Antipsychotic Agents

Question 1

What was the earliest antipsychotic

Answer 1

CHLORPROMAZINE

• 1951 Developed for antihistaminic properties to be used in anesthesia
• Serendipitously uncovered antipsychotic activity
• 1954 widely used in US for schizophrenia

Question 2

First gen antipsychotics MOA

Answer 2

Primarily D2 antagonist

Question 3

Second gen antipsychotics MOA

Answer 3

Antagonize 5HT2A receptors and D2 receptors

Question 4

What is the dopamine hypothesis

Answer 4

Abnormalities in dopaminergic activity results in schizophrenic symptoms

• Antipsychotic drugs act by blocking dopamine (D2) receptors
• Drugs that increase dopamine (cocaine, amphetamines) produce schizophrenic-like symptoms

Question 5

Four dopamine pathways

Answer 5

Question 6

Four dopamine pathways again!

Answer 6

Question 7

First Gen examples

Answer 7

• Phenothiazines
• Chlorpromazine

•Fluphenazine

• Thioridazine
• Thioxanthene
• Thiothixene
• Butyrophenone

•Haloperidol

Question 8

First gen side effects

Answer 8

•ExtraPyramidal Symptoms (D2)

•Hyperprolactinemia (D2)

• Anticholinergic symptoms (M1)
• Sedation, weight gain (H1)
• Hypotension (alpha 1)

Question 9

Second gen antipsychotics

Answer 9

• Clozapine – agranulocytosis, seizures, reduce suicidality, used in treatment resistance
• Olanzapine – metabolic syndrome
• Risperidone – hyperprolactinemia, Consta biweekly injection
• Quetiapine – sedation, metabolic syndrome
• Ziprasidone – QTc prologation
• Aripiprazole – partial agonist, akathisia, Maintena monthly injection
• Lurasidone – category B in pregnancy

Question 10

How do second gen antipsychotics reduce symptoms

Answer 10

Rapid dissociation allows for dopamine binding in nigrostrial and mesocorticalsystems and thus reduces risk of EPS and can potentially improve negative and cognitive symptoms

Question 11

Second gen side effects

Answer 11

•EPS (D2) - less likely

• Hyperprolactinemia (D2)
• Anticholinergic symptoms (M1)
• Sedation, weight gain (H1)
• Hypotension (alpha 1)

•Metabolic Syndrome

•Weight gain

•Glucose dysregulation

•Diabetes

•Dyslipidemia

Question 12

TYPICAL VS ATYPICAL ANTIPSYCHOTICS

Answer 12

Question 13

Third gen antipsychotics MOA

Answer 13

• Partial dopamine agonists
• Functionally an antagonist when dopamine levels are high and agonist when dopamine levels are low

Question 14

Third gen examples

Answer 14

•Aripiprazole and brexpiprazole

Question 15

Third gen benefits

Answer 15

•Reduce positive symptoms and possibly improve negative/cognitive symptoms

•Reduce risk of long term side effects

Question 16

What are extrapyramidal symptoms

Answer 16

Dopamine blockade in the nigrostriatal pathway

1. Acute dystonia – muscle spasm in neck, back, jaw, throat
2. Akathisia – motor restlessness
3. Parkinsonism – bradykinesia, rigidity, tremor
4. Tardive Dyskinesia – hyperkinetic movements of face and jaw

Question 17

What causes neuroleptic malignant syndrome

Answer 17

Dopamine blockade (antipsychotics)

Question 18

Neuroleptic malignant syndrome symptoms

Answer 18

• Confusion
• Agitation
• Hyperthermia
• Muscular rigidity
• Autonomic instability
• Seizures
• 50% mortality rate

- Hyporeflexia

Question 19

Treatment for neuroleptic malignant syndrome

Answer 19

Treat with dopamine agonist (bromocriptine) and skeletal muscle relaxants (dantroline

Question 20

Metabolism of antipsychotics

Answer 20

•Cytochrome P450 metabolism