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PR3136 PT IV > Antipsychotics (Orange) > Flashcards

Antipsychotics (Orange) Flashcards

1
Q

What is schizophrenia?

A
  • chronic disease
  • onset in late adolescence/ early adulthood
  • highly disabling to social & vocational functioning
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2
Q

what are the symptoms of schizophrenia?

A
  1. positive (abnormal behaviours added)
  2. negative (normal behaviours removed)

periods of both positive and negative symptoms, where negative symptoms predominate

as the disease progresses, negative sx become more dominant

  1. cognitive dysfunction
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3
Q

what are the positive symptoms of schizophrenia? why are these symptoms impt?

A
  • delusions (often paranoid)
  • hallucinations (e.g. exhortatory voices)
  • thought disorder including feeling that thoughts are controlled by an outside agency
  • abnormal behaviour (e.g. stereotypical aggressive behaviours
  • positive sx lead to first referral to a psychiatrist and detection of schizophrenia
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4
Q

what are the negative symptoms of schizophrenia? why are these symptoms impt?

A
  • withdrawal from social contacts
  • flattening of emotional responses
  • negative symptoms are the most distressing VS positive sx which lack insight (self-awareness of abnormal behaviour)
    (e. g. they really believe that aliens are coming)
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5
Q

what causes suicide in schizophrenia patients?

A

when schizophrenia patients become assoc/w depression

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6
Q

what are the cognitive dysfunction?

A
  • impairment of selective attention

- impairment of working memory

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7
Q

why is recognising cognitive dysfunction as a symptom of schizophrenia important?

A
  • it is a persistent core feature of the disease, and NOT iatrogenic (def: caused by physician/med)
  • it predicts the level of social and vocational functioning, and hence treatment outcome can be better than just using the +ve sx to treat
    (e. g. pt w +ve sx but no cognitive dysfunction –> can be treated better
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8
Q

what is a possible reason that schizophrenia onset in usually in late adolescence or early adulthood?

A
  • could be due to neurodevelopmental abnormality involving myelination of cortico-cortical pathways (myelination is usually completed only in early adulthood)

there’s evidence of enlarged ventricles, abnormalities in laminar organisation of cortical cells –> a possible neurodevelopmental disorder

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9
Q

Most neurochemical theories are based on which symptoms?

A

positive symptoms

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10
Q

what are the 3 neurochemical theories?

A
  1. dopamine theory
  2. 5-HT (serotonin) theory
  3. glutamate theory
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11
Q

what is the dopamine theory about? how was it founded?

A

The dopamine theory was based on the fact that Amphetamine (known dopaminergic compound) produces symptoms similar to acute schizophrenia.

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12
Q

what does the dopamine theory say about antipsychotic drugs?

A

that all antipsychotic drugs are D2 antagonists.

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13
Q

The affinity of antipsychotic drugs for D2 receptor was also found to correlate with mean clinically efficacious dose. (higher affinity = lower dose)
Typical Antipsychotics in order of efficacy: F____________> H___________ > T____________> Clozapine > C___________

A
  1. Fluphenazine
  2. Haloperidol
  3. Trifluoperazine
  4. Chlorpromazine
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14
Q

How did the 5-HT (Serotonin) Theory came about?

A

due to Lysergic acid diethylamide (LSD), primarily as a 5-HT2 agonist, producing symptoms similar to acute schizophrenia.

Many of the newer atypical antipsychotics have 5-HT2 antagonism which may explain the improved efficacy of newer antipsychotic drugs vs old.

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15
Q

How did the Glutamate Theory came about?

A

drugs that block the NMDA receptor channel, e.g. phencyclidine (PCP) and ketamine, produce symptoms similar to acute schizophrenia.

  • still has not produced any clinically useful drugs.
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16
Q

Typical Antipsychotics control ______ symptoms of schizophrenia and produce _______ side-effects. C___________ was the first antipsychotic drug derived from anti-histamine drugs.

A
  1. positive
  2. extrapyramidal (EPS)
  3. Chlorpromazine
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17
Q

what other drug was also derived from anti-histamine drugs

A

TCAs (anti-depressant)

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18
Q

What is the similarity and differences between typical and atypical antipsychotics?

A

similarity: control positive symptoms

typical produces extrapyramidal side-effects while atypical produces less of EPS

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19
Q

what are the names of the typical antipsychotic drugs?

A
  • chlorpromazine
  • haloperidol
  • fluphenazine
  • trifluoperazine
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20
Q

what are the names of the atypical antipsychotic drugs?

A

amisulpride
clozapine
olanzapine
risperidone

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21
Q

what are the side effects (other than EPS) of the typical antipsychotic drugs? and which typical drug has a better side effect profile?

A

Chlorpromazine:
M1 antagonism: dry mouth, constipation, blurred vision

H1 antagonism: sedation, weight gain

a1 (alpha-adrenergic receptor) antagonism: postural hypotension, dizziness

Haloperidol:
a1 (alpha adrenergic receptor) antagonism: postural hypotension, dizziness

Haloperidol

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22
Q

What are the extrapyramidal side-effects of the typical drugs?

A
  • acute dystonias

- tardive dyskinesia and Akathisia

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23
Q

what does the extrapyramidal pathway involve?

what is the pyramidal motor pathway

A

the basal ganglia, the striatum, and substantia nigra

pyramidal motor pathway: output from primary motor cortex via the pyramids of the medulla oblongata to the spinal cord

24
Q

What is acute dystonias and when does it occur?

A
  • parkinsonism-like syndrome
    (e. g. cogwheel rigidity and tremor at rest)
  • occurs within first few weeks of treatment
25
Q

can acute dystonias be reversed?

A

yes, when the drug is stopped

26
Q

which pathway is blocked by the typical drugs which causes the acute dystonias

A

D2 antagonism in the nigrostriatal pathway

connection from substantial nigra to striatum

27
Q

what is tardive dyskinesia?

A
  • develops slowly (tardive) over months or years of treatment
  • dyskinesia: repetitive and stereotyped involuntary movements of face, tongue, and limbs
28
Q

what is akathisia?

A
  • involuntary movements and compulsion to act assoc w restlessness, anxiety and agitation
29
Q

When does akathisia, and tardive dyskinesia occur with the use of typical drug?

A

akathisia but not dyskinesia correlates with duration on medication

30
Q

how prevelant is tardive dyskinesia and akathisia?

A

20-40% pts on typical antipsychotics

31
Q

can tardive dyskinesia and akathisia be reversed?

A

no, oftern irreversible

32
Q

what can be the cause of tardive dyskinesia and akathisia?

A

upregulation or supersensitivity of dopamine receptors in the nigrostriatal system

33
Q

what are the properties of atypical antipsychotics?

A
  • greater affinity at 5-HT2 receptors
  • greater affinity at D4 receptors
  • mixed antagonism at a-adrenoreceptors, H1 histamine receptors, muscarinic acetylcholine receptors, (but probably at a lower affinity) and 5-HT2 receptors
34
Q

what defines the “atypicality” of atypical antipsychotic drugs?

A
  • Serotonin-dopamine antagonism (SDA) is the ‘core’ of MOST atypical antipsychotics (e.g. amisulpride is NOT)
35
Q

does atypical drugs only have serotonin-dopamine antagonism?

A

no, they have complex mixtures of actions

36
Q

what are the SE of clozapine?

A
  1. M1 antagonism: dry mouth, constipation, blurred vision
  2. H1 antagonism: sedation, weight gain
  3. a1 (alpha-adrenergic receptor) antagonism: postural hypotension, dizziness
  4. Clozapine-induced agranulocytosis
37
Q

what is clozapine-induced agranulocytosis?

A
  • agranulocytosis as a SE in approx 1% of pts which can be fatal –> the lack of granulocyte type WBC
38
Q

therefore, which drug was developed to prevent the SE of agranulocytosis?

A

olanzapine

39
Q

what are the SE of olanzapine?

A
  1. M1 antagonism: dry mouth, constipation, blurred vision
  2. H1 antagonism: sedation, weight gain
  3. a1 (alpha-adrenergic receptor) antagonism: postural hypotension, dizziness
40
Q

what are the SE of risperidone

A
  1. a1 (alpha-adrenergic receptor) antagonism: postural hypotension, dizziness, reflex tachycardia

a1-adrenoceptor antagonism esp EVIDENT for risperidone

41
Q

what is an atypical antipsychotic drug that does not fit the definition of atypicality?

A

amisulpride

42
Q

what receptor antagonism does amisulpride have?

A

selective D2/D3 antagonist, 5-HT7 antagonism as well

  • atypical pattern of receptor affinities compared to the other atypical antipsychotic
43
Q

what are the adverse effects of amisulpride?

A
  • fewer SE due to selectivity for D2/D3 receptor
  • NO alpha-adrenoceptor block, antihistaminergic, and anticholinergic SE
  • mammary glands and tissues
  • -> increased prolactin secretion due to block of dopamine receptors in the anterior pituitary gland (tuberoinfundibular pathway = hypothalamus to anterior pituitary; regulate prolactin secretion into blood circulation)
  • -> breast swelling, pain, and lactation
  • -> presents as gynaecomastia in males
44
Q

what is the partial agonist drug name

A

aripiprazole

45
Q

how does the partial agonist work to reduce dopamine levels

A

in the presence of agonist (e.g. dopamine), aripiprazole have antagonistic effects –> reduce levels of dopamine

46
Q

what are the additional adverse effects of atypical antipsychotics found?

A

induce hyperglycemia and diabetes

weight gain

47
Q

what is the theory placed for the mechanism involved in the drug-induced diabetes SE?

A
  • 5-HT antagonism in hypothalamus

- 5-HT antagonism in pancreatic Beta cells

48
Q

what is the chances of atypical antipsychotics causing diabetes and its chances of reversibility?

A
  • ​new onset or exacerbation of diabetes –> Olanzapine > Risperidone > Clozapine
  • diabetes does not reverse when drug is stopped –> risperidone&raquo_space; olanzapine ~ clozapine

amisulpride may be an exception

49
Q

which drugs are to be labelled with the risk of hyperglycaemia and diabetes warning

A

all atypical antipsychotics

50
Q

the side effect of weight gain can be seen prominently in which atypical antipsychotics?

A

clozapine, olanzapine, risperidone

51
Q

what is the possible MOA theorised for the SE of weight gain with the use of the 3 types of atypical antipsychotics?

A
  1. sedation produced by H1 histamine receptor antagonism –> causing sedentary lifestyle??
  2. alpha-adrenoceptor & 5-HT2 receptor antagonism on the hypothalamus and feeding behaviour?

BUT these 2 hypotheses do NOT explain why chlorpromazine does not cause so much weight gain

52
Q

olanzapine is used in what experimental use?

A

treatment of anorexia nervousa

53
Q

why do atypical antipsychotics produce less EPS? (the 4 reasons)

A

typical antipsychotics: > D2 antagonism
and striatum have more potent D1 receptor antagonism

atypical:
1. potent 5-HT2A receptor antagonism vs weak D2 antagonism –> thus lower EPS and higher efficacy against negative symptoms
seen in: clozapine, olanzapine
(negative sx: due to serotonin receptors vs +ve sx: due to dopamine)

  1. high D3 to D2 antagonism ratio favours actions on the nucleus accumbens over the striatum
    seen in: amisulpride
  2. high D4 to D2 antagonism ratio favours actions in the prefrontal cortex over the striatum
    seen in: clozapine
  3. high D2 to D1 antagonism ratio reduces impact of antagonism in the striatum
    seen in: amisulpride, risperidone

note: least binding affinity to D1, highest affinity to bind to D3 for amisulpride

54
Q

why does high D2 to D1 antagonism ratio reduce impact of antagonism in the striatum?

A

confer less complete blockade of dopaminergic function in the striatum as D2 antagonism will increase dopamine release

concept:

  • D2 receptors are also found on the presynaptic (not just on the postsynaptic like D1)
  • these D2 receptors also regulate the release of dopamine to the synaptic space
  • thus, when an atypical binds more to D2 than D1, the stored dopamine at the presynaptic can be released a bit. this is because the D2 receptors are blocked and unable to regulate the flow of dopamine
55
Q

what are some additional benefits of atypical antipsychotics?

A
  1. some more effective against negative sx than typical antipsychotics
    eg: clozapine, olanzapine, risperidone
  2. some may ameliorate cognitive dysfunction better than typical antipsychotics
    e. g. :clozapine, risperidone
  3. some better at mood stabilisation than typical antipsychotics
    e. g. clozapine, olanzapine, risperidone
56
Q

however, when can atypical antipsychotics ACTUALLY can improve negative symptoms?

A

only when patients start out with more severe negative symptoms

  • as the effects of atypical antipsychotics on negative symptoms, cognition and stability of mood are weak and incomplete
57
Q

what has been the outcomes of antipsychotic treatments?

A
  • 15-20% schizophrenics remain treatment resistant and not respond to any antipsy
  • 60-75% respond to therapy BUT severely disabled in social and occupational function
  • 10-20% recover to near pre-illness level of function
  • <1% able to come off med and retain near pre-illness levels of function

THUS, its an unmet need for improved antipsychotics

PR3136 PT IV (17 decks)

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