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Antipsychotics Flashcards

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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
what have PM and PET studies shown ?
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
25
why is glutamate being the main transmitter for pyramidal cells an important factor ?
because these are the sources of efferent and interconnecting pathways of cerebral cortex and limbic system which are regions implicated in schizophrenia
26
how is glutamate thought to be implicated in schizophrenia ?
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
what do glutamate receptor antagonists (ketamine and phencyclidine) cause ?
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
why is it thought that serotonin may be implicated in schizophrenia ?
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
why do antipsychotic drugs need to be classified ?
due to the large number of drugs > 20 different ones are available
30
how are antipsychotics classified ?
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
what is main difference between the typical and atypical drugs ?
the atypical ones have fewer incidence of motor disturbances
32
describe the typical antipsychotics :
``` selective for dopamine 2/3 receptors treat positive symptoms no effect on negative symptoms no effect on cognitive symptoms serious side effects ```
33
describe the atypical antipyschotics ?
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
what are some examples of current antipsychotics ?
``` olanzapine risperidone quetiapine aripiprazole global market value for antipyschotics is about £10billion ```
35
what are some examples of typical antipsychotics ?
PHENOTHIAZINES - chlorpromazine, thioridazine- most commonly used in UK THIOXANTHENES - flupenthixol- similar to above BUTYROPHENONES - haloperidol- chemically different but long established
36
what are some examples of atypical antipsychotics?
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
what is a major problem with the treatments for schizophrenia ?
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
where has the evidence for blockade of dopamine receptors for antipyschotics come from ?
- receptor binding, functional assays - correlation of assays with clinical potency- however this is really just focussing on the positive symptoms - amphetamine in man
39
what are the effects of a single dose, single high dose and chronic abuse of amphetamine in man ?
single dose causes CNS excitation single high dose causes manic behaviour chronic abuse causes paranoia, delusions
40
what is a problem with the evidence for dopamines involvment in schizophrenia ?
its indirect evidence
41
what is a problem when you start taking antipsychotics ?
they have a therapeutic delay like antidepressants | - 2-3 weeks of treatment dopamine receptors are up regulated
42
how is dopamine synthesis increased ?
tyrosine hydroxylase activity increases | metabolites increase
43
what happens to the nigrostriatal and mesolimbic dopaminergic neurons ?
their firing rate increases then declines and this leads to the clinical effects but also the adverse effects
44
what pathway is the major one associated with the main unwanted side effects ?
nigrostriatial pathway | clozapine has less effect on this pathway
45
how does haloperidol effect dopaminergic pathways ?
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
what are the antipyschotic behavioural effects in man ?
neuroleptic syndrome: - sedation - decreased aggression - apathy - affective indifference- no reactions - no impairment of intellect
47
what are the antipyschotic effects in animals ?
- 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
what are the effects on antipsychotics on positive symptoms (type1)?
good response but delayed by 2-3 weeks before insight returns
49
what are the effects of antipsychotics on the negative symptoms (type2)?
poor responses to most | clozapine reportedly effective
50
what are the difficulties with treatment with antipsychotics ?
- 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
what is psychotherapy useful for and what is it not useful for ?
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
when were antipsychotics first implemted and what effect did this have ?
1956 | it caused a decline in resident patients so there were less patients in hospitals
53
what are the side effects of antipsychotics ?
most are related to dopamine antagonism - extrapyramidal syndrome- parkinson like symptoms, akathisia - these effects are dose dependent and reversible
54
what can be used to treat the side effects of dopamine block ?
use of atropinic drugs which affect muscarinic receptors | cant use levodopa
55
what is tardive dyskinesia ?
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
what are the endocrine effects caused by antipyschotics ?
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
what are the 4 main side effects of antipsychotics not related to dopamine ?
blockade of muscarinic receptors blockade of adrenoreceptors hypothermia and weight gain idiosyncratic/hypersensitivity reactions
58
what are the side effects caused by blockade of muscarinic receptors ?
- 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
what are the effects caused by blockade of adrenoreceptors ?
- 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
what are the effects caused by hypothermia and weight gain ?
- 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
what are the idiosyncratic/hypersensitivity effects ?
- 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
what are other difficulties with antipsychotics ?
- 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
why is dopamine considered a symptom, not a cause of schizophrenia ?
because dopamine antagonism is not effective in everyone and their effects are limited

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