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Pharmacology And Therapeutics > 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 four main dopaminergic pathways in the brain?

A

Nigrostriatal
Mesolimbic
Mesocortical
Tuberoinfundibular system

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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
Mesocortical
Tuburoinfundibular system– projecting from the arcuate nucleus in the hypothalamus to the median eminence and pituitary gland

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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

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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

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

L-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 percentage of all cases of Parkinson’s disease is accounted for by familial Parkinson’s disease?

A

8%

The rest are idiopathic

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8
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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9
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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10
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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11
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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12
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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13
Q

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

A

Substantia nigra

Other brain areas affected: locus coeruleus, dorsal vagus nucleus, nucleus basalis of Mynert

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14
Q

Describe the neuropathology of Parkinson’s disease.

A 
Putamen-projecting pathways degenerate significantly in SNpc  
Lewy bodies (large circular structure with bright core and white surrounding, packed with alpha-synuclein) also present – this is probably a defensive mechanism to protect against toxic altered proteins
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15
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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16
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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17
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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18
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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19
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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20
Q

State two different preparation of dopamine replacement therapy.

A 
Sinamet = Carbodopa + L-DOPA 
Madopar = Benserazide + L-DOPA
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21
Q

What does L-DOPA treat?

A

Hypokinesia
Tremor
Rigidity

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22
Q

Describe how the dosage of L-DOPA is changed with continued treatment.

A

It is started low and increased until maximum benefit of drug is achieved without side effects
Effectiveness of L-DOPA declines with time

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23
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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24
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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25
Q

Name three dopamine agonists.

A

Bromocriptine
Ropinerol
Pergolide

26
Q

Which receptors do they act on?

A

D2 receptor

27
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
28
Q

What are the adverse effects of dopamine agonists?

A

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

29
Q

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

A

Ergot ring

This caused problems with heart valves

30
Q

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

A

Development of addictive behaviour e.g. gambling

31
Q

Name two MAO inhibitors.

A

Deprenyl (selegiline)

Rasagiline

32
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%)

33
Q

What are the side effects of Deprenyl?

A

RARE
Hypotension
Nausea/vomiting
Confusion and agitation

34
Q

What are the effects of Rasagiline?

A

It has neuroprotective properties by inhibiting apoptosis (promotes anti-apoptosis genes)
NOTE: early clinical trials show this drug might slow down the progression of disease but subsequent studies haven’t been so promising

35
Q

Name two COMT inhibitors.

A

Tolocapone (CNS + PNS)

Entacapone (PNS)

36
Q

What are the effects of COMT inhibition in the CNS?

A

Prevents breakdown of dopamine in the brain

37
Q

What are the effects of COMT inhibition in the peripheral nervous system?

A

Peripheral COMT converts L-DOPA to 3-O-methyl DOPA (3-OMD) 3-OMD competes with L-DOPA for the transport system that transports it across the BBB
COMT inhibitors stop 3-OMD production and hence there is less competition for L-DOPA
Result: REDUCE L-DOPA DOSAGE

38
Q

What are the side effects of COMT inhibitors?

A

Cardiovascular complications

39
Q

What percentage of the general population is affected by schizophrenia?

A

1%

40
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

41
Q

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

A

Genetics

42
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

43
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)

44
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)

45
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

46
Q

What is the most robust gene associated with schizophrenia?

A

Neuregulin-1

47
Q

What are all the susceptibility genes for schizophrenia associatedwith?

A

Dopamine and glutamate neurotransmission

48
Q

What type of drug are all neuroleptics?

A

Dopamine receptor antagonists (D2 receptors)

NOTE: most neuroleptics block other receptors

49
Q

Which symptoms do neuroleptic drugs treat?

A

Positive symptoms ONLY

50
Q

What are the initial effects of neuroleptic drugs?

A

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

51
Q

What is meant by an atypical antipsychotic?

A

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

52
Q

Name an atypical antipsychotic.

A

Clozapine

53
Q

Name a typical antipsychotic.

A

Haloperidol

54
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

55
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

56
Q

What are the two main extra-pyramidal side effects? Acute Dystonia

A

 Involuntary movements
 Muscle spasm, protruding tongue, fixed upward gaze, neck spasm etc.
 Often accompanied by Parkinson’s like features
 Occur in the FIRST FEW WEEKS and often decline with ongoing therapy
 Reversible with withdrawal of the drug or anti-cholinergics
Tardive Dyskinesias
 Involuntary movements
 Involving the face and tongue, but also trunk and limbs
 Occur in 20% of patients after SEVERAL MONTHS/YEARS of therapy
 Made WORSE by drug withdrawal or anti-cholinergics

57
Q

What are the unwanted effects of antipsychotics?

A

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

58
Q

How is dopamine metabolised?

A

§ Dopamine (DA) removed from synaptic cleft by dopamine transporter and noradrenaline transporter

§ Three enzymes metabolise DA:

1) Monoamine oxidase A (MAOA) metabolises DA, NE and 5-HT
2) MAOB: metabolises only DA
2) Catechol-O-methyl transferase (COMT): wide distribution, metabolises all catecholamines

59
Q

What are the autonomic nervous system effects of Parkinson’s disease

A

Olfactory deficits, orthostatic hypotension, constipation

60
Q

What are the neuropsychiatric symptoms of Parkinson’s disease

A

Sleep disorders, memory deficits, depression, irritability

61
Q

What are some of the treatments of PD

A
  1. Dopamine replacement

§ Levodopa (L-DOPA): rapidly converted to DA by DOPA-D. Can cross BBB

§ Adjuncts:
++DOPA-D inhibitors (Carbidopa and benserazide) Do not cross BBB -> prevents peripheral breakdown of levodopa
++COMT inhibitors: entacapone and tolcapone

Pharmacology And Therapeutics (9 decks)

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