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???
??/
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
