神经系统药理 5 一、 抗精神病药和抗抑郁药 二、麻醉药

1. 神经系统药理5 一、抗精神病药和抗抑郁药 二、麻醉药

2. 一、抗精神病药和抗抑郁药 • Antidepressant and antimanic drugs • 抗抑郁和抗躁狂药 • Anxiolytics / antianxietics • 抗焦虑药 • Antipsychotic drugs • 抗精神分裂药

3. Disorders of Mood Disorders of mood (affective disorders情感障碍) are extremely common in medical practice. The severity of these conditions covers an extraordinarily broad range, from normal grief(悲伤) reactions and dysthymia(心境恶劣) to severe, incapacitating illness that may result in death. Emotion（情绪）refers to transient responses to environmental, internal, and cognitive stimuli, while mood（心境）refers to the predominant emotional state over time.

4. Disorders of Mood The symptoms of depression are intense feelings of sadness, hopelessness, despair, and inability to experience pleasure in usual activity. Mania is characterized by the opposite behavior, that is, enthusiasm, rapid thought and speech patterns, and extreme self-confidence and impaired judgment. Anxiety, a state characterized by arousal, vigilance, physiologic preparedness, and negative subjective states, may share certain critical circuits with fear.

5. Monoamine hypothesis of Depression（单胺假说） 5-HT  — genetic basis of depression & mania NE  — depression NE  — mania Modulation of monoamines in the synaptic space and/or the related post-synaptic receptors is of therapeutic importance

6. Long-term adaptations to antidepressant treatment

8. Classes of Antidepressants • Tricyclic Antidepressants (TCAs) • Monoamine Oxidase Inhibitors (MAOIs) • Norepinephrine Reuptake Inhibitors (NARIs) • Selective Serotonin Reuptake Inhibitors (SSRIs) • Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs) • Noradrenergic and specific serotonergic antidepressants (NaSSAs)

9. Model of the neurotrophic hypothesis of antidepressant treatments and stress-related disorders

10. A. Antidepressant Drugs • Tricyclic Antidepressants (TCAs) Imipramine 丙米嗪（米帕明） Tricyclic structure

12. 临床应用 副作用 阿米替林 氯丙咪嗪 多塞平 丙咪嗪

13. Imipramine 丙米嗪（米帕明） 1. Pharmacological effects (1) Central effects • Inhibiting reuptake of monoamine transmitters • Improving patient’s mood after 2 weeks • Sedative effects in normal subjects (anti-histaminergic or a-adrenergic blocking properties) (2) Autonomic effects • Muscarinic blocking effects (3) Cardiovascular effects • Hypotension, tachycardia, arrhythmia

14. Imipramine 丙米嗪（米帕明） 2. Clinical uses (1) Depression Endogenous, melancholic, etc. (2) Enuresis(遗尿) (3) Anxiety (焦虑) and panic disorder (惊恐症)

15. Imipramine 丙米嗪（米帕明） 3. Adverse effects (1) Antimuscarinic effects dry mouth, constipation(便秘), intraocular pressure increase, blurred vision, urinary retention, etc. Contraindicated in prostatauxe and glaucoma (2) CNS reactions Confusion or delirium(谵妄), depression-mania (bipolar patients) (3) CVS reactions Postural hypotension, sinus tachycardia, potential of arrhythmia

16. Imipramine 丙米嗪（米帕明） 4. Drug interactions (1) Plasma protein binding displacement by phenytoin, aspirin, scopolamine(东莨菪碱), phenothiazines (吩噻嗪类), etc. (2) MAO inhibitors potentiating the effects of TCA, contraindicated for combination with MAOIs (3) Potentiating the effects of CNS depressant drugs

17. Interaction of TCA with other types of drugs

18. A. Antidepressant Drugs • Monoamine oxidase inhibitors (MAOIs) • Selective for central MAO-B, less selective for enteric MAO-A; • Used in treatments of depression (non-sensitive to TCAs) and Parkinson disease • phenelzine(苯乙肼): non-selective • selegiline(司来吉兰): also used in Parkinson disease

19. MAOIs and Dietary Interactions • Tyramine(酪胺) is normally metabolized by MAO • Tyramine is sympathomimetic (it acutely displaces NE from terminals to activate receptors) • Ingesting tyramine during MAO inhibition results in hypertension, headache, palpitations, nausea, vomiting • Tyramine is present in a number of foodstuffs, such as aged cheese, red wine, etc.

20. A. Antidepressant Drugs • NE reuptake inhibitors (NRIs) • Selective norepinephrine reuptake inhibits • rapid actions • weaker sedative, anticholinergic and hypotensive effects • desipramine (地昔帕明) • maprotiline (马普替林) • nortriptyline (去甲替林) • protriptylin (普罗替林) • amoxapine (阿莫沙平)

21. A. Antidepressant Drugs • Selective 5-HT reuptake inhibitors • Selective serotonin reuptake inhibits (SSRIs) • weaker sedative effects • with anti-anxiety effects • fluoxetine (氟西汀，百忧解)：抑郁症、神经性贪食症 • paroxetine (帕罗西汀) • sertraline (舍曲林)

22. A. Antidepressant Drugs • 5-HT/NE reuptake inhibitors • Mixed serotonin/norepinephrine reuptake inhibits (SNRIs) • rapid action • less affinity with receptors • higher safety • venlafaxine (文拉法辛) • milnacipram (米那普仑) • lofepramine (洛夫帕明)

23. A. Antidepressant Drugs • Noradrenergic and specific serotonergic antidepressant(NaSSA) mirtezapine (米氮平) • blockingpresynaptic (auto- or hetero-) 2 receptor on both norepinephrine and serotonin (5-HT) pre-synaptic axons • - increasing NE and 5-HT release; • stimulating postsynaptic 1 receptors on serotonergic cell bodies • - increasing the firing rate of serotonergic neurons • potently blocking postsynaptic 5-HT2A, 5-HT2C and 5-HT3 receptors – attenuating 5-HT2C-mediated anxiety • The net outcome of these effects is： • increased noradrenergic activity • increased serotonergic activity, esp. 5-HT1A receptors

24. B.Antimanic Drugs • Lithium carbonate • Carbamazepine • Chlorpromazine • Other related antiepileptic and antipsychotic drugs

25. B. Antimanic Drugs Lithium carbonate 碳酸锂 1. Pharmacological effects and clinical uses • Mood-stabilizing agent (1) Inhibiting NE and DA release (2) Interfering phosphatidylinositol (PI) metabolism (3) Substitute for sodium in generating action potentials and in Na+-K+ exchange across the membrane.

27. B. Antimanic Drugs 2. Adverse effects Related to the serum concentration of Li+ • 0.8 – 1.5 mmol/L:therapeutic level • 1.6 – 2.0 mmol/L:GI reactions • > 2.0 mmol/L:CNS toxicity • Monitoring serum concentration of Li+ if possible

28. B. Antimanic Drugs (1) Side effects • Nausea, vomiting, abdominal pain, diarrhea, sedation, finger tremor, polyuria, etc. (2) Acute intoxication • Mental confusion, coma, hyperreflexia(反射亢进), gross tremor, dysarthria(构音困难), seizures, etc. (3) Others • Benign thyroid enlargement, renal damage

29. C. Anxiolytic drugs 1. Benzodiazepines see details in Sedative-Hypnotic Drugs 2. Buspirone（丁螺环酮） • 5-HT1A receptor selective partial agonist, lowering 5-HT release • Fewer sedative, hypnotic, memory-deficient effects • No cross tolerance to benzodiazepines, and less potential of dependence

30. Schizophrenia(精神分裂症) • Neurological Disorder - impairs ability to perceive, understand & interpret the environment • Impaired social and occupational function • Behavioral Syndrome – predictable or not • Etiology and biology remain unclear- familial tendency, DA and other neurotransmitters • History – early dementia, unremitting bad course

31. Signs & Symptoms • Positivesymptoms • Delusions (妄想) - fixed false belief outside cultural norm (bizarre vs. non bizarre) • Hallucinations (幻觉) - perceptual (hearing), have no outside source • “Like my voice” • Not an illusion (a mistaken perception for which there is an actual external stimulus) • Disorganization(思维紊乱) - pattern of speech or behavior, making up words without a meaning (neologisms)

32. Signs & Symptoms • Negativesymptoms • Affective flattening • Avolition / Amotivation (decreased motivation) • Autistic(孤独) behaviors (social withdrawal ) • Anhedonia (inability to experience pleasure ) • Ambivalence (coexistence of opposing attitudes or feelings，矛盾心态) • Anosognosia (疾病感缺失) (impaired awareness of illness )

33. D. Antipsychotic drugs Classified according to chemical structures 1. Phenothiazines（吩噻嗪类） • Chlorpromazine氯丙嗪 • perphenazine 奋乃静；fluphenazine 氟奋乃静 • trifluoperazine 三氟拉嗪；thioridazine 硫利达嗪 2. Thioxanthenes (硫杂蒽类) • Chlorprothixene氯普噻吨（泰尔登） 3. Butyrophenones（丁酰苯类） • Haloperidol 氟哌啶醇 • Droperidol 氟哌利多（氟哌啶） • Typical Typical antipsychotic drugs are dopamine D2 receptor antagonists

34. Others • Penfluridol五氟利多Longer duration of action, taking once weekly • Sulpride舒必利selectively acts on mesolimbic D2 receptors few extrapyramidal reactions • Clozapine氯氮平Blocking D4 and 5-HT receptors • Risperidone利培酮Blocking D2and 5-HT2 receptors • Atypical Actions of some secondary generation drugs

35. D. Antipsychotic drugs High potency Low potency 普马嗪 氟哌利多 三氟哌啶醇 苯哌利多 螺环哌啶酮

36. D. Antipsychotic drugs • The dopamine hypothesis of schizophrenia • The serotonin hypothesis of schizophrenia • The glutamate hypothesis of schizophrenia

37. D. Antipsychotic drugs • Phenothiazines（吩噻嗪类） Chlorpromazine 氯丙嗪

38. D. Antipsychotic drugs 1. Pharmacological effects • Central effects:Blocking central D2 dopamine receptors a) Antipsychotic effects (neuroleptic effects) • for treatment of schizophrenia • controlling excitation and then hallucinations (weeks to months) b) Antiemetic effects(镇吐作用) • inhibiting chemoreceptor trigger zone (CTZ) dopaminergic function c) Poikilothermic effects (体温调节作用) • hypothermic anesthesia • artificial hibernation (人工冬眠) d) Extrapyramidal effects • primary adverse effects e) Potentiating the effects of central depressants • sedative-hypnotics, analgesics, general anesthetics, ethanol

39. D. Antipsychotic drugs (2) Autonomic nervous system effects a) Hypotensive effects •  receptor blockade, postural hypotension b) Anticholinergic effects • dry mouth, constipation, blurred vision, urinary retention, etc. (3) Endocrine effects • prolactin  • ACTH, growth hormone 

40. D. Antipsychotic drugs 2. Clinical uses (1) Treatment of schizophrenia (2) Treatments of emesis and hiccough used foremesis （止吐） andhiccough（呃逆） but ineffective on motion sickness (3) Hypothermic anesthesia (combined with lowering room temperature) and artificial hibernation (combined with Pethidine 哌替啶 and promethazine异丙嗪)

41. D. Antipsychotic drugs 3. Adverse effects (1) Side effects Central depression Peripheral effects:postural hypotension, dry mouth, and other effects resulting from muscarinic and  receptor blockade

42. D. Antipsychotic drugs (2) Extrapyramidal effects Due to DA receptor block: a) Parkinsonism b) Akathisia (静坐不能) c) Acute dystonia (急性肌张力障碍) attenuated by central muscarinic antagonists Due to supersensitive to DA: Tardive dyskinesia(迟发性运动障碍)

43. D. Antipsychotic drugs (3) Other central reactions • neuroleptic maglinant syndrome (神经阻滞药恶性综合征） • psychotic reactions (药源性精神异常) • epilepsy and convulsion: lowering seizure threshold (4) Allergic and hemological reactions skin reactions, leukopenia, obstructive jaundice, liver damage

44. D. Antipsychotic drugs (5) CVS reactions • arrhythmia • hypotension: treated by receptor agonists • sudden death (elderly with CVS diseases) (6) Endocrine reactions • hyperplasia of mammary glands (乳腺增生), galactorrhea (溢乳), amenorrhea (闭经), child growth retard(生长抑制)

45. D. Antipsychotic drugs (6) Acute intoxication • severe CNS depression, coma, severe hypotension (7) Contraindications • epilepsy • coma • elderly with CVS disorders • severe hepatic and renal dysfunction

46. D. Antipsychotic drugs • Other phenothiazines • perphenazine 奋乃静 • fluphenazine 氟奋乃静 • trifluoperazine 三氟拉嗪 • thioridazine 硫利达嗪 • more potent therapeutic effects and extrapyramidal effects

47. D. Antipsychotic drugs • Thioxanthenes (硫杂蒽类) Chlorprothixene氯普噻吨（泰尔登） Used for the patients with symptoms of depression and anxiety

48. D. Antipsychotic drugs Butyrophenones（丁酰苯类） • Haloperidol 氟哌啶醇 • Droperidol 氟哌利多（氟哌啶） • Combined with fentanyl:neuroleptanalgesia（神经安定 [镇痛] 麻醉术）

49. D. Antipsychotic drugs Others • Penfluridol 五氟利多 • Longer duration of action, taking once weekly • Sulpride 舒必利 • selectively acts on mesolimbic D2 receptors • few extrapyramidal reactions • Clozapine 氯氮平 • Blocking D4 and 5-HT receptors • Risperidone利培酮 • Blocking D2and 5-HT2 receptors

50. 局部麻醉药