IDT - Antipsychotics Medchem Flashcards
Chlorpromazine
Antipsychotic - Phenothiazine
Antimuscarinic - Cant See, Spit, Pee, Shit
Sedative Action
Hypotensive (drops blood pressure)
Can lead to Photosensitivity
Phenothiazine SAR
What position is best for substitution?
What positions decrease antipsychotic activity?
How many carbons between nitrogens is required?
What Nitrogen group provides optimal activity, what group is required for transport through BBB?
Position 2 best fo substitution, activity increases with EWG
Substitution at 1 and 4 decrease AP activity
Three carbon chain required
Basic Nitrogen Substituent required, Tertiary required for BBB passage
What metabolisms of Chlorpromazine are active?
Cyp 2D6 –> N-demethyl CPZ
Cyp 2D6 (Major) or Cyp 1A2 (minor) –> 7-Hydroxy CPZ
7-hydroxy CPZ –> Glucoronidation/excretion
Fluphenazine HCL; Fluphenazine Decanoate
Which is prodrug form?
The Trifluoromethyl is more potent than CPZ
Hydroxy group off piperazine ring leads to reduced antimuscarinic effects
Decanoate is the prodrug form, the ester stays at site of injection, and is slowly released and hydrolyzed to the active fluphenazine.
Thioridazine
R Enantionmer (higher affinity for D2)
Metabolized by Cyp 2D6
- Sulfoxide Metabolite (active)
Prolongs QT interval, not to be used in 2D6 poor metabolizers
Clozapine
Dibenzazepine (Two N’s on central ring)
7 membered ring, not 6
Less EPS due to D4/D2 and 5HT2 antagonism
Metabolism
1A2 (major) and 3A4 (minor) -> N-Desmethyl Metabolite (active)
Risk of Agranulocytosis due to reactive Nitronium Intermediate that reacts with GSH or protein Nucleophiles
Olanzapine
Dibenzazepines
Thiophene Isostere
No risk of Agranulocytosis
Metabolism
N-Demethylation (1A2)
10-N-Glucuronide
Pamoate Anion
Binds 2 Olanzapines
Olanzapine Palmoate is much less water soluble (salt form)
Used as an IM injection and is effective for 2-4 weeks
Loxapine
Dibenzapine
Methyl and Chlorine are “cis” like
NOT an Atypical Antipsychotic
See EPS
Metabolism by 3A4 –> N-demethylation
- Amoxapine (active) Blocks NE reuptake
Quetiapine
Dibenzothiazepines
The Antimuscarinic Effects
Metabolism
(major) 3A4 –> Sulfoxide (inactive)
(minor) 3A4 –> 3-desalkylquetiapine (Active) Potent m1 receptor antagonist
Asenapine
Dibenzazepine-Like
Central ring is not aromatic
Weak 2D6 inhibitor
Possible Allergic Reactions
No M1 antagonism
Metabolism –> Both Inactive
(Major) Direct Glucoronidation
(Minor) N-Demethylation (1A2)
Haloperidol
Fluorobutyrophenones
Introduced in 1967,
High incidence of EPS
Low antimuscarinic activity
Metabolism
1) N-Dealkylation (3A4 / 2D6)
2) Reduction of Ketone
3) MPP+
Haldol Decanoate
Esther Prodrug
Depot Injection with 4 weeks effectiveness
Same Metabolism as Haloperidol
Risperidone
Benzisoxazole groups
Atypical Antipsychotic
Prodrug
Metabolism
Cyp 2D6 (Major) –> Paliperidone (Active)
Paliperidone
Active Metabolite of Risperidone
Available as seperate antipsychotic drug
No Major Role for 2D6 metabolism
60% excreted unchanged
Esther Prodrug (Paliperidone Palmitate) used for depot injections
Iloperidone
Atypical Antipsychotic
Action idential to Risperidone
Cyp 2D6 adds OH on ketone
(Extensive Metabolizer - 18hrs) (Poor Metabolizer - 33hrs)
Metabolism
1) Removal of Ketone Carbonyl (active)
2) 2D6 hydroxylation (active)
3) 3A4 O-demethylation (Inactive)
Ziprasidone
Atypical Antipsychotics
Risperidone features
Metabolism (3A4/1A2) –> Inactive
- Sulfoxide & Sulfane Metabolites
2) N-dealkylation
Metabolism
1) (Aldehyde oxidase) Mediates alpha reduction
2) S-methylation
Lurasidone
Same Action as Ziprasidone
Used as Single Enantiomer
Metabolized by Cyp3A4 (inactive)
1) Sulfoxide / Sulfoxone
Metabolized by Hydroxylation (Active)
Metabolized by N-dealkylation (inactive)
Aripiprazole
D2 partial Agonist
Slightly longer spacer, more lipophilic (longer action)
(Extensive - 75hrs; Poor - 146hrs)
Metabolism (2D6 and 3A4)
1) Dehydroaripripazole (Active, less potent)
Aripiprazole Lauroxil
Lipophilic prodrug for IM injections, once monthly or once every 6wks
Esterase cleaves long ester, spontaneously dealkylates
Brexpiprazole
Benzothiophene group
D2 partial agonist (also action at 5HT2 receptors)
Metabolized by 2D6 and 3A4 to inactive metabolites
t1/2 - 91 hrs
Cariprazine
Contains Urea group and same dichlorophenyl as aripiprazole
D3/D2 partial agonist
Metabolism by 3A4 (major)/2D6 (minor)
1) Desmethyl & Didesmethyl Metabolites (Active/Equipotent)
Pimavanserin
Urea group and piperidine heterocyclic group
Used to treat Parkinsons associated Psychoses
Acts at 5HT2 receptors
Metabolism by 3A4
1) N-desmethyl Metabolite (Active ~200 hrs)
