Dopaminergic pathways of the brain and drugs used to treat Parkinson’s Disease and Schizophrenia Flashcards Preview

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Flashcards in Dopaminergic pathways of the brain and drugs used to treat Parkinson’s Disease and Schizophrenia Deck (64)
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1

What are the 4 main dopaminergic pathways in the brain?

Nigrostriatal
Mesolimbic
Tuberoinfundibular system
Mesocortical pathway

2

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

3

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

4

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

5

Describe dopamine synthesis.

Tyrosine is converted by tyrosine hydroxylase to L-DOPA
DOPA is converted by DOPA decarboxylase to Dopamine

6

Is Parkinson’s disease more common in males or females?

Males – 4:1

7

What are the possible causes of idiopathic Parkinson’s disease?

Possibly a combination of environmental, oxidative stress, altered protein metabolism and risk genes

8

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 abnormality

9

What are the presenting symptoms of Parkinson’s disease?

Pill-rolling resting tremor
Difficulty with fine movements (micrographia)
Poverty of blinking
Hypomimic face
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

10

Describe the initial distribution of symptoms across the body.

Unilateral onset
Symptoms spread to both sides
Generally symptoms worsen with some patients becoming severely disabled

11

What are some non-motor symptoms of Parkinson’s disease?

Depression
Pain
Taste/smell disturbances
Cognitive decline/dementia
Autonomic dysfunction (constipation, postural hypotension, urinary frequency/urgency, impotence, increased sweating)

12

What is the main area of the brain that is affected by Parkinson’s disease?

Substantia nigra

13

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.

14

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

15

What is the main biochemical change seen in Parkinson’s disease?

Marked reduction in the caudate nucleus/putamen dopamine content

16

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

17

What is the reason for this?

There are compensatory mechanisms e.g. neurone overactivity and increase in dopamine receptors

18

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)

19

State two different preparation of dopamine replacement therapy.

Carbodopa + L-DOPA Benserazide + L-DOPA

20

What does L-DOPA treat?

Hypokinesia
Tremor
Rigidity

21

What are the acute side effects of L-DOPA?

Nausea (prevented by domperidone)
Hypotension
Psychological effects (schizophrenia like syndrome with dellusions, hallucinations, confusion, disorientation and nightmares)

22

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

23

Name 2 dopamine agonists.

Bromocriptine
Pergolide

24

Which receptors does bromocriptine act on?

D2 receptor

25

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

26

What are the adverse effects of dopamine agonists?

Common – confusion, dizziness, nausea/vomiting, hallucinations
Rare – constipation, headache, dyskinesia

27

What structure used to be present in older dopamine agonists that caused quite serious clinical problems?

Ergot ring
This caused fibrosis of heart valves

28

What has been the consequence of the removal of this structure within dopamine agonists?

Development of addictive behaviour e.g. gambling

29

Name two MAO inhibitors.

Deprenyl
Rasagiline

30

What are the effects of Deprenyl?

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 L-DOPA (reduce dose of L-DOPA by 30-50%)