27: Anti-Parkinson Drugs and Neuroleptics Flashcards
Summarise dopamine synthesis
- L-tyrosine - (i) ->L-DOPA -(ii)-> Dopamine (DA)
- This process utilises the enzymes:
- ii.DOPA decarboxylase
- i.Tyrosine hydroxylase (rate-limiting step)
Summariste the Metabolism of Dopamine
- DA removed from synaptic cleft by
- dopamine transporter (DAT)
- noradrenaline transporter (NET)
- Three enzymes metabolise DA:
- 1)Monoamine oxidase A (MAO-A): metabolises DA, NE & 5-HT
- 2)MAO-B: metabolises DA (both MAOs: Metochondrial emzymes)
- 3)Catechol-O-methyl transferase (COMT): wide distribution, metabolises all catecholamines
Name the neural dopaminergic pathways
- Nigrostriatal pathway
- Mesolimbic pathway
- Mesocortical pathway
- Tuberoinfundibular pathway
What is the Nigrostriatal pathway?
Explain its route and involvement in pathology
Dopaminergic pathway Goes from the
- Substantia niagra pas compacta (SNc) to the
- Striatum
- involvedn in fine-regulation of motor function (basal ganglia)
- disease: degradation involved in Parkinsons
What is the Mesolimbic pathway?
Explain its route and involvement in pathology
Dopaminergic pathway going from the
- Ventral Tegmental area to the
- Nucleus Accumbens
- involve in reward system
- pathology: upregulated in schitzophrenia
What is the Mescortical pathway?
Explain its route and involvement in pathology
Dopaminergic route going from the
- Ventral Tegmental Area to
- Cortex (Cerebrum)
- important in executive function and compex behaviour patterns
- downregulated in schitzophrenia
What is the Tuberoinfundibular pathway?
Endocrine- Dopaminergic pathway
- arcuate nucleus to the median eminence
- supresses prolactin secretion
Summarise the pathophysiology of Parkinsons disese
- Severe Loss of Dopaminergic neuron in the Nigralstriatal pathway (Substantia Niagra pas compacta)
- Abnormally phosphorylated neurofilaments, ubiquitin & a-synuclein leading to formation of
- Protein depositions called
- Lewy body in neuronal cell bodies
- Lewy Neurites in axony
- Protein depositions called
What are the main motor symptoms in Parkinsons disease?
Motor symptoms = Cardinal symptoms
- resting tremor,
- bradykinesia,
- rigidity,
- postural instability
What are the main non-motor symptoms in Parkinsons?
When do they appear?
- Autonomic nervous system effects = appear before onset of motor symptoms
- olfactory deficits
- orthostatic hypotension
- constipation
- Neuropsychiatric = appear in late stages
- sleep disorders
- memory deficits
- depression
- irritability
What are the drug classes used in the treatment of Parkinsons
Overall: try to increase dopamine or stimmulate dopaminergic receptors
- Dopamine replacement (e.g. Levodopa)
- Receptor activation
- Monoamine oxidase B (MAOB) inhibitors
Name and example and the MOA of Dopamine replacement in the treatment of Parkinsons
E.g. Levodopa
- L-DOPA administration –> can be directly converted dopamine (rapidly)
- Crosses BBB
- often administered with Adjuncts
- to reduce side effect of prolong duration
Explain the side-effects of Levodopa and how to reduce them
-
nausea & vomiting
- Peripheral breakdown by DOPA-D
- Long-term :dyskinesias & ‘on-off’ effects
- too much dopamine might lead to uncontrolled movements
- On-off: hard to get right amount of dopamine, if too little–> Development of symptoms again
- NOT disease-modifying
Therefore often administered with Adjuvants
-
DOPA decarboxylase inhibitors –> don’t cross BBB and therefore prevent peripheral breakdown
- decrease in required dose+ nausea and vomiting
-
COMT inhibitors
- increase the amount of Levodopa in the brain
What is the target of Dopamine in the brain
Dopamine (DA) can act on D1,5(Gs linked) or D2-4 (Gi-linked) receptors
Explain the different types and use of dopamine receptor agonists in the treatment of Parkinsons
Advantage: don’t need the presynaptic dopaminergic neuron
- Ergot Derivates (e.g. Bromocriptine + Pergolide)
- potent agonists of D2 receptor
- naturally occuring
- Associated with cardiac fibrosis
- Non-ergot derivatives (Ropinirole)
- synthetic
- no cardiac fibrosis (but hallucinations)
- available as extended release formulation (better mimmic natural dopamine release)or patch
Name an Example of a Monoamine oxidase B (MAOB) inhibitors in the treatment of Parkinsons and its advantages
E.g. Selegiline
Inhibits the breakdown of Dopamine
- Reduce the dosage of L-DOPA required
- Can increase the amount of time before levodopa treatment is required
But: also decreases breakdown of other Catecholamines –> side effect: cheese reaction
Summarise the principle neurotransmitter defects in schizophrenia
- An increase in Mesolimbic pathway
- leading to positive symptoms
- A decrease in Mesocortical pathway
- leading to negative symptoms
What are the symptoms of Schitzophrenia?
- Positive symptoms (increased Mesolimbic dopaminergic activity)
- Hallucinations: Auditory & visual
- Delusions: Paranoia
- Thought disorder: Denial about oneself
- Negative symptom (reduced Mesocortical dopaminergic activity)
- Affective flattening: lack of emotion
- Alogia: lack of speech
- Avolition/ apathy: loss of motivation
What are the main risk factors for development of schitzophrenia?
- genetics (genetic + environmental compnent)
- Age (onset between 15-35)
- Migration –> higher incidence in immigrated ethnic minorities
- have decreased life expectancy due to poor lifestyle choices
How can schitzophrenic drugs be classified?
Not really any useful classification (learn drug names!) – >Only can classify time of discovery
- First generation antipsychotics (Chlorpromazine, Haloperidol)
- Second generation antipsychotics (Clozapine, Risperidone, Quetiapine)
- Aripiprazole
Explain the MOA and effect of Chlorpromazine
It is an anti-schitzophrenic drug
- Is a histamine antagonist
- Use in schitzophrenia : thought to be du to D2 antagonist –> antipsychotic
What are the side-effects of the Chlorpromazine?
It is a first-generation antipschotic
- Mainly: Extrapyramidal side effects: motor side effects (a bit like parkinsons)
- but also: anti-cholinergic side-effects (expecially sedation)
Explain the MOA, use and effect of Haloperidol
Haloperidol= First generation antipsychotic
- potent D2 antagonist
- therapeutic effects develop over 6-8 Weeks
- Little impact on negative symptoms
What are the side-effects of Haloperidol
Haloperidol= first generation antipsychotic
–> extrapyramidal side effects
–> Motor side effects (almost parkinson -like)
