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MP422 > PARKINSON'S DISEASE > Flashcards

PARKINSON'S DISEASE Flashcards

1
Q

key molecular pathologies of Parkinson’s disease

A

oxidative stress
mitochondrial dysfunction
alpha-synuclein within Lewy Bodies
neuroinflammation

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2
Q

Parkinsonism symptoms

A

dysregulation of motor function
- bradykinesia slowness of movement)
- tremor at rest
- rigidity/freezing/expressionless face
- postural instability
- akinesia
- hypokinesia

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3
Q

factors that trigger PD

A

normal dopamine metabolism (oxidative stress)
environmental (pyridine, toxins)
genetic variants

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4
Q

Lewy body

A

toxic alpha-synuclein aggregates found in neurons in patients with PD

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5
Q

MPTP

A
  • contaminant found in a batch of synthetic heroin
  • several people developed PD-like symptoms after taking it
  • when given to experimental animals caused symptoms of PD and death of nigro-striatal cells (but not Lewy bodies)
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6
Q

chemistry of MPTP

A
  • can cross BBB and is taken up by astrocytes
  • oxidized to toxic metabolite MPP+ by glial MAO-B
  • MPP+ taken up via DAT (dopamine transporter) into dopaminergic neurons but also may enter via binding to neuromelanin
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7
Q

medication options for PD

A
  • Levodopa
  • dopamine agonists
  • MAO-B inhibitors
  • COMT inhibitors
  • amantadine
  • anticholinergics
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8
Q

Levodopa examples

A

co-beneldopa (levodopa + benserazide)
co-careldopa (levodopa + carbidopa)

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9
Q

dopamine agonist examples

A

pramipexole
ropinirole
rotigotine skin patch
apomorphine

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10
Q

MAO-B inhibitor examples

A

rasagiline
selegiline
safinamide

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11
Q

COMT inhibitor examples

A

entacapone
opicapone

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12
Q

anticholinergics in PD

A

procyclidine
trihexyphenidyl

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13
Q

TRAP

A

Tremor
Rigidity
Akinesia
Postural instability

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14
Q

why can’t you give Levodopa alone?

A
  • levodopa is hydrophilic but can cross the BBB, however will be metabolised and removed by the liver
  • L-Dopa alone has more peripheral side effects (higher dose needs to be given)
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15
Q

peripheral dopamine side effects

A

cardiac conduction abnormalities
tachycardia/bradycardia
angina
dyspnoea
hypertension/hypotension
nausea
vomiting
headache
anxiety

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16
Q

levodopa side effects

A

sleepiness
hypotensive reactions
impulse control disorders

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17
Q

suddenly stopping levodopa therapy - life-threatening symptoms

A

NEUROLEPTIC MALIGNANCY
- high fever
- sweating
- unstable BP
- muscular rigidity
- autonomic dysfunction

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18
Q

Parkinson’s disease

A

a neurodegenerative disorder featuring accumulation of alpha-synuclein forming Lewy bodies

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19
Q

alpha-synuclein

A

protein involved in regulation of synaptic vesicles and release of synaptic neurotransmitters

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20
Q

genetic cause of PD

A

mutation of genes:
- PINK1
- parkin
- alpha synuclein

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21
Q

neurodegenerative

A

progressive, irreversible loss of neurons

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22
Q

basal ganglia

A
  • regulates motor signalling
  • contains substantia nigra
23
Q

direct pathway

A
  • excitatory pathway facilitates movement
  • inhibitory signal via GABA from striatum to globus pallidus internal and substantia nigra
  • excitation of thalamus via GABA promoting movement
24
Q

indirect pathway

A
  • inhibitory pathway that terminates movement
  • inhibitory signal from striatum to globus pallidus external via GABA
  • stimulates inhibitory effect of globus pallidus internal on the thalamus
  • less movement
25
Q

impaired dopamine metabolism

A

generates reactive oxygen species (ROS) that damage mitochondria which produce more ROS leading to oxidative stress

26
Q

use of NSAIDs

A

decreases risk of developing PD by 45%

27
Q

treatment goals for managing PD

A

maintaining functionality and quality of life for as long as possible during progression of illness

28
Q

general management of PD

A
  • manipulation of standard oral drug therapy which aims to boost dopamine neurotransmission
  • more invasive drug treatments
  • neurosurgery - deep brain stimulation
29
Q

enzymes that metabolise DA and L-Dopa

A
  • COMT catechol-O-methyl transferase
  • AADC aromatic amino acid decarboxylase (dopa decarboxylase)
  • MAO monoamine oxidase
30
Q

carbidopa/benserazide

A
  • decarboxylase inhibitor
  • prevents L-Dopa breakdown in the periphery
  • increases plasma half-life of L-dopa from 50 to 90 min
31
Q

Later stage PD drugs - dealing with increased OFF periods

A
  • intraduodenal gel infusion of levodopa avoids erratic gastric emptying in PD
  • COMT inhibitors like entacapone
  • MAO-B inhibitors like selegiline that reduce off time and prolong levodopa action
  • anticholinergic drugs but beware of side effects
32
Q

apomorphine indications

A
  • titrated in patients during “off-stage”
  • once titrated, can be used in conjunction with levodopa
  • subcutaneous injection, fast acting but only lasts 100 minutes
  • infusion is possible but risks side effects
33
Q

Levodopa efficacy (NICE guidelines)

A
  • more improvement in motor symptoms
  • more improvement in day-to-day activities
  • more motor complications
  • fewer specified adverse effects
34
Q

dopamine agonist efficacy (NICE guidelines)

A
  • less improvement in motor symptoms
  • less improvement in day-to-day activities
  • fewer motor complications
  • more specified adverse effects
35
Q

MAO-B inhibitors efficacy (NICE guidelines)

A
  • less improvement in motor symptoms
  • less improvement in day-to-day activities
  • fewer motor complications
  • fewer specified adverse effects
36
Q

amantadine indication

A
  • mechanism unclear: NMDA antagonism, dopamine release increased
  • may also be prescribed if dyskinesias are difficult to manage conventionally
37
Q

late-stage PD - nil-by-mouth patients?

A

(swallowing affected by PD):
NG tube
subcutaneous apomorphine
transdermal rotigotine patch

38
Q

managing confusion/hallucinations/agitation

A
  • only if necessary treat with benzodiazepines
  • avoid first-generation antipsychotics e.g. haloperidol or chlorpromazine (quetiapine/clozapine suggested)
39
Q

managing dizziness and falls

A
  • PD medications and PD itself may be associated with orthostatic hypotension (check standing PB)
  • avoid drugs which precipitate postural hypotension
40
Q

managing nausea and vomiting (PD risk of aspiration of vomit - pneumonia)

A
  • use domperidone oral 10mg every 8 hours, max. duration one week (associated with cardiac complications)
  • cyclizine oral/IM/IV 50mg every 8 hours (in elderly use 25mg) or ondansetron (unlicensed use/constipation as s/e and not desirable in PD) are also appropriate
41
Q

management of constipation in PD

A
  • dopamine receptors in GI tract slows down peristalsis
  • bulk laxatives used
  • fybogel
42
Q

restless leg syndrome

A
  • discomfort, aching or twitching of legs
  • only improves with movement
  • ropinirole used in addition to L-dopa
43
Q

management of postural hypotension in PD

A
  • fludrocortisone first line
  • mineral corticoid that increases blood volume and BP
  • maintains sodium and water retention
  • caution in patients with hypertension
44
Q

management of urinary incontinence in PD

A
  • mirabegron used
  • avoid oxybutynin as anticholinergic
45
Q

non-pharmacological management of PD

A
  • provide written info
  • direct to support groups/IT access
  • review driving (DVLA)
  • lifestyle: exercise, diet, sleep hygiene
  • refer to MDT: speech/language therapy, physiotherapy, occupational therapists
46
Q

first-line treatment of PD in younger patients

A
  • monotherapy of dopamine agonists used to avoid extrapyramidal side effects with long term treatment with L-Dopa
  • more cost effective
  • more range of strengths allows more efficient titration and management of side effects
47
Q

ergot-derived dopamine agonists

A

bromocriptine
pergolide
cabergoline

48
Q

non ergot-derived dopamine agonists

A

pramipexole
ropinirole
rotigotine

49
Q

drug formulations used for ‘on and off’ periods of PD

A
  • IR formulations used in morning after waking
  • MR formulations used at bedtime to control symptoms like rigidity/insomnia
  • orodispersible formulation for rapid onset for acute cases during the day
50
Q

ergot-derived dopamine agonists complications

A

risk of lung and heart valve fibrosis

51
Q

molecular pathology - inflammation and PD

A
  • phagocytosis of debris and apoptotic cells initiates an immune response, but uncontrolled inflammation results in production of neurotoxic factors
  • increased levels of released inflammatory cytokines and NO production + recruitment of other immune cells (microglia and astrocytes (glial cells))
  • antibodies to proteins modified by dopamine oxidation products
52
Q

molecular pathology - mitochondrial dysfunction and PD

A
  • mitochondria provide cells with energy to perform vital functions (highly dynamic proteins)
  • in PD, mitochondria can’t sustain proper neuronal function
  • as they become old/damaged, they are removed and replaced however in PD, this recycling is disrupted leading to the accumulation of damaged mitochondria
53
Q

consequences of mitochondrial dysfunction in PD

A
  • increases oxidative stress
  • misfolding and aggregation of beta-amyloid, alpha-synuclein, tau proteins
  • neuroinflammation
  • neuronal apoptosis
  • chromosome dysregulation
54
Q

gender statistics in PD

A

men aged 50-89 are 1.4x more likely to be diagnosed with PD than women

MP422 (17 decks)

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