Antipsychotic Drugs Flashcards
What was the first approved antipsychotic?
Chlorpromazine
Chlorpromazine
- Structure
- SE’s
- Phenothiazine ring system - leads to photosensitivity Similar to M1 antagonist SAR - SE's: antimuscarinic - M1 antagonism sedative: H1 hypotension: alpha-1 Also antihistamine properties
Phenothiazine SAR
1) EWG substitution at 2, increases potency. Necessary.
2) Substitutions @ 1 and 4 decrease antipsychotic activity (1 > 4)
3) Three carbon chain connecting nitrogens is required. 2 or 4 decreases activity.
4) Branching on the side chain decreases activity. Branching at the y-carbon (the most distal) is tolerated.
5) Basic nitrogen substituents - tertiary amines provide optimal activity. 2ndary have decreased activity. Significant increases in size from dimethylmino groups decrease activity. Piperidine/piperazine rings are allowed. Addition of length on N2 of piperazine ring may increase receptor binding forces.
Which form of a phenothiazine is required for passage through the BBB? At the receptor?
Tertiary amine is needed for BBB, but the protonated form is needed at the receptor.
What are the metabolites of chlorpromazine?
CPZ sulfoxide - inactive
Nor1-CPZ - weakly active 2ndary amine
CPZ propionic acid - inactive
7-hydroxy CPZ - 2D6 major, 1A2 minor. Weakly active. Glucuronidation and excretion
Fluphenazine HCl
- structure
Phenothiazine with propyl piperazine side chain
Triflouromethyl - more potent than chlorpromazine
Piperazine ring with polar group - contributes to reduced antimuscarinic effects
Fluphenazine decanoate
Prodrug. This is an ester (formed from the primary hydroxyl group) that stays at the site of depot injection; slowly released and hydrolyzed to active fluphenazine in 3-4 weeks.
Thioridazine
- structure
- metabolism
- SE’s
- Phenothiazine with alkyl piperidyl side chain
- CYP 2D6 creates active sulfide metabolite at methyl group (0=S-Ch3)
- Used as racemate, but R enantiomer has higher D2 receptor affinity
- prolongs the QT interval. Not for use in 2D6 poor metabolizers.
Clozapine
- type
- structure
- metabolism
- Atypical antipsychotic, dibenzazepine (2 nitrogens)
- 7-membered ring instead of 6 (more flexible, less planar)
- Cl is EWG, trans-like to tertiary amine.
- D4/D2 antagonist, 5HT2 antagonist (less EPS)
- major 1A2, minor 3A4
- forms active N-desmethyl metabolite which may contribute to overall activity
What is the risk with clozapine? What reason?
Risk of agranulocytosis: 3A4 changes this to a reactive nitrenium ion, which can react with GSH or protein nucleophiles to lead to toxicities. Monitoring is required with this drug.
What is the half-life of clozapine?
12 hours
Olanzapine
- type
- structure
- metabolites
- Atypical Antipsychotic
- Dibenzazepine
- No EWG, thiophene isostere
- N-demethylation (1A2)
- 10-N-glucuronide
What is the half-life of olanzapine?
30 hours (once daily dosing)
What is olanzapine pamoate? When is it used? How is it released?
It is a decarboxylate, so a pamoate anion is attached to one olanzapine.
It is a less water-soluble salt form, used in IM formulations.
Effective in 2-4 weeks, released slowly.
Loxapine
- type
- structure
- metabolism
- Atypical?
- Dibenzooxazepine.
- Inhalation powder
- cis-like, Cl is EWG
- 3A4 N-demethylation produces amoxapine (antidepressant drug). This is an active metabolite that blocks NE reuptake.
- Not considered an atypical antipsychotic (still see EPS)
Quetiapine
- type
- structure
- metabolism
- dibenzothiazepine (sulfur substitution)
- atypical antipsychotic
- No EWG
- Long ether chain with OH at the end - reduces antimuscarinic effects
- 3A4 major metabolite is inactive sulfoxide, minor 3A4 metabolite is N-desalkyl quetiapine (active, but different pharmacological profile. Potent M1 receptor antagonist = antimuscarinic effects).
What is the half-life of quetiapine? It’s minor metabolite?
Drug = 7 hours and metabolite = 12 hours
What receptor type agonist/antagonist gives antimuscarinic effects?
M1 antagonist
What receptor type agonist/antagonist gives sedation?
H1 antagonism
What receptor type agonist/antagonist gives hypotension?
alpha-1