Parkinson's disease and Neuroleptics (04.03.2020) Flashcards
Dopamine synthesis
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)
Dopamine metabolism
- 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)
Most important dopaminergic pathways
1) Nigrostriatal pathway (SN pars compacta -> striatum)
2) Mesolimbic Pathway (VTA -> NAcc)
3) Mesocortical Pathway (VTA -> cortex)
4) Tuberoinfundibular Pathway (arcuate nucelus -> median eminence)
Lewy body dementia
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Pathophysiology of PD
- 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
Lewy body dementia
- 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
What are the commonly early and late onset symptoms in PD?
Early onset: tremor, ANS symptoms
Late: rigidity
brak staging of PD???
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Staging of PD
- “Braak staging”
- refers to two methods used to classify the degree of pathology in PD and AD.
- 6 stages
How can you identify PD early on?
look at early symptoms e.g. the loss of smell and other ANS symptoms such as postural hypotension
What are the different ways to treat PD?
- DA replacement
- Dopamine Receptor agonists
- Monoamine oxidase B inhibitors
Dopamine replacement at PD treatment
- 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
Dopamine replacements - adjuncts
- 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.
Dopamine Receptor agonists
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.
MAO-B inhibitors
- Selegiline (deprenyl) & Rasagiline
- Reduce the dosage of L-DOPA required
- Can increase the amount of time before levodopa treatment is required
Which receptors does dopamine act on?
- 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!!!
Schizophrenia epidemiology
- 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)
Symptoms of schizophrenia
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
Haloperidol
- 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
Chlorpromazine
- 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
Haloperidol
- 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
Clozapine
- 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
What is the only drug that treats the negative symptoms of schizophrenia?
Clozapine
Clozapine
- 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
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.
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
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
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.
What is a big problem with antipsychotics?
non-compliance due to the SE
Why are non-ergot derivative DA agonists recommended over ergot-derivatives?
got derivatives are associated with cardiac fibrosis
Which antipsychotic drug is associated with neutropenia and agranulocytosis?
Clozapine
Which enzymes that metabolise dompamine are mitochondrial and cytoplasmic?
- MAO-A and MAO-B are mitochondrial
- COM-T is cytoplasmic
What does MAO-A metabolise?
= monoamine oxidase A
-> metabolises DA, NE & 5-HT
What does MAO-B metabolise?
= monoamine oxidase B
-> metabolises dopamine
What does COM-T metabolise?
= catechol-O-methyl transferase
-> wide distribution, metabolises all catecholamines
Nigrostriatal pathway
- susbstantia nigra pars compacta (SNc) to the striatum.
- Inhibition results in movement disorders
Mesolimbic pathway
- ventral tegmental area (VTA) to the Nucleus Accumbens (NAcc)
- Brain reward pathway
- associated with schizophrenia
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
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.
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
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
Name some DOPA decarboxylase inhbitors
carbidopa
benserazide
Entacapone & Tolcapone
= COMT inhibitors
- increase the amount of dopamine in the brain
Carbidopa and Benserazide
DOPA decarboxylase inhibitors
- cannot cross the BBB
- added as an adjuvant to DOPA
- decrease peripheral DOPA effects
- less N&V
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
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
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
What drugs should you know for treatment of schizophrenia?
1st generation:
- chlorpromazine
- haloperidol
2nd generation:
- clozapine
- risperidone
- quetapine
- aripiprazole
=6
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
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
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
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
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
