PD Flashcards
What is the pathophysiology of parkinson’s?
Loss of SNc dopamine neurons
Increase of striatal cholinergic interneuron activity
Lewy bodies
Oxidative stress
What is the clinical presentation of PD?
Slow and progressive (sx onset is associated with degree of neuronal loss and spread of Lewy bodies through certain parts of the brain)
What are the cardinal features of PD?
Bradykinesia
Resting tremor (pill rolling/hands predominate)
Muscle rigidity
Gait dysfunction, postural instability - occurs later in disease
What are the motor sx of PD?
Decreased dexterity Diminished arm swing when walking Dysarthria Dysphagia Shuffling gait Festinating gait Flexed posture "freezing" at initiation of movement Hypomimia (reduced facial animation) Hypophonia Micrographia Slow turning
What are the autonomic sx of PD?
Bladder and sphincter disturbances Consitpation Diaphoresis Orthostatic BP changes Paroxysmal flushing Sexual disturbances Sialorrhea
What are the mental status changes in PD?
Anxiety Depression Bradyphrenia (slow thought) Confused state Dementia Hallucinations/psychosis Sleep disturbance
What are other sx in PD?
Fatigability Oily skin Pedal edema Seborrhea Weight loss
What are the goals for PD treatment?
Manage motor/non-motor sx so patients can maintain QOL.
Preserve ability to perform ADLs, improve mobility, minimize AEs or treatment complications.
When is treatment initiated in patients with PD?
When sx start to interfere with activities of daily living, employment, or WOL
What leads to cholinergic activity?
Decline in dopaminergic neurons/activity to increase in cholinergic activity
What is considered the most effective PD therapy?
Levodopa
What are limitations to levodopa?
Motor fluctuations
Dyskinesia
Neuropsychiatric complications
Often debilitating and difficult to manage
What may be initiate for mild-moderate PD?
Rasagiline or DAs (better SEs)
What is the drawback to starting MAOIs or DAs for mild-moderate PD?
Expensive
Less effective
What components of PD are not treated?
Freezing
Falling
Dementia
What therapy has been studied and shows benefit in PD?
Exercise
What are non-pharm interventions for PD?
Nutrition
Exercise
What are PD patients at an increased risk for when it comes to nutrition?
Poor nutrition
Weight loss
Loss of muscle mass
What are nutrition interventions for PD?
Encourage fluid and fiber intake to prevent/treat constipation
Adequate Ca intake for bone health
Take levodopa on empty stomach 1 hour before or after meals
What is L-dopa the precursor of?
Dopamine
Why do we give L-dopa and not dopamine for PD?
L-dopa crosses the BBB
Where is L-dopa converted?
Centrally - results in efficacy
What is the MOA of L-dopa?
Converted to dopamine by L-amino acid decarboxylase (L-AAD)
What are the most effective medications from least to most?
Anticholinergics/amantadine
COMTi/MAOIs
DA
Levodopa/carbidopa
What causes AE from levodopa?
Resulting from peripheral conversion of levodopa to dopamine by L-AAD
What are the AEs of levodopa alone?
N/V
Cardiac arrhythmias
Postural hypotension
What AE is associated with end-of-dose “wear off” of levodopa?
Motor complications
What class is carbidopa in?
Decarboxylase inhibitor
What is the starting L-dopa dose for relief of disability?
200-300 mg/d
What is the upper range of L-dopa doses for severe parkinsonism?
800-1000mg/d
Is there a hard max dose of L-dopa?
No
What dose of carbidopa is needed to prevent peripheral AEs of L-dopa?
75mg/d
What is the max dose of carbidopa?
200mg/d
What is peak plasma concentration for L-dopa variability usually attributed to?
Erratic gastric emptying
What can affect gastric emptying?
Meals delay
Antacids promote
Where is L-dopa primarily absorbed?
Duodenum
Is L-dopa protein bound?
No
What is the elimination 1/2 life for L-dopa alone?
1 hour
What is the elimination 1/2 life of L-dopa/carbidopa?
1.5 hours
What is the elimination 1/2 life of L-dopa/carbidopa + COMTi?
2-2.5 hours
Why do we increase the dose of controlled and extended release sinemet?
Not absorbed well?
Do we start with controlled or immediate release sinemet?
Immediate
Why would we switch to controlled release sinemet?
Motor sx
Will all patients eventually receive sinemet?
Yes
What formulations does L-dopa/carbidopa come as for use in feeding tubes?
Gel (Duopa)
What are the non-ergot derivative DAs?
Pramipexole
Ropinirole
Rotigotine (transdermal patch)
What are the AEs of DAs?
N/V Sedation Imuple control disorders (gambling, pathologic shopping etc) Daytime sedation including: Sleep attacks Lightheadedness & postural hypotension Hallucinations Vivid dreams Confusion
What is the ergot derivative DA?
Bromocriptine
Which DA requires renal dose adjustment?
Pramipexole
Why is bromocriptine no longer used?
Increased risk of pulmonary fibrosis
Lower efficacy compared to other DAs
How long do most patients use DA monotherapy?
A few years before requiring L-dopa
When are DAs used as L-dopa adjunct therapy?
With a deteriorating response to L-dopa
Experiencing fluctuations in L-dopa response
Experiencing motor fluctuations
What do DAs reduce the frequency of?
“off” epsiodes
What drug class produces a levodopa sparing affect?
DA
What is apomorphine?
Short acting injectable used for acute, intermittent treatment of “off” episodes of PD in patients already receiving levodopa therapy
Where is apomorphine given?
Setting where BP can be monitored continuously
What apoprophine dose do we give first?
a 0.2mL (2mg) test dose
How often do we monitor the apomorphine test dose?
Monitor supine and standing BP predose, 20, 40, 60 minutes postdose
If apomorphine is tolerated, how do we titrate?
Begin with 0.2mL as needed, and increase by 0.1mL if necessary
What do we do if the first apomorphine dose is ineffective?
Do not redose
What are AEs of apomorphine?
N/V --> severe Hypotension Injection site reactions Dyskinesia Hallucinations
How do we prophylax for apomorphine n/v?
Trimethobenzamide (antiemetic) should be initiated 3 days before test dose and continue for at least 2 months
What is the MOA of MAOIs?
Irreversible selective MAOI that block dopamine breakdown and can modestly extend the duration of action of levodopa
How long can MAOIs extend levodopa duration of action?
Up to 1 hour of “on” time during the day
What do MAOIs decrease the formation of?
Free radicals (possible neuroprotective effect)
Which MAOI is approved for initial monotherapy or adjunct to levodopa for PD treatment?
Rasagiline
Which MAOI can be used as adjunctive treatment to levodopa for PD?
Selegiline
What are AEs of MAOIs?
Dyskinesia Hallucinations Delusions Nausea Orthostatic hypotension
What are DDIs for MAOIs?
MAO-B receptors have less than MAO-A receptors
How is rasagiline administered?
Once daily
How is rasagiline metabolized?
To relatively inactive metabolite and is devoid of amphetamine like side effects
How is selegiline metabolized?
Metabolites are amphetamine type and can cause insomnia and jitteriness (negates theorized neuroprotective effect)
What is the brand of levodopa/carbidopa/entacapone?
Stalevo
What is Entacapone dosing?
200mg with each levodopa/carbidopa dose
What is the max number of entacapone doses per day?
8
What is the class for entacapone?
COMT-inhibitors (catechol-O-methyl transferase inhibitors)
What is the MOA of COMT-i?
Prevent conversion of levodopa to its metabolite 3-O-methyldopa (3OMD), thuse extending the effects of each levodopa dose
Can entacapone be used alone?
No, only effect when used with levodopa
What is entacapone used for?
Managing motor fluctuations
Where does entacapone work?
Inhibits COMT in periphery only
What are the AEs of entacapone?
Dyskinesia Hallucinations Confusion Nausea Orthostatic hypotension Brownish-orange urine discoloration
What are the SE of tolcapone?
Severe and fatal hepatotoxicity
Strict liver monitoring required
Must sign a consent form
When would patients take tolcapone?
Not responding to entacapone
What drugs are anticholinergic?
Benztropine
Trihexyphenidyl
Where do the anticholinergics work?
Centrally
What are anticholinergic MOA?
Blocks excessive cholinergic activity involved in PD pathology in the CNS at muscarinic sites
What PD features do anticholinergics not treat?
Bradykinesia
Gait disturbances
What PD feature might anticholinergics help with?
Dystonia
What is the efficacy of anticholinergics in PD?
Tremor is similar to DA
What are the AEs of anticholinergics?
Blurred vision Confusion Constipation Dry mouth Memory difficulty Sedation Urinary retention
What is the limiting factor for anticholinergics?
Can try to reduce dose but may need to continue
What is the ideal patient for anticholinergic therapy?
Younger and cognitively intact
Can be used with other therapies for PD
What is an NMDA receptor antagonist?
Amantadine
What is NMDA mainly used for/?
tremor
What is NMDA somewhat effective for?
Rigidity and bradykinesia
What is amantadine effective in suppressing?
Levodopa induced dyskinesia
What are the AEs for amantadine
Confusion in elderly at HD
Sedation and vivid dreams
Dry mouth
Livedo reticularis (diffuse mottling of the skin)
Hallucinations
Rare SE include depression, anxiety, dizziness, psychosis, and confusion
How is amantadine adjusted?
Renally
Which PD drug is best used for short term monotherapy?
Amantadine d/t tansient modest efficacy
What is the brand and dose of benztropine?
Congentin 0.5-0.4 1-2x/d
What are the brands and doses of carbidopa/levodopa?
Sinemet 2-6x/d 300-1000
Sinemet CR 3-6x/d 400-1000
Rytary (ER) 3-5x/d 435-1170
What are the brands and doses of DAs?
Pramipexole (Mirapex ER) 1.5-4.5 TID
Ropinorole (Requip) 8-24 TID
Rotigotine (Neuro patch) 2-8 Daily
What is the brand and dose of entacapone?
Comtan 200-1600 w/levodopa
What are the brands and doses of MAO-B inhibitors
Rasagiline (Azilect) 0.5-1 daily
Selegiline (Eldepryl) 5-10 BID
What is the brand and dose for amantadine?
Symmetrel 200-300 BID
What is the dose for stalevo?
600-1600 6-8 times daily
What is the brand and dose of pimavanserin?
Nuplazid 34 daily
If a patient has mild motor sx (any age) what is potential therapy options?
Consider rasagiline
Can add:
Amantadine
Anticholinergics (for tremor in younger, cognitively intact pts)
If a patient has mild/mod motor sx and is < 60yo w/no cognitive impairment, what are potential therapy options?
DA (initial therapy or addition to establish regimen)
If a patient has severe motor sx or is > 60yo or has cognitive impairment, what are potential therapy options?
Levodopa (inital therap or addition to established regimen)
How do we adjust levodopa therapy with motor fluctuations?
Increase dosing frequency
Add MAO-B or COMTi
Add DA
How do we adjust levodopa therapy if there is peak dose dyskinesia?
Reduce dopaminergic dose
Add amantadine
What is the wearing off period of levodopa?
End of dose deterioration
What are the possible treatments for wearing off?
Increase frequency of doses
Change to CR/ER formulation
Add DA, MAOI, COMTi, amantadine
SQ apomorphine
What can cause drug-resistant off periods?
Delayed gastric emptying or absorption
What are possible treatments of drug-resistant off periods?
Give on empty stomach Crush/chew and take on full glass of water Avoid CD form; ER may be ok Switch to ODT formula Increase dose and/or frequency
What is the treatment of rapid fluctuations?
Add DA, MAOI, COMTi that decrease clearance of levodopa
Drug free period/drug holiday
What are treatments of nocturnal off states and dystonia?
Bedtime dose of DA
ER form of levodopa or DA
What is treatment of dystonia?
Baclofen/botox
What are possible treatments for dykinesia?
Smaller, more frequent doses of levodopa
Use of sustained release product
Amantadine 200-400mg/d
What drugs may worsen dyskinesia?
DA, COMTi, MAOI
What is used to treat depression in PD?
Pramipexole
Consider MAOI as they are derived from antidepressants
TCA may be more effective than paroxetine/placebo
How do we treat dementia in PD?
Cholinesterase inhibitors
What are the preferred APXs for disruptive psychotic sx?
Pimavanserin
Quetiapine
Clozapine
What is pimavanserin?
SGA indicated for PD suffering with hallucinations and delusions
What is the MOA of pimavanserin?
Combined inverse agonist/antagonist at serotonin receptors; does not have affinity for dopamine receptors
How is quetiapine used in PD hallucinations?
Bedtime dose at first, low dose, gradually increase weekly if needed
What does clozapine work on in PD?
Motor sx and hallucinations
