Anti-parkinsonian drugs and neuroleptics Flashcards
(44 cards)
What are 4 major dopaminergic pathways in the brain
Nigrostriatal - MOST IMPORTANT for PD
Mesolimbic
Mesocortical
Tuberoinfundibular
What is the nigrostriatal pathway and what is it important in? What condition is this impacted in
Substantia nigra zona compacta -> striatum
Important in initiating, fine tuning and ending movement control
Impacted in parkinsons
What is the mesolimbic pathway and what is it important in? What condition is this impacted in
VTA -> NAcc (nucleus accumbens), frontal cortex, limbic cortex, olfactory tubercle
Involved in emotion, and is brain reward pathway
Impacted in schizophrenia
What is the mesocortical system and what is it important in
VTA (ventral tegmental area) -> cerebrum
Important in executive functions and complex behavioural patterns
What is the difference in the amount of men and women affected by parkinsons
4x as many men as women
What are causes of parkinsons
Familial cases are 8% of cases
Idiopathic is 92% of cases
What are the 4 cardial motor symptoms of parkinsons?
Resting tremor
Rigidity
Bradykinesia
Postural instability
What are ANS effects of parkinson’s disease
Olfactory deficits, orthostatic hypotension, constipation
What is the main affected area in PD
Substantia nigra (pars compacta) which projects into the caudate and putamen
What does the substantia nigra lose in PD
Loss of dopaminergic projection cells in SNc and neuro melanin pigment (the function of this is unknown)
What are lewy bodies and neurites, where are they found and what do they consist of?
Aggregations of proteins in neuronal cell bodies and axons respectively, and consist of abnormally phosphorylated neurofilaments; ubiquitin and alpha-synuclein
What are the different stages of parkinson’s and what happens in them
Stages 1 & 2 – Synuclein deposition in the DM, RN and LC – pre-symptomatic.
Stages 3 – Synuclein deposition in SN – onset of motor deficits.
Stage 4, 5, 6 – deposition in the amygdala and cortical areas.
Synthesis of dopamine
L-Tyrosine -> L-DOPA (via tyrosine hyroxylase - rate limiting) -> Dopamine (via DOPA decarboxylase) in the neurone and stored in the neurone vesicle
Dopamine metabolism
Different ways
- DA removed from synaptic cleft via dopamine transporter and noradrenaline transporter and sends it back to neuronal cell - recycles dopamine
- enzymatic metabolism with different enzymes:
- MAO-A breaks down DA, NE and 5HT, MAO-B breaks down DA, COMT breaks down all catecholamines
What is the tuberoinfundibular pathway and what is it involved in
Acuate nucleus -> median eminance
Endocrine pathway where inhibition leads to hyperprolactinaemia - not really targeted for PD/Schizophrenia drugs but can account for some side effects
What are neuropsychiatric symptoms of PD
Sleep disorders
Memory deficits
Depression
Irritability
PD treatment options:
- dopamine replacement
2. receptor activation via dopamine receptor activation
What drug is given for dopamine replacement and why is dopamine not given directly
Give L-DOPA aka levodopa because tyrosine hyroxylase making L-DOPA is the rate limiting step so you skip that step but dopamine not given directly because it causes effects in the periphery before reaching the CNS
Body can convert L-DOPA into DOPA decarboxylase
Why does dopamine replacement work as an effective treatment for PD symptoms
Because the dopamine D2 receptors in the brain still exist, it is only the dopamine forming cells in the nigrostriatal tract that are degenerating, therefore giving dopamine replacement makes the cells that still are there work overtime to make enough dopamine
Side effect of Levodopa
Can cause induced dyskinesias (sudden uncontrolled movement due to too much dopamine) and on/off effects as dopamine can just run out - doesn’t mimic natural dopamine release.
Peripheral breakdown of DOPA-D can lead to nausea and vomiting
And it is not disease modifying - increases quality of life but doesn’t affect survival
What some commonly used DOPA decarboxylase inhibitors
Carbidopa and benserazide
What drugs are given with Levodopa to help with nausea and vomiting
DOPA decarboxylase inhibitors - they don’t cross BBB but protects the levodopa from breaking down peripherally, this can also allow you to reduce dose of levodopa as it is not lost in periphery
What drugs can be given with Levodopa to increase time that levodopa is effective in the brain
COMT inhibitors eg Entacapone and tolcapone as they prevent breakdown of dopamine it increases the amount in the brain. Reduces on/off effect
What are examples of dopamine receptor agonists
- Ergot derivative: Bromocriptine or pergolide that act as potent D2R agonists
- Non-ergot derivatives (synthetic):
Ropinirole and Rotigotine - MAO B inhibitors eg selegilinen and rasagiline (cheese reaction)
