基础医学各论III课件：15_神经系统药理5_2013-10-28

1、神经系统药理5 一、抗精神病药和抗抑郁药 二、麻醉药,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,Disorders of mood (affective disorders 情感障碍) are extremely common in medical practice. The severity of these conditions covers an extraordinarily broad rang

2、e, 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.,Disorders of Mood,The sym

3、ptoms 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 s

4、tate characterized by arousal, vigilance, physiologic preparedness, and negative subjective states, may share certain critical circuits with fear.,Disorders of Mood,Monoamine hypothesis of Depression （单胺假说） 5-HT genetic basis of depression Used in treatments of depression (non-sensitive to TCAs) and

5、 Parkinson disease phenelzine (苯乙肼): non-selective selegiline (司来吉兰): also used in Parkinson disease,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 inh

6、ibition results in hypertension, headache, palpitations, nausea, vomiting Tyramine is present in a number of foodstuffs, such as aged cheese, red wine, etc.,A. Antidepressant Drugs,NE reuptake inhibitors (NRIs) Selective norepinephrine reuptake inhibits rapid actions weaker sedative, anticholinergic

7、 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),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

8、、神经性贪食症 paroxetine (帕罗西汀) sertraline (舍曲林),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),A. Antidepressant Drugs,Noradrenerg

9、ic and specific serotonergic antidepressant (NaSSA) mirtezapine (米氮平) blocking presynaptic (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

10、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,B. Antimanic Drugs,Lithium carbonate

11、Carbamazepine Chlorpromazine Other related antiepileptic and antipsychotic drugs,B. Antimanic Drugs,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

12、 potentials and in Na+-K+ exchange across the membrane.,Lithium carbonate 碳酸锂,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,B. Antimanic Drugs,(1)

13、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,B. Antimanic Drugs,C. Anxiolytic dru

14、gs,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,Schizophrenia(精神分裂症),Neurologica

15、l Disorder - impairs ability to perceive, understand Tidal Volume Ventilation; PaCO2; Hypoxia Risk,Liver toxicity,“Halothane Hepatitis” Incidence post Halothane 0.003% Symptoms fever, anorexia(胃口不好), nausea altered liver function Rare liver failure & death,Malignant hyperthermia,Hypermetabolic syndr

16、ome hyperthermia, CO2, tachycardia, cyanosis, muscle rigidity Triggered by halogenated anesthetics & depolarizing muscle relaxants Familial relationship, i.e. genetic heterogeneity mutation in Ca2+ reuptake Incidence, 1/14,000 anesthesia (0.01%) Specific Treatment Dantrolene (inhibit Ca2+ release fr

17、om the sarcoplasmic reticulum),Nitrous oxide toxicity,Bone Marrow Depression megaloblastic, inhibition of B12 dependant enzymes Peripheral neuropathy Expansion of closed air spaces bowel obstruction, pneumothorax, bullous emphysema, middle ear obstruction, pneumocephalus CNS injury adults & neonates,NITROUS OXIDE KILLS NEURONS IN THE YOUNG AND THE OLD,Developing rat brain Exposure to a combination including nitrous, isoflurane & midazolam Persistent learning deficits,Early apoptosis,Late apoptosis,control,exposed,Intravenous Anesthetics(静脉麻醉药),Usually activate