Antipsychotics

Question 1

Chlorpromazine metabolism

Answer 1

3A4 to CPZ Sulfoxide (inactive)
2D6 to Nor1-CPZ (weakly active)
Multiple steps to CPZ propionic acid (inactive)
2D6(major)/1A2 to 7-HydroxyCPZ (weakly active)

Question 2

Fluphenazine decanoate Brand, ROA, Duration

Answer 2

N/A
Depot injection.
3-4 weeks.

Question 3

Side Effects common to AD’s and corresponding receptor targets:

Answer 3

Antimuscarinic - M1
Sedative - H1
Hypotensive - alpha-1

Question 4

Thioridazine metabolism

Answer 4

2D6 to Sulfoxide metabolite (active)

Question 5

Clozapine metabolism*

Answer 5

1A2(major)/3A4 to N-desmethyl metabolite (active)

• Cigarette smoking induces 1A2
• 3A4 to Reactive Nitrenium Ion
• Can either react with GSH, or protein nucleophiles, which leads to toxicities.

Question 6

Olanzapine metabolism

Answer 6

1A2 to N-desmethyl metabolite
GSH to 10-N-glucuronide metabolite
(Both inactive?)

Question 7

Olanzapine pamoate Brand, ROA, Duration

Answer 7

Zyprexa Relprevv
IM injection
2-4 weeks

Question 8

Loxapine metabolism

Answer 8

3A4 N-demethylation to Amoxapine (active)

• Blocks NE reuptake: Antidepressant mechanism.
• Separate Antidepressant drug.

Question 9

Quetiapine metabolism

Answer 9

Major: 3A4 to Sulfoxide metabolite.
Minor: 3A4 to N-desalkylquetiapine (active).
- Different pharmacological profile
- Fairly potent as M1-antagonist

Question 10

Asenapine metabolism

Answer 10

Major: Glucuronidation at tertiary amine.
Minor: 1A2 to N-desmethyl metabolite.
(Both inactive)

Question 11

Haloperidol metabolism*

Answer 11

Major routes:
- 3A4/2D6 N-dealkylation
- Reduction of the ketone... by?
*Minor route; three steps:
1 - 3A4 (oxidation?) to positive N-species
2 - Dehydration (possibly by 3A4)
3 - Oxidation (by?)
Left with "HPP+"
- Like MPP+
- Potential neurotoxic metabolite

Question 12

Haldol decanoate Brand, ROA, Duration

Answer 12

Haldol decanoate
Depot injections
4weeks

Question 13

Risperidone metabolism

Answer 13

2D6 to +/=-9-hydroxyrisperidone or “Paliperidone”

Question 14

Paliperidone metabolism

Answer 14

60% excreted unchanged.

Question 15

Paliperidone palmitate Brand, ROA, Duration

Answer 15

Invega Sustenna
Depot Injections
N/A

Question 16

Iloperidone metabolism

Answer 16

Reuction of ketone by? (active)
2D6 hydroxylation (at terminal methyl) (active)
3A4 O-demethylation (inactive)

Question 17

Ziprasidone metabolism

Answer 17

1/3 metabolized by P450’s:
- 3A4major/1A2 to sulfoxide/sulfone/N-dealkylation
- Inactive
2/3 metabolized by another route
- 1: Aldehyde oxidase mediates a reduction
- 2: S-methylation by?
- Inactive
Cimetidine should cause an interaction, but it doesn’t for some reason.

Question 18

Aripiprazole metabolism

Answer 18

2D6/3A4 to Dehydroaripiprazole (active)

- less potent

Question 19

Aripiprazole Lauoxil Brand, ROA, Duration, AND Metabolism

Answer 19

Aristada
IM injection
4-6 weeks
Esterase cleaves ester, product undergoes spontaneous ( ) to form active Aripiprazole.

Question 20

Lurasidone metabolism

Answer 20

Major: 3A4 to sulfoxide/sulfone metabolites (inactive)
Hydroxylation (active) - contributes significantly
N-dealkylation (inactive)

Question 21

Brexpiprazole metabolism

Answer 21

2D6/3A4…. (inactive)

Question 22

Cariprazine metabolism

Answer 22

3A4major/2D6 to Desmethyl/Didesmethyl metabolites

• Both active
• Equipotent
• Contribute significantly

Question 23

Pimvanserin metabolism

Answer 23

3A4 to N-desmethyl metabolite (active)

Question 24

What is Adasuve

Answer 24

Loxapine as an inhalation powder.

Question 25

Clozapine Characteristics

Answer 25

``` Advantages: - Uniquely effective - No reported EPS Toxicities: Make it a 3rd line agent: - Leukopenia to agranulocytosis (1.3% patients) - Myocarditis - Cardiovascular collapse Decreases seizure threshold Typical SE's as well: Sedation, antimuscarinic effects (notably constipation), etc. ```

Question 26

Neutropenia definition

Answer 26

Neutrophil count under 1500cells/uL in whites | under 1200 in African/Middle eastern

Question 27

Leukopenia

Answer 27

WBC under 4000cells/uL

Question 28

FGA and SGA notable for Neutropenia

Answer 28

Haloperidol, Olanzapine, Quetiapine, Risperidone

Question 29

Olanzapine characteristics

Answer 29

Similar to Clozapine, but lacks toxicities. 2nd most effect of all antipsychotics. Weight gain very problematic - Now 3rd line agent.

Question 30

Quetiapine characteristics

Answer 30

``` Sedating - Can be useful Low EPS due to active metabolite Low adrenergic blockade Moderate weight gain / risk of metabolic syndrome ```

Question 31

Risperidone characteristics

Answer 31

Lack of sedation is attractive Restlessness/agitation can be a problem though Dose control to avoid EPS Also approved for irritability in autism spectrum disorder at age 5 and up.

Question 32

Paliperidone characteristics

Answer 32

Hydroxy metabolite of risperidone Similar profile including restlessness and EPS Sustained release form leads to once monthly dosing.

Question 33

Ziprasidone and Lurasidone characteristics

Answer 33

``` Low weight gain Low EPS Problems with QT elongation - Less with Lurasidone Cimetidine interaction with Ziprasidone ```

Question 34

Iloperidone characteristics

Answer 34

``` Low EPS Low anti-cholinergic effects Low weight gain Low tendency for metabolic syndrome but Hypotension is a problem - requires dose titration. Caution 2D6/3A4 inhibitors. ```

Question 35

Asenapine characteristics

Answer 35

Minimal weight gain and metabolic disturbance. Extreme sedation from H1-Antagonism. Off label for PTSD. Serious hypersensitivity reactions - anaphylaxis alert. EPS concern due to low M1-Antagonism May not be very efficacious anyways.. Weak 2D6 inhibitor

Question 36

Aripiprazole characteristics

Answer 36

``` D2-Partial Agonist - 30% Transient nausea No endocrine disturbances - Slight decrease in prolactin actually. No receptor sensitization - Low risk of EPS or TD Good efficacy but May increase psychoses in a subset of patients Agitating Alpha-1-Antagonism - decrease BP, increase HR Increasing reports of weight gain with time. Very long t1/2 (EM/PM?) ```

Question 37

Brexpiprazole

Answer 37

``` Newer Weaker D2-partial agonist than Aripiprazole Partial agonist at 5HT1A Antagonist at 5HT2 Low risk for EPS or TD Alpha-1-Antagonism Low H-1 affinity Common SE: Akathisia (agitation, distress, restlessness), moderate for weight gain. ```

Question 38

Cariprazine

Answer 38

``` Newer D2-partial (ant)?agonist 5HT1A Partial agonist 5HT2 Antagonist D3 Partial agonist > D2! EPS in 1/4 to 1/3 of patients... Low weight gain ```

Question 39

Pimvanserin Indication

Answer 39

Parkinson's associated psychoses