MedChem of Antipsychotics

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MedChem of Antipsychotics

Long-acting injectable antipsychotics

Olanzapine Pamoate: -insoluble salt that dissolves slowly after IM inj, thus its PK are an absorption-rate rather than elimination-rate controlled process -long-acting inj versions of risperidone and aripip are available that employ formulation approaches for engineering extended release of drug

-Pro-drugs: hydroxyl containing antipsychotics can be esterified w/ saturated fatty acids, which upon IM injection depot in tissue and are slowly cleaved by esterase to release parent drug over time -aripip lauroxil uses a methylene oxygen spacer to join the C12 fatty acid to the parent drug

Drugs: -fluphenazine -haloperidol -paliperidol

Aryl Piperazine antipsychotics

Apiprazole

-potential for DDI w/ inhibitors/inducers -modest elevation in plasma lvls in presence of CYP3A4 inhibitor/CYP2D6 inhibitor -Plasma lvls dec in presence carbamazepine

-Aryl piperazine -> 5HT antagonists, D2 partial agonist --> risk of EPS/hyperprolactinemia LOW -Brex --> higher affinity for D2/5HT -Cariprazine is a D3 preferring compound (6x) -these drugs lack anticholinergic activity + SE -weight gain minimal with aripiprazole

Drugs: -Aripiprazole -Brexipiprazole -Cariprazine

-Resperidone is oxidized by CYP2D6 or CYP3A4 to paliperidone --> excreted unchanged through renal elimination -CYP3A4/CYP2D6 mediated N-dealkylation is also observed -Aldehyde oxidase (AO) is the major metabolic path for zipra

SAR

-all have higher affinity for 5HT (except lurasidone) -EPS/hyperprolactinemia reduced -lack anticholinergic activity + assoc. SE -weight gain w/ ziprasidone and lurasidone is minimal -risk for orthostatic hypoTN is greatest with risperidone/iloperidone -Lura was designed w/ selectivity a1 adrenergic r in mind and has more than 100x preference for D2/5HT

Lura was so happy she could zip her pants because she didn't gain any extra holiday weight

Lurasidone + Ziprasidone => minimal weight gain

Lura felt light and Airy when she could Zip her pants and realizing she didn't gain weight

Lurasidone, Ziprasidone, Aripiprazole => minimal weight gain

Quetiapine

-formation of the major quetiapine metabolite are catalyzed by CYP3A4 -norquetiapine is an active metabolite -1st pass metabolism is extensive

Loxapine

-7-hydroxyloxapine metabolite has higher D2 affinity than loxapine --> contributes more atypical antipsychotic profile -N-demethylation generates the antidepressant amoxapine -Amox has affinity for SERT/NET -Amox treats depression, psychotic depression, and depression accompanied by anxiety or agitation

Clozapine/Olanzapine metabolism

-CYP1A2 = major enzyme responsible for metabolism of these drugs + potential DDI should be considered -caffeine consumption = inc EPS in pts taking clozapine -cig smoking decreases both cloz/olanz serum lvls

SAR:

-higher affinity for 5HT (except quetiapine) -EPS/Hyperprolactinemia SE are substantially reduced relative to 1st gen (except loxapine) -weight gain w/ clozapine/olanzapine is a major challenge + these drugs carry highest risk of new onset diabetes -Lybalvi is a combo of olanzapine/samidorphan that has reduced weight gain relative to olanzapine alone -Clozapine carries the most SE risk (sedation/orthostatic hypoTN/anticholinergic effects) + dose-dep seizure risk and agranulocytosis

Treatment of tardive dyskinesias

Deutetrabenazine

-derivative of DHTBZ -six deuterium atoms function as bioisosteres of the hydrogen atom + slow the rate of metabolism -1st example of deuterated drug to receive FDA approval -protium version of drug is known as tetrabenazine, a drug used in the treatment of chorea associated with Huntington's disease -reduce dose w/ strong CYP2D6 inhibitors or poor 2D6 metabolizers

Valbenazine

-prodrug --> forms active metabolite DHTBZ via hydrolysis of the L-valine in valbenazine -Val/DHBTZ inhibit vesicular monoamine transporter --> CI w/ MAOIs -Val is also metabolized by CYP3A4 --> dose red advised if using strong CYP3A4 inhibitors and NOT recommended to use w/ strong inducers

Lumateperone

-potent 5-HT antagonist w/ 60x higher affinity for 5HT than D2 --> atypical antipsychotic profile -reduced risk for EPS/hyperprolactinemia relative to Halo -favorable safety w/ weight gain and metabolic function

Metabolism: -Halo --> CYP3A4 -HPTP metabolite leads to a neurotoxic metabolite HPP+ that may be implicated in severe/irreversible dyskinesias seen w/ halo therapy

SAR: -EPS/hyperprolactinemia are prominent SE w/ Haloperidol -Sedation, weight gain, orthostatic hypotension, anticholinergic SE are less severe w/ Halo vs. phenothiazine chlorpromazine

-tertiary amine attached to 4th carbon of butyrophenone skeleton is essential for antipsychotic activity -lengthening, shortening, branching of the n-propyl group --> dec antipsychotic act. -replacement of the ketone functional group w/ a 2nd 4-fluorophenyl group is tolerated + inc DOA

-trace roots to an early class of antihistamine compounds

Metabolism

-Oxidative N-dealkylation is a common meta pathway w/ many CNS drugs -least sterically hindered carbon attached to the nitrogen atom will be hydroxylated by CYP450 -N-dealkylated metabolite is an active metabolite -extensively meta by P450 in liver -major diff for thiothixene metabolism relative to the phenothiazines is lack of ring-hydroxylated products

Chlorpromazine vs. thiothixene

-drugs have equal or > affinity for D2 r vs. 5HT r --> sig EPS/hyperprolactinemia side effects -sedation, orthostatic hypoTN, anticholinergic side effects are more severe with chlorpromazine/thioridazine -piperazine-containing analogs have reduced affinity for H/M/a1A

Major Structural Classes of Antipsychotics

Benzisoxazole-like

Drugs: -risperidone -paliperidone -ziprasidone -iloperi -lurasi -apiprazole -brexipiprazole -cariprazine

Benzazepine-like

Drugs: -loxapine -clozapine -olanzapine -quetiapine -asenapine

Butyrophenone-like

Drugs: -Haloperidol -pimozide -lumateperone

Phenothiazine-like

Drugs: -Chlorpromazine -Fluphenazine -perphenazine -thioridazine -trifluoperazine -thiothixene

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