Lecture 12 - Parkinson's Disease Flashcards
At what age do symptoms of Parkinson’s disease generally appear?
Around age 60
What are the symptoms of Parkinson’s disease?
- Rhythmic tremor - often occurs at first in one hand, resembles “pill rolling”
- Leaning forward or backward when upright
- Muscle rigidity - pushing on an arm causes it to move in jerky increments instead of smoothly
- Difficulty rising from a sitting position
- Speech*
What are marker’s of Parkinson’s disease?
- Muscle rigidity
- Slow movements
- Loss of spontaneous movements
- Resting tremor, first in one hand
Which motor pathways control voluntary movement?
- Upper motoneurons
- Lower motoneurons
- Corticospinal pathways
- Pyramidal tracts
Which motor pathways control involuntary movement?
- Extrapyramidal system
- Basal ganglia
- Reticular system
- Vestibular system
What is the neuropathophysiology of Parkinson’s disease?
- Loss of neurons in substantia nigra causing loss of dopamine innervation of striatum
- Balance btwn acetylcholine and dopamine is lost causing abnormal signalling and impaired mobility
At what stage of neuron loss do symptoms of Parkinson’s disease generally appear?
When about 70% of nigrostriatal neurons are lost
What normally inhibits and excites GABA neurons?
- Inhibited by dopamine
- Stimulated by acetylcholine
Which symptoms of Parkinson’s disease are controllable by drug therapy?
- Bradykinesia (slow initiation of movement)
- Tremor at rest
- Muscle rigidity
- Abnormal posture
- Early treatment for “neuronal sparing”
What are the pharmacological targets of drugs for Parkinson’s disease?
- Increase dopamine signalling in corpus striatum and substantia nigra
- Decrease cholinergic activity
- Decrease peripheral dopamine effects at D1/D2 dopamine receptors
- Decrease peripheral L-DOPA metabolism
What is the function of COMT w/ respect to dopamine synthesis in substantia nigra?
Catalyzes L-DOPA -> 3-OMD
What is the function of DDC (dopa decarboxylase) w/ respect to dopamine synthesis in substantia nigra?
Catalyzes L-DOPA -> dopamine
What is the function of TH (tyrosine hydroxylase) w/ respect to dopamine synthesis in substantia nigra?
Catalyzes tyrosine -> L-DOPA
What does the D1 subfamily of dopamine receptors do?
Increases cAMP
What does the D2 subfamily of dopamine receptors do?
Decreases cAMP
What are first line drugs to treat the early stage of Parkinson’s disease?
- MAO-B inhibitors (rasagiline, selegiline)
- Levodopa (levodopa/carbidopa or levodopa/benserazide)
Does L-Dopa cross the BBB?
Yes, but only 1% enters the brain, causing side effects in the periphery
Where is L-Dopa metabolized?
Intestine, blood, and peripheral tissues
What are the therapeutic effects of L-Dopa?
- Reduces rigidity and bradykinesia
- Improves motor function and speech
- Return of facial expression
What is the first choice drug for improving motor dysfunction from Parkinson’s disease?
L-Dopa
What is the most common side effect of L-Dopa that causes people to discontinue use of the drug?
Dyskinesias (abnormal involuntary movements)
What are some side effects of L-Dopa besides dyskinesias?
- Nausea, vomiting
- Hypotension and cardiac arrhythmias
- Wearing off
- “On-off” effect
- Insomnia, confusion
- Psychosis, hallucinations
What does carbidopa do?
- Inhibits dopa decarboxylase (DDC) or aromatic L-amino acid decarboxylase (AADC)
- Prevents breakdown of L-Dopa in periphery and allows more to cross BBB
What are common adjunct therapies w/ L-Dopa?
- L-Dopa and carbidopa = Sinemet
- L-Dopa and benserazide = Prolopa
What is entacapone used to treat?
- Later stage Parkinson’s disease
- Used to treat problems associated w/ long term therapy of L-Dopa (wearing off, on-off effects)
What does entacapone do?
- Selective and reversible inhibitor of peripheral COMT causing reduction of peripheral metabolism of L-Dopa
- Causes increased conversion of L-Dopa to dopamine in the brain
Does entacapone cross the BBB?
No
What is a disadvantage to entacapone?
Cause enhance adverse effects of L-Dopa like dyskinesias, nausea, psychosis, and confusion
What is entacapone normally used w/ and when?
- Sinemet (L-dopa + carbidopa) and entacapone = Stalevo
- Common use in pxs who have been on L-Dopa for over 10 years
What is amantadine?
Dopamine releaser
What are the therapeutic effects of amantadine?
- Increases dopamine release in CNS
- Reduce dyskinesia
When is amantadine used?
- Short term (under 6 months)
- Sometimes used w/ L-Dopa
What are the side effects of amantadine?
Similar to L-Dopa
What are ropinirole and pramipexole?
Selective dopamine agonists at D2/D3 receptors
What are the therapeutic effects of ropinirole and pramipexole?
- Act on D2 and D3 receptors in and outside of corpus striatum
- Improves depressive symptoms
- May be combined w/ L-Dopa to treat “on-off” effects
What are side effects of ropinirole and pramipexole and how can they be improved?
- Dyskinesia b/c act on D2 receptors outside of corpus striatum (dyskinesia is a result of peaks and troughs of drug delivery, so a patch will level out drug delivery and decrease dyskinesia)
- Suppresses prolactin secretion
- Hypotension
- Visual and auditory hallucinations
What are some muscarinic antagonists used for Parkinson’s disease treatment and what do they do?
- Trihexyphenidyl HCl
- Benzatropine mesylate
- Selective for muscarinic acetylcholine type 1 receptor
What are the therapeutic effects of muscarinic antagonists?
Tremors, but not rigidity (generally used in young px w/ severe tremor)
What is a contraindiction of trihexyphenidyl HCl and benzatropine mesylate?
Glaucoma
What does monoamine oxidase A do?
Metabolizes NE and serotonin
What does monoamine oxidase B do?
Metabolizes dopamine
What is selegiline?
Irreversible MAO B inhibitor
What does selegiline enhance the effects of?
L-Dopa
What are side effects of selegiline?
Insomina and cognitive problems
What occurs if selegiline is superceded by rasagiline?
- Less production of amphetamine-like by-products
- Better bioavailability
- Useful in px w/ depression and/or cognitive decline
What are some non-pharm therapeutics to treat Parkinson’s disease?
- Surgery - ablation and/or deep brain stimulation (to inhibit STN and reduce dyskinesia)
- Growth factors
- Stem cells - replacement of dopaminergic neurons
