Term
| examples of typical antipsychotics |
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Definition
phenothiazines
thioxanthenes
butyrophenones
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Term
| SAR of typical antipsychotics |
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Definition
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chlorpromazine
Substituents in the aromatic rings:
chlorpromazine is not symmetric making the molecule not able to freely rotate; the molecule fits perfectly into the DA receptor
promethazine doesn't have the groups and doesn't bind to the dopamine receptor as well.
Cl is electronegative and the N is electropositive; they draw each other together and stabilize the structure (for phenothiazines) the Cl (and other substituents) can only be on the 2 position
substitutions that will be GOOD for activity are electro-negative: CI3, SO2N, SO2C3, Cl
substituents that are BAD for activity: NH2, OH, CH3
side chain:
van der waal's interactions are important; alkyl side chain is active, but an alicyclic side chain increasing the van der waal's interactions and increases activity; CYCLE IS BETTER THAN A CHAIN (BUT NOT AN AROMATIC RING!!)
piperidine is good (only one N in the cycle and no double bonds)
if another N is added to the cycle, it becomes a very GOOD substituent (piperizine ring)
have to have 3 carbons between the tricyclic system and the tertiary amine; the tertiary amine must be in this position (not longer or shorter) to mimic the shape of dopamine
has to be a tertiary amine on the side chain!
phenothiazines vs. thioxanthenes:
phenothiazines: the structure of the molecule is maintained by the interaction between the 2 position substituent and the tertiary amine
thioxanthenes:
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the structure must be the cis isomer which is kept stable by the double bond.
only the cis isomer will have a high affinity for D2 receptors
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thioxanthenes have higher receptor affinity than phenothiazines |
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Term
pharmacokinetic properties of phenothiazines
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Definition
rapidly absorbed
peak plasma concentrations: interpatient variability
metabolism: phenothiazines = thioxanthenes
excretion: mostly in the urine
high plasma protein binding to albumin
very variable half life between agents |
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Term
metabolism of phenothiazines (and thioxanthenes)
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Definition
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Phase I reactions:
oxidative N-demethylation - once the N is demethylated, it loses activity at D2 but gains affinity for other receptors
aromatic hydroxylation
side chain reactions (N-oxide) - can happen to either N once it is dealkylated
S-oxication
oxidative deamination
N-dealkylation
conjugated metabolites
sulfoxide metabolites are thought to have anti-dopamine activity |
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Term
properties of chlorpromazine
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first generation/typical anti-psychotic |
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Definition
substrate of CYP1A2, 3A4, and 2D6
low EPS
high sedative, anticholinergic, and cardiovascular side effects (central and peripheral alpha1-adrenergic activity) |
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Term
| mechanism of long acting neuroleptics |
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Definition
long chain fatty-acid esters
decanoate and enanthate
less side effects than the unesterified form due to slow release
increased lipophilicity of the drugs
PRODRUGS, not active; have to be hydrolyzed in vivo to antagonize the DA receptor
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Term
| typical antipsychotics: butyrophenones |
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Definition
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Term
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Definition
[image]
tertiary amino group at the fourth carbon; cycle is preferred
para-substituted (F is preferred) phenyl ring at the 1-position
variations at the piperidine moiety:
at the 4 position of the ring
lengthening, shortening, or branching of the 3 carbon propyl chain
keto group
the tertiary amino group (piperidine ring)
para position to the piperidine ring is the ONLY PLACE THERE CAN BE SUBSTITUENTS!
conformationally restricted butyropheones
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diphenylbutylpiperidines:
pimozide is structurally related to droperidol
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Term
| pharmacokinetic properties of butyrophenones |
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Definition
well absorbed from GI tract
first pass metabolism reduces the bioavailability to approximately 60%
haloperidol undergoes extensive metabolism |
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Term
properties of haloperidol
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Definition
first generation/typical anti-psychotic
butyrophenone
haloperidol is well and rapidly absorbed and has a high bioavailability
it is more than 90% bound to plasma proteins
excreted slowly in the urine and feces
substrate for CYP1A2, 2D6, 3A4 |
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Term
metabolism of haloperidol
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Definition
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N-dealkylation
aromatization
carbonyl reduction
all metabolites are inactive |
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Term
properties of droperidol
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Definition
first generation/typical anti-psychotic
butyrophenone
centrally acting acetylcholinesterase inhibitors may increase the risk of antipsychotic releated EPS
CNS depressants may produce additive sedative effects |
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Term
properties of pimozide
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Definition
first generation/typical anti-psychotic
butyrophenone (carbonyl group is replaced by phenyl with F in para position)
50% absorbed after oral administration
metabolized by CYP3A4 and 1A2
excreted in the urine |
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Term
| examples of atypical anti-psychotics |
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Definition
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Term
| properties of atypical anti-psychotics |
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Definition
clozapine, olanzapine, quetiapine, risperidone, aripiprazole, and ziprasidone
affinity for 5HT-2A receptors (D2 receptor antagonism coupled with 5HT-2A receptor antagonism)
D2 occupancy theory: the magnitude of the response is directly proportional to the amount of drug bound, and the maximum response would be elicited once all receptors were occupied at equilibrium
high 5HT-2A receptor affinity does NOT mean it is an atypical anti-psychotic
clozapine "atypicality" may be related to its high affinity for D4 receptors
quetiapine, has no appreciable affinity for D4 receptors
no single theory to date has been able to globally define and/or differentiate the actions of atypical antipsychotics |
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Term
properties of clozapine
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Definition
atypical anti-psychotic
lack of EPS (preferential binding to mesolimbic than striatal DA receptors)
high affinity for 5HT-2A receptors
food does not affect absorption
97% bound to plasma proteins
extensively metabolized
50% excreted in the urine and 30% in the feces
high incidence of agranulocytosis (highly reactive nitrenium ion) |
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Term
clozapine metabolism
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Definition
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N-demethylation
N-oxide
Demethylclozapine (DMCZ) shows partial agonism at D2 and D3 receptors; potent M1 agonist
clozapine N-oxide (CZNO) is not active |
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Term
properties of olanzapine
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Definition
combined with fluoxetine for depression associated with bipolar disorder
93% bound to plasma proteins, half life is 27 hours
mood stabilizing and antidepressant effects through 5HT-2A receptor blockade and increased cortical DA and NE concentrations |
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Term
metabolism of olanzapine
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Definition
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oxidation
N-oxide
glucuronidation
the major metabolite of olanzapine is the N-glucuronide |
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Term
properties of quetiapine
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Definition
atypical anti-psychotic
antagonist at D2 and 5HT-2A; agonist at 5HT-1A
quetiapine dissociates rapidly from D2 receptors and this leads to lower D2 receptor occupancy compared to typical anti-psychotics such as chlorpromazine
83% bound to plasma proteins
CYP3A4 inducer or inhibitor
SE: orthostatic hypotension and somnolence |
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Term
metabolism of quetiapine
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Definition
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N-dealkylation
O-dealkylation
hydroxylation
sulfoxide
the major metabolite, sulfoxide is inactive
the 7-hydroxy and the 7-hydroxy-N-desalkyl are active metabolites |
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Term
properties of risperidone
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Definition
atypical anti-psychotic
90% bound to albumin
renal excretion
side effects: orthostatic hypotension, dose-related hyperprolactinemia, mild weight gain, EPS, and insomnia
high affinity at 5HT-2A, 5HT-7, D2, alpha1, alpha2, and H1 receptors |
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Term
metabolism of risperidone
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Definition
stereoselective metabolism
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Term
properties of palperidone
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Definition
extended release tablets - delivered at a constant rate using an osmotic drug release device
metabolized by dealkylation, hydroxylation, dehydrogenation, and scission of the benzoxazole ring
available as a racemic mixture; both isomers are active |
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Term
properties of iloperidone
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Definition
atypical anti-psychotic
high affinity for 5HT-2A and alpha1
protein binding: 98% |
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Term
metabolism of iloperidone
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Definition
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Term
properties of ziprasidone
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Definition
99% bound to plasma proteins (not displaced by warfarin and propranolol)
low incidnece of sedation, EPS, and postural hpotension
inhibits synaptic uptake of serotonin and NE (potential use as an anxiolytic and an antidepressant) |
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Term
| metabolism of ziprasidone |
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Definition
[image]
extensively metabolized
two major pathways:
oxidation by CYP3A4
reduction by aldehyde oxidase
4 major circulating metabolites (boxed) - inactive |
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Term
properties of aripiprazole
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Definition
low incidence of EPS, occupies 95% of striatal D2 receptors
effects at other monamine receptors
ADRs: headache, anxiety, and insomnia
different pharmacological profile from all other atypical anti-psychotics:
partial agonist activity at 5HT-1A receptor and antagonist action at 5HT-2A receptors
partial agonist at D2 receptors
dehydroaripiprazole, similar pharmacologic properties |
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Term
metabolism of aripiprazole
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Definition
extensively metabolized CYP2D6 and CYP3A4
the primary metabolite is dehydroaripiprazole (active)
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Term
properties of asenapine
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Definition
atypical anti-psychotic
no affinity for D2 receptors |
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Term
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Definition
lithium
NMDA antagonists
neuropeptides: corticotropin-releasing hormone, substance P, vasopresin, galanin, melanocyte-inhibiting factor |
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Term
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Definition
monovalent cation (Li+) that competes with:
Na
K
Ca
Mg
at intracellular binding sites, at sugar phosphatases, at protein surfaces, at carrier binding sites, at transport sites
effective in patients that do not respond to TCAs |
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