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Farmer > Anti-Parkinsonian drugs and Neuroleptics > Flashcards

Anti-Parkinsonian drugs and Neuroleptics 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 - projecting from ventral tegmental area to diffuse areas of cortex

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
Mesocortical - Emotions and behaviour
Tuburoinfundibular system – regulate prolactin 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

Tyrosine is converted by tyrosine hydroxylase to 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 percentage of all cases of Parkinson’s disease is accounted for by familial Parkinson’s disease?

A

8%
SNCA, LRRK2 Mutations cause Early onset (5%)
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)

Autonomic symptoms present before motor symptoms
Neuropsychiatric symptoms present after

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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

Lewy bodies (in cell body) and Lewy neurites (in axon) also present – this is probably a defensive mechanism to protect against toxic altered proteins

Abnormal phosphorylated neurofilaments ubiquitin and α-synuclein make them up

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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

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)

Also COMT inhibitors – Entacapone and Tolcapone enhance L-DOPA action

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19
Q

State two different preparation of dopamine replacement therapy.

A 
Sinamet = Carbodopa + L-DOPA 
Madopar = Benserazide + L-DOPA
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20
Q

What does L-DOPA treat?

A

Hypokinesia
Tremor
Rigidity

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21
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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22
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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23
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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24
Q

Name three dopamine agonists.

A

Bromocriptine (Ergot)
Ropinerol
Pergolide (Ergot)

25
Q

Which receptors do dopamine agonists act on?

A

D2 receptor

26
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
27
Q

What are the adverse effects of dopamine agonists?

A

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

28
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/Cardiac fibrosis

29
Q

What has been the consequence of the removal of ergot rings within dopamine agonists?

A

Development of addictive behaviour e.g. gambling

30
Q

Name two MAO inhibitors.

A

Deprenyl (selegiline)

Rasagiline

31
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%)

32
Q

What are the side effects of Deprenyl?

A

RARE
Hypotension
Nausea/vomiting
Confusion and agitation

33
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

34
Q

Name two COMT inhibitors.

A

Tolocapone (CNS + PNS)

Entacapone (PNS)

35
Q

What are the effects of COMT inhibition in the CNS?

A

Prevents breakdown of dopamine in the brain

36
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

37
Q

What are the side effects of COMT inhibitors?

A

Cardiovascular complications

38
Q

What percentage of the general population is affected by schizophrenia?

A

1%

39
Q

What are the positive symptoms of schizophrenia?

A 
Positive Symptoms (overt symptoms that should NOT 
be present)

Hallucinations
Delusions
Disorganised thoughts

40
Q

What are the negative symptoms of schizophrenia?

A

Negative Symptoms (lack of characteristics that SHOULD be present)

Alogia - Reduced speech
Affective flattening -Lack of emotional and facial expression
Anhedonia/Apathy/Avolition

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 the hypothesis of dopamine involvement in schizophrenia?

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 associated with?

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 (D2 mediated)

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 are the extrapyramidal side effects of antipsychotics caused by?

A

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

52
Q

What are the two main extra-pyramidal side effects?

A

Acute Dystonia

  • 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
53
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

54
Q

Describe Chlorpromazine as an anti-psychotic

A

Typical (1st Gen)

D2 antagonism/H1 antagonism/ACh antagonism
Low incidence of Extrapyramidal side effects (EPS) but high Anti-muscarinic effects

55
Q

Describe Haloperidol as an anti-psychotic

A

Typical (1st Gen)

50x more potent D2 antagonism than chlorpromazine, But high EPS

56
Q

Describe Clozapine as an anti-psychotic

A

Atypical (2nd Gen)

5-HT2A antagonist
MOST EFFECTIVE NEUROLEPTIC – Treats negative side effects to an extent (only licensed drug that does so)

Bad side effects – Can cause neutropenia, agranulocytosis, myocarditis and weight gain

57
Q

Describe Risperidone as an anti-psychotic

A

Atypical (2nd Gen)
5-HT and D2 Antagonist
EPS side effects/Hyperprolactinaemia

58
Q

Describe Quetiapine as an anti-psychotic

A

Atypical (2nd Gen)
H1 antagonist
Low EPS side effects

59
Q

Describe Aripiprazole as an anti-psychotic

A

Atypical (2nd Gen)

Partial agonist D2 and 5-HT1a (May be able to increase Mesocortical and reduce Mesolimbic)
But no more efficacious

Reduced hyperprolactinaemia and weight gain compared to other anti-psychotics

Farmer (33 decks)

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