2. Psychotropic drugs Liming Zhou ( 周黎明 ) Department of pharmacology

3. Classification Antipsychotic Drugs Antimanic drugs Antidepressants anxiolytics

4. Antipsychotic Drugs

5. Contents Overview Inreuduction of Schizophrenia Classification of antipsychotic drugs Chlorpromazine

6. Overview Antischizophrenic,neuroleptic drugs These agents are prescribed for treating schizophrenia or management of psychotic symptoms

7. Overview What is schizophrenia ? There appears to be a genetic component to schizophrenia. There is also evidence for changes in brain structure.

8. Schizophrenia schizophrenia Clinical Manifestations Characteristics-- perturbations affecting: language perception thinking volition Behavior social activity size of ventricles

9. Schizophrenia Syndrome overview: Typically begins in late adolescence Insidious onset. Poor outcome. Social withdrawal /perceptual distortions lead to chronic delusions （错觉） /hallucinations （幻觉）.

10. Schizophrenia Positive Symptoms: Conceptual disorganization Delusions Hallucinations

11. Schizophrenia Negative Symptoms: Anhedonia ( 快感缺乏 ) Decreased emotional expression Impaired concentration Diminished socialization

12. Classification of antipsychotic drugs Phenenothiazines （吩噻嗪类 ) (Chlorpromazine ) Thioxanthenes( 硫杂蒽类） (Tardan,flupenthixol) Butyrophenones （丁酰苯类） (Haloperidol) Atypicals )( 非典型药物） (Clozapine)

13. Chlorpromazine (wintermine ) Pharmaciolgical effects CNS effects 1.neuroleptic effect: hallucination and delusions （错觉） improvement

14. Mechanism of action Blockade dopaminergic neurotransmission -the limbic - nigrostriatal - hypothalamic system.

15. Dopamine Hypothesis : This idea was suggested by observation that drugs which reduced dopaminergic activity reduced acute symptoms/signs of psychoses. Symptoms notably Decreased --  agitation  anxiety  hallucinations

16. Four pathway of dopaminergic neurotransmission 1)Mesolimbic-mesocortical pathway (one most closely related to behavior ) 2)nigrostriatal pathway(it is involved in the coordination of voluntary movement) 3)tuberoinfundibular pathway (inhibits prolactin secreation) prolactin 4 ） medullary-periventricular pathway (the function is not clear,may be involved eating behavior)

17. Dopamin receptor: two type, five subtype - DA1 (D1-like receptor): D1,D5 - DA2 (D2-like receptor): D2,D3, D4

18. D2 like receptors (D2, D3, D4) Activate Gi   cAMP Block Ca++ channels Open K+ channels D2: putamen( 壳核）, olfactory tubercle （嗅结节） D3: frontal cortex, medulla, midbrain D4: ???

19. D2 receptor activation  motor activity  aggravates schizophrenia D2 receptor blockade  alleviation of schizophrenia

20. Neuroleptic effect: blocking DA2 Side effect (extra-pyramidal symptoms.): blocking DA2

21. Pharmalogical effects Antiemetic effect. - This is a results of blocking DA2 receptor. -In low doses, blocking DA2 receptor in chemoreceptor trigger zone(CTZ). -In high doses, chlorpromazine may directly depress the medulla vomiting center.

22. Pharmalogical effects Altering temperature-regulating mechanisms. in a cold climate it decrease temperature in body in a hot climate they can cause hyperthermia

23. Pharmalogical effects Sympathetic and parasympathetic nervous system effect: -Blocking α-adrenergic receptor  Orthostatic hypotension. -Blocking M-receptor. Blurred vision Constipation Dry mouth Decreased sweating

24. Pharmalogical effects Endocrine system effect Increasing the lactogenic hormone( 催乳 素 ).Increased levels of prolactin may lead to galactorrhea （溢乳 ). phenothiazines decrease FSH and ACTH. Decreasing release and secretion of pituitary growth hormone.

25. Prolactin FSH ACTH growth hormone.

26. Therapeutic uses  1. Psychotic disorders, all kind of schizophrenia.  2. Nausea and vomiting.(except carsickness).  3. Decrease the temperature.  4. Control of intractable hiccup （呃逆打 嗝 ).  5.Therapy gigantism( 巨人症 ).

27. untoward effects (1) Special side effect: Extrapyramidal symptoms A. Parkinsonian syndrome: the patients display rigidity( 僵化 )and tremor B. Acut dystonia: patients display facial grimacing ( 面部的歪扭,) torticollis( 斜颈 ) C.Akathisia ( 静坐不能 ) D. tardive dyskinesia ( 迟发性运动障碍）tardive dyskinesia

28. patient display sucking of the lips and other involuntary facial movement. (The dyskinesia may persist for after discontinuation of the therapy).

29. Untoward effects (2)General side effect: A. CNS depression B. M-receptor blocking: The symptom of M- receptor blocking C. Orthostatic hypotension

30. Untoward effects (3)Inducing psychosis by drug (4)seizure and epilepsy (5)allergic reaction (6)cardiovascular effect

31. Untoward effects (7)Endocrine disorder: Hyperprolactinemia--causes: For women: Amenorrhea(abnormal suppression or absence of menstrual flow), galactorrhea, infertility For men: impotence infertility,diminished libido For children: decreasing growth.

32. Drug interaction: 1)Increasing CNS inhibition with ethanol, sedative-hypnotics, morphine. 2)Inhibiting the of L-Dopa (agonist of the doparmin-receptor). 3)Increase the dose with phentoin and carbamazepine.

33. Atypical antipsychotic drugs Clozapine and Risperidone selectively inhibit D4 and 5-HT 2 -receptors. Risperidone selectively inhibit D2 and 5-HT 2 - receptors. Sulpiride selectively inhibit D2-receptors in the mesolimbic and mesocortical areas of the brain. Sulpiride,Clozapine and risperidone have low risk of extra-pyramidal adverse reaction.

34. Atypical antipsychotic drugs Sulpiride Selectively inhibit D2-receptors in the mesolimbic and mesocortical areas of the brain. Producing low extra-pyramidal adverse reaction.

35. Antimanic drug Lithium carbonate

36. Pharmacodynamics Possible mechanisms of action: -effects on electrolyte/ion transport neurotransmitter -neurotransmitter release modulation influence on second messengers. Lithium salts how to affect second messengers?(learning by yourself)

37. Antidepressants Overview Classification TCA Antidepressants

38. Overview Depression is an alteration of mood characterized by sadness, worry, and anxiety. The patient may suffer from losses of weight, libido, and enthusiasm.

39. Depression Clinical depression is a syndrome that may include: Sustained mood disturbances Impaired memory and concentration Disturbed sleep Reduced energy level Reduced libido Impaired sleep.

40. Depression Patient complaints suggestive of depression may include: Pain (headaches, body aches) A mood of apathy, anxiety, or irritability Sexual complaints low energy, excessive tiredness reduced capacity for enjoyment.

41. Classification of Antidepressant Drugs Five of antidepressant Tricyclic antidepressants (TCA) Monoamine oxidase inhibitors (MAO) NA reuptake inhibitors Serotonin-specific reuptake inhibitors (SSRIs) Serotonin and NA-specific reuptake inhibitors

42. Most antidepressants are believed to improve by increasing NT Catecholamine 5-HT stores

43. Tricyclic antidepressant TCAs Imipramine

44. Pharmalogic effects CNS -In the depressed patients, an elevation of mood occur 2-3 weeks after administration begins, the latency period can be as long as 4 weeks. -The imipramine blocks the re-uptake of serotonin and NA

45. Pharmalogic effects Autonomic nervous system Blocking m-receptor

46. Pharmalogic effects Cardovascular effect: Hypotensin (blocking α receptor) Tachycardia

47. Mechanism of TCA: Blocking re-uptake of neurotransmitter Norepinephrine(NA) Serotonin(5-HT)

50. Clinic use 1)Therapy depression 2)Therapy enuresis 3)Therapy anxiety and phobic- anxiety syndromes 4)Obsessive-compulsive neurosis companied by depression

51. Untoward effects 1)anticholinergic effect 2)cardiac arrhythmas 3)manic excitement can occur in patient with bipolar manic-deprssive illness

52. Untoward effects 4)The combination of a MAO inhibtor with tricyclic antipressants should not be avoided,since hyperpyrexia, convulsions and coma can result

53. Selective serotonin reuptake inhibitors A.Fluoxrtine B.Paroxrtine

54. Home work Suggested further readings Rojas-Corrales,MO.and Mico JA. Antipressant-like effects of tramadol and other central analgesics with activity on monoamines reuptake, inhelpless rats.life science.2002,72(2):143- 152

55. 1.How are agents in this chapter classified? 2.Describe the pharmacological effects of Chlorpromazine. What are the major differences between the TCA and SSRIs?