Antipsychotics Flashcards
Describe the 4 dopamine pathways and their relation to schizophrenia
- Mesolimbic: memory and emotions - hyperfunctional in schizophrenia, (+) symptoms. High dopamine activity
- Mesocortical: cognition and motivation - hypofunctional in schizophrenia, (-) symptoms. Low dopamime activity
- Nigrostriatal: motor movement, normal dopamine activity in schizophrenia
- Tuberoinfundibular: prolactin secretion, normal dopamine activity in schizophrenia
What is the dopamine hypothesis of schizophrenia?
-Drugs that increase dopamine -> psychotic symptoms
-Antipsychotics antagonize D2 receptors -> diminish symptoms
-Does not explain dopamine deficiency in pre-frontal cortex (mesocortical pathway) in schizophrenia
What do First Generation Antipsychotics (FGA) do?
Antagonize D2, H1, alpha-1, and M1 receptors
What are examples of FGAs (10)?
- Chlorpromazine
- Flupenthixol
- Fluphenazine
- Haloperidol
- Loxapine
- Perphenazine
- Pimozide
- Thiothixene
- Trifluoperazine
- Zuclopenthixol
How do FGAs antagonizing D2 affect the 4 dopamine pathways?
- Mesolimbic: 65-75% antagonism -> treates psychosis
- Mesocortical: cause secondary negative symptoms
- Nigrostriatal: >80% antagonism -> EPS
- Tuberoinfundibular: Significant antagonism -> prolactin secretion
What are side effects of FGAs antagonizing other non-D2 receptors?
H1: Sedation, increased appetite, weight gain
alpha-1: orthostatic hypotension, dizziness, drowsiness
M1: Dry mouth, urinary retention, blurred vision, constipation
Example and side effects of FGAs with low potency for D2 receptors
Example: Chlorpromazine
Side effects: H1, alpha-1, M1 receptor antagonism related
(sedation, weight gain, hypotension, urinary retention)
Example and side effects of FGAs with high potency for D2 receptors
Example: Haloperidol
Side effects: D2 receptor antagonism related (EPS, increased prolactin release)
What do Second Generation Antipsychotics (SGAs) do?
Antagonize D2, H1 alpha-1, M1 and 5HT2A receptors
What are examples of SGAs (8)
- Clozapine
- Asenapine
- Lurasidone
- Olanzapine
- Paliperidone
- Quetiapine
- Risperidone
- Ziprasidone
MOA of 5HT2A antagonism
-Serotonin inhibits dopamine release
-5HT2A receptor antagonism -> release of dopamine
How do SGAs antagonizing 5HT2A receptors affect the mesocortical and nigrostriatal pathways?
- Mesocortical: improve negative symptoms (from hypoactive -> release more D2)
- Nigrostriatal: reduce EPS liability
What do Third Generation Antipsychotics (TGAs) do?
D2, D3, 5HT1A receptor partial agonist
H1, alpha-1, M1, 5HT2A receptor antagonist
*some have high intrinsic activity - qualify as D2 agonists
What are examples of TGAs (3)?
- Aripiprazole
- Brexpiprazole
- Cariprazine
Taking all the different antipsychotics into account, rank them in order of treating:
-positive symptoms of schizophrenia
-negative symptoms of schizophrenia
Positive symptoms: TGA=SGA=FGA, with the exception of clozapine for treatment-resistant patients
Negative symptoms:
TGA>SGA>FGA
Antipsychotics therapeutic effect + side effect of D2
Therapeutic (antagonist or partial agonist): treat psychosis
Side effects (antagonist): EPS, (-) symptoms, increased prolactin
Antipsychotics therapeutic effect + side effect of D3
Therapeutic (antagonist or partial agonist): treat psychosis, improve (-) symptoms, antidepressant action, reduce drug-seeking/cravings, improve cognition
Side effects (agonist): craving
Antipsychotics therapeutic effect of 5-HT1A
Therapeutic (partial agonist): antidepressant and anxiolytic action, reduced EPS
Antipsychotics therapeutic effect + side effect of 5-HT2A
Therapeutic (Antagonist): reduce EPS, improve (-) symptoms
Side effects (agonist): agitation, anxiety, EPS, sexual dysfunction, insomnia, cognitive dulling, akathisia
Antipsychotics side effect of alpha-1
Side effect (antagonist): orthostatic hypotension, sedation, dizziness, reflex tachycardia, sexual dysfunction
Antipsychotics therapeutic effect + side effect of H1
Therapeutic (Antagonist): Anxiolytic
Side effect (Antagonist): sedation, increased appetite, weight gain
Antipsychotics therapeutic effect + side effect of M1
Therapeutic effect (Antagonist): Reduce EPS
Side effect (Antagonist): blurred vision, dry mouth, constipation, urinary retention, impaired memory, sinus tachycardia, QRS changes, confusion, worsening condition, delirium
What is the biggest clinical difference between SGAs and TGAs?
SGAs are D2 antagonist (w/ exception of clozapine and quetiapine - low D2 receptor affinity)
TGAs are partial D2 agonist
How do SGAs and TGAs clinically differ in managing prolactin?
SGAs = D2 antagonist -> increase prolactin
TGAs = D2 partial agonists -> reduce prolactin
What are side effects of increased prolactin levels?
increase risk of breast cancer (women)
How do SGAs and TGAs clinically differ in managing dysphoria (life dissatisfaction)?
SGAs = D2 antagonist -> cause dysphoria
TGAs = D2 partial agonist -> don’t cause dysphoria
How do SGAs and TGAs clinically differ in dopamine supersensitivty psychosis?
SGAs = D2 antagonist -> upregulate D2 receptors -> dopamine supersensitivity -> psychosis
TGas = D2 partial agonist -> don’t upregulate D2 receptors
What are the treatment guidelines of schizophrenia?
- Start/optimize trial of SGA or TGA
- Wait 6-8 weeks to evaluate treatment response
What if there is no response of the antipsychotic after initial 6-8 weeks of treatment?
-Gradual switch to new trial or different SGA/TGA
-Long acting injectable (LAI) antipsychotics
Why are Long-Acting Injectables (LAI) antipsychotics used?
-low risk of rehospitalization and treatment failure
-effective
What if there is no response even with different trials of SGAs or TGAs and LAIs?
Switch to clozapine
What is clozapine used to specifically treat?
-Treatment resistant schizophrenia (caused by dopamine supersensitivity)
-Clozapine downregulates D2 -> no psychosis
What if there is no response with clozapine?
Clozapine augmentation
