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PR3136 > Antipsychotics > Flashcards

Antipsychotics Flashcards

1
Q

Five symptom domains of schizophrenia

A

positive, negative, cognitive, aggressive, anxiety/depression

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2
Q

As disease progresses, which symptoms become more dominant in schizophrenia?

A

Negative symptoms

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3
Q

Examples of positive symptoms for schizophrenia

A

Hallucinations, delusions, thought disorders, abnormal behaviors

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4
Q

Negative symptoms in schizophrenia

A

Withdrawal from social contacts, flattening of emotional responses

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5
Q

How do negative symptoms arise in schizophrenia?

A 
Primary deficit of the illness
Secondary to depression
Secondary to extrapyramidal symptoms
Secondary to environmental deprivation 
Secondary to positive symptoms
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6
Q

What are cognitive dysfunction in schizophrenia?

A

Impairment of selective attention

Impairment of working memory

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7
Q

What is used to predict the prognosis of schizophrenia?

A

Social and vocational functioning (and hence treatment outcome) is predicted by cognitive dysfunction better than positive symptoms

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8
Q

Patient with low cognitive dysfunction but with positive symptoms, good or bad prognosis?

A

Good prognosis.

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9
Q

Aetiology of schizophrenia

A 
Genetic factors (50% risk in monozygotic twin of affected individual) 
Environmental factors: maternal viral infections during pregnancy, obstetric complications can predispose neurodevelopmental abnormalities
Onset in late adolescence/early adulthood is consistent with neurodevelopmental abnormality involving myelination of cortico-cortical pathways
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10
Q

What are the neurochemical theories proposed for positive symptoms of schizophrenia?

A

Alterations in:

Dopamine, serotonin, glutamate

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11
Q

Describe what led to the dopamine theory?

A

Amphetamine (a D2 agonist) produces symptoms similar to acute schizophrenia → hence antipsychotics are D2 antagonists

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12
Q

The smaller the Kd value, the higher or lower the affinity to the D2 receptor?

A

Higher affinity

Fluphenazine → haloperidol → trifluoperazine → clozapine → chlorpromazine

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13
Q

Dopamine pathways of the brain

A

Nigrostriatal pathway
Mesocortical/mesolimbic pathways
Tuberoinfundibular pathway

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14
Q

What is the nigrostriatal pathway?

A

Important in Parkinson’s (schizo is not a movement disorder)
Starts at the substantia nigra and ends in the dorsal striatum
Involved in voluntary movement
When nigrostriatal pathway is not doing well, patient has extrapyramidal symptoms → off-target effects

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15
Q

What is the mesocortical/mesolimbic pathway?

A

Ventral tegmental area to prefrontal cortex and limbic brain
Involved in emotion, cognition and attention
Mesolimbic: reward and emotion
Mesocortex: cognition and attention

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16
Q

What is the tuberoinfundibular pathway?

A

Pathway from hypothalamus to anterior pituitary regulates prolactin secretion into the blood circulation
Off target effect

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17
Q

Describe what led to the serotonin theory of schizophrenia?

A

LSD (5HT2 agonist) produces symptoms similar to acute schizophrenia → hence antipsychotics have 5HT2 antagonism

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18
Q

Describe what led to the glutamate theory of schizophrenia?

A

Drugs which block NMDA receptor channel (eg ketamine) produce symptoms similar to acute schizophrenia → hence antipyschotics which have NMDA agonism are likely to be effective

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19
Q

What are the 2 types of antipsychotic drugs?

A

Typical antipsychotics

Atypical antipsychotics

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20
Q

What is the main difference between typical and atypical antipsychotics?

A

Typical antipsychotics produce more extrapyramidal side effects

21
Q

What do antipsychotic drugs do?

A

They control positive symptoms of schizophrenia

22
Q

Typical antipsychotics

A

Chlorpromazine
Fluphenazine
Haloperidol
Trifluoroperazine

23
Q

Atypical antipsychotics

A 
Clozapine 
Olanzapine 
Risperidone
Amisulpride
Aripiprazole
24
Q

What are the side effects of chlorpromazine?

A

Muscarinic receptor antagonism - dry mouth, constipation, blurred vision
Histaminic receptor antagonism - sedation, weight gain
Adrenergic receptor antagonism - postural hypotension, dizziness
Dopamine receptor antagonism - extrapyramidal symptoms

25
Q

What are the side effects of haloperidol?

A

Only left 1 adrenergic receptor antagonist and D2 receptor antagonist
No more parasympatholytic side effects, sedation, but still have postural hypotension and extrapyramidal side effects

26
Q

What are the 3 types of extrapyramidal side effects?

A

Acute dystonia
Tardive dyskinesia
Akathisia

27
Q

Why do EPS arise?

A

D2 receptor antagonism blocks part of the dopamine signal in the nigrostriatal pathway, therefore precipitating a parkinsonian-like syndrome (simulating the same effect that people with PD have)

28
Q

What is acute dystonia? When does it occur? Is it reversible?

A

Cogwheel rigidity and tremor at rest
Occur within first few weeks of treatment
Reversible when drug is dropped
Caused by d2 antagonism in the nigrostriatal pathway

29
Q

What is tardive dyskinesia and akathisia? When does it occur? Is it reversible?

A

Tardive dyskinesia is repetitive and stereotyped involuntary movements of face, tongue and limbs
Akathisia - involuntary movements and compulsion to act associated with restlessness, anxiety and agitation
Develop slowly over months or years of treatment
Often irreversible
Caused by upregulation or supersensitivity of dopamine receptors in nigrostriatal system

30
Q

What defines atypicality?

A

Serotonin-dopamine antagonism (SDA) core

All have D2 antagonism and 5HT2 antagonism (except amisulpride, which only targets D2 and D3)

31
Q

Which atypical antipsychotic does not have parasympatholytic side effects?

A

Risperidone (lacks muscarinic M1 receptor)

32
Q

Side effects of clozapine

A

M1 receptor antagonism: Dry mouth, constipation, blurred vision
H1 histamine receptor antagonism: sedation, weight gain Alpha-adrenoreceptor antagonism: postural hypotension, dizziness
Clozapine induced agranulocytosis

33
Q

Which atypical antipsychotic requires full blood count monitoring?

A

Clozapine

34
Q

Which compound was made after clozapine?

A

Olanzapine (no agranulocytosis)

35
Q

Adverse effects of atypical antipsychotics

A

Dry mouth, constipation, blurred vision (especially clozapine and olanzipine) - m1 antagonism
Postural hypotension, reflex tachycardia (especially risperidone) - a1-adrenoreceptor antagonism
Sedation (esp clozapine and olanzapine) - H1 receptor antagonism

36
Q

Which drugs induce hyperglycaemia and diabetes?

Is diabetes reversible?

A

New onset or exacerbation of diabetes
Clozapine, olanzipine, risperidone
Diabetes not reversible when drug is stopped

37
Q

Which atypical antipsychotic does not induce hyperglycemia and diabetes?

A

Amisulpride

38
Q

Which drugs lead to drug-induced weight gain?

A

Clozapine, olanzipine, risperidone

39
Q

Which atypical antipsychotic is atypical and why?

A

Amisulpride

No 5HT2 antagonism - selective D2/D3 antagonist

40
Q

What adverse effect is avoided in amisulpride?

A

Postural hypotension, sedation, parasympatholytic

41
Q

What adverse effects of amisulpride?

A

Increased prolactin secretion due to block of dopamine receptors in the anterior pituitary gland → no longer negative feedback, so prolactin increases and leads to AE
Leads to breast swelling, pain and lactation
Gynecomastia in males

42
Q

What is the mechanism of action of aripiprazole?

A

It is a partial agonist that binds to dopamine receptors - activates receptor at a much lower level

43
Q

Why does EPS arise?

A

EPS is due to the effects of the drug on the nigrostriatal pathway, which normally requires dopamine to function - mainly D1 and D2 receptors.

44
Q

Which receptors found in the nigrostriatal pathway?

A

D1 and D2 (D1>D2)

45
Q

Why do atypical antipsychotics produce less EPS?

A

Clozapine and olanzipine: Potent 5HT2A receptor antagonism and weak D2 antagonism → lower EPS and higher efficacy against negative symptoms
Amisulpride: High d3 to d2 antagonism ratio → favours actions on the nucleus accumbens over the striatum
Clozapine: High d4 to d2 antagonism ratio → favors actions in the prefrontal cortex over the striatum
Amisulpride, risperidone: high d2 to d1 antagonism → reduces the impact of antagonism in the striatum

46
Q

Why will a higher D2 to D1 antagonism ratio lead to less complete blockade of dopaminergic function?

A

D2 receptors are autoreceptors as well as postsynaptic receptors - inhibit the release of dopamine
So if you block the autoreceptors, you block the inhibition, leading to more dopamine coming out and less EPS

47
Q

Can atypical antipsychotics improve negative symptoms?

A

Yes but only marginally better than typical antipsychotics

Only relevant for patients who start off with more severe negative symptoms

48
Q

Outcomes of antipsychotic treatment

A

15-20% remain treatment resistant
60-75% respond to antipsychotic but remain severely disabled in social and occupational function
10-20% recover to pre-illness levels of function
Very few able to come off medication and retain near pre-illness function

PR3136 (8 decks)

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