Part 8. Anti-psychiatric disorders ( 抗精神失常药 )

1. Part 8. Anti-psychiatric disorders (抗精神失常药)

2. Outline 1.Concept of mental disorders: Mental disorder =Psychiatric disorder (1)Morbidity (发病率)of mental disorder in our country: 16 million 1982: 12.67 ‰, 70’: 3.20 ‰, 1993: 13.47 ‰, 80’: 9.33 ‰, 2000: 15.56 ‰. 90’: 10.67 ‰, in Guangdong:16.36 ‰, in Beijing:34.34 ‰, in Shanghai:38.46 ‰. 2006/3/27: inZhejiang, 17.3 ‰.

3. (2)Etiology of mental disorder ▲ Genetic factor(遗传因素): monovular twins:61%~70%, binovular twins:10%~13%. ▲ Diathetic factor(素质因素): ▲ Social psychogenic factor (社会心理因素): ▲ Age and sex(年龄和性别)

4. (3)Classification of mental disorders(ICD-10, CCMD-2R) Schizophrenia√ (精神分裂症) Psychosis Mania√ (精神病) (燥狂症) Depression√ Mental (抑郁症) disordersAnxiety (焦虑症) Neurosis Hysteria (神经官能症) (癔症) Neurasthenia (神经衰弱)

5. Other mental disorders: 脑器质性精神障碍, 感染性精神障碍, 中毒性精神障碍, 心因性精神障碍, 老年期精神障碍, 儿童少年精神障碍, 酒与药物滥用相关精神障碍, 人格障碍, 精神发育迟缓, 等.

6. 2. Classification of drugs treated mental disorders: (1)Anti-schizophrenic drugs(抗精神分裂症药) =Anti-psychotic drugs(抗精神病药) (2)Anti-manic drugs(抗躁狂症) (3)Anti-depressant(抗抑郁症药) (4)Anti-anxiety drugs(抗焦虑症药)

7. Part 1. Anti-psychotic drugs: Ⅰ. Concept of Schizophrenia (精神分裂症) Ⅱ. Distribution ofD2 receptor in CNS Ⅲ. Specific drugs: Chlorpromazine(氯丙嗪) Chlorprothixene(氯普噻吨) Haloperidol(氟哌啶醇) Penfluridol(五氟利多) Sulpirine(舒必利) Clozapine(氯氮平)

8. Ⅰ. Concept of Schizophrenia: Schizophrenia (精神分裂症) is the most common kind of psychosis, more than 50% of psychosis. Schizophrenia frequently occurring in puberty (青春期), fall ill rarely after 40 years old. The causes of illness are not clear, probably owing to genetic factors and environmental factors together. Schizophrenia can be divided into 2 types: TypeⅠ and TypeⅡ. hallucination(幻觉), delusion(妄想)

9. Pathophysiology ofSchizophrenia: Functional disorder of CNSneurotransmitter andreceptors, especially CNStransmitterDopamineincreased. Experimental study showed that the symptoms of schizophrenia exacerbated when Dopamine in CNS increased, and the symptoms of schizophrenia abated when Dopaminein CNS decreased. There are 4 subtypes of dopamine receptor in CNS, they are D1, D2, D3, D4 receptor. The most effective anti-schizophrenia drugs are blocking agents of D2 receptor.

10. There are 4 neuralpathways of dopaminergic nerve in CNS: Ⅱ. Distribution ofD2 receptorin CNS (1)Meso-cortical pathway(中脑-皮质通路):与精神理智及行为活动有关; (2)Meso-limbic pathway(中脑-边缘系统通路):与情绪情感活动有关; (3)Nigro-striatal pathway(黑质-纹状体通路):与锥体外系的运动功能有关; (4)Tubero-infundibular pathway(结节-漏斗通路):与垂体内分泌功能有关.

11. In addition, D2 receptors distributedatthepostsynapticmembraneof: ①Chemoreceptor trigger zone(CTZ)of the medulla oblongata(延脑的催吐化学感受区); ②Heat-regulatingcenter of hypo-thalamus(下丘脑体温调节中枢)

12. The effects of anti-schizophrenia drugs blocking D2 receptorof some regions are therapeutic effect; The effects of anti-schizophrenia drugs blockingD2 receptorof other regions are adverse reaction, such as extrapyramidal symptoms(锥体外系症状).

13. Ⅲ. Specific drugs: Chlorpromazine(氯丙嗪,wintermin,冬眠灵) 1. Pharmacological effects : Effects ofChlorpromazine includeCNS effects&Peripheral effects. CNS effects:block D2 receptor of CNS, those effects are therapeutic effect or adverse reaction. Peripheral effects:block  receptorand M receptor of periphery, mainly cause adverse reaction.

14. (1)CNS effects: ①Anti-psychotic effects: Chlorpromazine block D2 receptor ofMeso-cortical pathway (中脑-皮质通路) and Meso-limbic pathway (中脑-边缘系统通路), to inhibit the mental activity of psychosis patients selectively. Therearemarkedlycurativeeffects in acute psychosis of unknown etiology, including acute idiopathic psychosis (特发性精神病) and acute exacerbations of schizophrenia (精神分裂急性发作). It is also effective to mania (躁狂症).

15. ②Anti-emetic effects(镇吐作用) to block D2 receptor of CTZ(催吐化学感受区) of the medulla oblongata (延髓), it can be used to treat emesis (呕吐). ③Affecting body heat regulation(影响体温调节作用) to block D2 receptor of heat-regulating center (体温调节中枢). This action is different to anti-pyretics (解热药).

16. ④Extra-pyramidal (锥体外系) effects Owing toblocking D2 receptor of Nigro-striatal pathway (黑质-纹状体通路). if taking chlorpromazine for long time, the functions of cholinergic nerve of CNS will be predominant: Extra-pyramidal symptoms: Parkinson’s syndrome(帕金森综合征) Acute myodystonia(急性肌张力不全) Akathisia(静坐不能) Tardive dyskinesia(迟发性运动障碍)

17. (2)Endocrine system Chlorpromazineblocking D2 receptor of tubero-infundibular pathway (结节-漏斗通路), to affect functions of hypothalamus (下丘脑) endocrine. ` —— Adverse reaction: menstrual (月经) disorder, feminization and lactation (女性化症状), exacerbation of breast cancer. —— Clinical use: to treat gigantism (巨人症), owing to reduce the secretion of pituitary (垂体) growth hormone.

18. (3)Automatic nervous system ①-receptor blockade: Vasodilatation, Blood pressure . Owing to tolerance, not be used to treat hypertension. Orthostatic hypotension(体位性低血压) ②M-receptor blockade: ADRs:dry in the mouth(口干), constipation(便秘), blurred vision(视力模糊), etc.

19. 2. Clinical uses: (1)to treat psychosis ★ Various typeschizophrenia (精神分裂).including acute and chronic patients, especially acute type. ★ Mania (躁狂). ★Other psychosis with exciting, tension and delusion. But Chlorpromazineis ineffective for depression (抑郁). The conditionofsome patients with depression will exacerbate after takingchlorpromazine.

20. (2)Emesis (呕吐) and intractable hiccough (顽固性呃逆) to treat various causative emesis, includingemesisresultofgastroenteritis, cancer, radiationdisease,uremia (尿毒症) and drug induced emesis. But, it is in-effective to emesis of car sickness and sea sickness. beside anti-emetic effect, also used to intractable hiccough(顽固性呃逆). Mechanism of anti-emetic effect: Small dose:blocking D2 receptor inCTZ of the medulla oblongata (延髓催吐化学感受区); Large dose:directlyinhibiting emetic center (呕吐中枢).

21. (3)Poikilothermic effects(变温作用) ★ Hypothermic anesthesia(低温麻醉) when anesthesia, injected Chlorpromazinewith physical cooling(ice bath), Body temperature  Hypothermic anesthesia(低温麻醉): ≤ 30℃. 15~20 min, Deep hypothermic anesthesia(深低温麻醉):≤ 18℃. 45~60 min, ★ Artificial hibernation(人工冬眠) Chlorpromazine(Wintermin, 冬眠灵) +Dolantin(度冷丁)+Phenergan(异丙嗪)

22. 3. Adverse reaction (1)Extra-pyramidal effects (锥体外系) Can be treated with central anti-cholinergic agents—— Artane(安坦),or Scopolamine(东莨菪碱),but can not be treated withL-dopa. (2)Allergy: Skin rash, dermatitis, leukopenia (白细胞减少), and obstructive jaundice (黄疸), etc. (3)Others:M and receptor blockade,andorthostatic hypotension (体位性低血压). Contraindication: Epilepsy (癫痫), glaucoma, cardiovascular disorders, severe hepatic damage, etc.

23. Chlorprothixene(氯普噻吨, Tardan, 泰尔登) Its anti-schizophrenic (精神分裂) effects is weaker, but with marked anti-depression and anti-anxiety (抗焦虑) effects. Clinical uses: used to schizophrenia with anxiety and anxiety-depression.

24. Haloperidol(氟哌啶醇) Its anti-schizophrenic effects and extra-pyramidal effects arestronger,and with stronger effects of anti-mania(抗躁狂), anti-hallucination(抗幻觉), and anti-delusion(抗妄想). Clinical uses: 1. To treat schizophrenia with exciting, hallucination and delusion, 2. To treat mania as well.

25. Penfluridol(五氟利多) longer-acting anti-psychoticeffects,by po. 1 time / 1 week. to treat chronic patients for long-term. Sulpirine(舒必利) ADR and extra-pyramidal effects are less, to treat acute and chronic schizophrenia for long-term, and effective to depression.

26. Clozapine(氯氮平) 1. Effects and characteristics: It is a new type of anti-psychotic drug, its anti-psychotic effect is high potency. It can not block D2 receptor, but can block D4 receptor. Its CNS anti-cholinergic effect is stronger, therefore, there is not extra-pyramidal effect almost. 2. Adverse reaction: WBC  (granulocytoponia)

27. Part 2. Anti-manic and anti-depressant drugs Mania(躁狂症): Depression(抑郁症): ——Affective psychosis(情感性精神病)

28. Pathophysiology ofMania andDepression: 5-HT (5 - 羟色胺) in the brainis the basis ofMania-depression, when 5-HT , NA :Mania when5-HT , NA :Depression

29. Ⅰ. Anti-manic drugs Antiepileptic drug——Carbamazepine (卡马西平), Antipsychotic drug——Chlorpromazine (氯丙嗪) andHaloperidol (氟哌啶醇), there are marked anti-manic effects. Let’sintroduce another anti-manic drug now: Lithium Carbonate(碳酸锂)

30. Lithium Carbonate(碳酸锂) 1. Pharmacological effects: therapeutic dose(1~2g/day, po)to normal subjects: no affection; to manic patients: marked curative effect. Mechanisms of anti-manic effects: inhibiting the release of NA and DA, promoting NA and DA reuptake,to decrease the concentration of the neurotransmitters in the synaptic cleft (突触间隙).

31. 2. Clinical uses: (1)Mania(躁狂症) (2)Manic-depressive psychosis(躁狂抑郁症) —— mood-stabilizing(情绪稳定药). (3)Manic symptomsofschizophrenia (有躁狂症状的精神分裂症). 3. Adverse reaction: GI reaction and CNS reaction

32. Relationship ofblood concentration (Cp) and drug reaction Cpdrug reaction 0.8~1.2mEq/L Therapeutic concentration 1.6~2.0mEq/L GI reaction, include: nausea, emesis, diarrhea, etc. ＞ 2.0 mEq / L CNS toxicity, include: hypermyotonia(肌张力增高), ataxia(共济失调), disturbance of consciousness(意识障碍), coma(昏迷). blood concentration monitoring, to control dosage.

33. Ⅱ. Antidepressants A.Tri-cyclic agents(TCAs,三环类药物): Imipamine (米帕明, 丙咪嗪) 1. Pharmacological effects: (1)CNS effects(Anti-depressant effects): to normal subjects: sleepiness, light headache, slight fall in blood pressure, and certain anti-cholinergic effects.

34. to depressed patients: It can elevate mood markedly, mental stimulation—— marked anti-depressive effect. The effect is different to CNS stimulants(such as caffeine), therefore, the mental stimulant effect of imipamine (米帕明) is selective.

35. (2)Cardiovascular effects: ①direct action: inhibiting heart, ——cardiac contractility , BP : ②indirect action: inhibiting NAreuptake of sympa-thetic nervous ending of heart,NA in synaptic cleft, activating 1 receptor of heart. ——ectopic cardiac rhythm and arrhythmia (心率失常). (3)M-cholinergic blockade ——Adverse reaction

36. Mechanisms of antidepressant effects: Experiments show thatTCAs (三环类药物) can block the reuptake of NA and 5-HT, to increase the concentration of NA and 5-HT in thesynaptic cleft (突触间隙), to promotethe transmission function of synapse, to exert anti-depressive effects.

37. 2. Clinical uses: (1)All depression The curative effects are well to endogenous(内源性), reactive, and involutional(更年期) depression. Depressive state of schizophrenia, the curative effect is bad. (2)Enuresis(遗尿症) (3)Anxiety and Phobia(恐惧症)

38. 3. Adverse reaction: (1)M-cholinergic blockade: Thirsty, constipation (便秘), blurred vision. (2)Cardiovascular effects: Hypotension, tachycardia (心动过速), arrhythmia. (3)Allergy. Other tricyclic drugs (三环类药物): Amitriptyline(阿米替林), Clomipramine (氯米帕明), Doxepin(多塞平, 多虑平), etc.

39. B. NA reuptake inhibitors (摄取抑制剂): The drugs of this kind can selectively inhibit NA reuptake, increase the concentration of NA in synaptic cleft of CNS. The curative effects of the drugs take place faster and ADRs are less. Such as Desipramine(地昔帕明), Maprotiline(马普替林), Nortriptyline (去甲替林), Protroptyline(普罗替林), Amoapine(阿莫沙平), etc.

40. C. 5-HT reuptake inhibitor: The drugs of this kind can selectively inhibit 5-HT reuptake, increase the concentration of 5-HT in synaptic cleft of CNS. Those drugs are effective to the patients whose 5-HT decreased in brain. Such as Fluoxetine(氟西汀), Paro-xetine(帕罗西汀), Sertraline(舍曲林), etc.

41. D. Other antidepressants There are many other anti-depressants mechanism, such as tryptophan (色氨酸), it is the pro-amino acid of 5-HT, can be used to treat some intractable(难治性的) depressant patients at abroad.

42. Part 9.Analgesics (镇痛药)

43. Outline ★ Classification ofanalgesics: 1. Opioid analgesics(阿片类镇痛药) (1)Opium alkaloids(阿片生物碱类) (2)Synthetic opioid analgesics(人工合成的阿片类镇痛药类) 2. Antipyretic, analgesic, and anti-inflammatory drugs(解热镇痛抗炎药)

44. Part 9. Analgesics Contents (A)Opium alkaloids: Morphine(吗啡), Codeine(可待因) (B)Synthetic opioid analgesics: Pethidine(哌替啶), etc. (C)Non-opioid analgesics: Rotundin(罗通定) (D)Antagonist of opium receptors: Naloxone(纳洛酮), etc.

45. Analgesics (A)Opium alkaloids: Opium alkaloids extracted from opium (阿片); Opium(阿片)came from poppy(罂粟).

47. Analgesics Opium as therapeutic drugs, it is called “阿片”; as dope(毒品),it is called “鸦片”, “大烟” 或 “烟土”. There are more than20 alkaloids in opium,the alkaloidsaccount for 25% ofopium. Morphine(吗啡)is 10% ofopium, Codeine(可待因)is 0.5% ofopium.

48. Opioid alkaloids Morphine(吗啡) Sertürner(German) extracted from opium in 1806. “Morphine” came fromGreece“morpheus” ––––Greekgodofdream (梦之神). Morphine(吗啡) Heroin(海洛因)

49. Morphine 1. Pharmacological effects: (1)CNS effects: ①Analgesia (镇痛) and sedation (镇静): (a)Analgesia: effective to various pain, including “sharp pain”(锐痛) and ‘‘Dull pain”(钝痛); (b)Sedation; (c)Improving mood: euphoria(欣快感).

50. Morphine Mechanisms of analgesic effects: Morphineand opioids canactivate opium receptor of different regions in CNS to effect analgesia. There are 4 subtypes of opium receptor in CNS at least:  receptor,与脊髓以上水平的镇痛, 以及缩瞳、呼 吸抑制、改善情绪、欣快感和精神依赖性有关;  receptor,与脊髓以上水平的镇痛, 缩瞳, 欣快感有关, 还与胃肠道平滑肌兴奋, 张力提高和活动减少有关;  receptor,与脊髓水平的镇痛有关, 并使病人烦躁不安;  receptor,与镇痛无关, 兴奋可引起幻觉, 焦虑和 烦躁不安.