Antipsychotic Medchem Flashcards
First approved antipsychotic
SEs: Antimuscarinic (M1), Sedative (H1), Hypotensive (a1)
Phenothiazine Ring System = Photosensitivity
Phenothiazine SAR
Position 2 is the best for substititurtion | the more electron withdrawing the better
Substitutions at positions 1 and 4 (1 more) decrease antipsychotic activity | unsubstituted phenothiazines have week antipsychotici activity
Three carbon chains connecting nitrogens is required (2 or 4 will decrease activity greatly)
Branching on the side chain with large groups will decrease activity (except for on gamma group)
On the basic nitrogen, tertiary amine group is the best, secondary not as good | anything more than di-methyl substitution starts to decrease activity | Piperidine and piperazine groups allowed | tertiary nitrogen required for passage through BBB but protonated ammonium has receptor activity
Fluphenazine
Tri-fluoromethyl makes more potent than chlorpromazine | polar group off of piperazine contributes to antimuscarinic effects
Fluphenazine deconoate (ester formed at primary hydroxy to then be used in depot injections) | stays at site of infection and slowly released/hydrolyzed to active fluphenazine (3-4 weeks)
Thioridazine
R-enantiomer has higher affinity for D2 receptor (used as racemate)
CYP2D6 metabolism to sulfoxide metabolite (active) | do not use in CYP2D6 poor metabolizers
QT prolongation
Clozapine
7-membered ring in the middle in place of central six-membered ring of phenothiazines
D4/D2 antagonist | 5HT2 antagonist
T1/2 = 12 hours | 1A2 (Major) 3A4 (minor) to N-desmethyl metabolite (may contribute to activity)
Risk of agranulocytosis | risk of reactive nitrenium ion formation which can react with GSH or protein nucleophiles, leading to toxicity
Olanzapine
No EWG | Thiophene isostere
T1/2 = 30 hours (dosed once daily) | N-demethylation (1A2) and 10-N-glucuronide are major metabolites
No agranulocytosis
Olanzapine Pamoate (Pamoate ion)
Much less water soluble salt form | used in IM injectable formulation (2-4 weeks effective)
Loxapine | Adasuve = inhalation powder
Not considered an atypical antipsychotic | still has EPS
3A4 metabolism (N-demethylation) to Amoxapine (active and blocks NE reuptake, antidperessant MOA)
Quetiapine (atypical)
T1/2 = 7 hours
Branching group (top right) reduces antimuscarinic effects
Major metabolite is sulfoxide (3A4) | minor metabolite (3A4) is N-desalkylquetiapine (T1/2 = 12 hours; active but different profile) | D-desalkylquetiapine is potent M1 antagonist
Asenapine | used as racemate
Central ring is no aromatic | minor catechol metabolite can be oxidized to reactive orthoquinone, leading to hypersensitivity (or arene oxide?)
T1/2 = 24 hours | Major metabolism is direct glucuronidation of 3 prime amine | minor is N-demethylation (1A2) | both inactive
No M1 antagonism (basic N is too close to ring system)
Weak 2D6 inhibitor
Haloperidol
T1/2 = 14-37 hours
High incidence of EPS | low antimuscarinic activity
Haldol decanoate
Ester prodrug for depot injections | lasts up to 4 weeks
Metabolism (major): N-dealkylation (3A4/2D6), Reduction of ketone
Metabolism (minor): 3A4 to form MPP like toxic metabolite of MPTP (HPP+ metabolite = potential neurotoxicities)
Risperidone
CYP2D6 metabolism is the major enzyme | T1/2 = 3 hours (EM), T1/2 = 20 hours (PM)
Metabolism to Paliperidone
Paliperidone | 9-hydroxyrisperidone | Invega Sustenna = Paliperidone palmitate (16 C) = ester prodrug for depot injections
T1/2 = 23 hours
Active metabolite of risperidone | available as separate drug
No major role for 2D6 metabolism (no major routes) | 60% excreted unchanged
Iloperidone
Identical side group to risperidone
T1/2 = 18 hours (EM), T1/2 = 33 hours (PM)
Metabolism: Reduction of ketone (active), 2D6 hydroxylation (active), 3A4 O-demethylation (inactive)
*recommended to decrease dose if taking strong 2D6/3A4 inhibitors
Ziprasidone
T1/2 = 7 hours
All major group are isosteres of the features of risperidone
3A4 (1A2) metabolism to sulfoxide and sulfone meatbolites and N-dealkylation (inactive) | P450 metabolism accounts for 1/3 overall
Aldeyhyde oxidase (2/3 of metabolism) alpha reduction followed by s-methylation
*Cimetidine has no effect
Lurasidone
Same side group as ziprasidone
Used as single enantiomer | T1/2 = 18 hours
CYP3A4 = major enzyme –> Sulfoxide/sulfone matabolites (inactive)
Hydroxylation to active metabolites (contribute to overall activity)
N-dealkylation to inactive metabolite
Aripiprazole
T1/2 = 75 hours (EM), T1/2 = 146 hours (PM)
Slightly longer spacer between structural elements
D2 partial agonist
2D6 and 3A4 are key enzymes involved in metabolism | dehydroariprazole is active but less potent (T1/2 = 94 hours)
Aripiprazole lauroxil (C12)
Esterase and spontaneous elimination of water gives active
Lipophilic prodrug for IM injections | Once monthly or once every 6 weeks
Brexipiprazole
Benzothiophene group (vs dichlorobenzene in aripirazole)
D2 partial agonist (also actions at 5HT2 receptors)
2D6 and 3A4 to inactive metabolites
T1/2 = 91 hours
Cariprazine
T1/2 = 2-4 days
D3/D2 partial agonist
3A4 (2D6 minor) to desmethyl and didesmethyl metabolites (both active and approximately equipotent) and T1/2 = 1-3 weeks
Primavanserin
T1/2 = 57 hours
Used to treeat Parkinson’s associated psychoses | Acts at 5HT2 receptors
CYP3A4 to N-desmethyl metabolite (Active w/ T1/2 = 200 hours)
