PD and Movement Disorders Flashcards
What are movement disorders caused by?
dysfunction within the basal ganglia
What are hyperkinetic movement disorders?
conditions that are associated with abnormal or increased body movements
What are hypokinetic movement disorders?
conditions that slow down body movements e.g. Parkinson’s disease
What are the 5 main categories of abnormal movement disorders?
- tremor – involuntary oscillating movement
- chorea – brief, semi-directed, non-rhythmic, dance-like movements
- dystonia – sustained or repetitive movements that result in twisting or other abnormal postures of the body
- myoclonus – rapid, lightning-like twitch of a muscle group that results in a brief jerk
- tics – sudden, repetitive, non-rhythmic movement or vocalisation involving discrete muscle groups
What is PD?
a hypokinetic extrapyramidal motor disorder characterised by bradykinesia, rigidity and tremor
What are the secondary manifestations of PD?
- shuffling gait
- mask like face
- sialorrhea
- autonomic dysfunction
- dementia
What are symptoms of end-stage PD?
- rigid
- unable to move
- unable to breath properly
- succumbs to chest infections/embolism
What is the most common form of PD?
primary idiopathic PD
What can secondary PD be caused by?
- stroke
- viral infections
- vascular lesions
- drugs
- gene mutations (Parkin, α-synuclein)
- neurotoxin (MPTP)
- the environment
What is the neuronal damage of PD?
selective loss of the pigmented, dopaminergic neurons in the substantia nigra
What is the neuronal damage of PD caused by?
- Lewy bodies
- excitotoxicity
- mitochondrial dysfunction
- oxidative stress
- inflammation
- apoptosis
What are Lewy bodies?
misfolding and aggregation of α-synuclein that causes it to degrade within the cells
What is the normal function of α-synculein?
vesicle recycling
What does a pathological specimen from a PD patient compared to a normal control demonstrate?
- reduction of pigment in SNc
- reduced number of cells in SNc
- Lewy bodies within melanised dopamine neurons
What are the 4 steps of the SN pathway in PD?
- destruction of substantia nigra prevents inhibitory action of dopamine on striatum D2 receptors
- striatum inhibits GPe
- GPe is unable to inhibit STN
- STN excites GPi which inhibits the thalamus
What are the 3 drug types used in PD?
- dopamine agents e.g. dopamine precursor, peripheral decarboxylase inhibitor, dopamine agonist, COMT inhibitor and MAO-B inhibitor
- non-dopaminergic agents e.g. anticholinergic, anti-glutamergic and GABAergic
- others e.g. atypical neuroleptic
What is the mechanism of action of levodopa?
transported into the CNS and converted to dopamine (also can be converted in the periphery)
What are the effects of levodopa?
- ameliorates all motor symptoms of PD
- causes significant peripheral dopaminergic effects
Why is levodopa not always used as the first drug to treat PD?
due to its potential of long-term complications (tolerance)
What is levodopa metabolised by?
decarboxylase
Why is levodopa administered alongside carbidopa?
- carbidopa inhibits peripheral metabolism of levodopa to dopamine
- reduces required dosage and toxicity
- more levodopa reaches the brain
- carbidopa does not enter CNS
What are strengths of levodopa?
- most effective symptomatic therapy in PD
- acceptable tolerability profile
- improvements in quality of life seen in short term
What are limitations of levodopa?
- short half life (~1 hour)
- only a small % reaches the brain
- early wearing-off leading to reduced quality of life
- motor fluctuations and dyskinesia will develop over longterm treatment
What is the mechanism of action of the dopamine agonist pramipexole?
direct agonist at D2 receptors (non-ergot)
What are the effects of pramipexole?
- reduces PD symptoms
- smooths out fluctuations in levodopa response
What are the side effects of pramipexole?
- nausea and vomiting
- postural hypotension
- dyskinesia
- confusion
- impulse control disorders
- sleepiness
What is the mechanism of action of the MAO inhibitor selegiline?
- inhibits MAO-B selectively
- higher doses inhibit MAO-A
What are the effects of selegiline?
- increases dopamine stores in neurons
- smooths levodopa response
- may have neuroprotective mechanisms
What are the side effects of selegiline?
serotonin syndrome with SSRIs and TCAs
What is the mechanism of action of the COMT inhibitor entacapone?
inhibits COMT in periphery and does not enter CNS
What are the effects of entacapone?
reduces metabolism of levodopa and prolongs its action
What are the side effects of entacapone?
nausea, dyskinesia and confusion
What do anticholinergic drugs aim to do?
decrease ACh levels and increase dopamine levels
What is the mechanism of action of the anticholinergic benztropine?
antagonist at M receptors in basal ganglia
What are the effects of benztropine?
reduces tremor and rigidity with little effect on bradykinesia
What are side effects of benztropine?
typical antimuscarinic effects e.g. sedation, mydriasis, urinary retention, constipation, confusion and dry mouth
What do dopaminergic neurons originating in the SN normally do?
inhibit the GABAergic output from the striatum (cholinergic neurons exert an excitatory effect)
Give examples of other PD drugs
- anti-glutaminergic drugs e.g. amantadine
- antipsychotic drugs e.g. quetiapine
- GABAergic drugs e.g. benzodiazepines (lorazepam and clonazepam)
Give examples of newer PD drug targets
- enhance the clearance of misfolded proteins and reduce their transmission and thereby the progress of neuronal damage
- improve the function of mitochondria
- target neuroinflammation
