Parkinson's Disease Flashcards
What is Parkinson’s disease? What is it characterised by?
progressive neurodegenerative disorder
- pathological hallmark is the presence of Lewy bodies
= this causes degeneration of the dopaminergic neurones in the substantia nigra
What is the pathophysiology of PD?
selective degeneration of the substantia and their connections to the striatum, results in a fall in the nigrostriatal dopamine (DA) levels
- this leads to excessive inhibition of the thalamus which in turn reduces cortical stimulation
there is also a relative increase in acetylcholine activity in the striatum
there is evidence for the role of oxidative stress in PD
the SN contains increased levels of iron which is a catalytic agent for the production of hydroxyl radical.
levels of reduced form of glutathione are decreased in the midbrain
impaired protein clearance or the overwhelming production of abnormal protein may play a role in the degeneration of dopamine-containing neurones
ubiquitin-proteosome system (UPS)
- is the main biochemical pathway responsible for the degradation of normal and abnormal intracellular proteins
= failure of the UPS could be a common factor underlying protein accumulation or lewy body formation
What are the possible causes of PD?
environmental factors
- exposure to pesticides shows the most association
- survivors of an encephalitis epidemic developed PD
- exposure to methylphenyltetrahydropyridine (MPTP)
= is transported into DAergic cells via DAT
= converted into MPP+ by MAOb
= MPP+ generates free radicals that causes mitochondrial poisoning leading DAergic cell death
most cases of PD are now believed to be “complex traits”
- attributable to a combination of 1 or more susceptibility genes with 1 or several environmental factors
What are the clinical symptoms of PD?
disorder of voluntary movement
- tremor at rest, rigidity, bradykinesia, akinesia, paucity of facial expressions, slow monotonous speech, micrographia
associated symptoms
- sialorrhoea, dysphagia, constipation, dementia, depression, postural hypotension, urinary problems, sensory impairment
What are the types of treatment?
monotherapy vs adjunct therapy
mono therapy
- levodopa + dopa decarboxylase inhibitor
- DA receptor agonists
- MAOb inhibitors
adjunct therapy
- COMT inhibitors = used alongside levodopa + dopa decarboxylase
anticholinergics are only used in drug induced PD
Should anti PD therapy ever be stopped immediately?
no
- there is a small risk of neuroleptic malignant syndrome occurring
How does levodopa work? What does it need?
levodopa is a precursor to dopamine
- is a prodrug
- is absorbed across the blood brain barrier
- is metabolised peripherally resulting in side effects (nausea, vomiting, postural hypotension)
must be given with a dopa decarboxylase inhibitor
- reduces peripheral conversion of levodopa to dopamine
- allows lower doses of levodopa to be given
= benserazide in co-beneldopa, carbidopa in co-careldopa
Who can levodopa be used in? How should it be used?
it can be used in elderly or frail patients with significant illnesses and those with more severe symptoms
levodopa therapy should be initiated at a low dose and increased in small steps
- the final dose should be as low as possible
What are the side effects of co-beneldopa and co-careldopa (levodopa combo)? How can they be countered?
nausea and vomiting
- can only use domperidone as an anti-emetic (does not cross the BBB)
is associated with development of motor complications
- response fluctuations
= characterised by large variations in motor function with ON and OFF periods
- end of dose deterioration
= the duration of benefit after each dose becomes progressively shorter (MR levodopa may be useful)
impulse control disorders
- gambling, binge eating, hyper sexuality
excessive daytime sleepiness and sudden onset of sleep
How do dopamine receptor agonists work? What are the different types? Which should be avoided and why?
acts directly on dopamine receptors
ergot derived - bromocriptine, carbergoline
non-ergot derived - pramipexole, rotigotine, ropinirole
avoid ergot derived (cannot be 1st line)
- fibrotic reactions can occur
What are two examples of dopamine receptor agonists?
apomorphine
- useful in patients with unpredictable OFF periods
- highly emetogenic
= patients must be on domperidone for at least two days before starting treatment
amantadine
- anti-viral
- improves mild bradykinetic disabilities and tremors/rigidity
- tolerance to effects may develop alongside hallucination/confusion
What are side effects of DA receptors agonists?
nausea & vomiting
hypotension
psychiatric - confusion/hallucination
sudden onset of sleep
fibrotic reactions (only ergot –derived dopamine receptor agonists)
- bromocriptine, cabergoline
How do MAOb inhibitors work? What are the different types?
inhibit the activity of MAOb which typically degrade dopamine in the CNS
- used in conjunction with levodopa to reduce end of dose deterioration and levodopa dose
dietary restrictions are not needed unlike MAOa inhibitors
selegiline, rasagiline, safinamide
How do COMT inhibitors work? What are the different types?
inhibits catechol-O-methyltransferase (COMT) which typically breaks down levodopa
- slows elimination of levodopa
= must be used as adjunct therapy with levodopa + dopa decarboxylase inhibitors
entacapone
- acts peripherally
- allows reduction of levodopa dose by 10-30%
- side effects = diarrhoea and abdominal pain
= stalevo is the levodopa, carbidopa and entacapone combination
tolcapone
- acts peripherally and centrally
- more effective than entacapone but can only be used under specialist therapy due to liver toxicity
What are other symptoms associated with PD medications? How can they be treated?
daytime sleepiness
- modafinil = inhibits DA reuptake by binding to DAT
rapid eye movement, sleep behaviour disorder
- clonazepam, melatonin
nocturnal akinesia
- rotigotine cannot be used if they have nocturnal akinesia (due to patches formulation)
orthostatic/postural hypotension
- midodrine (vasoconstrictor), fludrocortisone
sialorrhoea
- glycopyrronium bromide (anti-muscarinic) only if benefits outweigh the adverse effects
