Antipsychotic Medchem Flashcards Preview

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Flashcards in Antipsychotic Medchem Deck (22)
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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



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)



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



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



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



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)



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



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



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



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



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



Benzothiophene group (vs dichlorobenzene in aripirazole)

D2 partial agonist (also actions at 5HT2 receptors)

2D6 and 3A4 to inactive metabolites

T1/2 = 91 hours



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



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)