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LCRS 1 > Dopaminergic pathways of the brain and drugs used to treat Parkinson’s Disease and Schizophrenia > Flashcards

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

1
Q

What are the 4 main dopaminergic pathways in the brain?

A

Nigrostriatal
Mesolimbic
Tuberoinfundibular system
Mesocortical pathway

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2
Q

Where are each of these pathways found?

A

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

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3
Q

What are the roles of these pathways?

A

Nigrostriatal – control of movement
Mesolimbic – involved in emotion
Tuburoinfundibular system – regulate hormone secretion
Mesocortical- executive functions and complex behavioural patterns

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4
Q

What are the two families of dopamine receptors and which receptors fall into each of these families?

A

D1 family – D1 + D5

D2 family – D2, D3 + D4

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5
Q

Describe dopamine synthesis.

A

Tyrosine is converted by tyrosine hydroxylase to L-DOPA

DOPA is converted by DOPA decarboxylase to Dopamine

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6
Q

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

A

Males – 4:1

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7
Q

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

A

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

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8
Q

What are the cardinal signs of Parkinson’ disease?

A

Resting tremor (pill-rolling tremor)
Rigidity (stiffness – limbs feel weak and heavy)
Bradykinesia (slowness of movement)
Postural abnormality

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9
Q

What are the presenting symptoms of Parkinson’s disease?

A

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

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10
Q

Describe the initial distribution of symptoms across the body.

A

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

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11
Q

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

A 
Depression  
Pain  
Taste/smell disturbances  
Cognitive decline/dementia  
Autonomic dysfunction (constipation, postural hypotension, urinary frequency/urgency, impotence, increased sweating)
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12
Q

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

A

Substantia nigra

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13
Q

Describe the neuropathology of Parkinson’s disease.

A

There is a severe loss of dopaminergic projection cells in substantia nigra. Lewy bodies and neurites are found in these cell bodies and axons.

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14
Q

What are the stages of Parkinson’s disease?

A 
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
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15
Q

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

A

Marked reduction in the caudate nucleus/putamen dopamine content

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16
Q

What proportion of dopaminergic neurones of the nigrostriatal dopaminergic pathway must be lost before symptoms occur?

A

80-85% of dopaminergic neurones and 70% of striatal dopamine must be depleted before symptoms appear

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17
Q

What is the reason for this?

A

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

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18
Q

What other type of drug has to be given with L-DOPA in dopamine replacement therapy and why?

A

Peripheral DOPA decarboxylase inhibitor

This prevents the conversion of L-DOPA to dopamine by peripheral DOPA decarboxylase (this can cause nausea and vomiting)

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19
Q

State two different preparation of dopamine replacement therapy.

A

Carbodopa + L-DOPA Benserazide + L-DOPA

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20
Q

What symptoms does L-DOPA treat?

A

Hypokinesia
Tremor
Rigidity

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21
Q

What are the acute side effects of L-DOPA?

A 
Nausea (prevented by domperidone)  
Hypotension 
Psychological effects (schizophrenia like syndrome with dellusions, hallucinations, confusion, disorientation and nightmares)
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22
Q

What are the chronic side effects of L-DOPA?

A

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

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23
Q

Name 2 dopamine agonists.

A

Bromocriptine

Pergolide

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24
Q

Which receptors does bromocriptine act on?

A

D2 receptor

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25
Q

What are the benefits of dopamine agonists over L-DOPA?

A 
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
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26
Q

What are the adverse effects of dopamine agonists?

A

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

27
Q

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

A

Ergot ring

This caused fibrosis of heart valves

28
Q

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

A

Development of addictive behaviour e.g. gambling

29
Q

Name two MAO inhibitors.

A

Deprenyl

Rasagiline

30
Q

What are the effects of Deprenyl?

A

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%)

31
Q

Name two COMT inhibitors.

A

Tolocapone (CNS + PNS)

Entacapone (PNS)

32
Q

What are the effects of COMT inhibition in the CNS?

A

Prevents breakdown of dopamine in the brain

33
Q

What are the side effects of COMT inhibitors?

A

Cardiovascular complications

34
Q

What are the symptoms of schizophrenia?

A

Positive Symptoms (overt symptoms that should NOT be present)
 Hallucinations
 Delusions
 Disorganised thoughts
Negative Symptoms (lack of characteristics that SHOULD be present)
 Reduced speech
 Lack of emotional and facial expression
 Diminished ability to begin and sustain activity
 Decreased ability to find pleasure in everyday life
 Social withdrawal
Cognitive deficits
 Memory
 Attention
 Planning
 Decision making

35
Q

What appears to have quite a strong contribution to the development of schizophrenia?

A

Genetics

36
Q

Once schizophrenia has been diagnosed, what are the four main outcomes for patients?

A

1 – illness resolves completely, with or without treatment and never returns (10-20%)
2 – illness recurs repeatedly with full recovery between episodes (30-35%)
3 – illness recurs repeatedly with incomplete recovery and a persistent defective state develops, becoming more profound with each successive relapse (30-35%)
4 – illness pursues down a downhill course from the beginning (10-20%)
NOTE: most cases are relapsing and remitting

37
Q

Describe the involvement of dopamine in schizophrenia.

A

Positive symptoms – results from excessive dopamine transmission in the mesolimbic and striatal region (D2-mediated)
Negative symptoms – results from dopamine deficit in the pre-frontal region (D1-mediated)

38
Q

What evidence has arisen that supports this hypothesis?

A

Dopamine agonists can induce various psychotic reactions

Typical antipsychotics are dopamine receptor antagonists (blocking D2 receptors)

39
Q

Describe the involvement of glutamate in schizophrenia.

A

NMDA is a glutamate receptor
Glutamate exerts an excitatory influence over the GABA-ergic striatal neurones and dopamine exerts an inhibitory influence
These GABA-ergic striatal neurones project to the thalamus and constitute a sensory ‘gate’
Too little glutamate or too much dopamine disables this gate, allowing uninhibited sensory input to reach the cortex
NOTE: you find reduced glutamate concentration and reduced glutamate receptors in post-mortem schizophrenic brains. Also NMDA receptor antagonists can produce psychotic symptoms

40
Q

What are all the susceptibility genes for schizophrenia associated with?

A

Dopamine and glutamate neurotransmission

41
Q

What type of drug are all neuroleptics?

A

Dopamine receptor antagonists (D2 receptors)

NOTE: most neuroleptics block other receptors

42
Q

Which symptoms do neuroleptic drugs treat?

A

Positive symptoms ONLY

43
Q

What are the initial effects of neuroleptic drugs?

A

Initial increase in dopamine synthesis and neuronal activity – this declines with time

44
Q

What is meant by an atypical antipsychotic?

A

Newer antipsychotics are given this term – they have fewer extrapyramidal side effects

45
Q

Name an atypical antipsychotic.

A

Clozapine- potent antagonist of 5-HT2a

46
Q

Name a typical antipsychotic.

A

Haloperidol- potent D2 antagonist

47
Q

What is an important other action of neuroleptics?

A

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

48
Q

What are the extrapyramidal side effects of antipsychotics caused by?

A

Blockade of dopamine receptors in the nigrostriatal system can induce
Parkinson-like side effects

49
Q

How is dopamine metabolised

A

Removed from synaptic cleft by dopamine transporter and noradrenaline transporter then metabolised by 3 enzymes;
MAO-A
MAO-B
COMT

50
Q

Selectivity of dopamine metabolising enzymes

A

MAO-A metabolises DA, NE and serotonin
MAO-B metabolises just DA
COMT metabolises all catecholamines

51
Q

What are lewy bodies and neurites made of

A

Consist of the abnormally phosphorylated neurolfilaments ubiquitin and alpha-synuclein

52
Q

What are examples of COMT inhibitors

A

Entacapone

Tolcapone

53
Q

What age do people generally have symptoms of schizophrenia beginning

A

15-35

54
Q

Life expectancy of schizophrenia patients

A

20-30 lower than normal

55
Q

Where is there a higher incidence of schizophrenia

A

Immigrants

56
Q

What tends to cause positive symptoms of schizophrenia

A

Increased mesolimbic dopaminergic activity

57
Q

What tends to cause negative symptoms of schizophrenia

A

Decreased mesocortical dopaminergic symptoms

58
Q

MOA of chlorpromazine

A

D2 receptor antagonist

59
Q

2 first generation antipsycotics

A

Chlorpromazine

Haloperldol

60
Q

4 second generation antipsycotic

A

Clozapine
Risperidone
Quetiapine
Aripiprazole

61
Q

What is risperidone

A

Potent antagonist of 5-HT2a and d2

62
Q

What is quetiapine

A

Potent antagonist of H1 receptors

63
Q

What is aripiprazole

A

Partial agonist of D2 and 5-HT1a- affects reduced mesocortical

64
Q

Which antipyscotic drug is associated with neutropenia and agranulocytosis

A

Clozapine

LCRS 1 (58 decks)

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