Rockroth: Movement Disorders Flashcards
PD is a progressive neurodegenerative disorder associated with the loss of (blank) neurons contributing to the nigrostriatal tract. Degeneration of neurons within the (blank) leads to a shortage of dopamine in this extrapyramidal motor circuit
dopaminergic; substantia nigra
Which neurons are the primary victims of PD-related degeneration?
the dopaminergic neurons in the PARS COMPACTA of the substantia nigra
Mean age of onset of Parkinsons?
Who gets it, males or females?
55 years; 3:2 male:female
About what percentage of dopaminergic neurons are lost before motor signs of the disease emerge?
60-80%
**you have to lose lots of your motor neurons before you reach this threshold level
What causes Parkinson’s disease?
We don’t know!!
genetics, epigenetics, environmental toxins, diet, multiple causes??
lewy bodies of alpha-synuclein
In PD, the loss of dopamine results in a relative excess of (blank) activity via mACh receptors
cholinergic
Clinical manifestations of Parkinson’s disease?
TRAP!
Tremor (course resting tremor, “pill rolling”)
Rigidity (increase in muscle tone, “cogwheeling”)
Akinesia (inability to initiate movement) or bradykinesia (slowness of movement), masked facies (reptilian stare), short, shuffling steps
Postural changes (imbalance, loss of righting reflexes), stooped posture
Other: drool, trouble writing, low melody of speech
Parkinson’s is a disease characterized by asymmetry of (blank).
motor signs
dopamine vs ACh
What are some drugs that increase dopamine levels?
Drugs that increase dopamine:
levodopa combined with carbidopa (prevents peripheral breakdown of L-DOPA)
amantadine
MAO-B inhibitors
COMT inhibitors
dopamine agonists: ropinirole
anti-cholinergics
Why do you combine levodopa with carbidopa?
carbidopa is a DOPA decarboxylase inhibitor that doesn’t cross the BBB - it increases the effective concentration of levodopa getting to the brain by preventing its breakdown
How is levodopa different from dopamine?
it can cross the BBB via an L-amino acid transporter
What is one downside to the use of L-dopa?
it’s short-acting, so it wears off and causes an end-of-dose effect
**works for 2-3 hours, and then the pt returns to previous state of bradykinesia, etc
What is the on-off effect that can occur with patients treated with levodopa?
terrible parkinsonism which fluctuates with periods of hyperkinesia
**causes a roller-coaster effect, may be corrected with more continuous dopamine receptor stimulation
Side effects of levodopa?
nausea and vomiting
orthostatic hypotension
hallucinations and distorted thinking
dyskinesias (involuntary movements)
What is amantadine? How is it believed to work?
used to treat Parkinson’s disease; believed to promote release of dopamine from substantia nigra
One downside to amantadine? Side effects of amantadine?
tachyphylaxis: its benefit wears off easily;
restlessness, insomnia, agitation
hallucinations and confusion
livedo reticularis (discoloration of extremities)
How do MAO-B inhibitors increase dopamine levels?
inhibit dopamine metabolism to keep more around
When are MAO-B inhibitors used?
often used mono-therapeutically for early/mild PD;
in combo with levodopa/carbidopa for advanced PD
Give an example of an MAO-B inhibitor
rasagiline (Azilect)
Side effects of MAO-B inhibitors?
confusion, hallucinations
can enhance dopaminergic side effects when taken with levodopa
5HT syndrome
When are COMT inhibitors used? How do they work?
only in combo with levodopa/carbidopa;
these are catechol-o-methyltransferase inhibitors, they convert levodopa to 3-O-methyldopa which competes w levodopa to access the brain
Give an example of a COMT inhibitor?
entacapone
**acts at peripheral sites
Side effects of COMT inhibitors?
nausea/diarrhea
urine discoloration (bright red/orange)
sleep disturbances
If you have too much ACh around relative to dopamine, what do you get?
parkinsonism
**not to be confused w Parkinson’s disease; Parkinson’s is a cause of parkinsonism
If you have too much dopamine around relative to ACh, what do you get?
choreoathetosis
What things can cause parkinsonism?
dopamine inhibitors (antipsychotics)
provide more smooth and continuous DM receptor activation than levodopa and rarely cause dyskinesias
do not require functional DM neurons to produce their effects and are therefore sometimes helpful as adjuncts in advanced cases of PD in which few DM neurons remain
used as monotherapy in the early stages of PD
dopamine agonists
What is one dopamine receptor agonist we should know about?
Pramipexole (Mirapex)
**also indicated for treatment of restless leg syndrome
Side effects of D2 agonists like Pramipexole?
dizziness and hallucinations impulse control disorders hypotension insomnia nausea
Another D2 agonist that is an ergot alkaloid; rarely used for PD, but used for neuroleptic malignant syndrome
bromocriptine
What is this?
rigidity, tremulousness, fever, autonomic instability (BP), agitation>delirium>coma
plasma CPK markedly elevated due to rhabdomyolysis
rapidly progressive/manage aggressively
usually caused by “typical” antipsychotic drug
neuroleptic malignant syndrome
**use dopamine agonist like bromocriptine
may improve tremor in early PD but have little effect on rigidity and bradykinesis (thus most useful when TREMOR is the major clinical feature)
typically used as adjunctive Rx in combination with levodopa and other drugs that augment DM activity; also frequently used in
anticholinergics
What are some anticholinergics used in PD?
trihexyphenidyl
benztropine mesylate
How will your treatment strategy change for younger vs older patients with parkinsonism?
in younger pts (less than 65yo), more emphasis on long-term considerations bc they have more life to live! start with a dopamine agonist +/ MAOI, only add levodopa when motor symptoms are no longer in control
in older pts with cognitive impairment, emphasis on decreasing symptoms! start with levodopa/carbidopa
What to use for pts who have a disability due only to mild tremor?
anticholinergic monotherapy
Targeting the subthalamic nucleus (STN) and globus pallidus internus (GPi)
Complimentary to pharmacologic management
deep brain stimulation
**this is done in addition to medication, not used alone
What type of parkinson’s patient makes a good candidate for deep brain stimulation?
tremor is the main symptom, less likely to help balance/gait
excessive “off time”
dopamine-responsive
significant dyskinesia w current med regimen
Dopamine agonists and MAO-B inhibitors may be preferable as initial Rx, particularly in (blank) patients.
younger
COMT inhibitors are complimentary to l-dopa and are not useful as (blank) agents.
monotherapy
In more advanced patients who are reaching their limit with meds, consider whether they may be good candidates for (blank)
deep brain stimulation
This is a variant of Parkinson’s that looks a lot like it! It’s Parkinson’s disease “in extension,” because they have extension posture. They have impaired eye movements esp vertical gaze, axial rigidity, dysphagia, and typically don’t respond to PD meds
Progressive supranuclear palsy
Different types of action tremors?
physiologic tremor
***symmetric, high freq/low ampl; may involve speech; worse w/ fatigue, caffeine, exposure to cold; better w/ alcohol
essential tremor
**may involve head, central tremor, autosomal dominant pattern
benign familial tremor
**family history of essential tremor
cerebellar intention tremor
**as you get toward the target of the action, the tremor increases!
Type of resting tremor
parkinsonian
**asymmetric, low freq/high amplitude; tends to spare speech and head
