Antipsychotic Agents

Chlorpromazine

• aliphatic phenothiazines

• use: antipsychotic, control nausea and vomiting

• D2 receptors

• oxidation: sulfide —> sulfoxide —> sulfone

• oxidative n-dealkyation to secondary and primary amine

• aromatic hydroxylation

• stored in tightly sealed brown bottles

triflupromazine

• aliphatic phenothiazine

• use: antipsychotic, control severe nausea/ vomiting

• CF3 more EWG, inc lipo, inc CNS penetration (BBB cross)

promethazine

• aliphatic phenothiazine

• use: antiemetic, nausea/vomiting postoperative

• 2 carbon linker (less than 3 carbons) = weak antipsychotic

  • also no ewg @ 2 position

• antihistamine : H1 blocking activity

• 1/10 activity of chloropromazine

thioridazine

• piperidine phenothiazine

• use: treat schizophrenia when fail others antipsychotics so not first line

• block d2 receptors in CNS

  strong alpha adrenergic blocking

  high anticholinergic effects

• 3 carbon linker

• oxidation via CYP2D6

  • mesonidazine (sulfoxide s=o)

    • 2x potent and active

    • withdrawn b/c irregular heartbeat and QT prolongation

  • sulfaridazine (sulfone o=s=o)

    • 8x more potent and active

trifluoperazine

• CF3 may increase antipsychotic more than Cl

• use: schiz and short term non-psychotic anxiety

• both basic amines protonated

• piperazine phenothiazine

prochlorperazine

• use: manage schiz and short term non-psychotic anxiety and severe nausea/vomiting

• anti-psychotic and anti-emetic properties

• piperazine phenothiazine

perphenazine

• piperazine ethanol phenothiazine

• use: schiz and nausea/ vomiting

• anti-emetic and anti-psychotic

fluphenazine

• piperazine ethanol phenothiazine

• use: schiz and psychotic disorders

• admin route: oral and injection

• half life: 33 hr

• 3-4x day so poor compliance

• prodrug form (one of the 1st situations solved w/ prodrug revolutionated tx of schiz)

• fluphenazine Enanthate

  • prodrug

  • 7 carbon fatty acid

  • lipid soluble add sterile veg oil

• fluphenazine decanoate

  • veg oil IM inject

  • drug slowly leak out of depo then hydrolyzed by esterases so steady state

  • injection every 3-4 weeks so good patient compliance

thiothixene

• isosteric phenothiazine

• use: schiz

• biosteric replacement —> ring N with C so sp2 planar geo

• Z (cis) conformation

Molindone

• indole

• use: schiz

• extensive metabolism = 36 metabolites

Haloperidol

• butyrophenones

• use: schiz, tourette’s disorder

• moa=

  • inverse D2 agaonist , inc cAMP

    • activates but not turn on receptor

  • can antagonize alpha 1 and 5HT2 @ low conc

• extensive metabolism (inactive metabolites)

  • 1% elim unchanged in urine

  • glucoronidation 50-60%

  • dealkylation 20-30%

  • ketone reduction to OH 23%

• oral (tx schiz)

  • 2-3 x day

  • half life= 12-38 hr

• inject for other indications

• Haloperidol deconoate = prodrug

  • IM month

  • slow release

  • sesame oil or veg oil (sterile)

  • 10 carbon COOH fatty acid

  • half life= 3 weeks

• F and Cl block hydroxylation/ metabolism and inc antipsychotic activity

Droperidol

• butyrophenones

• use: anti emetic, prevent nausea/vomit from surg procedures, diagnostic procedures, cancer chemo

• d2 receptor antagonist w/ serotonin antagonism

• route admin= injection: IM slow IV infusion

• some antihistamine and anti serotonin activity

• some sedative properties

Pimozide

• butyrophenones

• use= tourette’s disorder, antipsychotic

  • suppresses motor and phonic tics of tourettes

• moa= blocks dopamine d2 receptor

• half life= 20-40 hr

• metabolism

  • cleaves between carbon of piperidine nitrogen to inactive

  • n-dealk on left, deamination right

Li2CO3

Lithium carbonate

• use= antipsychotic

Lithium citrate

• misc antipsychotic

• use= bipolar disorder (manic episodes)

• Lithium ions

  • mood stabilizing drug

  • distributed after injection

  • inc NE reuptake, dec NE @ neuron

  • increase 5HT receptor sensitivity

• elimination in urine as inorganic ions in urine (citrate —> carbonates)

  • problems= body eliminating lithium, dec sodium reabsorption and causing sodium depletion and dehydration

Loxapine

• misc antipsychotic

• use= 1st gen antipsychotic agent, tx schiz

• metabolism = demethylation , amoxapine (active)

• moa= unknown

Clozapine

• new agent

• use= 1st drug to treat both + and - aspects of schizo, last line tx, treats society withdrawal and depression

• moa= unknown, related to serotonin and dopamine?

• AE= agranulocytosis (serious, weekly blood tests to monitor)

Risperidone

• new agent

• use= schiz and bipolar disorder

• moa

  • serotonin receptor antagonism (5-HT 2C, 5-HT 2A, 5-HT 1A)

  • D2 antagonist (potent binder), mixed antagonist —> not pure antagonist

• 2nd gen, atypical

• DOA = 3-14 hr (short)

• no possibility for fatty acid attachment

• side effects= parkinsonian-like (tremor, slowness, stiffness)

• other formulations:

  • risperidone consta

    • active metabolite in polymeric nanosphere

      (poly- lactic acid- glycolic acid polymer) PLG

    • drug can slowly leak out as polymer is degraded

    • injection IM every 2 weeks

    • use schizo and bipolar

  • paliperidone

    • treat schiz

    • [OH] at c9 (active metabolite)

    • can attach fatty acid to OH for slow release

    • tablet, QD slow release or monthly injection

    • half life= 23-30 hr (longer half life)

    • non absorbable shell w/ drug enclosed

  • paliperidone palminate

    • prodrug w/ ester and fatty acid chain ( 15 C)

    • not oral!

    • once a month injection

    • suspension of nanocrystals

    • lipid soluble particles suspended in water

    • use= schiz

Illoperidone

• new agent

Ziprasidone

• new agent

Lurasidone

• new agent

Olanzapine

• new agent

Quetiapine

• new agent

Arpiprazole

• new agent

Brexipiprazole

• new agent

Cariprazine

• new agent

Asenapine

• new agent

Lumateprone

• new agent