Anti-psychotics

1. Anti-psychotics Dept. of Pharmaceutical Chemistry R.C.Patel Institute of Pharmaceutical Education and Research, Shirpur

3. Mental illnesses • Psychoses: (e.g., schizophrenia) most severe mental illness • Neuroses: An anxiety disorder • Mood: Depression (major and minor) • Schizophrenia: A long-term mental disorder whose symptoms include inappropriate actions and feelings and withdrawal from reality into fantasy. (splitting in mental functioning). • Neuroses: A mild mental illness involving symptoms such as depression, anxiety, or obsessive behavior. • Obsessive behavior: Thinking about someone or something continually and disturbingly. • Hallucination: To see something which is not actually present. • Delusions: A belief or impression that is not real. Psychoses, Neuroses, and Mood (depression, bipolar)

4. Antipsychotics Major tranquilizers Neuroleptic • Calming effect in agitated psychotic patients • They induce a lessening of reactivity to emotional stimuli, with little effect on conciousness

6. Anti-psychotics drugs are called as neuroleptic drugs

13. DA hypothesis for schizophrenia: rationale for drugtherapy (a) drugs that increase dopaminergic neurotransmission, such as levodopa (a DA precursor), amphetamines (a DA releaser), and apomorphine (a DA agonist), induce or exacerbate schizophrenia. (b) DA receptor density is increased in certain brain regions of untreated schizophrenics (c) many antipsychotic drugs strongly block postsynaptic D2 receptors in CNS (d) successful treatment of schizophrenic patients has been reported to change the amount of homovanillic acid (HVA), a DA metabolite, in the cerebrospinal fluid, plasma, and urine.

14. Binds- D1 & D2 Binds- D2

15. Some dopamine pathways in human brain

17. processes such as attention, the formation of knowledge, memoryandworking memory, judgment and evaluation, reasoning and "computation", problem solving and decision making, comprehension and production of language.

18. Negative symptons

19. Blocking of D2 in Nigrostriatal pathway causes tremors, muscle rigidity, dyskinesia  and Parkinsons like symptoms

21. Antipsychotics: Chemical Classification • Chlorpromazine (Propyl dialkylamino side chain) • Thioridazine (Alkyl piperidyl side chain) • Fluphenazine (Propyl piperazine side chain) Phenothiazines

22. Antipsychotics: Chemical Classification • Chlorprothixene • Loxapine • Clozapine • Haloperidol Thioxanthines Dibenzoxazepines Dibenzodiazepin Fluorobutyrophenones

23. Antipsychotics: Chemical Classification • Molindone • Sulpiride β- Aminoketones Benzamides (chlorpromazine*, triflupromazine, thioridazine, fluphenazine, chlorprothixene, loxapine, clozapine, haloperidol*,droperiodol, risperidone*, pimozide, molindone)

24. droperiodol,

25. Antipsychotics: Mechanism of action • Agents block dopamine at D-2 receptores, reducing euphoria and hyperactivity. • Agents blocks dopamine at D-2 receptors in mesolimbic area of the brain. • Many, but not all, of the agents are strongly anticholinergic. The drugs increase prolactin level by a block of dopamine receptors in the hypothalamus and have an atiemetic effect by a block of dopamine receptors in the chemoreceptor trigger zone. Manic disorders Schizophrenia Other action

26. Antipsychotics: Side effects • Extrapyramidal side effect: Includes Parkinsonism • Symptoms are acute dystonic reactions, characterized by spasm of tongue, face, and neck; and akethesia, characterized by a restlessness and a need to be in constant motion. • These effects are due to block of D-2 receptors in the striatum.

27. Phenothiazines: SAR General structure Important points • Substitution at 2-position (1,3 & 4) • cis form more active • Side chain • 3-carbon chain • Branching at side chain • Size of dimethylamino group

28. Substitution at Position 1,2,3 & 4 • Activity increases (with some exceptions) as electron-withdrawing ability of the substituent increases at position-2. • The presence of an unshared pair of electron pair on an atom or atoms of the 2- substituent, increase potency. • Substitution at the 3-position can improve activity over nonsubstituted compounds, but not as significantly as substitution at the 2-position. • Substitution at position-1 deleterious (harmful or damage) effect on antipsychotic activity, as to a lesser extent, does substitution at the 4-position.

29. Isomerism : cis form more active • The 2-chloro substitution imparts asymmetry to phenothiazine nucleus, cis-form is active. • From X-ray crystallography, proposed that the • Chlorine-substituted ring of chlorpromazine base could be superimposed on the aromatic ring of dopamine base with • The sulfur atom aligned with the p-hydroxyl of dopamine and • The aliphatic amino groups of the two compounds also aligned.