Dopamine is the main neurotransmitter involved in Parkinson’s, where in the brain does it take effect?
Brain stem - Vomiting Centres
Basal Ganglia - Initiating/Controlling Movement
Limbic System & Frontal Cortex - Reward Centres
How does Parkinson’s happen again?
Loss of dopaminergic nigrostriatal fibres in the substantia nigra. Causing a dopamine deficiency in the basal ganglia.
How/where is dopamine synthesised?
Dopamine is synthesised in both the brain and periphery but only its precursors can cross the BBB.
Tyrosine -> DOPA -> Dopamine
If Dopamine itself can’t cross the BBB how do we deliver it as a drug?
We give DOPA as a precursor.
We have to block the AAAD enzyme in the liver to prevent the DOPA being converted to dopamine before it reaches the Brain
Explain the variety of dopamine receptors?
D1-D5 receptors (All metabotropic i.e. G-protein coupled)
Different receptors appear in different parts of the brain
What drug categories are there for Parkinson’s?
Dopamine breakdown Inhibitors (used to extend half life of levodopa)
What enzymes are targeted by Dopamine breakdown Inhibitors?
What is used as a dopamine precursor?
What does it mean to say Levodopa has a “half Life”?
It becomes progressively less effective over time as dopaminergic neurons are lost and the brain can no longer convert it to dopamine
How do we extend levodopa’s half life?
With Dopamine breakdown Inhibitors acting on MAO-B and COMT
List some dopamine breakdown inhibitors?
Selegiline, Rasagiline & Safinamide
Entacapone & Tolcapone
We also use enzyme inhibitors to reduce Levodopa consumption in the periphery, how and why?
Carbidopa & Benserazide are AAAD inhibitors preventing conversion of Levodopa -> Dopamine in the periphery.
This allows more oral levodopa to reach the brain and reduces PNS side effects
List some dopamine agonists?
Ergots - Stimulate fibrosis and very dirty so no longer in use
Non-ergots - Not as effective as Levodopa
Apomorphine - Heavily stimulates brainstem dopamine receptors making it a powerful emetic
What are the benefits of dopaminergic drugs?
Improves motor features of parkinson’s:
But doesnt improve things like cognition, balance or dysarthia
What are the side effects of dopaminergic drugs?
Brainstem - N/V
Limbic system/frontal lobe - Psychosis and impulsive/abnormal behaviours
Given the side effects of dopaminergic drugs, what could dopamine antagonists be used for?
Long-term psychosis treatment
What is the obvious side effect of Dopamine antagonists?
Parkinson’s Syndrome, hence they really shouldnt be used in people with parkinsons in the first place
Domperidone is a notable dopamine antagonist, what is it used for?
As an anti-emetic because it doesnt cross the BBB, but the vomiting centre in the medulla is actually outside it.
This means domperidone won’t treat psychosis but will be anti-emetic without worsening parkinson’s.
Hence its used in conjunction with apomorphine to prevent the emetic effect of the dopamine agonist