptoms):
Describe Dystonia
- Sustained contraction
- Acute onset = hours to days
- Tardive onset = months to years
EPS (extrapyramidal symptoms):
Describe Akathisia
- Restlessness
- Acute onset = hours to days
- Tardive onset = months to years
EPS (extrapyramidal symptoms):
Describe Pseudo-parkinsonism
- Bradykinesia
- Cogwheel-like tone/rigidity
- Tremor
- Onset < 30 days
EPS (extrapyramidal symptoms):
Describe Tardive Dyskinesia
- Irregular/twisting movement
- Ex. cheek puffing, facial grimacing, lip smacking
- Onset: months to years (often irreversible)
______ is the worst for causing tar dive dyskinesia
haloperidol
What drugs can induce parkinson-like motor symptoms?
- Antipsychotics (FGA > SGA)
- Antiemetics (metoclopramide, prochlorperazine)
- Older antihypertensives such as methyldopa
- SSRI (serotonin may inhibit dopamine activity)
- Valproic acid (GABA - bradykinesia, tremors)
What drugs can cause a resting tremor?
- Lithium, VPA, SSRIs, TCAs
- Amiodarone
- Amphotericin B, co-trimoxazole
- Cocaine, EtOH, MDMA
What are some risk factors for drug-induced parkinsonism ?
- older age
- female
- high doses of offending drug
- history of movement disorder
Drug-induced parkinsonism:
______ presentation
symmetric
Drug-induced parkinsonism:
Onset ______ ______ of starting drug
within weeks
Drug-induced parkinsonism:
May take ___ months for symptoms to resolve after discontinuation
2-6
Describe Drug-Induced NMS (neuroleptic malignant syndrome)
- Life-threatening
- Thought to be a result of a sudden decrease in dopaminergic transmission
- Initiation or dose increase of antipsychotics (aka neuroleptics) = dopamine blocker»_space;> decrease in DA transmission = NMS
- Or sudden withdrawal or significant dose decrease of dopamine enhancers has resulted in NMS
What are the symptoms of Drug-Induced NMS (neuroleptic malignant syndrome)
- FARM: Fever, Autonomic instability (unstable HR, BP, sweating, drooling) , Rigidity, Mental status changes
- Delirium, severe immobility, mutism, tremor
- Leukocytosis, rhabdomyolysis, high SCr
When do symptoms of parkinson’s appear?
When 60-80% of neurons (in substantia nigra) have been lost
In Substantia nigra:
_____ dopamine = parkinson’s
low
In Substantia nigra:
_____ dopamine = dyskinesia
high
In parkinson’s, we want to ______ dopamine
increase
There are two ways (MOA) to treat parkinson’s
What are they?
1) Enhance/increase dopamine
- Dopamine precursor = L-dopa converts to dopamine
- Dopamine agonist = activate dopamine receptors
- NMDA receptor antagonist = increases dopamine release
- COMT or MAO-B inhibitor = decrease dopamine metabolism
2) Block acetylcholine
- Anticholinergics: Block ACh (“no go” neurotransmitter) in the striatum
What are goals of therapy?
To improve motor and non-motor symptoms to maintain the best possible quality of life:
1) Preserve the ability to perform activities of daily living
2) Minimize adverse effects and treatment complications
3) Improve non-motor features such as cognitive impairment, depression, fatigue, sleep disorders
Early mild symptoms causing no disability (clumsiness of hands, fatigue, sensory discomfort):
Do these symptoms warrant therapy ?
Nope
When is therapy warranted?
When disability interferes with patient’s social, emotional or work life, therapy is warranted
How long is therapy?
Usually lifelong
What is the general aim of the pharmacotherapy ?
General aim is to increase dopamine or the relative impact of dopamine present
Describe the 6 areas of pharmacotherapy
1) Anticholinergic (block acetylcholine, relative increase in DA)
2) Amantadine (NMDA Antagonist, increases DA release)
3) MAO-B inhibitor (reduce DA breakdown)
4) COMT inhibitor (reduce levodopa breakdown)
5) Dopamine Agonist (directly stimulates DA receptors)
6) Levodopa (converted to DA by dopa decarboxylase)
____ is a precursor to dopamine
Levodopa
Why can’t dopamine be given directly?
Because it can’t cross the BBB (and that’s where it needs to be)
*Levodopa can cross the BBB and then be converted into dopamine in the BBB
Levodopa is always given with _______
A COMT or DDCI
COMT: Entacapone, tolcapone
DDCI: Carbidopa, benserazide
Give examples of anticholinergics
- Trihexyphenidyl
- Benztropine
How to anticholinergics work?
Block acetylcholine in the striatum (in the CNS); increases relative effect of DA present
Describe the role of anticholinergics
Alone or Combination:
- Recommend in patients with bothersome tremor < 60 yo
- Modest antiparkinson effect - not as effective for more disabling features of PD
- Side effects limit use (younger may tolerate)
What are some anticholinergic side effects?
urinary retention, dry eyes, dry skin, constipation, blurred vision, confusion, constipation, dry mouth, cognitive impairment, sedation, headache, increased HR, overheating
_____ patients may tolerate anticholinergics better
Younger (< 60 years)
Do we need to taper anticholinergics (Trihexyphenidyl and Benztropine) ?
Need to taper over 1 week when stopping to prevent Parkinson’s exacerbation (even if no perceived benefit was realized).
What is the mechanism of Amantadine ?
-Inhibits NMDA receptors and increases dopamine release from presynaptic terminals
What is the role of Amantadine ?
- Modest antiparkinson effect
- Used early to help with tremor
- Used later to reduce L-dopa dyskinesia
- Better tolerated in young patients
Side effects of Amantadine ?
- CNS (confusion, insomnia, nervousness, hallucinations, dizziness, esp. elderly)
- Anticholinergic (dry mouth)
- GI upset
- Hypotension
- Abrupt withdrawal -> worsen PD/cause NMS
- Tachyphylaxis
- Livedo reticularis
When should you take Amantadine ?
Take at AM/lunch to decrease insomnia
What is Livedo reticularis ?
- Cosmetic, not life threatening
- Not dose-dependent
- Reversible diffuse purplish-red mottling of the skin
- Affects the upper or lower extremities +/- lower extremity edema
What do COMT’s do ?
Prevent levodopa breakdown in periphery
Ex. Entacapone, tolcapone
What do DDCI’s do ?
Prevents breakdown of dopamine
Ex. Carbidopa
What do MAO-B inhibitors do?
Prevents dopamine breakdown
What is the actual MOA of MAO-B inhibitors ?
Selective and irreversible MAO-B inhibitors in the brain.
Interferes with dopamine breakdown (in the CNS).
Describe the role of MOA-B inhibitors ?
- Mild to moderate symptomatic benefit
- Early parkinson’s disease monotherapy
- Add-on to Levodopa (1 hour extended “on time”)
- Neuroprotective ?
What are examples of MAO-B inhibitors ?
- Selegiline
- Rasagiline
MAO-B inhibitors:
When should you take Selegiline?
am/lunch to decrease insomnia
MAO-B inhibitors:
Is tyramine intake a concern with Selegiline?
Should not be a concern at typical doses
MAO-B inhibitors:
What should you avoid when taking Rasagiline?
High fat meals decrease levels
MAO-B inhibitors:
Is tyramine intake a concern with Rasagiline?
Theoretical tyramine hypertensive crisis (but no diet restrictions)
MAO-B inhibitors:
SE of Selegiline ?
insomnia, jitteriness, hallucinations, confusion, orthostatic hypotension, increased peak effects of L-dopa
MAO-B inhibitors:
What is Selegiline metabolized to?
L-methamphetamine and L-amphetamine
MAO-B inhibitors:
SE of Rasagiline ?
Minimal GI (ex. nausea - take with food), neuropsychiatric
MAO-B inhibitors:
What do they interact with?
Drug interaction with serotonergic agents (ex. meperidine contraindicated, some antidepressants used with caution)
Describe COMT inhibitors
Ex. entacapone, tolcapone
- Reversible peripheral COMT inhibitor
- Reduces GI metabolism of levodopa (prolongs half life and increases bioavailability)
- Mild improvement in ADL and QOL scores in stable levodopa responders
- *Typically used later as an add-on
COMT inhibitors have no effect without ______.
Levodopa
-May provide up to 1-2 hour of extended “on” time for patients with “wearing off” for levodopa
COMT Inhibitors:
Common side effects
- N/V, ab pain
- Brown orange urine/sweat discolouration (may stain clothes)
- Increased sweating (initially)
- Dopamine SE of L-dopa enhanced
COMT Inhibitors:
Serious side effects
- Delayed onset diarrhea (weeks-months later)
- Dyskinesia, NMS
- Hypotension
- Hallucinations
Dopamine agonist:
MOA
Directly stimulates dopamine receptors (i.e. mimics real dopamine)
Dopamine agonist:
Describe the two types
Ergot-derived agonist:
-Bromocriptine
Non-ergot agonist:
- Pramipexole
- Ropinirole
- Rotigotine
Dopamine agonist:
Why is an ergot-derived agonist (ex. Bromocriptine) not 1st line?
cardiac valve disease
Dopamine agonist:
What is the role of a non-ergot agonist ?
- Alone in mild PD
- Adjunct to levodopa in patients with motor fluctuations
What is more potent:
Dopamine agonist or Levodopa
Levodopa
Compare dopamine agonists to Levodopa
Dopamine agonists:
- Less potent than levodopa
- Less motor complications but more side effects (ex. CNS, edema) than levodopa
When would dopamine agonists be preferred over levodopa ?
in younger patients to delay levodopa dyskinesias
Dopamine agonists may reduce the frequency of ___ periods and may allow levodopa dose reductions
“off”
Dopamine agonists must be ______ slowly and up to therapeutic dose. (Otherwise - SE without much clinical benefit)
titrated
Examples of dopamine agonists
- Pramipexole
- Ropinirole
- Ritigotine ?
Describe Ritigotine
- Patch (good for people with difficulty swallowing or compliance issues)
- *Not covered
What are common side effects of dopamine agonists ?
nausea, cognitive impairment, hallucination, light-headed, lower extremity edema, postural hypotension, sedation, vivid dreaming
What are serious side effects of dopamine agonists ?
impulsivity (pathologic gambling, hyper sexuality, shopping), psychosis, sleep attacks
Ergot derivatives: erythromelalgia/cardiac valve fibrosis
Dopamine agonists can increase the frequency and severity of ??
levodopa-induced dyskinesias
Dopamine agonist:
What can abrupt withdrawl/significant dose reduction do?
risk of NMS and not resolved with other PD drugs (need to resume DA)
What is the most effective therapy for PD ?
Levodopa
Why is Levodopa the most effective therapy for PD ?
- Virtually all patients respond
- Improves disability, prolongs capacity to maintain employment and ADL
- Reduced mortality rate
Levodopa:
Superior motor benefit but also associated with _____
dyskinesias
If someone has early PD, should we automatically start with Levodopa ?
No way, consider amantadine or dopamine agonist first to “preserve” levodopa usefulness
When is Levodopa very valuable?
In elderly patients
DDCI
dopamine decarboxylase inhibitors (ex. carbidopa or benserazide)
Levodopa is combined with ______
DDCI’s
What do DDCI’s do ?
- Allows increased L-dopa to cross BBB
- Prevents conversion to dopamine in periphery
- Minimize acute peripheral side effects (nausea, decreased BP)
What does dopamine cause in the periphery and in the CNS?
Periphery: GI side effects (n/v) and can decrease BP
CNS: Movement (side effects can be h/a, vivid dreams, insomnia)
What dose of carbidopa is required for it to sufficiently inhibit peripheral decarboxylase?
75mg/day
Is it better to take LevoCarb with or without food ?
- Better absorption if taken before meals
- But if significant nausea occurs, you can take with meals
What types of food decrease Levocarb absorption?
protein rich foods
Why should Levocarb CR (controlled release) not be used as initial therapy?
- Less well absorbed
- Less noticeable response since reaches CNS more slowly
*Makes evaluating and monitoring initial disease response more difficult
What is Levocarb CR ineffective for?
Generally ineffective for “wearing off” effect in most:
- Middle of night/very early AM symptoms
- Likely adds about 90 mins to the duration of effect
How do we switch from Levocarb regular release to Levocarb controlled release?
- Only 70% bioavailable
- Increase Levodopa dose by 20-30% when switching to CR for equivalent dose
Regular release Levodopa = 400 mg/day
CR release Levodopa = 480-520 mg/day
**Delayed onset may require supplemental regular release for optimal control in the mornings
Compare peak times for regular release vs. controlled release Levocarb
Regular = 0.5 hr CR = 2 hr
Describe Duodopa Gel
- Levodopa/Carbidopa in a 100 mL cassette
- Intraduodenal infusion
When is Duodopa Gel indicated ?
- Severe, debilitating motor fluctuations and hyperdyskinesia
- Despite optimized treatment with available meds
- Long-term use of PEG-J tube
*Indicated and supervised only by neurologists/specialized providers in the management of Parkinson’s disease
$5000/month
List the 2 most common side effects of Levodopa and how they can be managed
Nausea:
- ensure 75-200mg carbidopa is being used
- take with food
- consider domperidone 5-10 mg PO TID before/with L-dopa/meals (max 30 mg/day -> arrhythmia)
Hypotension:
- may need to lower dose of anti-HTN’s
- ensure adequate water/salt intake
- consider midodrine 7.5-15mg/day, domperidone, fludrocortisone
List other SE of Levodopa
Other: hallucination, nightmares increased libido, motor fluctuations
When does “wearing off”/”on-off” occur after starting Levodopa?
5-6 months (often 1-5 years) after starting levodopa
Why does “wearing off”/”on-off” occur?
- Progressive loss of neuronal dopamine storage and short levodopa t1/2
- Waning effect of levodopa within 4 hours of last dose
How can we manage “wearing off”/”on-off” of Levodopa ?
- Smaller and more frequent levodopa dosing (take next dose 30-60 minutes earlier)
- Consider adding a dopamine agonist
- Consider adding a COMT inhibitor (Entacapone)
- Consider adding a MAO-B inhibitor (Rasagiline)
- Switch to CR Levodopa ?
- Reduce protein in diet
What are we watching for with Levodopa ?
watch for dyskinesia
Describe what “delayed-on” and “no-on” is and what it can be due to.
- A delayed or absent onset of drug effect, respectively
- Delayed gastric emptying or decreased absorption in the duodenum
How can we manage “delayed-on” and “no-on” response if it is due to delayed gastric emptying?
Management of delayed gastric emptying:
-Chew/crush tablet and drink a full glass of water
What can you give for a non-responsive/emergency of “delayed-on” and “no-on” ?
subcutaneous apomorphine
*recommended to take with domperidone (due to increased n/v)
What is “freezing” ?
Sudden or episodic inhibition of lower-leg motor function:
- Feet suddenly feel stuck to the floor
- Anxiety/perceived obstacles encountered
- Fall risk
Management of “freezing” ?
- physical therapy, assistance walking devices, sensory cues
* changes to antiparkinson drug regimen may not be helpful
What causes the peak-dose “on” dyskinesias? Describe them.
-Too much dopamine
- Involuntary repetitive, rapid/jerky movements
- Usually neck, truck and lower/upper extremities
How do we manage peak-dose “on” dyskinesias?
- Add amantadine (antidyskinesia effect)
- Decrease levodopa and add dopamine agonist
- Decrease or stop COMT inhibitor/MAOB inhibitor
*watch for worsening of parkinson’s symptoms
Describe “off-period” dystonia and when does it usually occur?
Sustained muscle contractions:
-Distal lower extremity (ex. clenching of toes, turning of foot)
-Usually occurs in early morning hours (waning drug levels)
When does “off-period” dystonia improve?
with the first levodopa dose of the day
Management of “off-period” dystonia
- Chew regular release Levocarb tabs and take with carbonated drink to increase absorption
- Controlled-release Levocarb (esp at bedtime)
- Other: baclofen; focal injections of botox (for persistent focal dystonia)
Parkinson disease therapy:
-Increase doses _____ until desired effect is seen, the max dose is achieved, or adverse effects become intolerable
*start low, go slow
weekly
Parkinson disease therapy:
If partial response is seen, what do we do?
continue this drug and add the next drug in the sequence
When adding adjuvant therapy to levocarb, we have to ____ the dose of levodopa?
reduce
Is there a role for drug holidays in PD ?
no role for drug holidays as any benefit is usually short lived and comes with risks such as immobility, aspiration/pneumonia, severe depression
Why should PD therapy not be d/c abruptly ?
parkinsonian crisis, NMS
Initial pharmacologic management:
If they have functional impairment and they are over 60 years old or have severe impairment, what is first line?
Levodopa
Initial pharmacologic management:
If they have functional impairment and they are under 60 with tremor ?
Anitcholinergic
or
Amantadine
Initial pharmacologic management:
If they have functional impairment and they are under 60 ?
- dopamine agonists
- MAO-B inhibitor
- levodopa
If they have predominant end of dose “wearing off” with MILD/NO dyskinesia, how do we manage this ?
- Increase levodopa
- add entacapone
- add dopamine agonist
- add MAO-B inhibitor
- change to slow release levodopa
If they have predominant end of dose “wearing off” with MODERATE dyskinesia, how do we manage this ?
- increase smaller dose levodopa frequency
- add amantadine
- decrease levodopa and add dopamine agonist
If they have predominant dyskinesia with mild/no wearing off, what do we manage this?
- decrease levodopa
- add amantadine
- discontinue anticholinergic
- discontinue MAO-B or COMT inhibitor
When will the pharmacologic response to levodopa deteriorate ?
within 6 months to 1 year
When should a pharmacist monitor ?
- weekly during titration period
- every 3 months once patient has been stabilized
What are the main side effects that a pharmacist should be monitoring ?
- monitor confusion, agitation, hallucinations, delusion, sleep disturbances, depression, increased appetite
- dyskinesias
- orthostatic hypotension
- n/v
List some non-pharms for parkinsons’
- Patient/family education and support
- Physical therapy to improve gait
- Speech therapy to improve volume
- Occupational therapy (for mobility, safety, driving skills, maintain social/family/work roles)
- Nutrition counselling
- Sleep hygiene
