Flashcards in Regulating Dopamine Levels Deck (81):
Describe the extrapyramidal motor system?
Dopaminergic neurons in substantia nigra give tonic inhibition to cholinergic neurons in corpus striatum
Cholinergic neurons in corpus striatum give excitatory input to inhibitory interneurons
Inhibitory interneurons give inhibitory input to spinal cord
Inhibition of output to skeletal muscle
What happens in Parkinson's disease (PD)?
Death of dopaminergic neurons in substantia nigra
Describe the time course of PD
What is PD a disorder of?
What are the motor signs and symptoms of PD?
Rigidity of limbs
Impairment of postural reflexes
- No blinking
- Decreased manual dexterity
What are the non-motor signs and symptoms of PD?
Raised anxiety levels
Bowel and bladder problems
What is one of the first symptoms of PD?
Lack of smell
How many dopaminergic neurons are destroyed by the time motor deficits emerge?
What is diagnostic of PD?
Reduced dopamine levels
Lewy bodies present at post-morten
How many cases of PD are genetic?
When do genetic cases of PD tend to develop?
At younger age
How many people have no known genetic mutations?
What is the biggest risk factor for developing PD?
What do drugs do in PD?
Provide symptomatic relief
How can dopamine deficiency be restored?
Increase dopamine synthesis
Increase dopamine release
Dopamine receptor agonists
Reduce dopamine metabolism
What is necessary to balance if you're exogenously increasing dopamine levels?
Decrease ACh levels to keep balance
- Via cholinergic antagonists
Does dopamine cross the BBB?
What is L-DOPA converted to in the body?
What is the effect of ingesting dopamine?
How is dopamine stored in the neuron?
Packaged into vesicles
What is reserpine?
What is the gold standard therapy of PD?
How do you increase dopamine synthesis?
What is levodopa?
Amino acid isomer
How much levodopa is metabolised in the periphery?
What is done to increase levodopa bioavailability?
Block dopadecarboxylases (DDC) in peripheral tissues
What are the peripheral effects of levodopa because of its conversion to dopamine and noradrenaline?
What is levodopa formulated with?
Peripheral DDC inhibitor
What is needed for levodopa to work?
Some functional dopaminergic neurons
What are the beneficial effects of levodopa?
Reduces other symptoms
When is levodopa given?
First line of treatment
When is levodopa rapidly absorbed from the stomach?
When it's empty
What does levodopa compete with for uptake?
Other neutral amino acids
What is the half life of levodopa?
What is the plasma concentration of levodopa?
How does the effectiveness of levodopa change over time?
Why does the effectiveness of levodopa change over time?
Continued degeneration of dopaminergic nerves
What is done when levodopa starts to become ineffective?
Incorporate other drugs
What are the peripheral adverse effects of levodopa?
What are the central adverse effects of levodopa?
Visual and auditory hallucinations
Abnormal motor movements
What are the drug interactions of levodopa?
Monamine (MAO) type A inhibitors
What are bromocriptine and cabergoline?
How are bromocriptine and cabergoline used?
Can be used as monotherapy
What are the beneficial effects of bromocriptine and cabergoline?
Improve bradykinesia and rigidity
Why may bromocriptine and cabergoline be preferred in young patients?
Some evidence suggests that giving L-DOPA accelerates progression of PD by increasing IC dopamine levels > causes oxidative stress in neuron > damage > death of dopaminergic neurons
What is pergolide?
How is pergolide used?
Adjunct to levodopa
Why aren't dopamine agonists as good as levodopa?
Because they bind indiscriminately to dopamine receptors, whereas levodopa is taken up selectively by dopaminergic neurons for synthesis of dopamine, and subsequent release
What are the side effects of dopamine agonists?
Similar to levodopa, but some more common:
Dyskinesias less prominent
What does it mean for dosage of levodopa if there is a titration effect?
Different doses for morning and evening
Different doses for different people because don't know how many neurons degenerated with each person
What is selegiline?
MAO type B inhibitor
How do MAO type B inhibitors work?
Reduce metabolism of dopamine
What are the benefits of using MAO type B inhibitors?
No hypertensive crises like with MAO type A inhibitors
Early use may delay disease progression
- Reduced formation of free radicals
What is entacapone?
Catechol-O-methyltransferase (COMT) inhibitor
What do COMT inhibitors do?
Reduce metabolism of L-DOPA
How are COMT inhibitors used?
Adjunct to L-DOPA > increase CNS levels
What are MOA and COMT?
Enzymes involved in the metabolism of dopamine
What is amantadine?
Antiviral in influenza
Observed to reduce rigidity and bradykinesia
How does amantadine work?
Enhances release of dopamine
What are the drawbacks of amantadine?
Less efficacious than L-DOPA
More rapid tolerance
What are the adverse effects of amantadine?
What is the cholinergic activity of amantadine?
Anticholinergic > don't need to give extra anticholinergic
Why are muscarinic receptor antagonists used in the treatment of PD?
Restore dopaminergic-cholinergic imbalance
How are muscarinic receptor antagonists used?
Adjunct to L-DOPA
What are the effects of muscarinic receptor antagonists?
Modest effect on
Little effect on
What are some examples of muscarinic receptor antagonists?
What are the classic anti-muscarinic side effects?
What are the peripheral adverse effects of muscarinic receptor antagonists?
What are the central adverse effects of muscarinic receptor antagonists?
Worsening of dyskinesias
Does deep brain stimulation work in all patients with PD?
What is required for deep brain stimulation to work in PD?
Relatively high levels of dopaminergic neurons
What is alph-synuclein?
Protein monomer of Lewy bodies
What are Lewy bodies made of?
Where are Lewy bodies found?
Deposits inside neurons in affected brain areas in PD
What can cause PD?
Several mitochondria-related genes when mutated
What is believed to be the toxic drivers of PD?
Small oligomers of alpha-synuclein
Does smoking increase or decrease your risk of developing PD?
Which pesticides have been linked to high incidence of PD?
Which areas are first affected in PD?
Loss of smell
Loss of gut motility
What does some evidence suggest stabilises alpha-synuclein oligomers?