Pharmacology of movement Flashcards
What are Lewy bodies?
intracellular formations enriched in the protein alpha-synuclein
What part of the brain is DaT imaging used on? In terms of Parkinson’s, what does this imaging show?
Looks at the striatum
Monitors the dopaminergic nigral cell loss
List some of the features/symptoms of Parkinson’s disease.
Frozen facial expression
Flexed posture
Altered (shuffling) gait
Difficulting initiating + stopping movements
Gradual development of micrographia
Non motor features: olfactory dysfunction, depression, sleep disturbance, cognitive dysfunction
What is the name of the scoring scale for disability that is commonly used for PD patients?
Schwaband England Activities of Daily Living
100% = independent, no slowness/impairment
0% = vegetative functions (swallowing, bladder + bowel) not functioning
List some of the genes implicated in PD.
SNCA LRRK2 GBA PARK2 and PARK7 PINK1
What is the result of defects in the SNCA gene?
it affects alpha-synuclein
it is a rare defect
duplications or triplications can cause autosomal dominant, familial PD
What does MPTP stand for?
Methyl-phenyl-tetrahydropyridine
What converts MPTP to MPP and why is this dangerous?
Monoamine oxidase B converts MPTP -> MPP (1-methyl-4-phenylpyridine)
This is dangerous as MPP is neurotoxic for dopaminergic neurones and can cause mitochondrial toxicity
Does this by inhibiting complex I in the mitochondrial respiratory chain - this reduces ATP production
Name the 3 main dopaminergic pathways in the CNS.
- Mesocortical - ventral tegmental area –> prefrontal cortex
- Nigrostriatal - substantia nigra pars compacta –> dorsal striatum
- Mesolimbic - ventral tegmental area –> ventral striatum
What type of receptors are dopamine receptors?
GPCRs
What receptor subtypes belong to the D1 and D2 families respectively?
D1 family = D1, D5
D2 family = D2, D3, D4
What is L-Dopa combined with peripherally and why?
DOPA decarboxylase inhibitors (Carbidopa and benserazide)
This prevents the conversion of L-Dopa to dopamine in the periphery (outside CNS)
This prevents adverse effects such as nausea and hypotension
Give examples of dopamine agonists.
- ropinirole
- pramipexole
- rotigotine
- pergolide
- bromocriptine
- cabergoline
What is the route of administration of rotigotine?
transdermal patch
What is the route of administration of apomorphine?
infusion
Why might a clinician prescribe MAOB inhibitors to a PD patient?
to preserve residual dopamine against oxidation
Give two examples of MAOB inhibitors.
Rasagiline
Selegiline
Why might a clinician prescribe anticholinergic/antimuscarininc compounds to a patient with PD?
Give examples of such compounds.
Dopamine loss can lead to hyperactivity in cholinergic cells
Examples = orphendarine, procyclidine, trihexyphenidyl
Why might amantadine be an appropriate drug to prescribe to someone with PD?
it inhibits dopamine reuptake and increases dopamine release
Give examples of motor complications associated with L-Dopa use.
“on-off” effect
“wearing off”/tolerance
dyskinesia, dystonia
On what chromosome is the Huntingtin gene found?
Chromosome 4
How is the Huntingtin gene mutated in Huntington’s disease?
gene presents with an abnormal number of repeats of glutamine (CAG codon)
An abnormal gene will contain >36 repeats leading to a GAIN of function (the mutated protein will aggregate inside of cells)
What physical changes to the brain occur in Huntington’s?
Cortical atrophy
Striatal degeneration
Loss of medium size spiny neurones
What are some of the mechanisms underlying neurodenegeration in Huntington’s?
Excitotoxicity (due to increases glutamate)
Loss of neurotrophic facotrs
Accumulation of aggregates of mutant huntingtin protein
Dysregulation of transcription
Increased oxidative stress
Abnormalities in axonal transport
Synaptic abnormalities
