2. CHAPTER 20 ANTIPSYCHIATRIC DRUGS CHAPTER 20 ANTIPSYCHIATRIC DRUGS

3. Psychotic Disorders Psychotic Disorders 1.Schizophrenia (thinking disorder) 2.Mania (mood disorder) 3.Depression (mood disorder) 4.Anxiety

4. Antipsychiatric Drugs Antipsychiatric Drugs 1.Antipsychotic drugs 2.Antimanic drugs 3.Antidepressive drugs 4.Antianxiety drugs

5. Section 1 Antipsychotic Drugs Section 1 Antipsychotic Drugs

6. Schizophrenia Schizophrenia Personality change and behavior disorders with environment Personality change and behavior disorders with environment Positive symptoms: thinking disorder, cognition disturbance, hallucination, paranoia, delusion( 妄想） paranoia, delusion( 妄想） Negative symptoms: disturbance of feeling, discommunication

7. Natures of Schizophrenia Natures of Schizophrenia Dopamine theory of schizophrenia pathogenesis Dopamine theory of schizophrenia pathogenesis overactivity of the meso-limbic dopaminergic neurons overactivity of the meso-limbic dopaminergic neurons

8. Natures of Schizophrenia Natures of Schizophrenia  ： promote DA release and induce Schizophrenia.  raphetamine ： promote DA release and induce Schizophrenia.  decrease synthesis and storage of DA can improve the condition  DA-R increase in putamen and nucleus accumbens septi

9. Antischizophrenic Agents Antischizophrenic Agents Phenothiazines （吩噻嗪类） Phenothiazines （吩噻嗪类） Thioxanthenes ( 硫杂蒽类） Thioxanthenes ( 硫杂蒽类） Butyrophenones ( 丁酰苯类） Butyrophenones ( 丁酰苯类） Others Others

10. The Main Pathways of DA and Functions in Brain The Main Pathways of DA and Functions in Brain 1.Nigra-striatum （黑质 - 纹状体） DA system 1.Nigra-striatum （黑质 - 纹状体） DA system From A 9 of meso-nigrosubstantia From A 9 of meso-nigrosubstantia to caudate nucleus, putamen. to caudate nucleus, putamen. Extrapyramidal function Extrapyramidal function （ regulation of movement ） （ regulation of movement ） Decrease - PD Decrease - PD Augmentation - Chorea （舞蹈症） Augmentation - Chorea （舞蹈症） (irregular,involuntary mucle jerks and impair voluntary activity) (irregular,involuntary mucle jerks and impair voluntary activity)

11. The Main Pathways of DA and Functions in Brain The Main Pathways of DA and Functions in Brain 2. Meso-limbic （中脑 - 边缘叶） DA system the center of emotion and feeling the center of emotion and feeling

12. The Main Pathways of DA and Functions in Brain The Main Pathways of DA and Functions in Brain 3. Meso-cortical （中脑皮层） DA system Cognition, thinking and consciousness Cognition, thinking and consciousness System 2 and 3 augmentation System 2 and 3 augmentation -schizophrenia -schizophrenia 4.Tubero-infundibular ( 结节 - 漏斗 ) DA system Regulate pituitary hormone release Regulate pituitary hormone release

13. The Main Pathways of DA and Functions in Brain The Main Pathways of DA and Functions in Brain 5.Area postrema of medulla DAergic system: DAergic system: Central vomitting Central vomitting (chemoreceptor trigger zone,CTZ) (chemoreceptor trigger zone,CTZ)

14. The Subtypes of DA Receptor The Subtypes of DA Receptor In the early, DA receptors are classified to four subtypes: D 1-4 In the early, DA receptors are classified to four subtypes: D 1-4 According to protein structure, transmembrane signaling mechanisms, effect properties and sites of receptors, DA receptor classified to D 1 and D 2 subtypes. According to protein structure, transmembrane signaling mechanisms, effect properties and sites of receptors, DA receptor classified to D 1 and D 2 subtypes.

15. The Subtypes of DA Receptor The Subtypes of DA Receptor D 1 is G S coupling receptor ，  AC ， cAMP  in brain. D 1 is G S coupling receptor ，  AC ， cAMP  in brain. D 2 is G i coupling receptor ，  AC ， cAMP  in brain. D 2 is G i coupling receptor ，  AC ， cAMP  in brain.

16. The Subtypes of DA Receptor The Subtypes of DA Receptor 分子克隆技术证实脑内存在 D 1 ， D 2 ， D 3 ， D 4 ， D 5 亚型受体。 分子克隆技术证实脑内存在 D 1 ， D 2 ， D 3 ， D 4 ， D 5 亚型受体。 D 1 -like receptors ： D 1 和 D 5 的分子同源 性超过 80% ，与 G S 偶联，药理学特性符 合 D 1 。 D 1 -like receptors ： D 1 和 D 5 的分子同源 性超过 80% ，与 G S 偶联，药理学特性符 合 D 1 。 D 2 -like receptors ： D 2 、 D 3 、 D 4 同源性 45% ，与 G i 偶联，药理学特性符合 D 2 。 D 2 -like receptors ： D 2 、 D 3 、 D 4 同源性 45% ，与 G i 偶联，药理学特性符合 D 2 。

17. The Subtypes of DA Receptor The Subtypes of DA Receptor Migro-striatal system ： D 1 -like receptors (D 1,D 5 ) and D 2 -like receptors(D 2 、 D 3 、 D 4 ). Migro-striatal system ： D 1 -like receptors (D 1,D 5 ) and D 2 -like receptors(D 2 、 D 3 、 D 4 ). Meso-cortical and mesolimbic system D 2 -like receptors(D 2 、 D 3 、 D 4 ). Meso-cortical and mesolimbic system D 2 -like receptors(D 2 、 D 3 、 D 4 ). Tubero-infundibular system: D 2. Tubero-infundibular system: D 2.

18. Mechanisms of Antipsychotic Drugs Mechanisms of Antipsychotic Drugs 1.Block Meso-limbic and Meso- cortical DA receptor 2.Block 5-HT receptor

19. Phenothiazines （吩噻嗪类） Phenothiazines （吩噻嗪类） Dimethylamine derivatives Dimethylamine derivatives 二甲胺类 二甲胺类 Piperazine derivatives Piperazine derivatives 哌嗪类 哌嗪类 Piperidine derivatives Piperidine derivatives 哌啶类 哌啶类

20. Chlorpromazine( 氯丙嗪 ) （ Wintermine, 冬眠灵） Chlorpromazine( 氯丙嗪 ) （ Wintermine, 冬眠灵） History History Originally developed as an antihypertensive agent. Originally developed as an antihypertensive agent. In 1952 chlorpromazine was used to In 1952 chlorpromazine was used to treat schizophrenia in France treat schizophrenia in France

21. Chlorpromazine( 氯丙嗪 ) （ Wintermine, 冬眠灵） Chlorpromazine( 氯丙嗪 ) （ Wintermine, 冬眠灵） 1.Blocks D 2 receptor in the mesolimbic and Meso- cortical and Meso- cortical 2. Block α-R 3. Block M-R

22. Pharmacological Actions Pharmacological Actions 1. Effets on CNS (1) Behavioral and psychological effects a. for animals: docile and friendly. a. for animals: docile and friendly. b. for normal person: sedation, induce b. for normal person: sedation, induce to sleep. to sleep.

23. Pharmacological Actions Pharmacological Actions c. for schizophrenia patients: c. for schizophrenia patients: Antipsychotic effect (neuroleptic effect): Antipsychotic effect (neuroleptic effect): 6 wks - 6 ms to Emax. 6 wks - 6 ms to Emax. Mechanism: Block D2 receptor in the mesolimbic and meso-cortical pathways of brain.

24. Chlorpromazine Chlorpromazine (2)Antiemetic action Blocks D2 receptor of CTZ on area postrema of medulla (IV ventricule) Large doses inhibit the vomiting center directly. Large doses inhibit the vomiting center directly.

25. Chlorpromazine Chlorpromazine (3) On temperature regulation inhibit temperature-regulating center in hypothalamus to poikilothermia inhibit temperature-regulating center in hypothalamus to poikilothermia a. The temperature changed dependent with environment temperature. a. The temperature changed dependent with environment temperature. cold environment,T (hypothermia) cold environment,T (hypothermia) hot environment, T (hyperthermia) hot environment, T (hyperthermia)

26. Chlorpromazine Chlorpromazine (4) Potentiate the effects of CNS depressants sedation and synergism with other CNS depressants ( analgesics,sedative-hypnotics, anesthetics) sedation and synergism with other CNS depressants ( analgesics,sedative-hypnotics, anesthetics)

27. Chlorpromazine Chlorpromazine (5)On extrapyramidal system Block DA receptors on Nigra- striatal DA system

28. Pharmacological Actions Pharmacological Actions 2. Autonomic nervous system (1) Block α-R result in orthostatic hypotension. (2) Block M-R induce atropine-like effects.

29. Pharmacological Actions Pharmacological Actions 3. Endocrine system Tuberoinfundibular DA pathway blockade. Tuberoinfundibular DA pathway blockade. a. ↓prolactin release-inhibiting factor. b. ↓corticotropin and growth hormone.

30. Pharmacological Actions Pharmacological Actions 3. Endocrine system c. ↓luteinizing hormone-releasing factor. d.↓follicl-stimulating hormone-releasing factor

31. Pharmacokinetics Pharmacokinetics 1. Absorption slow and unpredictable slow and unpredictable after oral administration after oral administration 2. Distribution PPBR >90% PPBR >90% 3. lipid solubility plays a major role

32. Clinical Uses Clinical Uses 1. Schizophrenia mania, paraniod states, schizophrenia and psychoses with chronic alcoholism. mania, paraniod states, schizophrenia and psychoses with chronic alcoholism. 2.Vomiting and intractable hiccups 3. Artificial hibernation Lyticcocktail (chlorpromazine plus dolantin plus promethazine) Lyticcocktail (chlorpromazine plus dolantin plus promethazine)

33. Adverse Reactions Adverse Reactions 1. Common adverse reactions Excessive sedation Excessive sedation M block effects M block effects

34. Adverse Reactions Adverse Reactions 2. Extrapyramidal reactions (1) Parkinson’s syndrome (1) Parkinson’s syndrome (2) Akathisia (2) Akathisia (3) Acute dystonia (3) Acute dystonia facial grimacing and torticollis facial grimacing and torticollis block DA receptors in the nigrostriatum block DA receptors in the nigrostriatum artane artane

35. Adverse Reactions Adverse Reactions (4) Tardive dyskinesia sucking and macking of the lips and other involuntary facial movements. sucking and macking of the lips and other involuntary facial movements. 3. Psychotic Disorders

36. Adverse Reactions Adverse Reactions 4.Convulsion and epilepsy 5. Allergic reactions 6.Cardiovascular and Endocrine system 7.Acute intoxation

37. Contraindictions Contraindictions 1.Epilepsy and Convulsion 2.Glaucoma 3.Cyclomastopathy and breast carcinoma 4. Coronary heart disease

38. 吩噻嗪类抗精神病作用比较 药物 抗精神病 副作用 药物 抗精神病 副作用 剂量（ mg/d) 镇静 锥体外作用 降压作用 剂量（ mg/d) 镇静 锥体外作用 降压作用 氯丙嗪 300-800 ++ ++ +++(iv) ++(po) ++(po) 氟奋乃静 1-20 + +++ + 三氟拉嗪 6-20 + +++ + 奋乃静 8-32 ++ +++ + 硫利达嗪 200-600 +++ + +

39. Thioxanthenes ( 硫杂蒽类 ) Thioxanthenes ( 硫杂蒽类 ) Chloprothixene Chloprothixene ( 氯普噻吨， tardan, 泰尔登 ) ( 氯普噻吨， tardan, 泰尔登 ) 1. Stronger sedative action. 1. Stronger sedative action. 2. Weak anti-depressant effect. 2. Weak anti-depressant effect.

40. Butyrophenones ( 丁酰苯类 ) Butyrophenones ( 丁酰苯类 ) Haloperidol ( 氟哌啶醇 ) 1. More effects in antipsychotic, to treat the schizophrenia and the mania. 2. The extrapyramidal reaction is very severe. very severe. 3. Strong antiemetic activity.

41. Clozapine ( 氯氮平 ) Other Antipsychotic Drugs Clozapine ( 氯氮平 ) It is an atypical antipsychotic agent. It is an atypical antipsychotic agent. 1. Low affinity for D 2, high affinity for D 4 and 5-HT 2A. 1. Low affinity for D 2, high affinity for D 4 and 5-HT 2A. 2. More effective for positive and negative symptoms of schizophrenia 2. More effective for positive and negative symptoms of schizophrenia

42. Clozapine Clozapine 3. Onset rapidly: a week 4. Lacking in extrapyramidal adverse effects 5. Major adverse effect is agranulocytosis ( 粒细胞缺乏）

43. Sulpiride Sulpiride 1. Stronger antipsychotic and antiemetic activity. antiemetic activity. 2. Having antidepressant efficacy. 3. The extrapyramidal reaction is slight. slight.

44. Risperidone （利培酮） Risperidone （利培酮） 1. Effective against negative as well as positive symptoms 2. Improve the cognition disturbance 3. Few adverse reactions

45. New Theory of Psychosis New Theory of Psychosis D 1 function↓, D 2 function↑ D 1 function↓, D 2 function↑ New drugs(by Jin Guo-zhang) New drugs(by Jin Guo-zhang) l-stepholidine l-stepholidine (l-SPD, 左旋千金藤啶碱） (l-SPD, 左旋千金藤啶碱） Stimuli D 1, block D 2 Stimuli D 1, block D 2

46. Section 2 Antimanic Drugs Section 2 Antimanic Drugs Manic-depressive disorder (bipolar affective), emotional disorders Manic-depressive disorder (bipolar affective), emotional disorders Biochemical bases: amine theory Biochemical bases: amine theory Mania 5-HT↓ NE↑ Mania 5-HT↓ NE↑ Depression 5-HT↓ NE↓ Depression 5-HT↓ NE↓

47. Lithium carbonate ( 碳酸锂 ) Lithium carbonate ( 碳酸锂 ) “Mood-stabilizing” agent “Mood-stabilizing” agent 1. Effects on neurotransmitters and their release. ↓NE and DA release from synapse in the brain, ↑those reuptake. ↓NE and DA release from synapse in the brain, ↑those reuptake.

48. Lithium carbonate( 碳酸锂 ) 2.Effects on second messengers that 2.Effects on second messengers that mediate transmitter action mediate transmitter action a.inhibits the transformation of inositol monophosphate (IP) to PIP 2, leads to a reduction of PIP 2, then IP 3 and DAG decrease. a.inhibits the transformation of inositol monophosphate (IP) to PIP 2, leads to a reduction of PIP 2, then IP 3 and DAG decrease. b. inhibits AC b. inhibits AC

49. Lithium Carbonate Lithium Carbonate Clinical Uses Clinical Uses 1. mania 1. mania 2. manic-depressive psychosis 2. manic-depressive psychosis

50. Lithium Carbonate Lithium Carbonate Adverse reactions Adverse reactions Lithium toxicity due to overdose: nausea, vomit, abdominal pain, profuse diarrhea, and ataxia Lithium toxicity due to overdose: nausea, vomit, abdominal pain, profuse diarrhea, and ataxia more severe: mental confussion, hyper-reflexia, tremor, convulsion more severe: mental confussion, hyper-reflexia, tremor, convulsion

51. Lithium Carbonate Lithium Carbonate Intoxication can be usually be reversed by osmotic diuresis or in more cases by dislysis. Intoxication can be usually be reversed by osmotic diuresis or in more cases by dislysis. Use Nacl by intravenous to treat Use Nacl by intravenous to treat Serum concentration is carefully maintainted between 0.8 and 1.5mmol/L. Serum concentration is carefully maintainted between 0.8 and 1.5mmol/L.

52. Section 3 Antidepressant Agents Section 3 Antidepressant Agents 1.Tricyclic agents Non-selective monoamine reuptake inhibitors Imipramine( 丙米嗪, 米帕明 ) Doxepin( 多塞平 )

53. Antidepressant Agents Antidepressant Agents 2. Norepinepherine reuptake inhibitors Desipramine( 地昔帕明 ) 3. 5 –HT reuptake inhibitors Fluoxetine( 氟西汀 ) 4.Others

54. Imipramine ( 丙米嗪, 米帕明 ) Imipramine ( 丙米嗪, 米帕明 ) Pharmacological effects and mechanism Pharmacological effects and mechanism 1. CNS effects 1. CNS effects Elevating the mood that is depressed. Elevating the mood that is depressed. It blocks the reuptake of NE or 5-HT. It blocks the reuptake of NE or 5-HT. onset is slow and requires 2~3w.The latency period can be as long as 4w. onset is slow and requires 2~3w.The latency period can be as long as 4w.

55. Imipramine Imipramine 2. Autonomic nervous system Anticholinergic activity Anticholinergic activity 3. Cardiovascular system Tachycardia, arrhythmias, Tachycardia, arrhythmias, orthostatic hypotension orthostatic hypotension quinidine-like action quinidine-like action

56. Imipramine Imipramine Clinical Uses 1. Depression 2. Enuresis （遗尿） 3. Anxiety and phobia （恐怖症） Adverse reactions 1. Atropine-like action 1. Atropine-like action 2. Cardiovascular reaction 2. Cardiovascular reaction

57. New developed antidepressants Maprotiline( 马普替林 ) Maprotiline( 马普替林 ) A “tetracyclic drug; ” reduce reuptake of NA A “tetracyclic drug; ” reduce reuptake of NA

58. New developed antidepressants New developed antidepressants Fluoxetine( 氟西汀 ) Fluoxetine( 氟西汀 ) Selectively inhibits reuptake Selectively inhibits reuptake of 5-HT of 5-HT Less adverse reactions Less adverse reactions