Parkinson's Flashcards
How common is Parkinson’s?
2nd most common neurodegenerative disease
What are classic symptoms of Parkinson’s?
Tremor
Rigidity
Slowness of movement - Bradykinesia
Balance problems
Causes of Parkinsonian symptoms
Parkinson’s disease
Stroke
Infection
Drug Induced - drugs that block dopamine receptors
What is Parkinson’s Disease?
Neurodegenerative disease of the basal ganglia and eventually brain stem
Where are neurons lost in Parkinson’s Disease?
The substantia Nigra
What % of neurons are lost in Parkinson’s Disease?
70-80% of neurons that produce dopamine
Why do other mechanisms occur in Parkinson’s Disease?
Compensatory mechanisms for the loss of dopamine
What other levels change in Parkinson’s Disease?
Noradrenaline, GABA, S-HT and neuropeptides
What drives tremors in Parkinson’s Disease?
Relative increase in ACh
What is dopamine?
A neurotransmitter and noradrenaline precursor
What are the 3 main dopaminergic pathways?
Motor control - nigrostriatal pathway - facilitates normal movement
Behaviour/emotion - mesocortical pathway
Endocrine/secretion - tuberohyophyseal pathway
What is used to treat tremors in Parkinson’s Disease?
Antimuscarnics due to increased levels of ACh
How do dopaminergic drugs work?
Increase levels of dopamine in the striatum
- Delivers a precursor to dopamine
- Prevent degradation of dopamine at the neurons
- Stimulates dopamine receptors
What do dopaminergic drugs improve?
Improve bradykinesia and reduce rigidity
How does dopamine replacement therapy work?
Dopamine precursor DOPA is used
Why is a dopamine precursor used?
Dopamine does not cross the BBB
What does Levodopa depend on and why?
Some dopa decarboxylase remaining in the striatal neurons as they break down l-dopa to dopamine
What does Levodopa help with?
Improvement in initiating and stopping movement
Smoother, faster and more controlled movement
Speech
Side Effects of Levodopa
Nausea and vomiting
Postural hypotension and cardiac arrhythmias
Psychiatric disturbances
Urine color change due to metabolic biproduct
GI bleeding
What breaks down dopamine?
COMT is an intra- and extra- cellular enzyme that breaks down dopamine to HVA
What is dopamine broken down into?
Homovanillic acid HVA
What does COMT do?
Breaks down dopamine to regulate dopamine levels to prevent overstimulation of dopaminergic pathways
How does COMT work with L-Dopa?
Breaks down L-Dopa to an inert substance to reduce the amount of active dopamine in peripheral tissue
What does drug therapy in Parkinson’s Disease aim to do?
Increase dopaminergic activity and reduce the relative cholinergic overactivity to restore balance in the basal ganglia
Examples of anti muscarinic drugs
Orphenadrine, trihexyphenidyl and benztropine
Why are antimuscarinic drugs used?
To reduce tremor in Parkinson’s Disease and Parkinsonian symptoms
Side effects of antimuscarinic drugs
Peripheral - dry mouth, constipation and urinary retention
Central - confusion, euphoria and insomnia
What does a loss of dopamine inhibition alter?
The output of the complex basal ganglia circuitry
The pathway of Levodopa
Taken up by the remaining dopaminergic neurons in the substantial nigra
Converted to dopamine by neuronal Dopa Decarboxylase (DDC)
Where is dopamine stored and why?
In the synaptic vessels which protect dopamine from degradation. It stores dopamine to act as a buffer to ensure that dopamine is available for release when needed
What is phasic dopamine release?
Dopamine is released in response to specific stimuli
What is tonic dopamine release?
Sustained, low-level dopamine release
How much of Levodopa is lost to the periphery?
99%
How does Levodopa cross the BBB?
By amino acid transporters including LAT1 and SLC7AA
What does the BBB consist of?
endothelia, glia and pericytes that work to prevent free diffusion
What is given to reduce peripheral side effects?
Peripheral dopa decarboxylase inhibitor
Co-Careldopa
Levodopa and Carbidopa
Reduces peripheral side effects by reducing conversion to dopamine in the periphery. More Levodopa also gets to the BBB
Carbidopa doesn’t cross the BBB
What do peripheral DDC inhibitors do?
Reduce peripheral side effects and increase the half life of Levodopa
1st Line for Parkinson’s Disease
Levodopa and DDC inhibitor
Oral or transdermal dopamine agonists
Mono-amide oxidase B inhibitor
2nd Line for Parkinson’s Disease
Anticholinergics - young people with severe tremor
Beta-adrenergics agonists - for postural tremor
What D do dopamine agonists usually affect?
D1, D2 and D
Dopamine agonist side effects
Excessive daytime fatigue
Peripheral oedema
Hallucination and confusion
Nausea and vomiting
What is dopamine disregulation syndrome?
Uncommon disorder in which dopamingeric medication is associated with behaviours such as pathological gambling, hyper sexuality and stereotypical motor acts
What is different about ergot dopamine agonists?
Specific side effects
Cannot be used in patients with risk of heart valve issues due to cardiac valvulopathy
Cannot be used in patients with serosal fibrosis
What tests are required before beginnging treatment with ergot dopamine agonists?
Regular ECGs
Blood tests
Echocardiograms
Chest x-rays for serosal fibrosis
Long term problems in Parkinson’s Disease
Progressive decline in efficacy of drug therapy
Fluctuations in motor performance
Psychiatric symptoms
What are MOA-B inhibitors?
Reduce breakdown of dopamine
When are COMT inhibitors used?
Used alongside Levodopa in late disease progression
