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Pharmacology > Lecture 10 - Antipsychotics > Flashcards

Lecture 10 - Antipsychotics Flashcards

1
Q

Typical = __ gen

A

1st

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2
Q

Atypical = ___ gen

A

2nd

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3
Q

Drugs used in as antipsychotics?

A 
clorpromazine
haloperidol
clozapine
quetiapine
aripiprazole
risperidone
olanzapine
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4
Q

Two common types of symptoms in schizophrenia?

A

positive

negative

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5
Q

Positive symptoms are associated with what pathway?

A

dopamine mesolimbic

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6
Q

Negative symptoms are associated with what pathway?

A

dopamine mesocortical

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7
Q

_% lifetime risk of schizophrenia

A

1

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8
Q

Which gender is more at risk?

A

males 1.4 times more at risk than females

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9
Q

Onset in males ?

A

15-24 years

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10
Q

Onset in females ?

A

25-34 years

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11
Q

Is there a genetic predisposition to schizophrenia?

A

yes

-if you have a first degree relative your changes go from 1% to 10%

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12
Q

_____ symptoms = excess cognition

A

positive

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13
Q

_____ symptoms = deficits in behaviour

A

negative

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14
Q

List some positive symptoms

A

hallucinations
delusions
disorganized speech

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15
Q

List some negative symptoms

A

avolition - lack of initiative or motivation
anhedonia - lack of pleasure
blunted affect - lack of mood, lack of expression
alogia - poverty of speech

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16
Q

____ symptoms - their presence is abnormal

A

positive

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17
Q

____ symptoms - the absence of normal characteristics

A

negative

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18
Q

Describe cognitive symptoms

A

-declines in attention, language, memory, executive function

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19
Q

Describe affective symptoms

A

-blunted, inappropriate, odd expression

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20
Q

Cognitive or affective:

often lead to social stigmatization

A

affective

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21
Q

Cognitive or affective:

probably present from birth

A

cognitive

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22
Q

What leads to positive symptoms?

A

too much mesolithic dopamine pathway activity

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23
Q

What leads to negative symptoms?

A

low dopaminergic activity in the mesocortical pathway

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24
Q

Describe the mesolimbic pathway

A

Starts - VTA (ventral tegmental area)
Ends - NAcc (Nucleus Accumbens)
NT = Dopamine D2

Positive symptoms!

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25
Q

What is the NAcc (Nucleus Accumbens) associated with?

A

Motivation
Reward
Addiction
Reinforcing behavior

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26
Q

Describe the mesocortical pathway

A

Starts - VTA
Ends - PFC (prefrontal cortex)
NT = Dopamine D1

Negative symptoms!

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27
Q

What is the PFC (pre frontal cortex) associated with?

A

cognition
communication
social function
stress response

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28
Q

Overactivity of Da from VTA to NAcc = ?

A
  • positive symptoms
  • D2
  • mesolimbic
29
Q

Overactivity of Da from VTA to PFC = ?

A
  • negative symptoms
  • D1
  • mesocortical
30
Q

How do antipsychotics work?

A

they strongly block D2 dopamine receptors

31
Q

What 2 key points support the dopamine hypothesis?

A

1 - most antipsychotics strongly block D2 dopamine receptors

2 - drugs that increase dopaminergic activity can produce psychosis

32
Q

What do typical (1st gen) antipsychotics work on?

A

Mesolimbic pathway

33
Q

What do atypical (2nd gen) antipsychotics work on?

A

Mesolimbic pathway

Mesocortical pathway

34
Q

How do typical antipsychotics work?

A
  • antagonism of D2 receptors in the mesolimbic pathway

- relief from positive symptoms

35
Q

Examples of typical antipsychotics

A

Chlorpromazine
Fluphenazine
Haloperidol
Thiothixene

Chlorpromazine and Haloperidol - 2 most common

36
Q

What are the adverse effects of typical antipsychotics related to?

A

1 - receptor non-selectivity (blocks other receptors other than the D2 receptors)

2 - blockade of non-mesolimbic D2 dopaminergic pathways

37
Q

What adverse effects result from receptor non-selectivity in typical antipsychotics?

A
  • tosic confusional state, dry mouth, urinary retention (antimuscarinic)
  • orthostatic hypotension, dizziness, tachycardia, impotence (alpha 1 blockade)
  • weight gain (histamine H1 blockade)
  • sedation (histamine H1 blockade)
38
Q

What are the off target receptors in receptor non-selectivity of typical antipsychotics?

A
  • alpha 1 adrenergic receptors
  • muscarinic receptors
  • histamine receptors
39
Q

Blockade of non-mesolimbic D2 dopaminergic pathways:

nigrostriatal pathway

A

Starts - SN (substantia nigra)
Ends - STR (striatum)
NT = dopamine D2

blocks D2 - results in EPS (extrapyramidal side effects):

  • parkinson’s syndrome
  • akathisia (pacing, shifting, shuffling)
  • acute dystonic rxns (abnormal muscle spasms)
  • tardive dyskinesia (no reliable treatment, can be irreversible) - abnormal involuntary muscle movements
40
Q

Blockade of non-mesolimbic D2 dopaminergic pathways:

Tuberoinfundibular pathway

A

Starts - HYPO
Ends - PIT
NT = dopamine D2

Blocks D2 - results in increased prolactin production

Side effects for women:

  • lactation
  • amenorrhea (abnormal absence of menstruation)
  • infertility

Side effects for men:

  • lactation
  • impotence
  • decreased libido
  • gynecomastia (developing female like features)
41
Q

List some other adverse effects of typical antipsychotics

A
  • pseudodepression related to drowsiness, restlessness, and autonomic effects
  • corneal and lens deposits (chlorpromazine)
  • retinal deposits (thioridizine)
  • cardiac arrhythmias in overdose (thioridazine)
  • neuroleptic malignant syndrome
42
Q

Describe neuroleptic malignant syndrome

A
  • severe muscle rigidity
  • impaired sweating
  • fever
  • autonomic instability
  • severe agitation
43
Q

Why are atypical antipsychotics an advantage over typical antipsychotics?

A

Just like typical:
-they block D2 in NAcc and cause decreased positive symptoms
BUT ALSO:
-have reduced D2 affinity for nigrostriatal pathway = decreased EPS symptoms
-block 5-HT2 receptors = decrease negative symptoms

44
Q

In what type of antipsychotics do you have a wider window between the antipsychotic effect and EPS side effects?

A

atypical

45
Q

How do you decrease negative symptoms?

A

*increased serotonin affinity

decrease negative symptoms by increasing mesocortical dopamine

Remember mesocortical pathway:
VTA —-D1—–> PFC

*you are improving low levels of dopaminergic activity

46
Q

List some atypical antipsychotics

A 
risperidone
olanzapine
quetiapine
Ziprasidone
clozapine
aripiprazole
47
Q

What is the common theme of atypical antipsychotics?

Exceptions?

A
  • bind to serotonin
  • bind to D2

Exceptions:
1 - clozapine binds to D4 not D2

2 - aripiprazole - partial agonist of D2 receptors

48
Q

Adverse effects of atypical antipsychotics?

A
  • generally, same as typical antipsychotics with lower risk, especially of EPS
  • risk of seizures in 2-5% in patients receiving clozapine
  • weight gain, hyperlipidemia, hyperglycaemia associated with 5-HT2 blockade (clozapine, olanzapine)
  • agranulocytosis (low white blood cell count) (1-2%) in its taking clozapine
  • higher death rate in elderly its with dementia
49
Q

slide 29 for adverse effects

A

ok man

50
Q

Aripiprazole metabolized by?

A

CYP 3A4, 2D6

51
Q

Clozapine metabolized by?

A

CYP 1A2, 3A4, 2C19

52
Q

Olanzapine metabolized by?

A

1A2, 3A4, FMO3

53
Q

Quetiapine metabolized by?

A

3A4

54
Q

Risperidone metabolized by?

A

2D6

55
Q

Ziprasidone metabolized by?

A

3A4

56
Q

What increases CYP 3A4 (clozapine, quietipaine, ziprasidone, aripiprazole) metabolism?

A

St john’s wort

57
Q

What decreases CYP 3A4 (clozapine, quietipaine, ziprasidone, aripiprazole) metabolism?

A 
nefazodone
erythormycin
fluoxetine
cimetidine
grapefruit juice
58
Q

What increases CYP 1A2 (clozapine, olanzapine, typicals) metabolism?

A

smoking

59
Q

What decreases CYP 1A2

(clozapine, olanzapine, typicals) metabolism?

A

fluvoxamine
cimetidine
ciprofloxacine

60
Q

What decreases CYP 2D6 (risperidone, phenothiazine, typicals) metabolism?

A

paroxtein
ketokonazole
quinidine

61
Q

Drug interactions:

What drug interactions with antipsychotics would cause excess sedation?

A

anxiolytics
alcohol
antidepressants
antihistamines

62
Q

Drug interactions:

Antipsychotics and another antimuscarinic have ?

A

additive antimuscarinic effects

amplify the effects

63
Q

Drug interactions:

antipsychotics and metoclopramide = ?

A

D2 antagonist, EPS

64
Q

Drug interactions:

antipsychotics and SSRI antidepressants ?

A

dopamine suppression in NGS and EPS

65
Q

dopamine ____ in mesolimbic pathway = positive symptoms

A

hyperactivity

66
Q

dopamine _____ in mesocortical pathway = negative symtpoms

A

hypoactivity

67
Q

Key points about typical antipsychotics

A

-block D2 in mesolimbic (decrease positive symptoms), nigrostriatal (EPS) and tuberoinfundibulnar (hyper-prolactin) pathways

68
Q

Key points about atypical antipsychotics

A
  • lower affinity block of D2 = decrease positive symptoms, decrease EPS and prolactin
  • block 5-HT2 receptors = decrease negative symptoms
  • EPS replaced by weight gain, hyperglycaemia as dominant adverse effect
69
Q

Briefly describe the stages of dosing for Pts with schizophrenia

A 
Stage 1 - single SGA
Stage 2 - switch SGA
Stage 3a - FGA or switch SGA
Stage 3b - clozapine
Stage 4 - switch FGA or SGA
Stage 5 - Combination therapy

Pharmacology (21 decks)

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