6. Pharmacology of movement disorders Flashcards
What is Parkinson’s disease?
Progressive disease of the NS associated with degeneration of the basal ganglia and a deficiency in dopamine
How can PD be recognised histologically?
Loss of dopaminergic cells in the substantia nigra pars compacta
Presence of Lewy bodies
What are Lewy bodies?
Intracellular aggregations of protein alpha-synuclein
What is the relevance for the basal ganglia of reduced cells in the SNpC?
There will be reduced dopaminergic transmission to the caudate and putamen nuclei
What are the common signs and symptoms of PD?
Motor: Rigidity Tremor Bradykinesia (three hallmarks of PD) Also slow gait
Non-motor: Dementia Depression Anxiety Sleep disturbances Olfactory dysfunction - loss of sense of smell Constipation Microphagia - gradual development
What is the pathophysiology of PD?
The substantia nigra pars compacta releases dopamine to the striatum (caudate + putamen)
The dopamine receptor for the direct pathway is D1 and the dopamine is excitatory to this receptor
The dopamine receptor for the indirect pathway is D2 and the dopamine is inhibitory to this receptor
SO the SNpc is tonically activating the direct pathway when movement is required
In PD, there is degeneration of the dopaminergic neurones in the SNpc
The excitatory input to the D1 receptors decreases (direct) and the inhibitory input to the D2 receptors (indirect) increases
SO the indirect pathway is facilitated and becomes dominant
There is an inhibition of the thalamus and this results in a decreased level of activity
What is the prognosis of PD?
This is a progressive disease - motor symptoms will advance aggressively if not treated
The length of the disease is variable - patients typically lose independence after an average of 8 years
What is MTPT and what is it’s effect on PD?
MTPT is methyl-phenyl-tetrahydropyridine
This is transformed into metabolite MPP+ which is neurotoxic to dopaminergic neurones due to increased oxidative stress
This can result in the development of very toxic PD
This may be present in several illicit drugs
What is the problem with the oxidisation of dopamine and how does this occur?
Dopamine is oxidised by MAO (monoamine oxidases)
Dopamine is highly oxidisable by these MAOs and this metabolism results in the production of free radicals which can be damaging
What are the different treatment options for PD?
Dopaminergic compounds e.g. L-dopa MAOb inhibitors Anticholinergic (antimuscarinic) compounds Amantadine COMT inhibitors Surgical grafts Deep brain stimulation
What is the mechanism of action of L-dopa?
Natural precursor of dopamine via DOPA decarboxylase
Formed from L-tyrosine via tyrosine hydroxylase
What are the adverse effects of L-dopa?
Nausea/vomiting Postural hypotension Psychosis Impulse-control disorders Excessive day-time sleepiness
Motor complications: “On-off” effect - start to feel better as soon as you take a dose and then feel worse as your next dosage is due “Wearing-off” Dyskinesia Dystonia
What is the advantage of selegeline?
Reduces oxidation of dopamine so this allows a lower dose of L-dopa to be administered - reduces the motor complications of L-dopa that are experienced by the patient
What is the advantage of rotiglotin?
Administered as a transdermal patch with a slow release over 24 hours - this means that patients do not suffer the ‘on-off’ effect associated with L-dopa
What is the one problem with prescribing ritoglitone for PD?
Not effective in advanced PD - this is problematic when there is disease progression
