Parkinson's patho + drugs Flashcards
Parkinson’s Disease epidemiology
-major cause of disability for pt over 60 (more men)
-mean onset is 62 yo
-chronic, progressivve, IRREVERSIBLE
-neurological deficit in extrapyramidal system (noncortical voluntary motor control)
PD symptoms (TRAP)
-resting TREMOR (one side of bosy)
-Rigidity
-AKINESIA/bradykinesia (slow movement)
-Postural instability (balance, coordination)
-mask-like appearance
-speech difficulties, cognitive defects, depression
-olfactory deficits
-sleep disturbances
PD patho
-loss of dopaminergic neurons in SN
-gradual loss of darkly pigmented, dopamine-releasing neurons in SN par sompacta (SNpc) in midbrain
-dopaminergic neurons in SNpc project to striatum in basal ganglia
-PD involves loss of transmission throught he NIGROSTRIATAL SYSTEM
-some studies suggest 50% of nigral dopamine neurons of 70-80% of nerve terminals in striatum are lost before pt presents w motor sx!
-presence of Lewy bodies
-a-Synuclein neuropathology: may begin in brainstem
Lewy bodies
-presence in brain indicates PD
-dense, spherical protein deposits in survivng brain neurons
-found in SN and other regions (cortexx)
-enriched with fibrillar forms of protein a-syniclein
a-Synuclein neuropathology: Braak stages
-PD might begin in brain stem
Stage 1: lower brainstem
2. raphe (link to REM sleep disorder?)
3. SN (classic PD sx)
4. mesocortex/thalamus
5. neocortex/prefrontal cortex
6. entire neocortex (link to cognitive defects)
-stage 3 is classic sx but progression in other stages accounts for non-motor sx
Midbrain (review)
-SN part of basal ganglia
-SN pars compacta:
-input to basal ganglia
-dopamine to striatum
-voluntary motor control and some cognition
-neurodegeneration in PD
Basal ganglia
-striatum (caudate nucleus, putamen)
-globus pallidus (external and internal segments)
-subthalamic nucleus (STN)
-know where
direct dopamine signaling pathways
-D1 receptors in striatum
-SNpc -> striatum -> Gpi/SNpr -> thalamus -> cortex
indirect dopamine signaling pathway
-D2 receptors in striatum
-SNpc -> striatum -> Gpe -> STN -> Gpi/SNpr -> thalamus -> cortex
dopamine signaling from SNpc to both striatum D1 and D2 receptors favor:
-thalamocorticol signaling
-effect disrupted in PD
PD tx options
-antimuscarinics
-L-DOPA
-DA agonists
-MAO-B inhibitors
-COMT inhibitors
Antimuscarinics for PD
-adjunct for tremor
-low doses (cognitive side effects)
-dopamine is inhibitory in motor control (indirect)
-loss of dopamine = xs of ACh and cholinergic pathways
-antimuscs can compensate for overactivity
-most effective tx inc dopaminergic transmission by inc endogenous DA or directly stimulating DA receptors
Antimuscarinic for PD drug
-benztropine (Cogentin)
L-DOPA
-gold standard
-precursor of SA
-orally active and can enter CNS (DA is not)
-can lower dose by adding carbipoda, peripherally acting DOPA decarboxylase inhibitor
-combo is call sinemet
Sinemet
-combo L-DOPA w carbidopa
-lower L-DOPA dose
-carbidopa is peripheral DOPA decarboxylase inhibitor
L-DOPA conversion
-must be converted to DA in SN (decarboxylation COOH) but not in periphery
-carbidopa inhibits DOPA decarboxylase (DDC) in the periphery
-carbidopa doesnt penetrate BBB and thus is cannot inhibit DDC in SN
Why is there a difference in L-DOPA and DA bioavailability
-DA has net positive charge at pH 7, cannot enter CNS
Challenges associated with L-DOPA therapy
-on/off oscillations
-prodrug conversion
on/off oscillations L-DOPA
-in “on” state shortly after dosage, drug can produce exaggerated and aberrant motor effects called dyskinesias
-drug in “off” state after plasma levels decline
-shorter duration motor response as PD progresses
-window between “on” state and dyskinesia skrinks as PD progresses = inc incidence
How to prevent dyskinesia and extended off periods
-admin L-DOPA in continuous instead of pulsatile manner
-new formulation of foslevodopa and foscarbidopa approved 2024
L-DOPA limited pro-drug conversion issues
-L-DOPA needs to be converted to DA by DCC in surviving nigral dopaminergic neurons
-pt become unresponsive to L-DOPA as PD progresses
-use DA agonists to combat this bc receptors are still present in striatum
Dopamine receptor agonist drugs
-apomorphine (ergoline)
-ropinirole (non-ergoline)
-pramipecole (ne)
-rotigotine (ne)
Apomorphine (Apokyn)
-mixed D1/D2 agonist
-strucutre is DA w catechol and aminoethyl groups held in rigid conformation
-admin SQ in late-stage to relieve off state
-potent emetic effects tho (N/V)
-Onapago 2025`
Non-ergoline DA agonists (ropinirole, pramipexole, rotigotine)
-D2/D3 agonists
-fewer side effects than apomorphine
-give in ascending schedule, inc dose q5-7days to dec SE
-monotherapies for early stage for 2-4 years
-totigotine is transdermal patch
