Exam 3 lecture 4 (PD) Flashcards
PD definition
PD is an age related irreversible neurodegenerative disease that affects 1,000,000 people in the US
males more susceptible than females
PD symptoms
TRAP
Resting TREMOR (primarily on one side of body
RIGIDITY (muscle stiffness)
Akinesia/bradykinesia (slow movement)
POSTURAL instability (impaired balance/coordination)
Mask like appearance, speech difficulties, cognitive deficits, depression
PD is characterized by a loss of
Dopaminergic neurons in SUBSTANTIA NIGRA
What is SNPC
substantia nigra pars compacta
What is the nigrostriatial system and what is its relevance
PD involves a loss of neurotransmission through the nigrostriatal system
What percent of nigral dopamine neurons or nerve terminals are lost before patient presents with motor symptoms
50% of nigral dopamine neurons or 70-80% of nerve terminals in striatum
Where do dopaminergic neurons project to
Striatum in basal ganglia
What else is PD characterized by that is worth noting
Lewy bodies in various regions in brain
What are lewy bodies?
Dense spherical protein deposits on surviving neurons in brain
Where are Lewy bodies found
Not only found in SN but also other brain regions including cortex
Lewy bodies are enriched with a protein called
α-synuclein
What is the Braak stages of PD (!)
Stage 1- lower brainstem
Stage 2- raphe
Stage 3- substantia nigra (necessary for classic PD symptoms)
stage 4- mesocortex/thalamus
stage 5- neocortex/ prefrontal cortex
stage 6- entire neocortex
Where is substantia nigra located
In midbrain (part of basal ganglia)
SN pars compacta function and pathology
supplies dopamine to striatum.
It undergoes neurodegeneration in PD
Basal ganglia structures
Striatum (caudate nucleus, putamen) and globus pallidus (external and internal)
What are the two structures in striatum?
What are the two structures in Globus pallidus
Striatum- caudate nucleus and putamen
Globus pallidus- external and internal
What are the two pathways dopamine neurons signal through
D1 and D2
What is the difference between D1 and D2 signaling
D1 is DIRECT
D2 is indirect
What happens to D1 and D2 signaling in PD (!)
signaling from SNPC to both D1 and D2 receptors in the striatum favors thalamocortical steroids, and this effect is disrupted in PD
describe the role of antimuscarinic drugs in PD (!)
antimuscarinics are used as adjunct therapies for tremor in PD
antimuscarinics are only used at low doses due to their side effects (cognitive deficits)
Role of dopamine and acetylcholine in control of muscle movements (!)
Dopamine is inhibitory while acetylcholine is excitatory
in indirect pathway
What is the gold standard tx for PD
L-DOPA
Know L-DOPA structure for exam
Know carbidopa structure for exam (!)
rationale for treating PD pt with L-DOPA? difference between L-DOPA and Dopamine (!)
L-DOPA is an immediate precursor to dopamine
L-DOPA is orally active
why is there a difference in bioavailability between L-DOPA and dopamine
dopamine does not cross BBB
Why does L DOPA cross BBB but dopamine does not
L DOPA crosses because it is a neutral molecule, Dopamine is positive at PH 7
side effects of L dopa
Nausea, HTN, psychosis
What is sinemet
carbidopa
L-DOPA
why is L-DOPA mixed with carbidopa
The dose of L-DOPA can be lowered by 4X by coadministering carbidopa
Challenges associated with L DOPA(!)
-On/OFF oscilliations after several years of DOPA usage
-Immediately after dosage, it can produce dyskinesia (motor effects)
-Pro drug conversion
How can we alleviate challenges shown in L DOPA usage
Oscilliations and dyskinesia Can be alleviated by administering DOPA in a continous manner instead of a pulsatile manner.
Pro drug can be alleviated by using dopamine receptor agonists – this is reasonable because the postsynaptic dopamine receptors are still present in the striatum
How is L DOPA converted dopamine
by dopamine decarboxylase
What is a DA receptor agonist that can alleviate pro drug symptoms
apomorphine
What kind of drug is apomorphine
mixed D1/D2 agonist
Selegiline structure remember
What are some major problems with long term therapy with levodopa
Dyskinesia and on/off states. This is after plasma levels decline. Pro drug conversion is also a problem. (eventually pts become unresponsive to L-DOPA, treat by dopamine receptor agonist like apomorphine)
Name DA receptor agonists (non-ergolines)
Ropinrole
Pramipexole
Rotigotine (patch)
have fewer side effects than ergolines
How do you take non-ergoline drugs
-These drugs are typically given in ascending order
-increase dose every 5-7 days to minimize side effects
-generally used as a monotherapy for early stage PD
PD drugs that interfere with dopamine metabolism
MAO-B inhibitor
COMT inhibitor
MAO-B inhibitor drugs
Selegiline and rasagiline
Safinamide
COMT inhibitor drugs
Entacapone
Tolcapone
Opicapone
Know selegiline structure for exam
Which is irreversible MAO or COMT
MAO-I
Distinct features of selegiline and rasagiline? What is their use
Triple bonds, indications of irreversible inhibitor.
both propargylamines
Both drugs can be used initially as monotherapies to delay the 1st use of L-Dopa
MOA of COMT-I drugs for PD
Inhibit methylation of 3-OH group of DA or L-DOPA by COMT
