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
