Parkinson’s Disease and Schizophrenia Flashcards
What are the three main dopaminergic pathways in the brain?
Nigrostriatal
Mesolimbic
Mesocortical
Where are the three main dopaminergic pathways in the brain found?
Nigrostriatal– projecting from the substantia nigra pars compacta to the striatum
Mesolimbic– ventral tegmental area (VTA) to the Nucleus Accumbens (NAcc)
Tuburoinfundibular system– VTA to the cerebrum.
What are the roles of the three main dopaminergic pathways in the brain?
Nigrostriatal – control of movement
Mesolimbic – involved in emotion
Mesocortical pathway - Important in executive functions & complex behavioural patterns.
What are the two families of dopamine receptors and which receptors fall into each of these families?
D1 family – D1 + D5 (Gs linked)
D2 family – D2, D3 + D4 (Gi linked)
Describe dopamine synthesis.
L-Tyrosine is converted by tyrosine hydroxylase to L-DOPA
L-DOPA is converted by DOPA decarboxylase to Dopamine
Is Parkinson’s disease more common in males or females?
Males – 4:1
What percentage of all cases of Parkinson’s disease is accounted for by genetic mutations?
5%
The rest are idiopathic
What are the possible causes of idiopathic Parkinson’s disease?
Possibly a combination of environmental, oxidative stress, altered protein metabolism and risk genes
What are the cardinal signs of Parkinson’ disease?
Resting tremor (pill-rolling tremor)
Rigidity (stiffness – limbs feel weak and heavy)
Bradykinesia (slowness of movement)
Postural instability
What are the ANS effects of parkinsons?
Olfactory deficits
Orthostatic hypotension
Constipation
What is the main area of the brain that is affected by Parkinson’s disease?
Substantia nigra
Describe the neuropathology of Parkinson’s disease.
Lewy bodies and Lewy neurites (composed of the same material but in different cellular locations) found in dopaminergic neurones
Strongly associated with neurodegeneration
What is the main biochemical change seen in Parkinson’s disease?
Marked reduction in the caudate nucleus/putamen dopamine content
What proportion of dopaminergic neurones of the nigrostriatal dopaminergic pathway must be lost before symptoms occur?
80-85% of dopaminergic neurones and 70% of striatal dopamine must be depleted before symptoms appear
What is the reason for this loss of neurones before symptoms appear?
There are compensatory mechanisms e.g. neurone overactivity and increase in dopamine receptors
What other type of drug has to be given with Levodopa in dopamine replacement therapy and why?
DOPA decarboxylase inhibitor
This prevents the conversion of L-DOPA to dopamine by peripheral DOPA decarboxylase
They dont cross the BBB so conversion of L-DOPA (Levodopa) occurs in the brain where it is needed
e.g. Carbidopa or Benserazide
What drug is also sometimes administered with levodopa?
A COMT inhibitor to increase the amount of levodopa in the brain
e.g. Entacapone or Tolcapone
What is the treatment for Parkinsons?
No disease modifying treatment, can only teat symptoms
- Dopamine replacement
- Dopamine receptor agonsits
- MAOb inhibitors
Explain what is used for dopamine replacement?
Levodopa (L-DOPA)
Rapidly converted to DA by DOPA decarboxylase (DOPA-D)
Can cross blood-brain barrier (BBB)
Explain the side effects of levodopa
Nausea and vomiting
Explain the chronic side effects of levodopa
Dykinesias - unknown cause
‘On-Off positive effects’ - possibly due to fluctuations in plasma L-DOPA and a loss in the neurons ability to store DA.
Give 2 examples of the classes of dopamine receptor agonsits
Ergot derived:
Bromocriptine
Pergolide
Non-ergot derived:
Ropinirole
Rotigotine
Which receptors do dopamine receptor agonsits act on?
D2 receptor
What are the benefits of dopamine agonists over L-DOPA?
Longer duration of action
Smoother and more sustained response
Actions independent of dopaminergic neurones
Incidence of dyskinesias is less
NOTE: L-DOPA is still the gold standard
Name two MAO inhibitors.
Selegiline (Deprenyl)
Rasagiline
What are the effects of benefits of using a MAOb inhibitor?
Selective for MAO-B (this predominates in dopaminergic areas of CNS)
Does NOT have the peripheral side effects of non-selective MAO inhibitors
Can be given in combination with Levodopa (reduce dose of Levodopa by 30-50%)
Delays the amount of time before Levodopa must be started to give the patient more years of treatmetn (extends available treatment from 7 years to 9 years)
What are the effects of COMT inhibition in the CNS?
Prevents breakdown of dopamine in the brain
What’s the epidemiology of schizophrenia?
1% of population effected
Strong genetic link
Onset of symptoms between 15-35 years
Higher incidence in ethnic minorities (eg Afro-Caribbean immigrants)
What are the symptoms of schizophrenia?
Positive Symptoms (overt symptoms that should NOT be present)
Hallucinations (auditory and visual)
Delusions (paranoia)
Disorganised thoughts (denial about oneself i.e. dont believe they have schizophrenia)
Negative Symptoms (lack of characteristics that SHOULD be present)
Alogia (Reduced speech)
Affective flattening (lack of emotion)
Avolition/apathy (loss of motivation
What appears to have quite a strong contribution to the development of schizophrenia?
Genetics
What are all the susceptibility genes for schizophrenia associated with?
Dopamine and glutamate neurotransmission
Which symptoms do neuroleptic drugs treat?
Positive symptoms ONLY
What are the initial effects of neuroleptic drugs?
Initial increase in dopamine synthesis and neuronal activity – this declines with time
What is meant by an atypical antipsychotic?
Newer antipsychotics are given this term also called 2nd generation anti psychotics
What is an important other action of neuroleptics?
Anti-emetic
Because they block dopamine receptors in the chemotactic trigger zone
Phenothiazine is a neuroleptic that is really good at preventingnausea/vomiting caused by drugs
NOTE: many neuroleptics also block histamine receptors – this is effective at controlling motion sickness
What are the extrapyramidal side effects of antipsychotics caused by?
Blockade of dopamine receptors in the nigrostriatal system can induce
Parkinson-like side effects
What are the unwanted effects of antipsychotics?
Endocrine effects – loss of inhibition of prolactin secretion leads to hyperprolactinaemia (can lead to breast swelling and sometimes lactation)
Blocking alpha-adrenoceptors – postural hypotension
Blocking 5-HT receptors – weight gain
Blockade of muscarinic receptors – typical anti-muscarinic effects e.g. blurring of vision, increased intra-ocular pressure, dry mouth, constipation, urinary retention
Which dopaminergic pathway in the brain is sometimes inadvertently inhibited when treating parkinsons and Schizophrenia?
Tuberoinfundibular pathway
Projects from the arcuate nucleus to the median eminance.
What is the consequence of inhibiting the Tuberoinfundibular pathway?
Hyperprolactinaemia
How is Dopamine removed from the synaptic cleft?
Dopamine transporter (DAT) or noradrenaline transporter (NET) on glial cells or the pre synaptic membrane
What kind of glial cells are found in the CNS?
Astrocytes
What is the rate limiting step in dopamine synthesis?
Tyrosine hydroxylase enzyme is rate limiting
How is dopamine metabolised?
1) Monoamine oxidase A (MAO-A):
It metabolises DA, NE and 5-HT
2) MAO-B:
It metabolises DA
3) Catechol-O-methyl transferase (COMT):
It metabolises all catecholamines
Where are the enzymes that metabolise dopamine found?
MAO only found on mitochondrial membranes
COMT is found in the cytosol and on the cell membranes of a wide distribution of cells
What are the neuropsychiatric effects of parkinsons?
Sleep disorders
Memory deficits
Depression
Irritability
In what order do the symptoms of parkinsons develop?
Olfactory deficits
Cardinal symptoms
Depression and irritability
Why are COMT inhibitors not effective as a mono therpay?
Most of DA breakdown is by MAO so CMOT inhibitors only help a little bit
What happens when DA activates the D2 receptors?
Activates adenylate cyclase
Converts ATP to cAMP
Activates PKA
What’s the advantage of non-ergot dervied over ergot derived DAR agonists?
Non-ergot derived:
Ropinirole is available as an extended release formulation
Rotigotine is available as a patch
Erogt derived are associated with cardiac fibrosis
Explain the reduction in life expectancy associated with schizophrenia
20-30 year lowering of life expectancy
Due to recreational drug use associate with schizophrenia
What is the pathology of schizophrenia?
Increased dopamine levels in the mesolimbic pathway
Decreased dopamine levels in the mesocortical pathway
What is the issue with the drugs for schizophrenia?
They treat the positive symptoms well but leave the patient with the negative symptoms
What are the main classes of drugs for treating schizophrenia?
1st generation antipsychotics:
D2 antagonists
2nd generation anti psychotics:
5-HT receptor antagonsits
Other mechanisms of action
Give 2 examples of 1st generation anti psychotics
Chlorpromazine
Haloperidol
What is the advantage and disadvantage of haloperidol over chlorpromazine?
Haloperidol is 50x more potent than chlorpromazine
Haloperidol takes 6-8 weeks to develop its theraputic effects
What are the side effects of the 1st generation anti psychotics?
Chlorpromazine:
High incidence of anti-cholinergic effects (especially sedation) as it is a muscarinic receptor antagonist
Haloperidol:
High incidence of extrapyramidal side effects.
Give 4 examples of 2nd generation anti psychotics
Clozapine - most effective
Risperidone
Quetiapine
Aripipazole
What is the mechanism of clozapine?
Very potent antagonist of 5-HT2a receptors
What is different about clozapine compared to other anti psychotics?
Clozapine is the only licensed drug to show reduction in both positive and negative symptoms of schizophrenia
Why is clozapine only used as a last resort treatment?
Can cause potentially fatal neutropenia, agranulocytosis, myocarditis & weight gain
What is the mechanism of risperidone?
Very potent antagonist of 5-HT2A & D2 receptors
What is the disadvantage of risperidone?
More EPS & hyperprolactinaemia than other 2nd gen antipsychotics
What is the mechanism of quetiapine?
Very potent antagonist of H1 receptors
What is the advantage of quetiapine?
Lower incidence of EPS than other antipsychotics
What is the mechanism of aripiprazole?
Partial agonist of D2 & 5-HT1A receptors
In theory this means when there is too much dopamine activity (positive symptoms) it acts as an antagonist, and when there is too little dopamine activity (negative symptoms) it acts as a agonsit
What is the advantage of aripiprazole?
Reduced incidences of hyperprolactinaemia & weight gain than other antipsychotics
What are the neuropsychiatric symptoms of Parkinsons
sleep disorders, memory
deficits, depression, irritability
