1. Antipsychotics are drugs used to treat psychoses, which is a disorder associate with loosely organized thoughts, bizarre and illogical behaviors, hallucinations (usually auditory) and delusions. Schizophrenia is associated with these characteristics (positive symptoms). Psychoses can be organic and related to drugs such as central anticholinergic agents, NMDA antagonist (PCP, phenyclidine) and dementia. Idiopathic psychoses possibly caused by stress. Drugs are used in psychotic patients to produce a calming effect thus some are classified as major tranquilizers. The ones the lessen response to emotional stimuli without altering consciousness are called neuroleptics. Typical antipsychotic blocks the dopamine at mesolimbic D 2 and D 3 receptors. Atypical antipsychotic blocks the dopamine at mesolimbic D 2 and D 3 receptors in addition 5-HT 2A Antipsychotics

2. Amphetamine and lysergic acid diethylamide (LSD) used in animal models to produce schizophrenia. Central anticholinergic produce schizophrenia by blocking M 1 or M 3. Phenyclidine (PCP) induce psychosis a CNS stimulation (Dissociative Agents) Drugs that cause schizophrenia

3. Treatment for psychosis Phenothiazine SAR Substitution at the 2-position with electron withdrawing groups increase activity alone with unshared electron pair. Substitution at the 3-position can increase activity in comparison with unsubstituted but lesser of effect than substitution at 2-position. Three-carbon atom chain is essential for activity. Shortening or lengthening will decrease activity (pseudo ring formation). Branching  -position by methyl activity varies. Dextro isomers are more activity of chiral isomers. Alkyl groups larger than methyl cause a decrease activity.

4. Dimethyl amino require for optimal activity. The monomethyl amino has less activity. Activity can be enhanced by fusion the dimethyl groups to form a piperidine piperazines groups The substitutes are believed to for a pseudo ring with the protonated amino group (X-ray crystal structure). Align the p-hydroxyl of Dopamine with sulfur and aliphatic amine portions. Substitution at 1-position is believe interfere with the pseudo ring formation thus a decrease in activity. SAR continued

5. Important Notes for Antipsychotics Side effects associated with antipsychotics Extrapyramidal Side Effects (EPS): dystonia, motor restlessness Parkinson-like (rigidity and tremor), tardive dyskinesia (irreversible); alone with tachycardia, hypotension, hyperprolactinemia, gynecomastia. Atypical antipsychotics have less risk of producing EPS Atypical antipsychotics are effective in treating negative symptoms (social withdraw, apathy, speech deficit) Both cause increase risk of weight gain and diabetes but more so with atypical psychotics

6. Metabolism: Major metabolism is hydroxylation aromatic ring para to 10-nitrogen (not ring bearing EW) follow by conjugation with glucuronic acid. Dialkylamino Sparine (Promazine) It was introduce after 2-chloro substituted Thorazine. It is less activity than Thorazine. Thorazine (Chlorpromazine) It was the first phenothiazine used as antipsychotic. Uses include nausea and vomiting and hiccough alone psychoses. It has significant sedative and hypotensive properties. Contraindication with antidepressant and anesthetics as with other antipsychotics.

7. Vesprin (Triflupromazine hydrochloride) Greater activity per mg in comparison with Thorazine. Lower sedative and hypotensive side effects than Thorazine

8. Piperidine subgroup Mellaril (Thioridazine hydrochloride) High anticholinergic activity. Sedation and hypotension are its side effects. Pigmentary retinopathy Serentil (Mesoridazine Besylate) Metabolite of Mellaril Does not cause pigmentary retinopathy.

9. Piperazine Compazine (Prochlorperazine maleate) More activity per mg in comparison with Thorazine. Mainly use as antiemetic. Trilafon (Perphenazine) Use as antipsychotic and antiemetic. Ester (decanoate) IM Depot

10. Stelazine (Trifluperazine)Tindal (Acetophenazine) Ester (IM Depot) Torecan (Triethylperazine)

11. Prolixin (Fluphenazine HCl) Most potent on the mg basis Ester (IM Depot) Thioxanthene Navane (Thiothixene) Replacement of the nitrogen with a double bonded carbon. Z isomers is the most active. Modified Ethyl alcohol ester (Decanoate) (Flupenthixol)

12. Fluorobutyrophenones SAR AR 1 is a aromatic system (p-fluoro increase activity) X is carbonyl (highest activity) CHOH and CH aryl (good activity) When n=3 (highest activity) longer or shorter chain decrease activity Piperidine ring (highest activity) AR 2 is required attached at 4-position. Y group as hydroxyl can improve activity. Neurotoxic metabolite (pyridine quaternary salt form) Student tried to make meperidine meperidine

13. Toxicity of Haldol

14. Haldol (Haloperidol) Use as antipsychotic in the treatment schizophrenia, psychoses caused by brain damage and Tourette’s syndrome. Inapsine (Droperidol) Antipsychotic with antiemetic properities Used in combination Fentanyl preanesthetic (Innovar)

15. Risperdal (Risperidone) Atypical antipsychotic Hydroxyl active metabolite (*) Antipsychotic/antidepressant (Trazodone) Structure like Combination with Haldol for Parkinson 5HT 2A and D 2 antagonist Invega (Paliperidone) Approved Dec. 2006 Atypical antipsychotic

16. Daxopin (Loxapine succinate) Dibenzoxazepine Side effects similar to phenothiazines. Clozaril (Clozapine) Dibenzodiazepine Not potent antipsychotic on mg basis Agranulocytosis (clinical monitoring Weekly for 6 months) **Atypical psychotics**

17. Zyprexa (Olanzapine) Atypical antipsychotic Thienobenzodiazepine D 2 and strongly 5HT 2 receptor antagonist Loxitane (Loxapine) Typical antipsychotic Undergoes N-dealkylation to an active metabolite Use often as anti-depressant

18. Seroquel (Quetiapine) Dibenzothiazepine Binds to H 1 and  1 and  2 ; 5-HT 2A Receptors and low affinity D 2 receptors Asendin (Amoxapine) Use often as anti-depressant

19. Reglan (Metoclopramide) D 2 receptor antagonist Antiemetic (chemoreceptor trigger in brain stem) Prokinetic (GI emptying) Roxiam(S-Remoxipride) Benzamide Less EPS than Haldol Benzamide