Parkinson's disease and Neuroleptics (04.03.2020) Flashcards
(53 cards)
1
Q
Dopamine synthesis
A
Tyrosine -> L-DOPA (via tyrosine hydroxylase -> this is the rate limiting step, even if you have loads of tyrosine, you can only make so much DOPA as tyrosine hydroxylase can make)
L-DOPA -> Dopamine (via DOPA decarboxylase)
2
Q
Dopamine metabolism
A
- DA removed from synaptic cleft by dopamine transporter (DAT) & noradrenaline transporter (NET)
- DAT is on presyn and glial cells; NET is on presyn cells;
- Three enzymes metabolise DA:
1) Monoamine oxidase A (MAO-A): metabolises DA, NE & 5-HT (mitochondrial)
2) MAO-B: metabolises DA (mitochondrial)
3) Catechol-O-methyl transferase (COMT): wide distribution, metabolises all catecholamines (cytoplasmic)
3
Q
Most important dopaminergic pathways
A
1) Nigrostriatal pathway (SN pars compacta -> striatum)
2) Mesolimbic Pathway (VTA -> NAcc)
3) Mesocortical Pathway (VTA -> cortex)
4) Tuberoinfundibular Pathway (arcuate nucelus -> median eminence)
4
Q
Lewy body dementia
A
x
5
Q
Pathophysiology of PD
A
- severe loss of dopaminergic projection cells in SNc pars compacta
- Lewy bodies & neurites -> Found respectively within neuronal cell bodies & axons
- Consist of abnormally phosphorylated neurofilaments, ubiquitin & alpha-synuclein
6
Q
Lewy body dementia
A
- second most common cause of neurodegenerative dementia
- associated with PD
- there is currently no cure
- there are treatments to help with some of the synmptoms
7
Q
What are the commonly early and late onset symptoms in PD?
A
Early onset: tremor, ANS symptoms
Late: rigidity
8
Q
brak staging of PD???
A
??/
9
Q
Staging of PD
A
- “Braak staging”
- refers to two methods used to classify the degree of pathology in PD and AD.
- 6 stages
10
Q
How can you identify PD early on?
A
look at early symptoms e.g. the loss of smell and other ANS symptoms such as postural hypotension
11
Q
What are the different ways to treat PD?
A
- DA replacement
- Dopamine Receptor agonists
- Monoamine oxidase B inhibitors
12
Q
Dopamine replacement at PD treatment
A
- levodopa
- Rapidly converted to DA by DOPA decarboxylase (DOPA-D)
- Can cross blood-brain barrier (BBB)
- Peripheral breakdown by DOPA-D -> Leads to NAUSEA & VOMITING
- too much DA can cause dyskinesias
- Long-term side-effects: dyskinesias & ‘on-off’ effects.
- NOT disease-modifying (does not prolong life, just makes the QoL better in terms of motor symptoms. does not halt the progression of the disease
- can utilise adjuvants to optimise treatment
13
Q
Dopamine replacements - adjuncts
A
- DA causes N&V
- this is due to effects in the periphery
- we add adjuncts to prevent some SE
- DOPA decarboxylase inhibitors: Carbidopa & Benserazide
*Do not cross BBB -> prevent peripheral breakdown of levodopa
Reduce required levodopa dosage - COMT inhibitors: Entacapone & Tolcapone
- increased amount of levodopa in the brain
- increased duration of action in the brian, less likely to see the ‘off’ effects following DA usage.
14
Q
Dopamine Receptor agonists
A
Ergot derivatives:
- Bromocriptine & Pergolide
- Act as potent agonists of D2 receptors
- Associated with cardiac fibrosis
Non-ergot derivatives:
- Ropinirole & Rotigotine
- Ropinirole also available as extended-release formulation
- Rotigotine also available as a patch
- there is not necessarily loss of neurones that the DA-ergic neurones are targeting (postsynaptic) so if you give DOPA it is helpful.
15
Q
MAO-B inhibitors
A
- Selegiline (deprenyl) & Rasagiline
- Reduce the dosage of L-DOPA required
- Can increase the amount of time before levodopa treatment is required
16
Q
Which receptors does dopamine act on?
A
- Dopamine (DA) can act on D1,5(Gs linked) or D2-4 (Gi-linked) receptors
- DA is re-uptaken by the dopamine transporter (DAT) & metabolised by monoamine oxidase (MAO) enzymes
- DA receptor agonists and MAO-B inhibitors work via receptor activation!!!
17
Q
Schizophrenia epidemiology
A
- Affects around 1% of population & has genetic influence
- Onset of symptoms: between 15-35 years
- Higher incidence in ethnic minorities (eg Afro-Caribbean immigrants)
- Patients’ life expectancy - 20-30 years lower than average
=> there are genetic and environmental risk factors for schizophrenia (not all monozygotic twins get i)
- late teens and 20s os onset of symptoms (most common)
18
Q
Symptoms of schizophrenia
A
Positive symptoms
- increased Mesolimbic dopaminergic activity
- Hallucinations: Auditory & visual
- Delusions: Paranoia
- Thought disorder: Denial about oneself
Negative symptoms: - decreased Mesocortical dopaminergic activity - Affective flattening: lack of emotion - Alogia: lack of speech Avolition/ apathy: loss of motivation
19
Q
Haloperidol
A
- Very potent D2 antagonist (~ 50x more potent than chlorpromazine)
- Therapeutic effects develop over 6-8 weeks
- Little impact on negative symptoms
Side effects
- High incidence - EPS
20
Q
Chlorpromazine
A
- Discovered whilst developing new antihistamines
- Primary MoA – possibly D2 receptor antagonism
Side effects
- High incidence - anti-cholinergic, especially sedation
- Low incidence - extrapyramidal side-effects (EPS)
-> the SE are mainly anti-cholinergic for this drug
21
Q
Haloperidol
A
- Very potent D2 antagonist (~ 50x more potent than chlorpromazine)
- Therapeutic effects develop over 6-8 weeks
- Little impact on negative symptoms
- binding affinity highest for D2 but also acts on D3, D4 and alpha 1
Side effects
- High incidence - EPS
- > the side of this drug are mainly EPS
22
Q
Clozapine
A
- second generation / atypical antipsychotic
- Most effective antipsychotic
Very potent antagonist of 5-HT2A receptors - Only drug to show efficacy in treatment resistant schizophrenia & negative symptoms
Side effects
- Can cause potentially fatal neutropenia, can cause fatal agranulocytosis, myocarditis & weight gain
23
Q
What is the only drug that treats the negative symptoms of schizophrenia?
A
Clozapine
24
Q
Clozapine
A
- second generation / atypical antipsychotic
- Most effective antipsychotic
- Very potent antagonist of 5-HT2A receptors
- Only drug to show efficacy in treatment resistant schizophrenia & negative symptoms
Side effects
- Can cause potentially fatal neutropenia, can cause fatal agranulocytosis, myocarditis & weight gain
25
Aripiprazole
- more recent drug (2000s)
- Partial agonist of D2 & 5-HT1A receptors (when you have too much activity it will cause inhibition, if you have too little it will cause activation)
- No more efficacious than typical antipsychotics
Side effects
- Reduced incidences of hyperprolactinaemia & weight gain than other antipsychotics
First antipsychotic with a nano chip to control compliance.
26
Risperidone
- Very potent antagonist of 5-HT2A & D2 receptors (also some affinity for D4 and alpha 1)
- Side effects: More EPS & hyperprolactinaemia than other atypical antipsychotics
27
Quetiapine
- Very potent antagonist of H1 receptors
- Side effects: Lower incidence of EPS than other antipsychotics
- highest affinity for alpha 1 and H1; after that D2
28
Aripiprazole
- more recent drug (2000s)
- Partial agonist of D2 & 5-HT1A receptors (when you have too much activity it will cause inhibition, if you have too little it will cause activation)
- No more efficacious than typical antipsychotics
- highest affinity for D2 and D3 and after that 5HT1A
Side effects
- Reduced incidences of hyperprolactinaemia & weight gain than other antipsychotics
First antipsychotic with a nano chip to control compliance.
29
What is a big problem with antipsychotics?
non-compliance due to the SE
30
Why are non-ergot derivative DA agonists recommended over ergot-derivatives?
got derivatives are associated with cardiac fibrosis
31
Which antipsychotic drug is associated with neutropenia and agranulocytosis?
Clozapine
32
Which enzymes that metabolise dompamine are mitochondrial and cytoplasmic?
- MAO-A and MAO-B are mitochondrial
| - COM-T is cytoplasmic
33
What does MAO-A metabolise?
= monoamine oxidase A
-> metabolises DA, NE & 5-HT
34
What does MAO-B metabolise?
= monoamine oxidase B
-> metabolises dopamine
35
What does COM-T metabolise?
= catechol-O-methyl transferase
-> wide distribution, metabolises all catecholamines
36
Nigrostriatal pathway
- susbstantia nigra pars compacta (SNc) to the striatum.
| - Inhibition results in movement disorders
37
Mesolimbic pathway
- ventral tegmental area (VTA) to the Nucleus Accumbens (NAcc)
- Brain reward pathway
- associated with schizophrenia
38
Mesocortical pathway
- VTA to the cerebrum (more diffuse pathway than some other DA-ergic pathways)
- Important in executive functions & complex behavioural patterns.
- associated with schizophrenia
39
Tuberoinfundibular pathway
- arcuate nucleus to the median eminence
- Inhibition results in hyperprolactinaemia
- this pathway is not targeted but we see side effects due to drugs also working on this pathway.
40
Dopamine and pathways summary
```
Synthesis & Metabolism
- L-tyrosin -> (i) L-DOPA (ii) -> Dopamine (DA)
This process utilises the enzymes:
- Tyrosine hydroxylase
- DOPA decarboxylase
```
Neuronal pathways
- Nigrostriatal pathway: inhibition results in movement disorders
- Mesolimbic pathway: activation associated with positive schizophrenia symptoms
- Mesocortical pathway: inhibition associated with negative schizophrenia symptoms
- Tuberoinfundibular pathway: inhibition results in hyperprolactinaemia
41
Dopamine and pathways summary
```
Synthesis & Metabolism
- L-tyrosin -> (i) L-DOPA (ii) -> Dopamine (DA)
This process utilises the enzymes:
- Tyrosine hydroxylase
- DOPA decarboxylase
```
Neuronal pathways
- Nigrostriatal pathway: inhibition results in movement disorders
- Mesolimbic pathway: activation associated with positive schizophrenia symptoms
- Mesocortical pathway: inhibition associated with negative schizophrenia symptoms
- Tuberoinfundibular pathway: inhibition results in hyperprolactinaemia
42
Name some DOPA decarboxylase inhbitors
carbidopa
| benserazide
43
Entacapone & Tolcapone
= COMT inhibitors
| - increase the amount of dopamine in the brain
44
Carbidopa and Benserazide
DOPA decarboxylase inhibitors
- cannot cross the BBB
- added as an adjuvant to DOPA
- decrease peripheral DOPA effects
- less N&V
45
PD summary
Pathophysiology & Symptoms
- Severe loss of dopaminergic cells in SNc: Lewy bodies & neurites
- Cardinal Symptoms: Resting tremor, bradykinesia, rigidity, postural instability
- Non-motor symptoms: Olfactory & autonomic dysfunction, sleep disorder
Dopamine replacement
- Levodopa
- DOPA decarboxylase & COMT
Receptor activation
- DA receptor agonists: ropinirole
- MAOB inhibitors: selegiline
46
Schizophrenia summary
Background
- Mesolimbic pathway: Positive symptoms -> hallucinations
- Mesocortical pathway: Negative symptoms affective flattening
First generation antipsychotics
- Chlorpromazine: sedative & anti-muscarinic effects
- Haloperidol: potent DA receptor antagonist; extrapyramidal side-effects
Second generation antipsychotics
- Clozapine: Resistant schizophrenia; agranulocytosis
- Risperidone: D2, 5-HT2A; EPS & weight gain
- Quetiapine: H1 antagonist; low EPS
- Aripiprazole: Partial D2 & 5-HT1A agonist
47
What drugs should you know for treatment of PD?
Dopamine replacement
- Levodopa
- DOPA decarboxylase & COMT inhibitor
Receptor activation
- DA receptor agonists: ropinirole
- MAOB inhibitors: selegilin
=5
48
What drugs should you know for treatment of schizophrenia?
1st generation:
- chlorpromazine
- haloperidol
2nd generation:
- clozapine
- risperidone
- quetapine
- aripiprazole
=6
49
LO1: Parkinson’s disease neuropathology: Identify the dopaminergic pathway in the brain which degenerates and how the loss of dopamine triggers the motor clinical symptoms; and explain which other neuronal pathways are affected in Parkinson’s and what is the underlying pathological process
Nigrostriatal pathway - substantia nigra pars compacta (SNc) to the striatum. Inhibition results in movement disorders
Severe loss of dopaminergic cells in SNc: Lewy bodies & neurites
50
LO2: Parkinson’s disease clinical features: summarise the principle motor and non-motor clinical feature of the disease
Motor deficits - Bradykinesia, resting tremor, rigidity, postural instability
Non-motor deficitis - Olfactory & autonomic dysfunction, sleep disorders
51
LO3:Anti-parkinsonian drugs: summarise and compare the mechanisms of action of drugs used to treat PD. Explain why they are used in conjunction and their limitations
- DA replacement - Levodopa acts as DA precursor
- DA receptor stimulation - D2 agonists: Bromocriptine, ropinirole
- Prevention of breakdown - MAOB inhibitors (selegiline), COMT inhibitors (entacapone)
- L-DOPA & carbidopa & selegiline - used in conjunction to reduce side-effects & required dosage
- Limitations - not disease-modifying
- Long-term side-effects associated with levodopa - Dyskinesias & on-off symptoms
52
LO4: Schizophrenia: identify the principle neurotransmitter defects in schizophrenia
- Increased DA in mesolimbic pathway: Positive symptoms -> hallucinations
- Reduced DA in mesocortical pathway: Negative symptoms -> affective flattening
53
LO5:
Dopaminergic drugs: explain how drugs targeting the dopaminergic system are utilized in the treatment of schizophrenia, which symptoms they treat and discuss the side effects associated with these treatments
- Chlorpromazine: phenothiazine causing antimuscarinic side-effects
- Haloperidol: potent D2 antagonist causing extrapyramidal side-effects
- Clozapine: very effective but causes agranulocytosis
Risperidone: effective but associated with weight gain & EPS
- Quetiapine: low incidence of EPS
- Aripiprazole: partial agonist, low incidence of hyperprolactinaemia
