FINALS PMOC Antipsychotic

Reserpine and chlorpromazine

first drugs found to be useful to reduce symptoms of schizophrenia

Psychosis

denotes a variety of mental disorders

SCHIZOPHRENIА

Characterized by clear sensorium but a marked thinking disturbance.

Excess dopamine in mesolimbic system (involved in emotions)

POSITIVE SCHIZOPHRENIА

NOT present in the NORMAL individual but are added to the schizophrenic person

POSITIVE SCHIZOPHRENIА

DELUSIONS (False beliefs) HALLUCINATIONS (Perceptional distortion

NEGATIVE SCHIZOPHRENIА

PRESENT in NORMAL person but MISSING in the schizophrenic individual

NEGATIVE SCHIZOPHRENIА

Flat affect

Alogia

Avolition

Asociality

Anhedonia

TYPICAL NEUROLEPTICS

Blockade of dopamine 2 receptors in the CNS especially in mesolimbic system

Chlorpromazine, Haloperidol

TYPICAL NEUROLEPTICS examples

ATYPICAL NEUROLEPTICS

Blockade of dopamine 2 and serotonin 2a receptors in the brain.

Clozapine, Olanzapine

ATYPICAL NEUROLEPTICS examples

Phenothiazine derivatives

Butyrophenones

Thioxanthenes

Diphenylbutylpiperidine

Pimozide

TYPICAL ANTIPSYCHOTICS

Loxapine - succinate

Dibenzoxazepines

Clozapine

Dibenzodiazepines

Olanzapine

THIOBENZODIAZEPINE

Sertindole

FLUOROPHENYLINDOLE

MOLINDONE

beta - Aminoketone

Extrapyramidal symptoms (EPS)

-First-generation antipsychotics

- dystonia, parkinsonism, and akathisia

Weight gain

Drowsiness

NEUROLEPTICS Side effects:

SAR

Phenothiazine

Phenothiazine

a three carbon side chain =

Inc. potency

Increase D2 blocking effect

Modifications of alkyl side chain at R10:

nitrogen of phenothiazine and basic amino group is connected by:

Chlorpromazine (Thorazine®)

Chlorpromazine (Thorazine®)

First phenothiazine compound introduced

antihistaminic and sedative effect only

Modifications of alkyl side chain at R10:

the ring and side-chain nitrogens if separated by the two-carbon chain exhibits only

stable, highly lipophilic esters

fluphenazine and long-chain alcohols form

Promethazine

Ethopropazine

eplaced with piperidyl or Piperazine groups.

The activity is retained or increased if the amino group is

Piperidine

Piperazine

Introduction of hydroxyl, methyl, hydroxy ethyl groups of piperidine and Piperazine moieties

what would be added to increase the potency.

Phenothiazine ring substituents at R2:

substitution produces greatest antipsychotic property

Chlorpromazine

Promazine

triflupromazine

Propyl dialkyl side chain

Thioridazine

Mesoridazine

Alkyl piperidyl side chain

Prochlorperazine

Trifluoperazine

Perphenazine

Fluphenazine

Propyl piperazine side chain

Promazine (Sparine®)

2 Cl: ↓ antipsychotic

Promazine (Sparine®)

Triflupromazine (Vesprin®)

2 CF3: ↑ antipsychotic

Triflupromazine (Vesprin®)

Thioridazine (Mellaril)

Low EPS

High anticholinergic

At high doses, pigmentary retinopathy

Mesoridazine (Serentil)

No pigmentary retinopathy

Thioridazine (Mellaril)

Mesoridazine (Serentil)

Prochlorperazine (Compazine)

High EPS but low sedative and autonomics effects

Perphenazine (Trilafon)

Effective antipsychotic and anti-emetic

Prochlorperazine (Compazine)

Perphenazine (Trilafon)

Fluphenazine (Permitil)

2-CF3 • Most potent

Fluphenazine (Permitil)

Thioxanthenes

lacks the ring nitrogen of phenothiazines and have side chain attached to the double bond

Thioxanthenes

Chlorprothixene

Thiothexene

Clozapine (Clozaril®)

Effective against both positive and negative symptoms

Low EPS

agranulocytosis

Clozapine

Olanzapine (Zyprexa®)

Quetiapine (Seroquel®)

Quetiapine (Seroquel®)

Used in depression and bipolar

Off-label use: for patients with PTSD

LOXAPINE (Daxolin®)

EWG at pos 2 .

M: Aromatic hydroxylation

Metabolite; amoxapine (antidepressant)

LOXAPINE (Daxolin®)

Fluorobutyrophenones

Chemically unrelated to phenothizines but have similar activity

Fluorobutyrophenones

HALOPERIDOL (Haldol)

Chemically unrelated to phenothiazines but have similar activity

HIGH EPS

Most widely used antipsychotic

Used for intractable hiccups

Droperidol

Short acting, highly sedating

Droperidol + Fentanyl

InnovarⓇ

HALOPERIDOL

Droperidol

CH2CH2CH2 - important in its activity

3o amine - neuroleptic acitivity

Fluorobutyrophenones SAR

Risperidone (Risperdal)

Low risk of tardive dyskinesia

Decrease EPS

Risperidone (Risperdal)

Risperidone (Risperdal) parts