Anti-PD drugs & Neuroleptics Flashcards
Summarise the synthesis pathway of dopamine in the presynaptic cell, stating the enzymes involved.
Step 1: L-tyrosine => L-DOPA
Step 2: L-DOPA => Dopamine (DA)
This process utilises the enzymes: Tyrosine hydroxylase (Step 1) DOPA decarboxylase (Step 2)
Summarise the metabolism of dopamine after it has had its effects on the post-synaptic cell
DA removed from synaptic cleft by dopamine transporter (DAT) & noradrenaline transporter (NET) found on the pre-synaptic cell and glial cell membrane.
Three enzymes metabolise DA:
- MAO-A metabolises DA, NE & 5-HT
- MAO-B: metabolises DA
- Catechol-O-methyl transferase (COMT): wide distribution, metabolises all catecholamines
*MAO-A/B are mitochondrial
What are the four dopaminergic pathways in the brain?
Nigrostriatal pathway
Mesolimbic pathway
Mesocortical pathway
Tuberoinfundibular pathway
For each of the four dopaminergic pathways in the brain, state the brain regions that are connected. Give details on what each pathway is important for.
Nigrostriatal pathway - susbstantia nigra pars compacta (SNc) to the striatum
Mesolimbic pathway - ventral tegmental area (VTA) to the Nucleus Accumbens (NAcc) = brain reward pathway.
Mesocortical pathway - VTA to the cerebrum. Important in executive functions & complex behavioural patterns.
Tuberoinfundibular pathway - arcuate nucleus to the median eminence (inhibition results in hyperprolactinaemia)
Describe the epidemiology of Parkinson’s disease;
- major risk factor
- hereditary aspect
Major risk factor is age
Around 5% of cases are due to mutations in certain genes
Identify the main cause of Parkinson’s disease.
Severe loss of dopaminergic projection cells in SNc
What is also seen in the brains of patients with Parkinson’s disease? What do they consist of specifically and where in the neurone are they each found?
Lewy bodies found within neuronal cell bodies
Lewy neurites found within neuronal cell axons
Consist of abnormally phosphorylated neurofilaments, ubiquitin & 𝛼-synuclein
Clinical presentation of PD; motor symptoms (cardinal symptoms)
resting tremor
bradykinesia
rigidity
postural instability
What other non-motor symptoms are associated with PD? Why are these symptoms important to detect for the treatment of PD?
Autonomic nervous system effects;
- olfactory deficits
- orthostatic hypotension
- constipation
Neuropsychiatric;
- sleep disorders, memory deficits, depression, irritability
These symptoms usually appear early in the disease progression (before any motor symptoms) and so early treatment for PD = better prognosis.
State the rate limiting enzyme in the dopamine synthesis pathway.
Tyrosine hydroxylase (TH)
State the first form of treatment for PD
Dopamine replacement by administering L-DOPA aka Levodopa
Explain why L-DOPA is administered instead of dopamine directly
Levodopa can cross blood-brain barrier and be rapidly converted to dopamine by DOPA-D.
Dopamine when administered directly, will not be able to get into the CNS where it is required.
What are the long-term side effects of Levodopa use?
- Dyskinesias (abnormal movements)
- ‘on-off’ effects (fluctuations in clinical state)
- Improves quality of life but doesn’t prolong life
Peripheral breakdown of Levodopa by DOPA-D causes what negative symptoms?
Nausea & Vomiting
What adjuncts may be used to prevent peripheral breakdown of Levodopa? Explain why
DOPA decarboxylase inhibitors = Carbidopa & Benserazide
that importantly do not cross the BBB (remember that Levodopa CAN)
Therefore they prevent peripheral, and not central, breakdown of levodopa
=> Reduces required levodopa dosage and reduce the acute side effects
