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Neuropharmacology > Antipsychotics > Flashcards

Antipsychotics Flashcards

0
Q

what is schizophrenia ?

A

major CNS disorder
its debilitating
progressive illness with serious consequences

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1
Q

what is another name for antipsychotics?

A

neuroleptics

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2
Q

why has schizophrenia been called the most devastating disease to affect mankind?

A

because it is not just a single disease but a spectrum of disorders
- its symptoms can change over time

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3
Q

when is its peak onset?

A

it strikes young people with little warning
- in males peak onset is 15-25 years
- in females peak onset is 25-35 years and often another peak post menopause
each gender is affected equally

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4
Q

what is the prevalence of schizophrenia ?

A

1.3%

about 40-50% of hospitalised psychiatric patients suffer from schizophrenia

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5
Q

what influences schizophrenia ?

A

genetic element is polygenic- in twin studies, if one twin has it then then other twin has a 50% chance of developing it
large environmental component

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6
Q

what are the different symptom category groups in schizophrenia ?

A 
positive symptoms
negative symptoms 
cognitive symptoms 
mood symptoms 
- range of symptoms which often occur at the same time
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7
Q

what are the positive symptoms ?

A

delusions
hallucinations
disorganised speech
- these are symptoms added onto normal behaviours

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8
Q

what are the negative symptoms ?

A 
decreased emotion
decreased motivation 
decrease in interests
decreased thoughts and speech 
decreased pleasure
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9
Q

what are the cognitive symptoms ?

A

attention
working and verbal memory
executive function
- it is NOT an intellectual impairment

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10
Q

what are the mood symptoms ?

A

depression/anxiety- they tend to just stare at a space on the floor and dont really interact with people
hostility
aggression
suicide
- these symptoms are often part of the negative symptoms
- patients cant hold eye contact, they have less flashes of eyes and less smiles

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11
Q

what are the 2 main neurotransmitter systems affected in schizophrenia?

A

dopamine and glutamate - these were discovered by accident

serotonin is also thought to be involved

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12
Q

what is dopamine hypothesis ?

A
  • dysregulation of dopamine neurotransmission - abuse of stimulants leads to schizophrenic like pyschosis via release of dopamine e.g chronic cannabis - this is probably more prevalent in individuals which have a predisposition to schizophrenia
  • animal models have shown that dopamine release produces specific stereotypy seen in schizophrenia
  • dopamine2 receptor agonists such as bromocriptine and apomorphine produces similar stereotypy and exacerbates schizo symptoms
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13
Q

what is difficult to determine about the dopamine hypothesis ?

A

it is difficult to know if it is a cause of schizophrenia or a symptoms of it but it is more likely to be a symptoms

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14
Q

what do antipyschotic drugs that block dopamine 2 receptors do and what do drugs that block neuronal dopamine storage do ?

A

e,g, reserpine
they are able to control the positive symptoms
DA2 receptor antagonists reduce positive symptoms

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15
Q

what do dopamine 2 receptor anatagonists have a strong correlation with ?

A

strong correlation between clinical antipsychotic potency and dopamine receptor blocking activity
- as the clinical antipsychotic potency increases the dopamine receptor blocking activity increases

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16
Q

how much of the dopamine 2 receptors have to be occupied to induce clinical efficacy ?

A

from imaging studies it is thought that it requires about 80% occupancy

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17
Q

what is schizophrenia linked to ?

A

a hyperactive dopamine system- dopamine mesolimbic pathway= positive and dopamine mesocortical pathway= negative

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18
Q

when were antipsychotics discovered ?

A

by accident in the 1950s

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19
Q

where have all the antipsychotics shown clinical effectiveness?

A

all of them have been dopamine antagonists

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20
Q

what does high dopamine 2 receptor occupancy cause ?

A

side effects

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21
Q

what do dopamine 2 antagonists have little effect upon ?

A

limited or no effect on negative and cognitive symptoms

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22
Q

how many patients dont respond to antipyschotic drugs nd what is the compliance in out patients ?

A

> 30% of patients are poor responders
50% of patients are non compliant in out patients which indicates that the drugs are either not that effective or they have side effects

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23
Q

why do antipyschotics have many side effects ?

A

because of their promiscuous receptor profile

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24
Q

what have PM and PET studies shown ?

A

these studies have not been consistent with the dopamine hypothesis

  • controversy as to whether there are abnormal levels of dopamine 2 receptors in untreated schizophrenics - could antipsychotics be increasing the receptors
  • thought that there is a genetic based aetiology for dopamine dysfunction
  • there are other neurochemical dysfunctions such as glutamate and in the phasic/tonic hypothesis this neurochemical dsyfunction was demonstrated but there were no changes in dopamine receptor number
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25
Q

why is glutamate being the main transmitter for pyramidal cells an important factor ?

A

because these are the sources of efferent and interconnecting pathways of cerebral cortex and limbic system which are regions implicated in schizophrenia

26
Q

how is glutamate thought to be implicated in schizophrenia ?

A

thought to be less glutamate transmission
- genetic factors thought to affect the signalling of ion channel receptors and GPCRs - leading to hypofunction of glutamate- this is relevant for the negative symptoms

27
Q

what do glutamate receptor antagonists (ketamine and phencyclidine) cause ?

A

cause the positive and negative symptoms

ketamine is directly implicated in schizophrenia and it could induce it if you have a predisposition to schizophrenia

28
Q

why is it thought that serotonin may be implicated in schizophrenia ?

A

based on the fact that LSD produces schizophrenic like symptoms - this is a theory
also effective antipyschotics seem to act as serotonin receptor antagonists because serotonin has a modulatory effect on dopamine pathways
- particularly serotonin 2a is a feature of newer antipsychotics which confer fewer side effects

29
Q

why do antipsychotic drugs need to be classified ?

A

due to the large number of drugs > 20 different ones are available

30
Q

how are antipsychotics classified ?

A

typical and atypical drugs - old and new
there is not a great deal of differences between these 2 types but the newer ones have fewer side effects but they still have serious side effects - however the newer ones are less effective

31
Q

what is main difference between the typical and atypical drugs ?

A

the atypical ones have fewer incidence of motor disturbances

32
Q

describe the typical antipsychotics :

A 
selective for dopamine 2/3 receptors 
treat positive symptoms 
no effect on negative symptoms 
no effect on cognitive symptoms 
serious side effects
33
Q

describe the atypical antipyschotics ?

A

dopamine 2/3 antagonists and other affinities
treat positive symptoms
limited effect on negative symptoms - virtually none for majority
limited effect on cognitive symptoms
serious side effects

34
Q

what are some examples of current antipsychotics ?

A 
olanzapine 
risperidone 
quetiapine
aripiprazole 
global market value for antipyschotics is about £10billion
35
Q

what are some examples of typical antipsychotics ?

A

PHENOTHIAZINES
- chlorpromazine, thioridazine- most commonly used in UK
THIOXANTHENES
- flupenthixol- similar to above
BUTYROPHENONES
- haloperidol- chemically different but long established

36
Q

what are some examples of atypical antipsychotics?

A

sulpriride, pimozide, remoxipride
- all D2 receptor antagonists, less side effects but less effective
clozapine
- non-selective D1/D2 antagonist but has affinity for D4
- effective for negative and positive symptoms
- current gold standard antipsychotic but its not great

37
Q

what is a major problem with the treatments for schizophrenia ?

A

there is no cure the drugs are just trying to control the symptoms
- the best drug for each individual is bases upon a balance between the beneficial relief of symptoms vs the adverse effects caused

38
Q

where has the evidence for blockade of dopamine receptors for antipyschotics come from ?

A
  • receptor binding, functional assays
  • correlation of assays with clinical potency- however this is really just focussing on the positive symptoms
  • amphetamine in man
39
Q

what are the effects of a single dose, single high dose and chronic abuse of amphetamine in man ?

A

single dose causes CNS excitation
single high dose causes manic behaviour
chronic abuse causes paranoia, delusions

40
Q

what is a problem with the evidence for dopamines involvment in schizophrenia ?

A

its indirect evidence

41
Q

what is a problem when you start taking antipsychotics ?

A

they have a therapeutic delay like antidepressants

- 2-3 weeks of treatment dopamine receptors are up regulated

42
Q

how is dopamine synthesis increased ?

A

tyrosine hydroxylase activity increases

metabolites increase

43
Q

what happens to the nigrostriatal and mesolimbic dopaminergic neurons ?

A

their firing rate increases then declines and this leads to the clinical effects but also the adverse effects

44
Q

what pathway is the major one associated with the main unwanted side effects ?

A

nigrostriatial pathway

clozapine has less effect on this pathway

45
Q

how does haloperidol effect dopaminergic pathways ?

A

after initially taking it it peaks in both the nigrostriatal and mesolimbic pathways

  • it then decreases in both pathways as the weeks of treatment continue and it appears to plateau
  • the decrease seems to cause some sort of clinical effects
  • the decrease is greater in the mesolimbic pathway compared to the nigrostriatal
46
Q

what are the antipyschotic behavioural effects in man ?

A

neuroleptic syndrome:

  • sedation
  • decreased aggression
  • apathy
  • affective indifference- no reactions
  • no impairment of intellect
47
Q

what are the antipyschotic effects in animals ?

A
  • decreased spontaneous movement
  • suppression of conditioned avoidance response
  • large doses= catalepsy- pharmacological assay in which it produces a state in animals where they dont move, they are not sedated they just dont move- waxy rigidity
  • antagonism of amphetamine effects
48
Q

what are the effects on antipsychotics on positive symptoms (type1)?

A

good response but delayed by 2-3 weeks before insight returns

49
Q

what are the effects of antipsychotics on the negative symptoms (type2)?

A

poor responses to most

clozapine reportedly effective

50
Q

what are the difficulties with treatment with antipsychotics ?

A
  • delayed effects means its difficult to decide effective dose
  • individual variation to different drugs- therefore you need to find the best one
  • psychotherapy is still important
51
Q

what is psychotherapy useful for and what is it not useful for ?

A

its useful for helping to cope, educating them and the family
it is not useful for gaining insight, they still dont see that anything is wrong with them

52
Q

when were antipsychotics first implemted and what effect did this have ?

A

1956

it caused a decline in resident patients so there were less patients in hospitals

53
Q

what are the side effects of antipsychotics ?

A

most are related to dopamine antagonism

  • extrapyramidal syndrome- parkinson like symptoms, akathisia
  • these effects are dose dependent and reversible
54
Q

what can be used to treat the side effects of dopamine block ?

A

use of atropinic drugs which affect muscarinic receptors

cant use levodopa

55
Q

what is tardive dyskinesia ?

A

it is a big problem

  • develops after months/years in 20-40% of patients treated with typical drugs, there is less incidence with atypicals
  • chorea type symptoms- loss of neurons
  • oral symptoms are common
  • symptoms change with activity
  • not usually reversible and may be worsened by drug withdrawal
56
Q

what are the endocrine effects caused by antipyschotics ?

A

increase prolactin release because dopamine in the hypothalaus acts as release inhibiting factor for prolactin
- this causes galactorrhea, infertility, gynacomastia in men (moobs)
dopamine controls other hormones and therefore aps cause a decrease in growth hormone

57
Q

what are the 4 main side effects of antipsychotics not related to dopamine ?

A

blockade of muscarinic receptors
blockade of adrenoreceptors
hypothermia and weight gain
idiosyncratic/hypersensitivity reactions

58
Q

what are the side effects caused by blockade of muscarinic receptors ?

A
  • dry mouth, blurred vision
  • often subject to tolerance
  • may be beneficial in extrapyramidal syndrome as less disturbance of balance between excitation (ach)/inhibition (da)
    e.g. thioridazine- effective atropinic, causes little eps
    whereas in comparison haloperidol is very selective for dopamine receptors and causes severe eps
59
Q

what are the effects caused by blockade of adrenoreceptors ?

A
  • leads to hypotension particularly orthostatic
  • this occurs less with selective dopamine blockers
    e.g. butyrophenones, thioxanthenes
    this is more severe with typical chlorpromazine- blocks adrenoreceptors, dopamine, serotonin and muscarinic receptors
60
Q

what are the effects caused by hypothermia and weight gain ?

A
  • hypothermia due to actions in the hypothalamus
  • weight gain is associated with serotonin antagonism in atypical drugs- patients put on a lot of weight and this is often an element for poor compliance
61
Q

what are the idiosyncratic/hypersensitivity effects ?

A
  • jaundice- especially with chlorpromazine
  • leucopenia= reduced number of leucocytes, agranulocytosis=reduced PMN leucocytes - this occurs especially with clozapine , have to monitor blood, the levels are recovered if clozapine admin is stopeed
  • antipsychotic malignant syndrome- muscle rigidity, hyperthermia, confusion– fatal in 10-20% (renal/CVS failure)
62
Q

what are other difficulties with antipsychotics ?

A
  • compliance- 50% of patients fail to take medication due to the unwanted side effects - often use intramuscular depot injection which lasts 2-4 weeks because it slowly releases the drug
  • only effective in about 70% of patients , others are pharmacoresistant
  • most only control the positive symptoms, only clozapine has some effect on the negative symptoms
  • the receptor specificity and functional and therapeutic effects are not understood
63
Q

why is dopamine considered a symptom, not a cause of schizophrenia ?

A

because dopamine antagonism is not effective in everyone and their effects are limited

Neuropharmacology (15 decks)

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