Parkinson's disease Flashcards
Which dopaminergic pathway in the brain degenerates in Parkinson’s disease?
Nigrostriatal pathway - cell bodies originate in substantia nigra zona compacta (SNC) and project to striatum (putamen and caudate nucleus) - involved in movement
How does loss of dopamine trigger motor clinical symptoms?
Nigrostriatal pathway that is degenerated is involved in movement
Which other neuronal pathways are affected in Parkinson’s disease? What are they involved in?
- Mesolimbic pathway - ventral tegmental area (VTA) –> nucleus accumbens, frontal cortex, limbic cortex, olfactory tubercule - emotion
- Tuberoinfundibular system - arcuate nucleus of hypothalamus –> median eminence + pituitary gland - hormone secretion
- Mesocortical pathway - VTA to cerebrum - executive functions + behaviour patterns
What is the underlying pathological process of PD?
- Severe loss of dopaminergic projection cells in substantia nigra leads to a marked reduction in caudate nucleus/putamen dopamine content
- Lewy bodies (in neuronal cell bodies) + neurites (in axons) - consist of abnormally phosphorylated neurofilaments (ubiquitin, a-synuclein)
- Genetics (5% cases) - SRRK2
What are the principle clinical features of PD?
Motor:
- Postural instability
- Rigidity
- Bradykinesia
- Resting tremor
Non-motor:
- Orthostatic hypotension
- Olfactory deficits
- Neuropsychiatric: sleep disorders, instability, memory loss, depression
- Autonomic NS: constipation
Which drugs are used to treat PD?
- Levodopa - dopamine replacement
- Dopamine receptor agonists
- DOPA-D inhibitors
- MAO-B inhibitors
- COMT inhibitors
Why are anti-Parkinsonian drugs used in conjunction with one another?
- MAO-B inhibitors reduce the dosage of levodopa required + can increase time before levodopa treatment is needed
- The effectiveness of L-dopa declines with chronic use
What is Parkinson’s disease?
Progressive neurodegenerative disorder of movement
How does levodopa alleviate the symptoms of PD?
- Levodopa rapidly crosses BBB
- Converted to dopamine by DOPA-D
How do dopamine receptor agonists alleviate the symptoms of PD?
- Ergot derivatives or non-ergot derivatives
- Potent agonists of D2Rs
How do MAO-B inhibitors alleviate the symptoms of PD?
Selegiline:
- Prevent breakdown of dopamine within brain
- Can be given on its own in early stages of disease
- Or in combination w/L-DOPA –> reduces dose of L-DOPA required –> reduce side effects
Rasagiline (new):
- Neuroprotective effects in-vivo by inhibiting apoptosis
- May also slow disease down?
How do COMT inhibitors alleviate the symptoms of PD?
E.g. tolcapone, entacapone
- Prevent breakdown of dopamine within brain
- Prevents breakdown of L-DOPA –> 3-OMD in periphery
- Tf 3-OMD can’t compete w/L-DOPA for same transport mechanism to cross BBB –> can’t gain access to brain
- Increases amount of L-DOPA in brain
What are the side effects of levodopa?
Acute:
- Nausea and vomiting (also converted to dopamine in periphery)
- Hypotension
- Psychological effects – schizophrenia like syndrome w/delusions and hallucinations
- Confusion, disorientation
- Insomnia, nightmares
Chronic:
- Dyskinesias – abnormal movements which affect face+limbs; start within 2y; disappear if dose reduced but clinical symptoms reappear
- “On-Off” Effects – rapid fluctuations in clinical state, where hypokinesia and rigidity may suddenly worsen
What are the side effects of dopamine receptor agonists?
Ergot derivatives:
- Cardiac fibrosis
- Valvular disease
Non-ergot derivatives do not have these effects
Why are COMT inhibitors given with L-DOPA?
Increase amount of L-DOPA in brain
