Parkinsons and Neuroleptic Flashcards
Describe dopamine pathway of transmission
Synthesis- L-tyrosine–tyrosine hydroxylase–> L-DOPA—DOPA decarboxylase–>DOPA (can continue to noradrenaline)
Tyrosine hydroxylase is rate limiting step-
DA then release to synapse, act, etc
Reuptake via Dopamine transporter (DAT) & Noradrenaline Transporter (NET) (either on pre-synaptic terminals AND Glial cells around cleft)
metabolism-3 enzymes acting (MAO at mitochondria)
1) Monoamine oxidase A (MAO-A-breakdown DA, NA, 5-HT
2) MAO B-more selective for DA
3) cathechol-o-methyl transferase (COMT)-more diffuse around the cell
What are the important dopimanergic pathways in brain
Nigrostrialal-Subtantia nigra to striatum
Mesolimbuc pathway-Ventral tegmental area (VTA) to Nuceleux accumbense—brain reward pathway
Mesocortical pathway-VTA to cerebellum-executive function and complex behaviour
Tuberoinfundibular pathway-arcuate nucleus to median eminance-more endocrine-can cause side effects
Nigrostriatal-parkinsons associated
Mesolimbic/cortical-maybe schizophrenia related
Epidiemology of parkinsons?
2% of people above 60
5% of cases causes by mutations, but main risk factor is age
Pathophysiology of parkinsons
Severe loss of dopaminergic projection cells in the subtancia Nigra
Motor symptoms tend to appear after 70% of loss
Why do the neurons degenerate? Unsure
Found lewy bodies and neurites-aggregates of certain proteins in cell bodies and axons (respectivly) but unsure what they do
Clinical presentation of parkinsons?
4 cardinal motor symptoms-vast majority have at least that
Resting tremor, bradykinesia, rigidity, postural instability
not all arrive with that, some can take longer to develop
ANS system effects-olfactory defecits, orthostatic hypotension, constipation -> usually early signs
Neuropsychiatry-sleep disoder, memory deficits, depression, irritability -> usually later signs of disease
What is LevoDopa and side effects? and things it can be given with?
Provide more precusors- (cant really give tyrosine or dopamine)
LevoDopa (L-DOPA)-> and as this is after rate limting enzyme->increase Dopamine production. can cross BBB easy
It works because the post-synaptic dont get loss-increasing dopamine amount work
side effects
very short acting-can be a pain
Can cause dyskinesia -motor movement not in control off-and gets worse //
on&off effects-works well just after taking it (try and give slow release levodopa pills)
Can cause nausea and vomiting
NOT DISEASE MODIFYING-not prolongation of life-just alleviation of symptoms
can be combined with COMT inhbitors-dopamine lasts longer
To prevent nausea and vomiting, prevent convertion of Levodopa to dopamine in periphery
Give Carbidopa/Benserazide at the same time as levodopa
act as carrier proteins to the BBB (but can pass-Levodopa passes alone)–> reduce off site effects
What is a way to minimise Levodopa side effects?
To prevent nausea and vomiting, prevent convertion of Levodopa to dopamine in periphery
Give Carbidopa/Benserazide at the same time as levodopa
act as carrier proteins to the BBB (but can pass-Levodopa passes alone)–> reduce off site effects
What are Dopamine receptor agonists?
Again the post synaptic cells dont disappear-and dont need the pre-synaptic neuron at all (levodopa needs at least a few)
Target and activate the post synaptic dopamine D1/5 receptors
2 categories:
Ergot derivative (natural)-Pergolid
work well but increase cardiac valve fibrosis
Non egrot derivative-Ropinirole
Small molecules, dont cause cardiac fibrosis
Extended release formulation and can be given in patch
side effects can cause hallucinations, gamblic addiction (via off target effects(
What is a parkinson treatment that targets Dopamine metabolism?
MAO B inhbitors-reduce dosage of L dopa required
But cheese reaction-if eat cheese/wine, can clear the dopamine as well and be in danger
not used much anymore
Epidiemology of schizophrenia
Affects about 1% of population
genetic influence-quite marked than parkinsons-
Age related component but for YOUNG age-15-35
Higher incidence in ethic minorities that emmigrate and that integrate less
Patients life expenctancy tend to be 25y lower-because of lifestyle choices resulting
Pathophysiology of schizophrenia
-mostly the mesolimbic and mesocortical pathays
Usually either positive symptoms-hallucinations and stuff
Thought to result from inrease mesolimbic pathway
usually cause paranoia, thought disorder
negative symptoms
associates with lower mesocoritcal dopamine activity
lack of emotion, lack of speech, loss of motivation
=> very hard to treat
What are the frist generation treatment options available for shcizphrenia?
Antipsychotic (1st generation or typical)-side effects more motor
1st one: Chloromazine-randomly found-anti muscarinic drug and D2 receptor antagonism
-> side effects from muscarinic effects
lead to development of Haloperidol
potent D2 antagonist
Reduce positive symptoms of schizophrenia
Little effects on negative affects
-> extrapyrimidal effects (like parkinsons effects
What are the second generation treatment options available for shcizphrenia?
antiphyschotic 2nd generation-atypical-side effects more metabolic
Clozapine-potent antagonist of 5HT2 receptor-very effect antipsychotic (unsure why)
has some effects treating negative symtoms (only drug that does), and good with positive symptoms
can cause agranulocytosis/neutropenia. weight gain, myocarditis
Risperidone-potent 5HT and D2 receptor antagonist
Like a 1st generation but classified as gen 2
cause EPS, hyperprolacteneamia
Questiapine-Optent H1 receptor antagonist
Lower incidence of EPS than other antipsychotics
Aripriprazole
Partial D2 and 5HT agonist-when too much activity will inhbit, and when too little activity would increase
so perfect to treat positive and negative symtpoms? not in practice–
