Flashcards in Dopaminergic pathways of the brain and drugs used to treat Parkinson’s Disease and Schizophrenia Deck (64)
What are the 4 main dopaminergic pathways in the brain?
Where are each of these pathways found?
Nigrostriatal– projecting from the substantia nigra pars compacta to the striatum
Mesolimbic– projecting from the ventral tegmental area to the nucleus accumbens, frontal cortex, limbic cortex and olfactory tubercle
Tuburoinfundibular system– projecting from the arcuate nucleus in the hypothalamus to the median eminence and pituitary gland
Mesocortical- VTA to cerebrum
What are the roles of these pathways?
Nigrostriatal – control of movement
Mesolimbic – involved in emotion
Tuburoinfundibular system – regulate hormone secretion
Mesocortical- executive functions and complex behavioural patterns
What are the two families of dopamine receptors and which receptors fall into each of these families?
D1 family – D1 + D5
D2 family – D2, D3 + D4
Describe dopamine synthesis.
Tyrosine is converted by tyrosine hydroxylase to L-DOPA
DOPA is converted by DOPA decarboxylase to Dopamine
Is Parkinson’s disease more common in males or females?
Males – 4:1
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)
What are the presenting symptoms of Parkinson’s disease?
Pill-rolling resting tremor
Difficulty with fine movements (micrographia)
Poverty of blinking
Monotony of speech and loss of volume of voice
Disorders of posture – flexion of the neck and trunk
Lack of arm swing
Loss of balance – lack of righting reflex, retropulsion
Short steps, shuffling gait
Describe the initial distribution of symptoms across the body.
Symptoms spread to both sides
Generally symptoms worsen with some patients becoming severely disabled
What are some non-motor symptoms of Parkinson’s disease?
Autonomic dysfunction (constipation, postural hypotension, urinary frequency/urgency, impotence, increased sweating)
What is the main area of the brain that is affected by Parkinson’s disease?
Describe the neuropathology of Parkinson’s disease.
There is a severe loss of dopaminergic projection cells in substantia nigra. Lewy bodies and neurites are found in these cell bodies and axons.
What are the stages of Parkinson’s disease?
1-2 = dorsal motor nucleus of vagus, raphe nucleus, locus coeruleus
3 = substantia nigra pars compacta
4 = amygdala, nucleus of Meynert, hippocampus
5-6 = cingulate cortex, temporal cortex, frontal cortex, parietal cortex, occipital cortex
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?
There are compensatory mechanisms e.g. neurone overactivity and increase in dopamine receptors
What other type of drug has to be given with L-DOPA in dopamine replacement therapy and why?
Peripheral DOPA decarboxylase inhibitor
This prevents the conversion of L-DOPA to dopamine by peripheral DOPA decarboxylase (this can cause nausea and vomiting)
State two different preparation of dopamine replacement therapy.
Carbodopa + L-DOPA Benserazide + L-DOPA
What does L-DOPA treat?
What are the acute side effects of L-DOPA?
Nausea (prevented by domperidone)
Psychological effects (schizophrenia like syndrome with dellusions, hallucinations, confusion, disorientation and nightmares)
What are the chronic side effects of L-DOPA?
Dyskinesias (abnormal movement of limbs and face – can occur within 2 years of treatment – disappear with reduced dose)
Rapid fluctuations in clinical state (off periods may last for minutes to hours
Name 2 dopamine agonists.
Which receptors does bromocriptine act on?
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
What are the adverse effects of dopamine agonists?
Common – confusion, dizziness, nausea/vomiting, hallucinations
Rare – constipation, headache, dyskinesia
What structure used to be present in older dopamine agonists that caused quite serious clinical problems?
This caused fibrosis of heart valves
What has been the consequence of the removal of this structure within dopamine agonists?
Development of addictive behaviour e.g. gambling
Name two MAO inhibitors.