Pharmacology and treatment of basal ganglia disorders Flashcards
What is Parkinson’s disorder?
Motor neurodegenerative disorder which affects the basal ganglia.
What is the basal ganglia composed of?
the corpus striatum - putamen and globus pallidus, the caudate nucleus, and the substantia nigra
What dopaminergic pathways does the basal ganglia regulate?
nigro stratal, mesocortical and mesolimbic.
What pathway does Parkinsons affect?
The dopaminergic nigro striatal pathways
What is the role of the basal ganglia?
Regulate movement.
Symptoms of Parkinsons?
tremor, muscle rigidity and hypokinesia.
Why does Parkinson’s cause these symptoms?
Degeneration of the nigro-striatal pathway - loss of DAergic neurons. reduced level of dopamine in the corpus striatum. and this is what causes the motor problems.
What is the tremor caused by?
Low levels of dopamine means ACh levels rise (as they inhibit each other) this activates the muscarinic pathways causing tremors.
Causes of Parkinson’s in heroic addicts>
a breakdown product of heroin is MPTP - this is uptaken by the DA transporter. Inside it is metabolised by MAO and become MPP. this acts on mitochondria and causes the production of ROS - toxic and kills the DAergic neurones.
Treatment of Parkinson’s?
no cure but you can treat the symptoms. Parkisons causes degeneration of the nigrostriatal neurones leading to low levels of DA. treatments involve increasing levels of DA.
How can you increase levels of DA?
block DA reuptake - with drugs derived from cocaine.
activate D2 receptors by a D2 agonist, mimicking DA activity.
increase DA release - more action of D2 receptor
Block MAO which breaks down DA- increasing levels in the synaptic cleft.
What is the main drug used in Parkinson’s treatment and how does it work?
L-dopa: precursor of DA which crosses the blood brain barrier- it enters DAergic neurones and is broken down by decarboxylates to DA.
Given alongside a DC inhibitor to ensure Ldopa isn’t broken down in the periphery, however DC inhibitor can’t pass blood brain barrier.
Side effects of Ldopa?
causes increased DA throughout the brain therefore acts on mesolimbic and mesocortical pathways too. mesolimbic pathway effects - liked with schizophrenia and hyperactive rewards centre causes addiction.
induces vomiting as is acts on the chemoreceptive trigger zone (D2 receptors).
Dyskinesia - due to over treatment - over stimulation of the motor systems causes lack of control.
Narrow therapeutic window
what is the on off effect of Ldopa?
DAergic neurones continue to deteriorate whilst taking Ldopa, and in late stage 5 or 6 people will depend on Ldopa fro any motor control.
At this point Ldopa will have an ‘on/off’ effect with
What is the new treatment of parkinsons?
Deep brain stimulation - a probe is implanted in the dorsal motor region of the sub thalamic nucleus- stimulates motor control
