Antipsychotics Flashcards
Chlorpromazine metabolism
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)
Fluphenazine decanoate Brand, ROA, Duration
N/A
Depot injection.
3-4 weeks.
Side Effects common to AD’s and corresponding receptor targets:
Antimuscarinic - M1
Sedative - H1
Hypotensive - alpha-1
Thioridazine metabolism
2D6 to Sulfoxide metabolite (active)
Clozapine metabolism*
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.
Olanzapine metabolism
1A2 to N-desmethyl metabolite
GSH to 10-N-glucuronide metabolite
(Both inactive?)
Olanzapine pamoate Brand, ROA, Duration
Zyprexa Relprevv
IM injection
2-4 weeks
Loxapine metabolism
3A4 N-demethylation to Amoxapine (active)
- Blocks NE reuptake: Antidepressant mechanism.
- Separate Antidepressant drug.
Quetiapine metabolism
Major: 3A4 to Sulfoxide metabolite.
Minor: 3A4 to N-desalkylquetiapine (active).
- Different pharmacological profile
- Fairly potent as M1-antagonist
Asenapine metabolism
Major: Glucuronidation at tertiary amine.
Minor: 1A2 to N-desmethyl metabolite.
(Both inactive)
Haloperidol metabolism*
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
Haldol decanoate Brand, ROA, Duration
Haldol decanoate
Depot injections
4weeks
Risperidone metabolism
2D6 to +/=-9-hydroxyrisperidone or “Paliperidone”
Paliperidone metabolism
60% excreted unchanged.
Paliperidone palmitate Brand, ROA, Duration
Invega Sustenna
Depot Injections
N/A
Iloperidone metabolism
Reuction of ketone by? (active)
2D6 hydroxylation (at terminal methyl) (active)
3A4 O-demethylation (inactive)
Ziprasidone metabolism
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.
Aripiprazole metabolism
2D6/3A4 to Dehydroaripiprazole (active)
- less potent
Aripiprazole Lauoxil Brand, ROA, Duration, AND Metabolism
Aristada
IM injection
4-6 weeks
Esterase cleaves ester, product undergoes spontaneous ( ) to form active Aripiprazole.
Lurasidone metabolism
Major: 3A4 to sulfoxide/sulfone metabolites (inactive)
Hydroxylation (active) - contributes significantly
N-dealkylation (inactive)
Brexpiprazole metabolism
2D6/3A4…. (inactive)
Cariprazine metabolism
3A4major/2D6 to Desmethyl/Didesmethyl metabolites
- Both active
- Equipotent
- Contribute significantly
Pimvanserin metabolism
3A4 to N-desmethyl metabolite (active)
What is Adasuve
Loxapine as an inhalation powder.
Clozapine Characteristics
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.
Neutropenia definition
Neutrophil count under 1500cells/uL in whites
under 1200 in African/Middle eastern
Leukopenia
WBC under 4000cells/uL
FGA and SGA notable for Neutropenia
Haloperidol, Olanzapine, Quetiapine, Risperidone
Olanzapine characteristics
Similar to Clozapine, but lacks toxicities.
2nd most effect of all antipsychotics.
Weight gain very problematic - Now 3rd line agent.
Quetiapine characteristics
Sedating - Can be useful Low EPS due to active metabolite Low adrenergic blockade Moderate weight gain / risk of metabolic syndrome
Risperidone characteristics
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.
Paliperidone characteristics
Hydroxy metabolite of risperidone
Similar profile including restlessness and EPS
Sustained release form leads to once monthly dosing.
Ziprasidone and Lurasidone characteristics
Low weight gain Low EPS Problems with QT elongation - Less with Lurasidone Cimetidine interaction with Ziprasidone
Iloperidone characteristics
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.
Asenapine characteristics
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
Aripiprazole characteristics
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?)
Brexpiprazole
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.
Cariprazine
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
Pimvanserin Indication
Parkinson’s associated psychoses
