Parkinson's Disease Flashcards
Nigrostriatal pathway
Substantia Nigra (DA producing cells) --> Dorsal Striatum (DA released here) Voluntary motor control
Mesolimbic pathway
VTA –> ventral striatum
psychosis: positive symptoms of schizophrenia
pleasure and reward
Mesocortical pathway
VTA –> frontal cortex (pre-frontal)
Higher order processing
attention, decision making
psychosis: negative symptoms
Tuberoinfundibular pathway
Arcuate nucleus of the Hypothalamus –> median eminence of the Hypothalamus
DA goes to pituitary gland –> control of pituitary hormones (such as prolactin)
Rate limiting enzyme in DA synthesis
Tyrosine hydroxylase (slower enzyme)
Dopamine release and trafficking
- DA released upon depolarization of presynaptic terminal
- DA binds to pre- & post-synaptic DA receptor and activates them.
- DA is transported back into the pre-synaptic terminal by the dopamine transporter.
First step in dopamine inactivation
COMT degrades DA in periphery and in synapse
Second step in dopamine inactivation (2)
- physical removal –> removed via DA transporter (DAT) back into presynaptic terminal. Once there, DA is either repackaged for future use or degraded by MOA-B
- Terminal inactivation by MOA-B in presynaptic terminal. Metabolizes DA into DOPAC.
Dopamine receptors (5)
D1-like: D1 and D5 –> stimulatory
D2-like: D2, D3, and D4 –> inhibitory
What does the alpha unit do in a D1-like receptor?
activation of the alpha receptor leads to activation of adenylate cyclase, which converts ATP–>cAMP. cAMP activates protein kinase C, which opens Na+ and Ca2+ channels to allow those ions to flow into the cell. More positive = depolarization = more potential for an AP
What does the beta-gamma unit do in a D1-like receptor?
Opens K+ channels, which leads to an efflux of K+ out of the cell. Overall net ion exchange (more Na+ and Ca2+ into cell) leads to depolarization
What does the alpha unit do in a D2-like receptor?
activation of the alpha receptor INHIBITS adenylate cyclase. No AC prevents the conversion of ATP–> cAMP. Decrease in protein kinase C, which prevents the opening of Na+ and Ca2+ channels. No sodium or calcium ions flow into cell
What does the beta-gamma unit do in a D2-like receptor?
Opens K+ channels, which leads to an efflux of K+ out of the cell. Overall net ion exchange (LESS Na+ and Ca2+ into cell) leads to hyperpolarization = less likely to generate an AP
Key features of PD
- Bradykinesia: Hallmark feature. Slowed ability to start/stop movements - cannot walk in a straight line. Voluntary movements take energy and focus -> initiation of movement is difficult.
- Muscular Rigidity: Muscles tense, not sore, hard to move
- Resting tremor: hand shakes at rest but stops when holding something/action completed (think picking up coffee cup). See in early to mild stages. Pt shakes all the time as disease progresses.
- Impairment of postural balance: cardinal feature –> cannot keep balance if pushed over.
Advanced stages: depression due to disease limitations on life; dementia due to old age
What leads to PD?
Degeneration of dopaminergic neurons in the substantia nigra. 60-80% degeneration is needed for sx. NOT curable
Role of DA in a HEALTHY brain
DA released from SUBSTANTIA NIGRA –> binds D1 and D2 located on GABAergic neurons in DORSAL STRIATUM.
D1: stimulates GABA release
D2: inhibits GABA release
More D2 than D1, so effect of DA is to DECREASE GABA.
Muscarinic –> DA does not bind. Ach binds, leading to increased GABA release.
Net effect is to inhibit GABA
Are there more D1 or D2 receptors in a healthy brain?
more D2
Is GABA inhibited or released in a healthy brain
Inhibited
Role of DA in a PD brain?
DA cells in SUBSTANTIA NIGRA die –> less DA released in DORSAL STRIATUM.
D2 receptors not activated as much, so less inhibition of GABA
Muscarinic receptors not affected –> excitatory, lead to GABA release.
Lots of GABA release leads to poor motor control
Is GABA increased or decreased in a PD brain?
Increased
Where are dopaminergic neurons located?
Substantia Nigra
Where are DA receptors located?
Dorsal Striatum
What is the role of muscarinic receptors?
Excitatory. Lead to increased released of GABA
What is L-DOPA
Precursor to DA
If L-DOPA is given orally, what metabolizes it
AAD in GI
What can you give with L-DOPA that inhibits AAD
Carbidopa
How much L-DOPA normally reaches the brain
1%
How much L-DOPA reaches the brain if given with carbidopa
approx. 10%
Why does combo tx with L-DOPA and carbidopa reduce side effects?
Lower L-DOPA dose can be given because more will reach the brain, thus reducing the SE of L-DOPA
Can L-DOPA be used long term
No. It becomes less effective as neurons die. It also leads to dyskinesias.
Motor complications of long term L-DOPA use
“wearing off” effect: due to loss of DA neurons, same dose doesn’t last as long. Sx appear before the next dose. Need to supplement with other drugs (such as MAO-I or COMT inhibitor) at this point or increase dose frequency of L-DOPA
Peak Dose Dyskinesia
Thought to be due to excessive stimulation of striatal DA receptors. L-DOPA dose is moving target - too much drug, patient gets dyskinesia, not enough drug patient displays PD sx. Pt will be okay with reduced dose for a while but dyskinesias will return.
Adverse side effects of L-DOPA
GI side effects: N/V, anorexia - most common with L-DOPA alone b/c you need a higher dose
Dyskinesias: occurs in 80% of patients
Arrhythmias, tachycardias, etc: due to increased catecholamine release (L-DOPA converted to DA, NE, and Epi in periphery). PVC is classic issue
Tolcapone
Tamsar. COMT inhibitor. CNS and PNS action -Crosses BBB
Entacapone
Comtan. COMT inhibitor. Peripherally acting only. Blocks conversion of L-DOPA to 3-O-M DOPA
MOA of COMT Inhibitors
Used ONLY in COMBO Tx.
Work to increase t1/2 of L-DOPA so more gets to the brain.
Centrally acting –> increases amount of DA in brain by preventing breakdown
Stalevo
Combo of L-DOPA, Carbidopa, and Entacapone
MOA of MAO-B inhibitors
MAO-B inhibitors prevent the breakdown of DA in pre-synaptic terminals. Thus allowing more DA to be repackaged into vesicles.
A - better at breaking down DA; B - better at breaking down NE. End up blocking both with needed doses. Same issues with MAO-I apply, less risk for Tyramine toxicity.
Selegiline
Deprenyl. MOA-B inhibitor
Rasagiline
Azilect. MAO-B inhibitor
Peripherally - Prevent breakdown of L-DOPA to 3-O-MD via COMT
Entacapone and Tolcapone
Peripherally - Prevent breakdown of L-DOPA to DA via AAD
Carbidopa
Centrally - prevent breakdown of DA to 3MT via COMT
tolcapone (crosses BBB)
Centrally - prevent breakdown of DA to DOPAC via MAO-B
Selegiline
Rasagiline
MOA of D2-receptor Agonists
Mimic DA effects on D2 to decrease GABA
Benefits of D2 agonists
fewer dyskinesias
Not as much peak-dose dyskenesia
How do you dose PD drugs
based on sx and age
should you start with L-DOPA or D2-agonist in pt with mild sx only?
No. Drugs lose efficacy over time. Start with MAO-I as monotx in mild sx
Bromocriptine
Parlodel. D2 agonist/D1 partial agonist. Not used much
Ropinirole
Requip. Selective D2 agonist. Mild to moderate sx, can be used as monotx
Pramipexole
Mirpex. Selective D2 and D3 agonist. Mild to moderate, can be used as monotx
Rotigotine
Neupro. D2 agonist, skin patch. Mild and early stage PD monotx
D2 agonist side effects
GI: N/V, anorexia
Cardiovascular: Hypotension, especially at beginning of tx. Arrhythmia
Mental disturbances: Due to D2 activation –> mimics positive sx of schizophrenia b/c D2 is everywhere.
Should you start a pt on L-DOPA or D2 agonist first?
Either. Some controversial data says D2 is slightly less effective than L-DOPA, however, you can start with either knowing you will have to switch drugs at some point.
Amantadine
Symmetrel. Anti-viral agen
Believed to increase DA and have anti-cholinergic properties
Used for tx of tremors
Muscarinic and NMDA antagonist = REDUCE GABA
NOT a monotx
Becomes less effective over time as DA neurons die
What effects do muscarinic antagonists have
can reduce tremors. NOT effective in tx of bradykinesia. NOT a monotx
Trihexyphenidyl
Artane. Modest effects, binds to muscarinic receptor. Anticholinergic SE
