26. Anti-Parkinsonian drugs and neuroleptics Flashcards
How is dopamine produced?
- L-tyrosine => L-DOPA [Tyrosine hydroxylase]
* L-DOPA => Dopamine [DOPA decarboxylase]
What is the rate-limiting enzyme in the production of dopamine?
Tyrosine hydroxylase (TH)
What transporters removed dopamine from the synaptic cleft?
Dopamine transporter (DAT) and noradrenaline transporter (NET)
Which 3 enzymes metabolised DA?
MAO-A, MAO-B and Catechol-O-methyl transferase (COMT)
Where are MAO and COMT enzymes found?
- MAO - intracellular, associated with mitochondria
* COMT - in mitochondria and post-synaptic
Is DA breakdown mainly done by MAO or COMT?
MAO
What are the 4 different dopaminergic pathways and what does inhibition (or increased activation of 1) of each cause?
- Nigostriatal - Parkinson’s
- Mesolimbic - activation => positive schizophrenia
- Mesocortical - negative schizphrenia
- Tuberoinfundibular - hyperprolactinaemia
Describe the nigrostriatal pathway (location)?
- Cell bodies in substantia nigra pars compacta (SNc)
* Nerve project to the striatum
Describe the mesolimbic pathway (location)?
- Cell bodies in the ventral tegmental area (VTA)
* Axons project to the nucleus accumbens (NAcc)
Describe the mesocortical pathway (location)?
- Cell bodies in the VTA
* Project into the cerebrum (various areas of the cortex)
What is activation of the mesocortical pathway associated with?
Positive schizophrenia symptoms
Describe the tuberoinfundibular pathway (location)?
- Cell bodies in the arcuate nucleus
* Project to the median eminence
Describe the pathophysiology of PD
• Sever loss of dopaminergic projection cells in nigrostriatal tract
• 80% of cells lost before symtpoms
• Lewy bodies + neurites found within cell bodies and axons
= abnormally phosphorylated neurofilaments, ubiquitin and α-synuclein
Outline the clinical presentation of PD (3 types)
- Motor symptoms - resting tremor, bradykinesia, rigidity, postural instability
- ANS effects - olfactory deficits, orthostatic hypotension, constipation
- Neuropsychiatric - sleep disorders, memory deficits, depression, irritability
What is the order of onset of the different types of PD clinical presentations
Autonomic => motor => neuropsychiatric
Describe the gold standard treatment for PD
Levodopa (L-DOPA)
• Converted to DA by DOPA -D
• Can cross the BBB
• However it can cause nausea due peripheral breakdown by DOPA-D and CTZ actions
• Therefore, given with DOPA-D inhibitor e.g. Carbidopa
Only treats symptoms, not disease progression
What can L-DOPA be given with to reduce the dosage and increase its effectiveness?
DOPA-D inhibitor and COMT inhibitor
Why don’t DOPA-D inhibitors prevent conversion to DA in the brain?
Can’t cross the BBB
What are the long-term side effects of L-DOPA?
- Dyskinesias
* On-off effects
Describe the second option for PD treatment and any-side effects
Dopamine receptor agonists
• Useful if too many neurones have been broken down
Ergot derivatives e.g. bromocriptine
• Agonists of D2 receptors - (post-synaptic)
• Associated with cardiac fibrosis
Non-ergot derivates e.g. ropinirole
• Agonists of D2 receptors (post-synaptic)
• Available as extended-release formulation
• Not associated with cardiac fibrosis
Describe the third option for PD treatment
MAO-B inhibitors e.g. selegiline
• Reduce the dosage of L-DOPA
• Can increase amount of time before before L-DOPA is needed
• Overall increase treatment time, as long-term L-DOPA usage has side-effects then no longer works
Can schizophrenia be genetically influenced and why?
Yes - DISC1 gene known to be involved
What is a main reason why a schizophrenia patient’s life expectancy decrease?
Increased likelihood to abuse drugs
Explain and describe the ‘positive’ and ‘negative’ symptoms of schizophrenia
Positive
• Increased mesolimbic dopaminergic activity
• Hallucinations (auditory and visual)
• Delusions - paranoia
• Thought disorder - denial about oneself
Negative • Decreased mesocortical dopaminergic activity • Affective flattening - lack of emotion • Alogia - lack of speech • Avolition/apathy
Which type of symptoms do treatment of schizophrenia aim to reduce and why is this good/bad?
- Aim to reduce positive symptoms
- Negative symptoms still present
- Good for society but bad for the patient
What was the treatment for psychosis before chlorpromazine was discovered in the 1950s?
Lobotomy and electroconvulsive therapy
How does chlorpromazine work as an antipsychotic and what are the side-effects?
D2 receptor antagonism - first generation antipsychotic
Side effects (it is a histamine, muscarinic antagonist):
• High incidence: anti-cholinergic - sedation
• Low incidence: extrapyramidal side-effects (EPS) - problems with motor system
How does Haloperidol work as an antipsychotic and what are the side-effects?
Very potent D2 receptor antagonist - first generation antipsychotic
• Good DA antagonism in mesolimbic pathway, but not mesocortical pathway
• Alleviate the positive symptoms
• Little impact on negative symptoms, maybe even worsening
Side effects:
• High incidence: EPS - problems with motor system
What do second generation antipsychotics affect?
Serotonin, rather than dopamine
How does clozapine work and what are the side-effects (second-generation)?
- Most effective antipsychotic - only drug that works in resistant schizophrenia and negative symptoms
- Potent 5-HT receptor antagonist
- Also acts on H1 and α-1 receptors, and inhibits D2 receptor
Side effects: • Potentially fatal neutropenia • Agranulocytosis • Myocarditis • Weight gain
Describe how the following second-generation antipsychotics work:
• Risperidone
• Quetiapine
• Aripiprazole
- Risperidone - potent 5-HT and D2 receptor antagonist
- Quetiapine - potent H1 receptor antagonist
- Aripiprazole - partial 5-HT and D2 receptor agonist
Describe how Aripiprazole work as an antipsychotic, even though it is an agonist
‘Partial’ 5-HT and D2 receptor agonist
• Where there is too much activity, it acts as an inhibitor - reduces positive symptoms
• When there is too little activity, it acts as an agonist - reduces negative symptoms
Why is the heterogenous mechanism of action significant in schizophrenia treatment?
- Affects many different receptors
* This does not relate to clinical efficacy
What are the side-effects of the following second-generation antipsychotics:
• Risperidone
• Quetiapine
• Aripiprazole
- Risperidone - hyperprolactinaemia (inhibition in tuberoinfundibular pathway)
- Quetiapine - EPS (lower incidence than others)
- Aripiprazole - hyperprolactinaemia and weight gain (lower incidence than others)
