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Y2 LCRS Pharm RI > Parkinson’s Disease and Schizophrenia > Flashcards

Parkinson’s Disease and Schizophrenia Flashcards

1
Q

What are the three main dopaminergic pathways in the brain?

A

Nigrostriatal
Mesolimbic
Mesocortical

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2
Q

Where are the three main dopaminergic pathways in the brain found?

A

Nigrostriatal– projecting from the substantia nigra pars compacta to the striatum

Mesolimbic– ventral tegmental area (VTA) to the Nucleus Accumbens (NAcc)

Tuburoinfundibular system– VTA to the cerebrum.

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3
Q

What are the roles of the three main dopaminergic pathways in the brain?

A

Nigrostriatal – control of movement

Mesolimbic – involved in emotion

Mesocortical pathway - Important in executive functions & 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 (Gs linked)

D2 family – D2, D3 + D4 (Gi linked)

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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 genetic mutations?

A

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 instability

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10
Q

What are the ANS effects of parkinsons?

A

Olfactory deficits

Orthostatic hypotension

Constipation

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11
Q

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

A

Substantia nigra

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12
Q

Describe the neuropathology of Parkinson’s disease.

A

Lewy bodies and Lewy neurites (composed of the same material but in different cellular locations) found in dopaminergic neurones

Strongly associated with neurodegeneration

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13
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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14
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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15
Q

What is the reason for this loss of neurones before symptoms appear?

A

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

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16
Q

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

A

DOPA decarboxylase inhibitor

This prevents the conversion of L-DOPA to dopamine by peripheral DOPA decarboxylase

They dont cross the BBB so conversion of L-DOPA (Levodopa) occurs in the brain where it is needed

e.g. Carbidopa or Benserazide

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17
Q

What drug is also sometimes administered with levodopa?

A

A COMT inhibitor to increase the amount of levodopa in the brain

e.g. Entacapone or Tolcapone

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18
Q

What is the treatment for Parkinsons?

A

No disease modifying treatment, can only teat symptoms

  1. Dopamine replacement
  2. Dopamine receptor agonsits
  3. MAOb inhibitors
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19
Q

Explain what is used for dopamine replacement?

A

Levodopa (L-DOPA)

Rapidly converted to DA by DOPA decarboxylase (DOPA-D)

Can cross blood-brain barrier (BBB)

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20
Q

Explain the side effects of levodopa

A

Nausea and vomiting

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21
Q

Explain the chronic side effects of levodopa

A

Dykinesias - unknown cause

‘On-Off positive effects’ - possibly due to fluctuations in plasma L-DOPA and a loss in the neurons ability to store DA.

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22
Q

Give 2 examples of the classes of dopamine receptor agonsits

A

Ergot derived:
Bromocriptine
Pergolide

Non-ergot derived:
Ropinirole
Rotigotine

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23
Q

Which receptors do dopamine receptor agonsits act on?

A

D2 receptor

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24
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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25
Q

Name two MAO inhibitors.

A

Selegiline (Deprenyl)

Rasagiline

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26
Q

What are the effects of benefits of using a MAOb inhibitor?

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 Levodopa (reduce dose of Levodopa by 30-50%)

Delays the amount of time before Levodopa must be started to give the patient more years of treatmetn (extends available treatment from 7 years to 9 years)

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27
Q

What are the effects of COMT inhibition in the CNS?

A

Prevents breakdown of dopamine in the brain

28
Q

What’s the epidemiology of schizophrenia?

A

1% of population effected

Strong genetic link

Onset of symptoms between 15-35 years

Higher incidence in ethnic minorities (eg Afro-Caribbean immigrants)

29
Q

What are the symptoms of schizophrenia?

A

Positive Symptoms (overt symptoms that should NOT be present)
 Hallucinations (auditory and visual)
 Delusions (paranoia)
 Disorganised thoughts (denial about oneself i.e. dont believe they have schizophrenia)

Negative Symptoms (lack of characteristics that SHOULD be present)
 Alogia (Reduced speech)
 Affective flattening (lack of emotion)
Avolition/apathy (loss of motivation

30
Q

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

A

Genetics

31
Q

What are all the susceptibility genes for schizophrenia associated with?

A

Dopamine and glutamate neurotransmission

32
Q

Which symptoms do neuroleptic drugs treat?

A

Positive symptoms ONLY

33
Q

What are the initial effects of neuroleptic drugs?

A

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

34
Q

What is meant by an atypical antipsychotic?

A

Newer antipsychotics are given this term also called 2nd generation anti psychotics

35
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

36
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

37
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

38
Q

Which dopaminergic pathway in the brain is sometimes inadvertently inhibited when treating parkinsons and Schizophrenia?

A

Tuberoinfundibular pathway

Projects from the arcuate nucleus to the median eminance.

39
Q

What is the consequence of inhibiting the Tuberoinfundibular pathway?

A

Hyperprolactinaemia

40
Q

How is Dopamine removed from the synaptic cleft?

A

Dopamine transporter (DAT) or noradrenaline transporter (NET) on glial cells or the pre synaptic membrane

41
Q

What kind of glial cells are found in the CNS?

A

Astrocytes

42
Q

What is the rate limiting step in dopamine synthesis?

A

Tyrosine hydroxylase enzyme is rate limiting

43
Q

How is dopamine metabolised?

A

1) Monoamine oxidase A (MAO-A):
It metabolises DA, NE and 5-HT

2) MAO-B:
It metabolises DA

3) Catechol-O-methyl transferase (COMT):
It metabolises all catecholamines

44
Q

Where are the enzymes that metabolise dopamine found?

A

MAO only found on mitochondrial membranes

COMT is found in the cytosol and on the cell membranes of a wide distribution of cells

45
Q

What are the neuropsychiatric effects of parkinsons?

A

Sleep disorders

Memory deficits

Depression

Irritability

46
Q

In what order do the symptoms of parkinsons develop?

A

Olfactory deficits

Cardinal symptoms

Depression and irritability

47
Q

Why are COMT inhibitors not effective as a mono therpay?

A

Most of DA breakdown is by MAO so CMOT inhibitors only help a little bit

48
Q

What happens when DA activates the D2 receptors?

A

Activates adenylate cyclase

Converts ATP to cAMP

Activates PKA

49
Q

What’s the advantage of non-ergot dervied over ergot derived DAR agonists?

A

Non-ergot derived:
Ropinirole is available as an extended release formulation

Rotigotine is available as a patch

Erogt derived are associated with cardiac fibrosis

50
Q

Explain the reduction in life expectancy associated with schizophrenia

A

20-30 year lowering of life expectancy

Due to recreational drug use associate with schizophrenia

51
Q

What is the pathology of schizophrenia?

A

Increased dopamine levels in the mesolimbic pathway

Decreased dopamine levels in the mesocortical pathway

52
Q

What is the issue with the drugs for schizophrenia?

A

They treat the positive symptoms well but leave the patient with the negative symptoms

53
Q

What are the main classes of drugs for treating schizophrenia?

A

1st generation antipsychotics:
D2 antagonists

2nd generation anti psychotics:
5-HT receptor antagonsits
Other mechanisms of action

54
Q

Give 2 examples of 1st generation anti psychotics

A

Chlorpromazine

Haloperidol

55
Q

What is the advantage and disadvantage of haloperidol over chlorpromazine?

A

Haloperidol is 50x more potent than chlorpromazine

Haloperidol takes 6-8 weeks to develop its theraputic effects

56
Q

What are the side effects of the 1st generation anti psychotics?

A

Chlorpromazine:
High incidence of anti-cholinergic effects (especially sedation) as it is a muscarinic receptor antagonist

Haloperidol:
High incidence of extrapyramidal side effects.

57
Q

Give 4 examples of 2nd generation anti psychotics

A

Clozapine - most effective

Risperidone

Quetiapine

Aripipazole

58
Q

What is the mechanism of clozapine?

A

Very potent antagonist of 5-HT2a receptors

59
Q

What is different about clozapine compared to other anti psychotics?

A

Clozapine is the only licensed drug to show reduction in both positive and negative symptoms of schizophrenia

60
Q

Why is clozapine only used as a last resort treatment?

A

Can cause potentially fatal neutropenia, agranulocytosis, myocarditis & weight gain

61
Q

What is the mechanism of risperidone?

A

Very potent antagonist of 5-HT2A & D2 receptors

62
Q

What is the disadvantage of risperidone?

A

More EPS & hyperprolactinaemia than other 2nd gen antipsychotics

63
Q

What is the mechanism of quetiapine?

A

Very potent antagonist of H1 receptors

64
Q

What is the advantage of quetiapine?

A

Lower incidence of EPS than other antipsychotics

65
Q

What is the mechanism of aripiprazole?

A

Partial agonist of D2 & 5-HT1A receptors

In theory this means when there is too much dopamine activity (positive symptoms) it acts as an antagonist, and when there is too little dopamine activity (negative symptoms) it acts as a agonsit

66
Q

What is the advantage of aripiprazole?

A

Reduced incidences of hyperprolactinaemia & weight gain than other antipsychotics

67
Q

What are the neuropsychiatric symptoms of Parkinsons

A

sleep disorders, memory

deficits, depression, irritability

Y2 LCRS Pharm RI (34 decks)

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