PARKINSON'S DISEASE Flashcards
key molecular pathologies of Parkinson’s disease
oxidative stress
mitochondrial dysfunction
alpha-synuclein within Lewy Bodies
neuroinflammation
Parkinsonism symptoms
dysregulation of motor function
- bradykinesia slowness of movement)
- tremor at rest
- rigidity/freezing/expressionless face
- postural instability
- akinesia
- hypokinesia
factors that trigger PD
normal dopamine metabolism (oxidative stress)
environmental (pyridine, toxins)
genetic variants
Lewy body
toxic alpha-synuclein aggregates found in neurons in patients with PD
MPTP
- 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)
chemistry of MPTP
- 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
medication options for PD
- Levodopa
- dopamine agonists
- MAO-B inhibitors
- COMT inhibitors
- amantadine
- anticholinergics
Levodopa examples
co-beneldopa (levodopa + benserazide)
co-careldopa (levodopa + carbidopa)
dopamine agonist examples
pramipexole
ropinirole
rotigotine skin patch
apomorphine
MAO-B inhibitor examples
rasagiline
selegiline
safinamide
COMT inhibitor examples
entacapone
opicapone
anticholinergics in PD
procyclidine
trihexyphenidyl
TRAP
Tremor
Rigidity
Akinesia
Postural instability
why can’t you give Levodopa alone?
- 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)
peripheral dopamine side effects
cardiac conduction abnormalities
tachycardia/bradycardia
angina
dyspnoea
hypertension/hypotension
nausea
vomiting
headache
anxiety
levodopa side effects
sleepiness
hypotensive reactions
impulse control disorders
suddenly stopping levodopa therapy - life-threatening symptoms
NEUROLEPTIC MALIGNANCY
- high fever
- sweating
- unstable BP
- muscular rigidity
- autonomic dysfunction
Parkinson’s disease
a neurodegenerative disorder featuring accumulation of alpha-synuclein forming Lewy bodies
alpha-synuclein
protein involved in regulation of synaptic vesicles and release of synaptic neurotransmitters
genetic cause of PD
mutation of genes:
- PINK1
- parkin
- alpha synuclein
neurodegenerative
progressive, irreversible loss of neurons
basal ganglia
- regulates motor signalling
- contains substantia nigra
direct pathway
- excitatory pathway facilitates movement
- inhibitory signal via GABA from striatum to globus pallidus internal and substantia nigra
- excitation of thalamus via GABA promoting movement
indirect pathway
- 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
impaired dopamine metabolism
generates reactive oxygen species (ROS) that damage mitochondria which produce more ROS leading to oxidative stress
use of NSAIDs
decreases risk of developing PD by 45%
treatment goals for managing PD
maintaining functionality and quality of life for as long as possible during progression of illness
general management of PD
- manipulation of standard oral drug therapy which aims to boost dopamine neurotransmission
- more invasive drug treatments
- neurosurgery - deep brain stimulation
enzymes that metabolise DA and L-Dopa
- COMT catechol-O-methyl transferase
- AADC aromatic amino acid decarboxylase (dopa decarboxylase)
- MAO monoamine oxidase
carbidopa/benserazide
- decarboxylase inhibitor
- prevents L-Dopa breakdown in the periphery
- increases plasma half-life of L-dopa from 50 to 90 min
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
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
Levodopa efficacy (NICE guidelines)
- more improvement in motor symptoms
- more improvement in day-to-day activities
- more motor complications
- fewer specified adverse effects
dopamine agonist efficacy (NICE guidelines)
- less improvement in motor symptoms
- less improvement in day-to-day activities
- fewer motor complications
- more specified adverse effects
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
amantadine indication
- mechanism unclear: NMDA antagonism, dopamine release increased
- may also be prescribed if dyskinesias are difficult to manage conventionally
late-stage PD - nil-by-mouth patients?
(swallowing affected by PD):
NG tube
subcutaneous apomorphine
transdermal rotigotine patch
managing confusion/hallucinations/agitation
- only if necessary treat with benzodiazepines
- avoid first-generation antipsychotics e.g. haloperidol or chlorpromazine (quetiapine/clozapine suggested)
managing dizziness and falls
- PD medications and PD itself may be associated with orthostatic hypotension (check standing PB)
- avoid drugs which precipitate postural hypotension
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
management of constipation in PD
- dopamine receptors in GI tract slows down peristalsis
- bulk laxatives used
- fybogel
restless leg syndrome
- discomfort, aching or twitching of legs
- only improves with movement
- ropinirole used in addition to L-dopa
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
management of urinary incontinence in PD
- mirabegron used
- avoid oxybutynin as anticholinergic
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
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
ergot-derived dopamine agonists
bromocriptine
pergolide
cabergoline
non ergot-derived dopamine agonists
pramipexole
ropinirole
rotigotine
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
ergot-derived dopamine agonists complications
risk of lung and heart valve fibrosis
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
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
consequences of mitochondrial dysfunction in PD
- increases oxidative stress
- misfolding and aggregation of beta-amyloid, alpha-synuclein, tau proteins
- neuroinflammation
- neuronal apoptosis
- chromosome dysregulation
gender statistics in PD
men aged 50-89 are 1.4x more likely to be diagnosed with PD than women
