Dopaminergic pathways of the brain and drugs used to treat Parkinson’s Disease and Schizophrenia Flashcards
List the 4 main dopaminergic pathways in the brain
Nigrostriatal
Mesolimbic
Mesocortical
Tuberoinfundibular system
Where are each of the dopaminergic pathways found?
Nigrostriatal: substantia nigra pars compacta to striatum
Mesolimbic: VTA to nucleus accumbens, frontal cortex, limbic cortex + olfactory tubercle
Mesocortical: VTA ot cerebrum
Tuburoinfundibular system: arcuate nucleus in hypothalamus to median eminence + pituitary gland
What are the roles of the dopaminergic pathways?
Nigrostriatal: control of movement
Mesolimbic: Reward pathway
Mesocortical: Executive functions + complex behavioural patterns
Tuburoinfundibular system: regulate hormone secretion
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?
What percentage of all cases of Parkinson’s disease is accounted for by familial Parkinson’s disease?
Males – 4:1
5% due to genetic mutations
What are the cardinal signs of Parkinson’ disease?
Resting tremor
Rigidity (stiffness: limbs feel weak + heavy)
Bradykinesia (slowness of movement)
Postural instability
Describe the pathophysiology of Parkinsons disease
Degeneration of nigrostriatal tract
Associated with formation of Lewy bodies + Neurites
What non-motor symptoms accompany Parkinson’s disease?
Neuropsychiatric: Sleep disorders, depression, memory defects, irritability
ANS: olfactory defects, orthostatic hypotension, constipation
What proportion of dopaminergic neurones of the nigrostriatal dopaminergic pathway must be lost before symptoms occur?
80-85% of dopaminergic neurones + 70% of striatal dopamine must be depleted before symptoms appear
Why do such high proportions of dopaminergic neurones of the nigrostriatal dopaminergic pathway have to be lost before symptoms occur?
There are compensatory mechanisms e.g. neurone overactivity + increase in dopamine receptors
What other type of drug has to be given with L-DOPA in dopamine replacement therapy and why? List examples
Peripheral DOPA decarboxylase inhibitors (that don’t cross BBB)
Prevents conversion of L-DOPA to dopamine by peripheral DOPA decarboxylase (can cause nausea + vomiting)
Carbidopa + Benserazide
Why is Levodopa prescribed to Parkinsons patients?
Can cross BBB
L DOPA is rapidly converted by DOPA decarboxylase to DA
Post synaptic D2 receptors intact, so DA can bind
What are the acute side effects of L-DOPA?
Nausea
Vomiting
What are the chronic side effects of L-DOPA?
Dyskinesias
Rapid fluctuations in clinical state (“on-off” effects)
Name three dopamine agonists. What types of derivatives are these?
Bromocriptine + Pergolide (Ergot derivatives)
Ropinerol (Non-ergot derivative)
Which receptors do dopamine agonists act on?
D2 receptor
What are the benefits of dopamine agonists over L-DOPA?
Longer duration of action
Smoother + more sustained response
Actions independent of dopaminergic neurones (which are progressively degenerating)
Incidence of dyskinesias is less
What unwanted effect arose due to ergot derived dopamine receptor agonists?
Increased likelihood of cardiac fibrosis, leading to valve disorders
What unwanted effect arises due to non-ergot derived dopamine receptor agonists?
Development of addictive behaviour e.g. gambling
Name two MAO-B inhibitors.
Selegiline
Rasagiline
Why is use of MAO-B inhibitors limited in treatment of Parkinsons disease?
MAO-B is also responsible for breakdown of Tyramine
Thus, cheese reaction may result
Name two COMT inhibitors.
Tolocapone (CNS + PNS)
Entacapone (PNS)
What are the effects of COMT inhibition in the CNS?
Prevents breakdown of dopamine in the brain
Thus less likely to experience OFF effects
What percentage of the general population is affected by schizophrenia? What is linked to development of schizophrenia? What is the age of onset of symptoms?
1%
Genetic influence
Age 15-35
What are the positive symptoms of schizophrenia?
Overt symptoms that should NOT be present
Hallucinations (auditory + visual)
Delusions + Paranoia
Thought disorder (denial)
What is meant by an atypical antipsychotic?
Newer antipsychotics
Have fewer extrapyramidal side effects
Name 3 second generation/ atypical antipsychotics
Clozapine
Risperidone
Quetiapine
Name and describe the most effective antipsychotic
Clozapine
Very potent antagonist of 5-HT 2A receptors
Only drug effective in treatment resistant schizophrenia + negative symptoms
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 negative symptoms of schizophrenia?
Affective flattening: Lack of emotion
Alogia: Lack of speech
Avolition/ apathy: loss of motivation
Availability of which enzyme in dopamine synthesis is the rate limiting step?
Tyrosine hydroxylase
How is dopamine metabolised?
Transporters on presynaptic + glial cells take DA back into cells (DAT + NET) Enzymatic degradation (mitochondrial MAO-A + MAO-B and COMT enzyme in glial cells + membrane of postsynaptic cell)
Which dopaminergic pathway is primarily effected in Parkinson’s disease?
Nigrostriatal pathway
What are the positive and negative symptoms of schizophrenia thought to be caused by?
Positive: Increased mesolimbic dopaminergic activity
Negative: Decreased mesocortical dopaminergic activity
List 2 first generation (typical) antipsychotic drugs and their mechanism of action
Chlorpromazine: D2 receptor antagonist
Haloperidol: Potent D2 antagonist
What side effects accompany the 2 first generation (typical) antipsychotic drugs?
Chlorpromazine: Anticholinergic side effects + EPS
Haloperidol: EPS
What are the side effects of Clozapine?
Neutropenia
Agranulocytosis
Myocarditis
Weight gain
Describe the action and side effects of Risperidone
Very potent antagonist of 5-HT 2A + D2 receptors
EPS, weight gain + hyperprolactinaemia
Describe the action and side effects of Quetiapine
Very potent antagonist of H1 receptors
Lower EPS
Describe the action, efficacy and side effects of Aripiprazole
Partial agonist of D2 + 5-HT 1A receptors
No more efficacious than typical antipsychotics
Reduced incidences of hyperprolactinaemia + weight gain
