T2 EX5 L3 (ANTIPSYCHOTICS, EPS MEDCHEM) (KINDY)

"Positive" symptoms of schizophrenia (four)

Delusions

Hallucinations

Thought disorder

Abnormal behaviors

"Negative" symptoms of schizophrenia? (two)

Withdrawal from social contacts

Flattening of emotional responses

Pathogenesis of schizophrenia? (two)

1. A combination of genetic and environmental factors (Neuregulin-1 and NMDA receptor expression level; consumption of cannabis)

2. Dopamine theory

T/F: In all forms of schizophrenia, there is altered connectivity, altered synaptic regulation of inhibitory NTs, inter-and intra-cellular signaling differences affecting neurotransmission, cellular signaling cascades, and/or enzyme phosphorylation.

True

Four hypotheses of psychotic disorders?

1. Dopamine hypothesis

2. Serotonin hypothesis

3. Glutamate hypothesis

4. Neuro-developmental hypothesis

Function of the nigrostriatal dopamine pathway?

EPS, movement

Dopamine antagonists' effect on nigrostriatal dopamine pathway?

Movement disorders

Function of mesolimbic dopamine pathway?

Arousal, memory, stimulus processing, motivational behavior

Dopamine antagonists' effect on mesolimbic dopamine pathway?

Relief of psychosis

Function of mesocortical dopamine pathway?

Cognition, communication, social function, response to stress

Dopamine antagonists' effect on mesocortical dopamine pathway?

Relief of psychosis, akathisia

Function of tuberoinfundibular dopamine pathway?

Regulates prolactin release

Dopamine antagonists' effect on tuberoinfundibular dopamine pathway?

Increased prolactin concentrations

Precursor (amino acid) to dopamine?

Tyrosine

Effect of phencyclidine?

Blocker of NMDA type of glutamate receptors -> glutamatergic system dysfunction

Describe the dopamine hypothesis of schizophrenia

Abnormal dopamine transmission (too much or too little)

Increased number of receptors

T/F: Most antipsychotics also affect serotonin receptors.

True

First-generation antipsychotics? (three classes)

Butyrophenones

Diphenylbutylpiperidines

Phenothiazines

Butyrophenones examples? (two)

Droperidol

Haloperidol

Diphenylbutylpiperidine examples? (three)

Fluspirilene

Penfluridol

Pimozide

Phenothiazines examples? (three)

Chlorpromazine

Fluphenazine

Thioridazine

Describe the glutamate hypothesis of schizophrenia

Those with schizophrenia have an underactivation of glutamate receptors (because PCP can evoke schizo like states)

Second generation (atypical antipsychotic) examples? (six)

1. Aripiprazole

2. Clozapine

3. Risperidone

4. Brexpiprazole

5. Cariprazine

6. Pimavanserin

Differences between typical and atypical antipsychotics

Second gen have less/fewer EPS

Second gen have less prolactinemia

2nd gen do D2 blockade AND 5HT2 blockade

Perchance better at treating negative symptoms

T/F: Clozapine blocks D4 receptors in addition to D2 receptors.

True

Clinical uses of antipsychotics? (two)

1. Acute behavioral emergency (for these we use IM classical antipsychotics)

2. Schizophrenia (we can use both 1st and 2nd gen here)

T/F: Obstructive jaundice sometimes occurs with administrations of phenothiazines.

True

T/F: With clozapine, leukopenia is common and requires routine monitoring.

True

Possible consequences of D2 blockade?

EPS, movement disorders, sexual dysfunction, endocrine side effects (prolactin elevation)

Possible consequences of 5-HT1 blockade

Ejaculatory disturbances

Possible consequences of 5-HT2 blockade

Hypotension, weight gain, reduced sexual dysfunction, insomnia

Possible consequences of anticholinergic receptor blockade?

Anticholinergic symptoms

Anti EPS side effects tho

Possible consequences of H1 blockade

Sedation

Weight gain

Anti-EPS side effects

Possible consequences of a1-adrenergic blockade

Orthostatic hypotension

Dizziness

Syncope

Reflex tachycardia

Sedation

Priapism

T/F: Haloperidol is a dopamine antagonist.

False; inverse agonist.

Antipsychotic therapy has limited efficacy against... (three)

1. Negative symptoms

2. Affective symptoms

3. Cognitive deficits

What are MARTAs? Three examples?

MARTA - Multi-acting receptor targeted agents

Clozapine, olanzapine, quetiapine

What are SDAs? Two examples?

SDA - serotonin-dopamine antagonists

Risperidone, ziprasidone

Give me one example of a selective D2/D3 antagonist

Aripiprazole

Two examples of D2/D3 partial agonists?

Brexpiprazole (Rexulti)

Cariprazine (Vraylar)

What do we like about clozapine?

Selective D2 blocker; blocks 5-HT2 in cortex, which then acts to modulate some dopamine activity

Works reasonably well for refractory cases

Mostly minor adverse effects

DDIs of note with clozapine?

Interacts with SSRIs (probably serotonin syndrome or something)

Interacts with valproic acid (increased clozapine levels)

MOA of ziprasidone?

Antagonist/inverse agonist of 5-HT, dopamine receptor, adrenergic receptor, mACh receptor, AND NE transporter.

bruh

MOA brexpiprazole?

Partial agonist of D2

Serotonin-dopamine activity modulator

In which of the antipsychotics is weight gain most common (and most in general)?

Clozapine

Olanzapine runner up