PARKINSON'S DISEASE Flashcards
1
Q
key molecular pathologies of Parkinson’s disease
A
oxidative stress
mitochondrial dysfunction
alpha-synuclein within Lewy Bodies
neuroinflammation
2
Q
Parkinsonism symptoms
A
dysregulation of motor function
- bradykinesia slowness of movement)
- tremor at rest
- rigidity/freezing/expressionless face
- postural instability
- akinesia
- hypokinesia
3
Q
factors that trigger PD
A
normal dopamine metabolism (oxidative stress)
environmental (pyridine, toxins)
genetic variants
4
Q
Lewy body
A
toxic alpha-synuclein aggregates found in neurons in patients with PD
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)
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
7
Q
medication options for PD
A
- Levodopa
- dopamine agonists
- MAO-B inhibitors
- COMT inhibitors
- amantadine
- anticholinergics
8
Q
Levodopa examples
A
co-beneldopa (levodopa + benserazide)
co-careldopa (levodopa + carbidopa)
9
Q
dopamine agonist examples
A
pramipexole
ropinirole
rotigotine skin patch
apomorphine
10
Q
MAO-B inhibitor examples
A
rasagiline
selegiline
safinamide
11
Q
COMT inhibitor examples
A
entacapone
opicapone
12
Q
anticholinergics in PD
A
procyclidine
trihexyphenidyl
13
Q
TRAP
A
Tremor
Rigidity
Akinesia
Postural instability
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)
15
Q
peripheral dopamine side effects
A
cardiac conduction abnormalities
tachycardia/bradycardia
angina
dyspnoea
hypertension/hypotension
nausea
vomiting
headache
anxiety
16
Q
levodopa side effects
A
sleepiness
hypotensive reactions
impulse control disorders
17
Q
suddenly stopping levodopa therapy - life-threatening symptoms
A
NEUROLEPTIC MALIGNANCY
- high fever
- sweating
- unstable BP
- muscular rigidity
- autonomic dysfunction
18
Q
Parkinson’s disease
A
a neurodegenerative disorder featuring accumulation of alpha-synuclein forming Lewy bodies
19
Q
alpha-synuclein
A
protein involved in regulation of synaptic vesicles and release of synaptic neurotransmitters
20
Q
genetic cause of PD
A
mutation of genes:
- PINK1
- parkin
- alpha synuclein
21
Q
neurodegenerative
A
progressive, irreversible loss of neurons
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
impaired dopamine metabolism
generates reactive oxygen species (ROS) that damage mitochondria which produce more ROS leading to oxidative stress
26
use of NSAIDs
decreases risk of developing PD by 45%
27
treatment goals for managing PD
maintaining functionality and quality of life for as long as possible during progression of illness
28
general management of PD
- manipulation of standard oral drug therapy which aims to boost dopamine neurotransmission
- more invasive drug treatments
- neurosurgery - deep brain stimulation
29
enzymes that metabolise DA and L-Dopa
- COMT catechol-O-methyl transferase
- AADC aromatic amino acid decarboxylase (dopa decarboxylase)
- MAO monoamine oxidase
30
carbidopa/benserazide
- decarboxylase inhibitor
- prevents L-Dopa breakdown in the periphery
- increases plasma half-life of L-dopa from 50 to 90 min
31
Later stage PD drugs - dealing with increased OFF periods
- 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
apomorphine indications
- 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
Levodopa efficacy (NICE guidelines)
- more improvement in motor symptoms
- more improvement in day-to-day activities
- more motor complications
- fewer specified adverse effects
34
dopamine agonist efficacy (NICE guidelines)
- less improvement in motor symptoms
- less improvement in day-to-day activities
- fewer motor complications
- more specified adverse effects
35
MAO-B inhibitors efficacy (NICE guidelines)
- less improvement in motor symptoms
- less improvement in day-to-day activities
- fewer motor complications
- fewer specified adverse effects
36
amantadine indication
- mechanism unclear: NMDA antagonism, dopamine release increased
- may also be prescribed if dyskinesias are difficult to manage conventionally
37
late-stage PD - nil-by-mouth patients?
(swallowing affected by PD):
NG tube
subcutaneous apomorphine
transdermal rotigotine patch
38
managing confusion/hallucinations/agitation
- only if necessary treat with benzodiazepines
- avoid first-generation antipsychotics e.g. haloperidol or chlorpromazine (quetiapine/clozapine suggested)
39
managing dizziness and falls
- PD medications and PD itself may be associated with orthostatic hypotension (check standing PB)
- avoid drugs which precipitate postural hypotension
40
managing nausea and vomiting (PD risk of aspiration of vomit - pneumonia)
- 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
management of constipation in PD
- dopamine receptors in GI tract slows down peristalsis
- bulk laxatives used
- fybogel
42
restless leg syndrome
- discomfort, aching or twitching of legs
- only improves with movement
- ropinirole used in addition to L-dopa
43
management of postural hypotension in PD
- fludrocortisone first line
- mineral corticoid that increases blood volume and BP
- maintains sodium and water retention
- caution in patients with hypertension
44
management of urinary incontinence in PD
- mirabegron used
- avoid oxybutynin as anticholinergic
45
non-pharmacological management of PD
- 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
first-line treatment of PD in younger patients
- 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
ergot-derived dopamine agonists
bromocriptine
pergolide
cabergoline
48
non ergot-derived dopamine agonists
pramipexole
ropinirole
rotigotine
49
drug formulations used for 'on and off' periods of PD
- 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
ergot-derived dopamine agonists complications
risk of lung and heart valve fibrosis
51
molecular pathology - inflammation and PD
- 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
molecular pathology - mitochondrial dysfunction and PD
- 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
consequences of mitochondrial dysfunction in PD
- increases oxidative stress
- misfolding and aggregation of beta-amyloid, alpha-synuclein, tau proteins
- neuroinflammation
- neuronal apoptosis
- chromosome dysregulation
54
gender statistics in PD
men aged 50-89 are 1.4x more likely to be diagnosed with PD than women
