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Pharm > Antiparkinsons and neuroleptics > Flashcards

Antiparkinsons and neuroleptics Flashcards

1
Q

Differentiate neuroleptics and anti-psychotics and what tey are used to treat

A

SAME….. used to treat schizophrenia

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2
Q

Outline synthesis of dopamine a the dopamine receptor

A

L-tyrosine–> (TH) (i) L-DOPA –> (DOPA-D) (ii) Dopamine (DA)

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3
Q

Which is the rate limiting enzyme in dopamine production

A

TH (i.e you cant just add more tyrosine you have to increase tyrosine)

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4
Q

Outline the metabolism of dopamine

A
  1. DA removed from synaptic cleft by transporters (which?)
  2. Three enzymes beaking down DA:
    - Monoamine oxidase A (MAO-A): metabolises DA, NE & 5-HT
    - MAO-B: metabolises DA (more selective)
    - Catechol-O-methyl transferase (COMT): wide distribution, metabolises all catecholamines
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5
Q

Which transporters take up dopamine

A

dopamine transporter (DAT) & noradrenaline transporter (NET)

(as they are both monoamines)

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6
Q

Why do dopaminergic cells not produce NA which is produced by same pathways

A

Don’t contain the enzymes needed to convert the dopamine to the other MA

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7
Q

Where are MAOs usually found

A

Intracellular and on membrane of the mitochondria on the dopaminergic neuronal cell

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8
Q

Where is COMT found

A

Not just in neuon like the MOA,

found in glial cell, post synaptic membrane, and the neurone

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9
Q

What are the important dopaminergic pathways

A
  1. Nigrostriatal pathway
  2. Mesolimbic pathway
  3. Mesocortical pathway
  4. Tuberoinfundibular pathway
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10
Q

What locations do the nigrostriatal tract run

A

susbstantia nigra pars compacta (SNc) to the striatum. Inhibition results in movement disorders

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11
Q

What locations do the mesolimbic tract run

A

ventral tegmental area (VTA) to the Nucleus Accumbens (NAcc). Brain reward pathway.

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12
Q

What locations do the mesocortical tract run

A

VTA to the cerebrum. Important in executive functions & complex behavioural patterns.

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13
Q

What locations do the tuberoinfundibular pathway tract run

A

arcuate nucleus to the median eminence. Inhibition results in hyperprolactinaemia

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14
Q

What conditions associated with each dopaminergic pathway

A
  1. Nigrostriatal pathway (movement)

2. Mesolimbic pathway (schizophrenia)

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15
Q

Compare parkinsons and schizophrenia

A

Parkinsons, like alzheimers, is NEURODEGENERATIVE

Schizophrenia is NEUROEFFECTIVE

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16
Q

Genetic component to parkinsons

A

SNCA, LRRK2

associated with the early onset parkinsons, not the late onset, whch is more prevalent

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17
Q

Pathophysiology of parkinsons

A

Severe loss of dopaminergic projection cells in SNc

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18
Q

What molecular signs are seen in parkinsons

A

Lewy bodies & neurites –> Found respectively within neuronal cell bodies & axons

these are associated with the neurodegeneraton

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19
Q

What are lewy bodies and neurites made up of

A

Consist of abnormally phosphorylated neurofilaments, ubiquitin & a-synuclein

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20
Q

Symptoms of parkinsons – motor

A

resting tremor, bradykinesia, rigidity, postural instability

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21
Q

Autonomic NS effects of parkinsons

A

olfactory deficits, orthostatic hypotension, constipation

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22
Q

Psychiatric symptoms of parkinsons

A

sleep disorders, memory deficits, depression, irritability

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23
Q

Progression of parkinsons)

A

Loss of smell (ANS deficit) as neurites start here

Motor

Neuropsychiatric (late stage)

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24
Q

What is the action of levadopa

A

Effecting the 20 % of remaining dopaminergic neurons

It is basically L-DOPA It is rapidly conerted to DA by DOPA decarboxylase (DOPA-D)

Can cross the BBB

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25
Q

What is the consequence of levadopa being converted to dopamine in the periphery

A

Because DOPA decarboxylase is present in periphery

It can make dopamine from the levadopa

This can act on areas outsde the BBB…. ie the CTZ and can activate comiting

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26
Q

Why can L-tyrosine not be given as PD treatment

A

The rate limiting step is TH so you need to surpass this step

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27
Q

What are the long term effects of levadopa

A

dyskinesias & ‘on-off’ effects. NOT disease-modifying

On/off refers to the changes from motor control to lack of motor control near to end of dose

Dyskinesia is muscle movements that people with Parkinson’s can’t control. They can include twitches, jerks, twisting or writhing movements

https://www.parkinsons.org.uk/information-and-support/wearing-and-dyskinesia

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28
Q

Adjuncts given with levadopa

A

DOPA decarboxylase inhibitors

COMT inhibitors

29
Q

Name 2 DOPA decarboxylase inhibitors and how they help in parkinsons

A

Carbidopa & Benserazide

Do not cross BBB …. this prevent peripheral breakdown of levodopa into dopamine but not that in the CNS

Reduce required levodopa dosage

30
Q

Name the different COMT inhibitors

A

Entacapone & Tolcapone

31
Q

What does COMT do to help in parkinsons

A

Increase amount of levodopa in the brain

32
Q

……

A

….

33
Q

Which receptors can dopamine act on

A

Dopamine (DA) can act on D1,5(Gs linked) or D2-4 (Gi-linked) receptors

34
Q

Second treatment of PD other than levadopa

A

DOPAMINE RECEPTOR AGONISTS

Ergot derivatives: Bromocriptine & Pergolide

Non-ergot derivatives: Ropinirole

35
Q

How do dopamine receptor agonists work

A

Act as potent agonists of D2 receptors

36
Q

Disadvantage or ergot derivative dopamine receptor agonist

A

Cardiac fibrosis

37
Q

Third treatment of PD

A

Monoamine oxidase B (MAOB) inhibitors (i.e. the MAO specific to dopamine)

Selegiline (deprenyl) & Rasagiline

38
Q

Why are MAO used in PD

A

Reduce the dosage of L-DOPA required

Can increase the amount of time before levodopa treatment is required

39
Q

Outline the formulatins of the non-ergot derivatives

A

Ropinirole also available as extended-release formulation

Rotigotine also available as a patch

40
Q

….

A

……

41
Q

Onset of symptoms of schizophrenia

A

Onset of symptoms: between 15-35 years

42
Q

T/f schizophrenia is 100% genetic

A

F.. in twin studies with monozygotic twins there is 50% concordance

so genetic and environmental factors

43
Q

Higher incidence of schizophrenia in which populations

A

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

44
Q

Patient’s life expctancy with schizophrenia

A
  • 20-30 years lower than average
45
Q

Positive symptoms of schizophrenia

A

Inceased mesolimbic dopaminergic activity

Hallucinations: Auditory & visual

Delusions: Paranoia

Thought disorder: Denial about oneself

memory aid that increased mesolimbic is like drugs do cos of reward and drugs lead to simlar things

46
Q

Negative symptoms of schizophrenia

A

Reduced Mesocortical dopaminergic activity

Affective flattening: lack of emotion

Alogia: lack of speech

Avolition/ apathy: loss of motivation

memory aid that these are cortical function

47
Q

Why is schizophrenia associated with early death

A

More recreational drug use to alleviate symptoms

48
Q

Pathophysiology of schizophrenia

A

Increase mesolimbic dopaminergic activity

Reduced mesocortical dopamiergic activity

49
Q

What aspects of schizophrenia do the drugs deal with

A

Only the positive ones

50
Q

Outline types of neuropleptics

A

=antipsychotic

first generation= typical

second generation= atypical

51
Q

Action of chlorpromazine

A

Discovered by serendipity

Primary mechanism of action – possibly D2 receptor antagonism. This Gi linked. Reduced AC, cAMP and PKA

(also histamine antagonist)

52
Q

Side effects of chlorpromazine

A

High incidence - anti-cholinergic, especially sedation

Low incidence - extrapyramidal side-effects (EPS)

53
Q

Outline mecahnism of haloperidol action

A

Very potent D2 antagonist (~ 50x more potent than chlorpromazine)

Therapeutic effects develop over 6-8 weeks

Little impact on negative symptoms

54
Q

Side effects of haloperidol

A

High incidence of EPS (in contrast to the chlorpromazine which has low EPS and high anticholinergic)

55
Q

Action of clozapine

A

MOST EFFECTIVE ANTI-PSYCHOTIC

Potent antagonist of 5-HT2A receptors

56
Q

T/f clozapine has highest affinity for the 5-HT2A receptor

A

F…. it binds M1 most effectively but the 5-HT2A is where the effect lies

57
Q

What is the effectiveness of clozipine

A

Only drug to show efficacy in treatment resistant schizophrenia & negative symptoms

(most liit positive systems but not negatie)

58
Q

Side effects of clozapine

A

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

59
Q

If clozapine is most effective why not used as first line

A

Because of the side effects, patients ahve to be monoted on them

60
Q

Difference btween first and second generation antipsychtics

A

first mostly anti D2

second mostly 5HT angatonist

61
Q

Action of risperiodne

A

Very potent antagonist of 5-HT2A & D2 receptors

62
Q

Side effects of risperiodone

A

More EPS & hyperprolactinaemia than other atypical antipsychotics

63
Q

Ation of quetiapine

A

Very potent antagonist of H1 receptors

64
Q

Side effects of quetiapine

A

Lower incidence of EPS than other antipsychotics

65
Q

T/F these drugs have good selectivity

A

F….. they are dirty drugs

66
Q

What is the problem with dopamine antagonist drugs

A

They are blocking mesolimbic system which is good because this is increased dopamine in schiz

but

it is also reducing dopamine in the mesocortical system, which is bad because these levels are already reduced in schiz

67
Q

Outline the mechanism of aripiprazole

A

Partial agonist of D2 & 5-HT1A receptors

68
Q

Why was aripirazole thought to be more effective , and was it

A

Because it is partial agonist so would incrase dopamine action at the mesocortical tract (where dopamine it is reduced in schiz) but reduce it where dopamine is too high (i.e. mesolimbic)

No more efficacious than typical antipsychotics (ie first line)

69
Q

Side effects of aripirazole

A

Reduced incidences of hyperprolactinaemia & weight gain than other antipsychotics

Pharm (33 decks)

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