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3153 IC9,10,11,12,14 Psychiatric > Pharmaco: Antipsychotics > Flashcards

Pharmaco: Antipsychotics Flashcards

1
Q

[Dopamine theory of schizophrenia]

A
  • Amphetamine induces dopamine release, overactive dopamine produces symptoms similar to acute schizophrenia
  • ALL antipsychotics are D2 antagonists
  • D2 receptor antagonism correlated with clinical efficacy (Kd decrease => higher affinity => higher efficacy with lower dose)
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2
Q

[Dopamine theory of schizophrenia]

Dopamine pathways of the brain:

  • List them, their location, and what they are involved in
A
  1. Nigrostriatal pathway
  • Substantia nigra in basal ganglia to dorsal striatum
  • Involved in voluntary body movement
  • Part of the Extrapyramidal Motor System
  1. Mesocortical pathway
  • Ventral tegmental area in the midbrain to prefrontal cortex
  • Involved in cognition and attention
  1. Mesolimbic pathway
  • Ventral tegmental area to nucleus accumbens and other limbic structures in the brain
  • Involved in reward and emotion
  1. Tuberoinfundibular pathway
  • Hypothalamus to anterior pituitary
  • Regulates prolactin secretion into the blood circulation
  • Normal circumstance: dopamine increase => prolactin pdn decrease)
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3
Q

[Dopamine theory of schizophrenia]

Dopamine antagonism of the nigrostriatal pathway:

A

Extrapyramidal side effects (EPSE)

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4
Q

[Dopamine theory of schizophrenia]

Dopamine antagonism of the mesocortical pathway:

A

Dopamine blockade or hypofunction in this region results in negative symptoms

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5
Q

[Dopamine theory of schizophrenia]

Dopamine antagonism of the mesolimbic pathway:

A

Main target:

  • Blockade of Dopamine receptors in the mesolimbic tract can control positive symptoms (e.g., delusions, hallucinations)
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6
Q

[Dopamine theory of schizophrenia]

Dopamine antagonism of the tuberoinfundibular pathway:

A

Hyperprolactinemia

  • Increase prolactin release
  • Gynaecomastia (in male)
  • Sexual dysfunction - reversible, can be treated
  • Decrease BMD - osteoporosis
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7
Q

[Serotonin theory of schizophrenia]

A
  • Many atypical antipsychotics ahev 5-HT2 antagonism
  • Evidence: Lysergic acid diethylamide (LSD) which acts primarily as a 5HT2 agonist, showed symptoms similar to acute schizophrenia
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8
Q

[Glutamate theory of schizophrenia]

A
  • No clinically useful drug yet, but evidence: drugs which block NMDA receptor channel (calcium channel) such as phencyclidine and ketamine, produce symptoms similar to acute schizophrenia
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9
Q

[Typical Antipsychotics]

Uses:

A
  • Control positive symptoms via D2 antagonism at the mesolimbic tract
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10
Q

[Typical Antipsychotics]

Side effects:

A
  • EPSE due to D2 antagonism in nigrostriatal tract
  • Increased prolactin secretion due to D2 antagonism in tuberoinfundibular tract
  • Sedation and weight gain due to H1 antagonism
  • Postural hypotension and dizziness, reflex tachycardia due to a1 adrenergic antagonism
  • Dry mouth, constipation, blurred vision due to M1 antagonism

Chlorpromazine: antagonises H1, a1, and M1; Haloperidol only antagonizes a1

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11
Q

[Atypical Antipsychotics]

Uses:

A
  • Improve positive symptoms via D2 antagonism at mesolimbic tract
  • May improve negative symptoms via 5HT2A antagonism (?)

Atypicality defined by serotonin-dopamine antagonism

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12
Q

[Atypical Antipsychotics]

Side effects:

A
  • LESS SEVERE EPSE possibly due to more receptor specificity in the non-nigrostriatal pathway
  • Sedation and weight gain due to H1 antagonism (e.g., Clozapine, Olanzapine)
  • Postural hypotension and dizziness, reflex tachycardia due to a1 adrenergic antagonism (e.g., Risperidone)
  • Dry mouth, constipation, blurred vision due to M1 antagonism (e.g., Clozapine, Olanzapine)
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13
Q

[Atypical Antipsychotics]

Notable adverse effect of Clozapine:

A

Clozapine-induced agranulocytosis

  • Low neutrophils (dcr in ANC)
  • Mandatory routine haematological monitoring required
  • Can result in opportunistic infections
  • Fatal
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14
Q

[Atypical Antipsychotics]

Amisulpride - MOA and SEs

A

MOA:

  • Selective D2/D3 antagonist, with 5-HT7 antagonism

SEs:

  • Absence of a1, M1, H1 antagonism
  • Adverse effects on mammary glands and tissues: increased prolactin secretion due to block of dopamine receptors in anterior pituitary gland in the tuberoinfundibular pathway (D3 antagonism?) => Gynaecomastia (in male), Sexual dysfunction, Breast swelling, breast pain, lactation, Decrease BMD - osteoporosis
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15
Q

[Atypical Antipsychotics]

Drug-induced diabetes or weight gain

A

SGAs may induce hyperglycemia and diabetes
(Metabolic SEs: weight gain, emergent diabetes, increase lipids)

Risks:

  • High: Clozapine, Olanzapine (CO)
  • Mod: Chlorpromazine, Quetiapine, Risperidone
  • Low: Aripiprazole, Brexpiprazole, Cariprazine, Lurasidone, Ziprasidone, Haloperidol

Mechanism: unknown (possibly 5-HT antagonism in hypothalamus, or in pancreatic beta cells)

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16
Q

[Atypical Antipsychotics]

Why do atypical antipsychotics produce less EPSE?

A

Key takeaway: relative affinity for the different dopamine receptors

  1. Potent 5-HT2A receptor antagonism > weak D2 antagonism
  • lower EPSE, higher efficacy against negative symptoms (e.g., Clozapine, Olanzapine)
  1. High D3 to D2 antagonism ratio
  • favor action on nucleus accumbens (mesolimbic) over striatum
  • also favor tuberoinfundibular pathway (e.g., Amisulpride)
  1. High D4 to D2 antagonism ratio
  • favor action in prefrontal cortex (mesocortical) over striatum (e.g., clozapine)
  1. High D2 to D1 ratio
  • reduces impact of antagonism in the striatum (e.g., amisulpride, risperidone)

Conclusion: D1 and D2 act on striatum, D1 to greater extent hence causes most EPSE; D3 acts on tuberoinfundibular and mesolimbic, D4 act on mesocortical

In terms of EPSE: D1 => D2 => D3 => D4

17
Q

[Atypical Antipsychotics]

Balance of D2 to D1 antagonism

A

D2 antagonism causes less EPSE than D1 antagonism

Because D2 antagonism confers less complete blockade of dopaminergic function in the striatum

  • D2 antagonism blocks D2 receptors on postsynaptic membrane
  • (ADDITIONALLY) D2 antagonist also blocks the D2 autoreceptors on the presynaptic membrane, therefore inhibiting the negative feedback, causing more D2 to be released, hence less EPSE

VS if only D1 antagonism, autoreceptors will sense dopamine in the synaptic cleft and cause a negative feedback that will dcr dopamine release (more dopamine deficit => more EPSE)

3153 IC9,10,11,12,14 Psychiatric (10 decks)

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