Antiparkinsons and neuroleptics Flashcards
Differentiate neuroleptics and anti-psychotics and what tey are used to treat
SAME….. used to treat schizophrenia
Outline synthesis of dopamine a the dopamine receptor
L-tyrosine–> (TH) (i) L-DOPA –> (DOPA-D) (ii) Dopamine (DA)
Which is the rate limiting enzyme in dopamine production
TH (i.e you cant just add more tyrosine you have to increase tyrosine)
Outline the metabolism of dopamine
- DA removed from synaptic cleft by transporters (which?)
- Three enzymes beaking down DA:
- Monoamine oxidase A (MAO-A): metabolises DA, NE & 5-HT
- MAO-B: metabolises DA (more selective)
- Catechol-O-methyl transferase (COMT): wide distribution, metabolises all catecholamines
Which transporters take up dopamine
dopamine transporter (DAT) & noradrenaline transporter (NET)
(as they are both monoamines)
Why do dopaminergic cells not produce NA which is produced by same pathways
Don’t contain the enzymes needed to convert the dopamine to the other MA
Where are MAOs usually found
Intracellular and on membrane of the mitochondria on the dopaminergic neuronal cell
Where is COMT found
Not just in neuon like the MOA,
found in glial cell, post synaptic membrane, and the neurone
What are the important dopaminergic pathways
- Nigrostriatal pathway
- Mesolimbic pathway
- Mesocortical pathway
- Tuberoinfundibular pathway
What locations do the nigrostriatal tract run
susbstantia nigra pars compacta (SNc) to the striatum. Inhibition results in movement disorders
What locations do the mesolimbic tract run
ventral tegmental area (VTA) to the Nucleus Accumbens (NAcc). Brain reward pathway.
What locations do the mesocortical tract run
VTA to the cerebrum. Important in executive functions & complex behavioural patterns.
What locations do the tuberoinfundibular pathway tract run
arcuate nucleus to the median eminence. Inhibition results in hyperprolactinaemia
What conditions associated with each dopaminergic pathway
- Nigrostriatal pathway (movement)
2. Mesolimbic pathway (schizophrenia)
Compare parkinsons and schizophrenia
Parkinsons, like alzheimers, is NEURODEGENERATIVE
Schizophrenia is NEUROEFFECTIVE
Genetic component to parkinsons
SNCA, LRRK2
associated with the early onset parkinsons, not the late onset, whch is more prevalent
Pathophysiology of parkinsons
Severe loss of dopaminergic projection cells in SNc
What molecular signs are seen in parkinsons
Lewy bodies & neurites –> Found respectively within neuronal cell bodies & axons
these are associated with the neurodegeneraton
What are lewy bodies and neurites made up of
Consist of abnormally phosphorylated neurofilaments, ubiquitin & a-synuclein
Symptoms of parkinsons – motor
resting tremor, bradykinesia, rigidity, postural instability
Autonomic NS effects of parkinsons
olfactory deficits, orthostatic hypotension, constipation
Psychiatric symptoms of parkinsons
sleep disorders, memory deficits, depression, irritability
Progression of parkinsons)
Loss of smell (ANS deficit) as neurites start here
Motor
Neuropsychiatric (late stage)
What is the action of levadopa
Effecting the 20 % of remaining dopaminergic neurons
It is basically L-DOPA It is rapidly conerted to DA by DOPA decarboxylase (DOPA-D)
Can cross the BBB
What is the consequence of levadopa being converted to dopamine in the periphery
Because DOPA decarboxylase is present in periphery
It can make dopamine from the levadopa
This can act on areas outsde the BBB…. ie the CTZ and can activate comiting
Why can L-tyrosine not be given as PD treatment
The rate limiting step is TH so you need to surpass this step
What are the long term effects of levadopa
dyskinesias & ‘on-off’ effects. NOT disease-modifying
On/off refers to the changes from motor control to lack of motor control near to end of dose
Dyskinesia is muscle movements that people with Parkinson’s can’t control. They can include twitches, jerks, twisting or writhing movements
https://www.parkinsons.org.uk/information-and-support/wearing-and-dyskinesia
Adjuncts given with levadopa
DOPA decarboxylase inhibitors
COMT inhibitors
Name 2 DOPA decarboxylase inhibitors and how they help in parkinsons
Carbidopa & Benserazide
Do not cross BBB …. this prevent peripheral breakdown of levodopa into dopamine but not that in the CNS
Reduce required levodopa dosage
Name the different COMT inhibitors
Entacapone & Tolcapone
What does COMT do to help in parkinsons
Increase amount of levodopa in the brain
……
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Which receptors can dopamine act on
Dopamine (DA) can act on D1,5(Gs linked) or D2-4 (Gi-linked) receptors
Second treatment of PD other than levadopa
DOPAMINE RECEPTOR AGONISTS
Ergot derivatives: Bromocriptine & Pergolide
Non-ergot derivatives: Ropinirole
How do dopamine receptor agonists work
Act as potent agonists of D2 receptors
Disadvantage or ergot derivative dopamine receptor agonist
Cardiac fibrosis
Third treatment of PD
Monoamine oxidase B (MAOB) inhibitors (i.e. the MAO specific to dopamine)
Selegiline (deprenyl) & Rasagiline
Why are MAO used in PD
Reduce the dosage of L-DOPA required
Can increase the amount of time before levodopa treatment is required
Outline the formulatins of the non-ergot derivatives
Ropinirole also available as extended-release formulation
Rotigotine also available as a patch
….
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Onset of symptoms of schizophrenia
Onset of symptoms: between 15-35 years
T/f schizophrenia is 100% genetic
F.. in twin studies with monozygotic twins there is 50% concordance
so genetic and environmental factors
Higher incidence of schizophrenia in which populations
Higher incidence in ethnic minorities (eg Afro-Caribbean immigrants)
Patient’s life expctancy with schizophrenia
- 20-30 years lower than average
Positive symptoms of schizophrenia
Inceased mesolimbic dopaminergic activity
Hallucinations: Auditory & visual
Delusions: Paranoia
Thought disorder: Denial about oneself
memory aid that increased mesolimbic is like drugs do cos of reward and drugs lead to simlar things
Negative symptoms of schizophrenia
Reduced Mesocortical dopaminergic activity
Affective flattening: lack of emotion
Alogia: lack of speech
Avolition/ apathy: loss of motivation
memory aid that these are cortical function
Why is schizophrenia associated with early death
More recreational drug use to alleviate symptoms
Pathophysiology of schizophrenia
Increase mesolimbic dopaminergic activity
Reduced mesocortical dopamiergic activity
What aspects of schizophrenia do the drugs deal with
Only the positive ones
Outline types of neuropleptics
=antipsychotic
first generation= typical
second generation= atypical
Action of chlorpromazine
Discovered by serendipity
Primary mechanism of action – possibly D2 receptor antagonism. This Gi linked. Reduced AC, cAMP and PKA
(also histamine antagonist)
Side effects of chlorpromazine
High incidence - anti-cholinergic, especially sedation
Low incidence - extrapyramidal side-effects (EPS)
Outline mecahnism of haloperidol action
Very potent D2 antagonist (~ 50x more potent than chlorpromazine)
Therapeutic effects develop over 6-8 weeks
Little impact on negative symptoms
Side effects of haloperidol
High incidence of EPS (in contrast to the chlorpromazine which has low EPS and high anticholinergic)
Action of clozapine
MOST EFFECTIVE ANTI-PSYCHOTIC
Potent antagonist of 5-HT2A receptors
T/f clozapine has highest affinity for the 5-HT2A receptor
F…. it binds M1 most effectively but the 5-HT2A is where the effect lies
What is the effectiveness of clozipine
Only drug to show efficacy in treatment resistant schizophrenia & negative symptoms
(most liit positive systems but not negatie)
Side effects of clozapine
Can cause potentially fatal neutropenia, agranulocytosis, myocarditis & weight gain
If clozapine is most effective why not used as first line
Because of the side effects, patients ahve to be monoted on them
Difference btween first and second generation antipsychtics
first mostly anti D2
second mostly 5HT angatonist
Action of risperiodne
Very potent antagonist of 5-HT2A & D2 receptors
Side effects of risperiodone
More EPS & hyperprolactinaemia than other atypical antipsychotics
Ation of quetiapine
Very potent antagonist of H1 receptors
Side effects of quetiapine
Lower incidence of EPS than other antipsychotics
T/F these drugs have good selectivity
F….. they are dirty drugs
What is the problem with dopamine antagonist drugs
They are blocking mesolimbic system which is good because this is increased dopamine in schiz
but
it is also reducing dopamine in the mesocortical system, which is bad because these levels are already reduced in schiz
Outline the mechanism of aripiprazole
Partial agonist of D2 & 5-HT1A receptors
Why was aripirazole thought to be more effective , and was it
Because it is partial agonist so would incrase dopamine action at the mesocortical tract (where dopamine it is reduced in schiz) but reduce it where dopamine is too high (i.e. mesolimbic)
No more efficacious than typical antipsychotics (ie first line)
Side effects of aripirazole
Reduced incidences of hyperprolactinaemia & weight gain than other antipsychotics
