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physiology and pharma > L17 - Parkinsons > Flashcards

L17 - Parkinsons Flashcards

1
Q

what is parkinsons

A

an age related neurodegenerative disease that affects motor symptoms

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2
Q

motor symptoms of PD

A
  • resting tremor
  • postural instability
  • bradykinesia (slow movement, hesitation movement)
  • rigidity - increased resistance to passive limb movement (muscle and joint stiffness)
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3
Q

what are the non motor symptoms of PD

A 
REM sleep disorders
autonomic dysfuntion 
cognitive decline
pain 
anxiety and depression

many more

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4
Q

describe the aetiology of PD

A

sporadic, late onset
underlying cause unknown

genetic
environmental

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5
Q

describe the genetic influence in PD

A

~10% of cases have a genetic involvement (associated with mutations in PARK1-10 genes)

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6
Q

what are the PARK1-10 genes involved in?

A

mitochondrial function / ability lysosomes and proteasomes in brain to breakdown abnormally processed proteins

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7
Q

what is the role of the PARK 1 gene

A

encodes alpha -synuclein protein, which is over expressed in PD

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8
Q

explain environmental influence of PD

A
  1. some toxins (MPTP) can induce PD in humans (addicts believed it was heroin)
  2. some pesticides can trigger PD in rats
  3. influence of gut microbiome - a-synuclein aggregates found in GI tract -PD could originate in gut
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9
Q

describe the pathology of PD

A
  1. degeneration of pigmented (neuromelanin, and so DA containing) cell bodies in substantia nigra pars compacta
    (neuromelanin is a by-product of DA oxidation)
  2. presence of lewy bodies in DAergic neurones (and throughout brain) which contain aggregates of a-synuclein
  3. reduced DA in DAergic terminals in striatum
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10
Q

what do lewy bodies contain

A

aggregates of a-synuclein

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11
Q

what is the significant DA pathway in PD

A

nigrostriatal pathway

from substantia Nigra projecting to striatum (caudate nuclei and putamen)

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12
Q

what pathway is degraded in PD?

A

nigrostriatal

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13
Q

what contributes to degradation of the nigrostriatal pathway in PD?

A
  • oxidative stress
  • faulty protein degradation (a-synuclein aggregation)
  • inflammation
  • glutamate toxicity
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14
Q

what is the major brain pathway circuit in movement

what NTs are involved

A

basal ganglia motor circuit

ACh (striatal interneuroens)
DA (nigrostriatal)
GABA (striatal and thalamic pathways)
Glutamate (corticostriatal and thalamocortical pathways)

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15
Q

what are the major ACh pathways in the basal ganglia motor circuit

A

striatal interneuroens

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16
Q

what are the major DA pathways in the basal ganglia motor circuit

A

nigrostriatal patwhay

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17
Q

what are the major GABA pathways in the basal ganglia motor circuit

A

striatal and thalamic pathways

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18
Q

what are the major glutamate pathways in the basal ganglia motor circuit

A

corticostriatal and thalamocortical pathways

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19
Q

what is the overal main fucntion of the basal ganglia pathway

A

receive inputs from SNc and striatum

filter this info and send it back via thalamus to cortex which sends signals for movement

this can occur via a direct or indirect pathway

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20
Q

describe the route of brain regions involved in the direct basal ganglia motor circuit

A 
SNc                      motor cortex 
             striatum
GPi / SNr (internal globus pallidus / substantia nigra reticulata)
thalamic relay nuclei 
thalamocortical patwhay 
motor cortex
21
Q

what pathway is what triggers movement and how is this affected in PD

A

thalamocortical pathway

reduced firing in PD

22
Q

describe the direct basal ganglia pathway and transmission

A
  1. glutamate released from motor cortex acts on AMPA receptors on striatum causing excitation
    DA from SNc acts on D1 receptors on SNc causing excitation
  2. this excitation causes Ca2+ influx and mediates GABA release from striatum
  3. GABA acts on GPi/SNr causing inhibiton
    this inhibits the release of GABA from the GPi/SNr (disinhibiton)
  4. in turn leads to increased firing of the thalamocortical pathway - movement
23
Q

describe the route of brain regions involved in the indirect basal ganglia circuit

A 
SNc and motor cortex 
striatum 
GPe (globus palladus externus)
STN (subthalamic nucleus) 
GPi/SNr 
thalamocortical pathway
24
Q

describe the indirect basal ganglia pathway and transmission (glutamate only)

A
  1. glutamate released from motor cortex acts on AMPA Rs of striatum casing excitation
    this excitation causes Ca2+ mediated NT (GABA) release from the striatum
  2. this GABA causes inhibition of GABA release from the GPe
  3. this disinhibition means less GABA acts on the NTN, so more glutamate is released from the STN
  4. this increased glutammate causes excitation of the GPi/SNr
    causing increased GABA release from here
  5. this increased GABA release from GPi/SNr causes inhibitoon of firing of the thalamocortical pathway
    blocking of movement
25
Q

why is DA important in the indirect basal ganglia pathway

describe its transmission

A
  1. DA released from SNc acts on D2 receptors of striatum causing inhibiton
    this inhibits release of GABA from striatum (disinhibition)
  2. less GABA released from striatum means less inhibition of GABA release from GPe (so more GABA released from GPe)
  3. this increased GABA released from GPe acts on the STN to inhibit glutamate release
  4. less glutamate then acts on the GPi/SNr, causing less GABA release
  5. this means there is less inhibition of the firing of the thalamocortical pathway

movement

26
Q

what are the changes to the basal ganglia pathways in PD

A

direct pathway underactive

indirect pathway overactive

27
Q

what happens to the ACh interneurones in the striatum in PD?

A

there are ACh interneurones in the striatum that have D2 receptors

normally they are inhiibited, but in PD less DA means they’re not inhibited so the striatum is flooded with ACh

increased [ACh] contributes to tremor (unknown mechanism)

28
Q

what are the main drug classes used in PD treatment

A
  1. muscarinic antagonists

2. drugs that aim to increase DA transmisison

29
Q

explain the treatment of muscarinic antagonists in PD

A
  1. act on M1 receptors, blocking the ability of the increased ACh in striatum to have effects anywhere

treat tremor

30
Q

examples of M1 antagonists used in PD

A

benzhexol

benzatropine

31
Q

side effects of M1 antagonists

A

constipation
dry mouth
blurred vision
confusion and cognitive dysfunction

32
Q

what side effect of M1 antagonists is useful in PD and why

A

dry mouth - as PD patients struggle with swallowing so it prevents saliva buildup

33
Q

list the classes of drugs that increase DA transmission in PD

A
  1. L-DOPA
  2. DOPA decarboxylase inhibitors
  3. MAOIs
  4. COMT inhibitors
  5. DA agonists
34
Q

explain mechanism of action of L-DOPA in PD

A
  1. L-DOPA is the DA precursor, so increased DA production
35
Q

what symptoms does DA help

A 
rigidity 
bradykinesia 
speech 
handwriting 
other
36
Q

what are acute side effects of L-DOPA

A

nausea -> peripheral DA activation

postural hypotension

in elevated doses - hallucinations, confusion, insomnia, nightmares

37
Q

what drug is given as an adjunct to L-DOPA and why?

A
  1. Dopa Decarboxylase inhibitors
    because DDC is also found in gut, so 90% of administered L-DOPA is broken down in intestinal wall
    DDCI’s increase [L-DOPA] reaching brain
  2. peripheral DA antagonist domperidone (cant cross BBB) combats nausea side effects
38
Q

what are chronic side effects of L-DOPA

A
  1. L-DOPA induced dyskinesia - excess involuntary movements, face and limbs mostly affected)
  2. motor fluctuations - fluctuations in clinical state and drug effectiveness due to fluctuations in DA R activation
39
Q

what drug can provide some relief to dyskinesia?

A

amantidine (NMDA antagonist)

40
Q

explain mechanism of action of DDC inhibtiors

A

block the breakdown of L-DOPA in the gut

important that they cat cross the BBB

41
Q

describe the mechanism of action of COMT inhibitors in PD

A

COMT breaksdown DA and L-DOPA

inhibiting them means more L-DOPA can reach brain and less DA is metabolised increasing DA transmission

oftenn given in adjunct to L-DOPA also

42
Q

explain mechanism of action of MAOIs in PD

A
  1. inhibit MAO and so inhibit metabolism of DA prolonging its activity
43
Q

when is MAOI use in PD most effective

A

in early stages when DAergic not fully degraded, can boost remaining DA

44
Q

explain the L-DOPA sparing effects on MAOIs

A

used in combination with L-DOPA they can lower the dose of L-DOPA needed, because the DA formed from L-DOPA is less broken down and lasts longer

45
Q

explain mechanism of DA agonists in PD treatment

A

D2 selective agonists can inhibit the indirect basal ganglia pathway

46
Q

what are acute side effects of DA agonists

A

similar to L-DOPA

nausea
at high doses - confusion, hallucinations
postural hypotension

47
Q

describe the chronic side effects of DA agonists in PD

A

less incedence of dyskinesia due to less fluctuations of receptor activation

less effective than L-DOPA

48
Q

describe the order of drugs used in PD

A

MAOIs
DA agonists
L-DOPA + DDCIs + COMT (in combination with MAOI or DA agonist to lower dose needed)

49
Q

what are the limitations of current treatments?

A

only symptom management not disease modifying

side effects - dyskinesia very dibilitating.

physiology and pharma (18 decks)

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