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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withdrawn b/c irregular heartbeat and QT prolongation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