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1、神经系统药理5一、抗精神病药和抗抑郁药抗精神病药和抗抑郁药二、麻醉药二、麻醉药一、抗精神病药和抗抑郁药抗精神病药和抗抑郁药Antidepressant and antimanic Antidepressant and antimanic drugsdrugs 抗抑郁和抗躁狂药抗抑郁和抗躁狂药抗抑郁和抗躁狂药抗抑郁和抗躁狂药Anxiolytics / Anxiolytics / antianxieticsantianxietics 抗焦虑药抗焦虑药抗焦虑药抗焦虑药Antipsychotic Antipsychotic drugsdrugs 抗精神分裂药抗精神分裂药抗精神分裂药抗精神分裂药Diso
2、rders of mood Disorders of mood ( (affective disordersaffective disorders 情感障碍情感障碍情感障碍情感障碍) ) are are extremely common in medical practice. The severity extremely common in medical practice. The severity of these conditions covers an extraordinarily broad of these conditions covers an extraordinaril
3、y broad range, from normal grief(range, from normal grief(悲伤悲伤悲伤悲伤) reactions and ) reactions and dysthymia(dysthymia(心境恶劣心境恶劣心境恶劣心境恶劣) to severe, incapacitating illness ) to severe, incapacitating illness that may result in death.that may result in death.EmotionEmotion（情绪）（情绪）（情绪）（情绪）refers to tran
4、sient responses to refers to transient responses to environmental, internal, and cognitive stimuli, while environmental, internal, and cognitive stimuli, while moodmood （心境）（心境）（心境）（心境）refers to the predominant emotional refers to the predominant emotional state over time.state over time.Disorders o
5、f MoodThe symptoms of The symptoms of depressiondepression are intense feelings of are intense feelings of sadness, hopelessness, despair, and inability to sadness, hopelessness, despair, and inability to experience pleasure in usual activity.experience pleasure in usual activity.ManiaMania is chara
6、cterized by the opposite behavior, is characterized by the opposite behavior, that is, enthusiasm, rapid thought and speech that is, enthusiasm, rapid thought and speech patterns, and extreme self-confidence and impaired patterns, and extreme self-confidence and impaired judgment.judgment.AnxietyAnx
7、iety, a state characterized by arousal, vigilance, , a state characterized by arousal, vigilance, physiologic preparedness, and negative subjective physiologic preparedness, and negative subjective states, may share certain critical circuits with states, may share certain critical circuits with fear
8、fear. .Disorders of MoodMonoamine hypothesis of Depression （单胺假说）（单胺假说）（单胺假说）（单胺假说） 5-HT 5-HT genetic basis of depression & mania genetic basis of depression & mania NE NE depressiondepression NE NE maniamaniaModulation of monoamines in the synaptic space Modulation of monoamines in the synaptic spa
9、ce and/or the related post-synaptic receptors is of and/or the related post-synaptic receptors is of therapeutic importancetherapeutic importanceLong-term adaptations to antidepressant treatmentLong-term adaptations to antidepressant treatmentClasses of AntidepressantsTricyclic Antidepressants (TCAs
10、)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)Model of the neurotrophic Model of the neurotrophic hy
11、pothesis ofhypothesis ofantidepressant treatments and antidepressant treatments and stress-related disordersstress-related disordersImipramine 丙米嗪丙米嗪丙米嗪丙米嗪（米帕明）（米帕明）（米帕明）（米帕明）Tricyclic Tricyclic structurestructureA. Antidepressant DrugsTricyclic Antidepressants (TCAs)丙咪嗪丙咪嗪阿米替林阿米替林氯丙咪嗪氯丙咪嗪多塞平多塞平临床应用
12、临床应用副作用副作用1. Pharmacological effects(1) Central effects(1) Central effectsInhibiting reuptake of monoamine transmittersInhibiting reuptake of monoamine transmittersImproving patients mood after 2 weeksImproving patients mood after 2 weeksSedative Sedative effects effects in in normal normal subjects
13、 subjects (anti-(anti-histaminergic histaminergic or or -adrenergic -adrenergic blocking blocking properties)properties)(2) Autonomic effects(2) Autonomic effectsMuscarinic blocking effectsMuscarinic blocking effects(3) Cardiovascular effects(3) Cardiovascular effectsHypotension, tachycardia, arrhyt
14、hmiaHypotension, tachycardia, arrhythmiaImipramine 丙米嗪丙米嗪丙米嗪丙米嗪（米帕明）（米帕明）（米帕明）（米帕明）2. Clinical uses(1) Depression(1) DepressionEndogenous, melancholic, Endogenous, melancholic, etc.etc.(2) Enuresis(2) Enuresis ( (遗尿遗尿遗尿遗尿) )(3) Anxiety (3) Anxiety ( (焦虑焦虑焦虑焦虑) ) and panic disorder and panic disorder
15、 ( (惊恐症惊恐症惊恐症惊恐症) )Imipramine 丙米嗪丙米嗪丙米嗪丙米嗪（米帕明）（米帕明）（米帕明）（米帕明）3. Adverse effects(1) Antimuscarinic effects(1) Antimuscarinic effects dry mouth, constipation( dry mouth, constipation(便秘便秘便秘便秘), intraocular pressure increase, ), intraocular pressure increase, blurred vision, urinary retention, blurred
16、 vision, urinary retention, etc.etc. Contraindicated in prostatauxe and glaucoma Contraindicated in prostatauxe and glaucoma(2) CNS reactions(2) CNS reactions Confusion or delirium( Confusion or delirium(谵妄谵妄谵妄谵妄), depression-mania (bipolar ), depression-mania (bipolar patients)patients)(3) CVS reac
17、tions(3) CVS reactions Postural hypotension, sinus tachycardia, potential of Postural hypotension, sinus tachycardia, potential of arrhythmiaarrhythmiaImipramine 丙米嗪丙米嗪丙米嗪丙米嗪（米帕明）（米帕明）（米帕明）（米帕明）4. Drug interactions(1) Plasma protein binding(1) Plasma protein binding displacement by phenytoin, aspiri
18、n, scopolamine( displacement by phenytoin, aspirin, scopolamine(东莨菪碱东莨菪碱东莨菪碱东莨菪碱), ), phenothiazines (phenothiazines (吩噻嗪类吩噻嗪类吩噻嗪类吩噻嗪类), ), etc. etc. (2) MAO inhibitors(2) MAO inhibitors potentiating the effects of TCA, potentiating the effects of TCA, contraindicated for combination with MAOIscontr
19、aindicated for combination with MAOIs(3) Potentiating the effects of CNS depressant drugs(3) Potentiating the effects of CNS depressant drugsImipramine 丙米嗪丙米嗪丙米嗪丙米嗪（米帕明）（米帕明）（米帕明）（米帕明）Interaction of TCA with other types of drugs Interaction of TCA with other types of drugs A. Antidepressant DrugsMon
20、oamine oxidase inhibitors (MAOIs) Selective Selective for for central central MAO-B, MAO-B, less less selective selective for for enteric enteric MAO-A; MAO-A; U Used sed in in treatments treatments of of depression depression (non-sensitive (non-sensitive to to TCAs) and Parkinson diseaseTCAs) and
21、Parkinson disease phenelzine phenelzine ( (苯乙肼苯乙肼苯乙肼苯乙肼): non-selective): non-selective selegiline selegiline ( (司来吉兰司来吉兰司来吉兰司来吉兰): also used in Parkinson disease): also used in Parkinson diseaseMAOIs and Dietary InteractionsTyramine(酪胺) is normally metabolized by MAOTyramine is sympathomimetic (it
22、acutely displaces NE from terminals to activate receptors)Ingesting tyramine during MAO inhibition results in hypertension, headache, palpitations, nausea, vomitingTyramine is present in a number of foodstuffs, such as aged cheese, red wine, etc.A. Antidepressant DrugsNE reuptake inhibitors (NRIs) S
23、elective norepinephrine reuptake inhibitsSelective norepinephrine reuptake inhibits rapid actions rapid actions weaker sedative, anticholinergic and hypotensive effects weaker sedative, anticholinergic and hypotensive effects desipramine desipramine ( (地昔帕明地昔帕明地昔帕明地昔帕明) ) maprotiline maprotiline ( (
24、马普替林马普替林马普替林马普替林) ) nortriptyline nortriptyline ( (去甲替林去甲替林去甲替林去甲替林) ) protriptylin protriptylin ( (普罗替林普罗替林普罗替林普罗替林) ) amoxapine amoxapine ( (阿莫沙平阿莫沙平阿莫沙平阿莫沙平) )A. Antidepressant DrugsSelective 5-HT reuptake inhibitors Selective serotonin reuptake inhibits (SSRIs)Selective serotonin reuptake inhibi
25、ts (SSRIs) we weaker sedative effectsaker sedative effects with anti-anxiety effects with anti-anxiety effects fluoxetine fluoxetine ( (氟西汀，百氟西汀，百氟西汀，百氟西汀，百忧忧忧忧解解解解) )：抑郁症、神经性贪食症：抑郁症、神经性贪食症：抑郁症、神经性贪食症：抑郁症、神经性贪食症 paroxetine paroxetine ( (帕罗西汀帕罗西汀帕罗西汀帕罗西汀) ) sertraline sertraline ( (舍曲林舍曲林舍曲林舍曲林) )A.
26、Antidepressant Drugs5-HT/NE reuptake inhibitors Mixed serotonin/norepinephrine reuptake inhibits Mixed serotonin/norepinephrine reuptake inhibits (SNRIs)(SNRIs) rapid action rapid action less affinity with receptors less affinity with receptors higher safety higher safety venlafaxine venlafaxine ( (
27、文拉法辛文拉法辛文拉法辛文拉法辛) ) milnacipram milnacipram ( (米那普仑米那普仑米那普仑米那普仑) ) lofepramine lofepramine ( (洛夫帕明洛夫帕明洛夫帕明洛夫帕明) )A. Antidepressant DrugsNoradrenergic and specific serotonergic antidepressant (NaSSA) mirtezapine mirtezapine ( (米氮平米氮平米氮平米氮平) ) blockingblocking presynapticpresynaptic (auto- (auto- or o
28、r hetero-) hetero-) 2 2 receptor receptor on on both both norepinephrine and serotonin (5-HT) norepinephrine and serotonin (5-HT) pre-synaptic pre-synaptic axonsaxons - increasing NE and 5-HT release- increasing NE and 5-HT release; ; stimulating postsynaptic stimulating postsynaptic 1 1 receptors r
29、eceptors on serotonergic cell bodies on serotonergic cell bodies - increasing - increasing the firing rate of serotonergic neuronsthe firing rate of serotonergic neurons potently blocking postsynaptic 5-HT potently blocking postsynaptic 5-HT2A2A, 5-HT, 5-HT2C2C and 5-HT and 5-HT3 3 receptors recepto
30、rs attenuating 5-HT attenuating 5-HT2C2C-mediated anxiety-mediated anxiety The net outcome of these effects The net outcome of these effects is is： increased increased noradrenergicnoradrenergic activity activity increased increased serotonergic activityserotonergic activity, , esp. 5-HTesp. 5-HT1A1
31、A receptorsreceptorsB. Antimanic DrugsLithium carbonateCarbamazepine ChlorpromazineOther related antiepileptic and antipsychotic drugs B. Antimanic Drugs1. Pharmacological effects and clinical usesMood-stabilizing agent(1) Inhibiting NE and DA release(1) Inhibiting NE and DA release(2) Interfering p
32、hosphatidylinositol (PI) metabolism(2) Interfering phosphatidylinositol (PI) metabolism(3) Substitute for sodium in generating action potentials and (3) Substitute for sodium in generating action potentials and in Nain Na+ +-K-K+ + exchange across the membrane.exchange across the membrane.Lithium ca
33、rbonate 碳酸锂碳酸锂碳酸锂碳酸锂2. Adverse effectsRelated to the serum concentration of LiRelated to the serum concentration of Li+ + 0.8 1.5 mmol/L:0.8 1.5 mmol/L: therapeutic leveltherapeutic level 1.6 2.0 mmol/L:1.6 2.0 mmol/L: GI reactionsGI reactions 2.0 mmol/L: 2.0 mmol/L: CNS toxicityCNS toxicityMonitori
34、ng serum concentration of Li+ if possibleB. Antimanic Drugs(1) Side effects(1) Side effects Nausea, vomiting, abdominal pain, diarrhea, Nausea, vomiting, abdominal pain, diarrhea, sedation, finger tremor, polyuria, sedation, finger tremor, polyuria, etc.etc.(2) Acute intoxication(2) Acute intoxicati
35、on Mental confusion, coma, hyperreflexia(Mental confusion, coma, hyperreflexia(反射亢进反射亢进反射亢进反射亢进), ), gross tremor, dysarthria(gross tremor, dysarthria(构音困难构音困难构音困难构音困难), seizures, ), seizures, etc.etc.(3) Others (3) Others Benign thyroid enlargement, renal damageBenign thyroid enlargement, renal dam
36、ageB. Antimanic DrugsC. Anxiolytic drugs1. Benzodiazepines see details in Ssee details in Sedative-Hypnotic Drugsedative-Hypnotic Drugs2. Buspirone（丁螺环酮）（丁螺环酮）（丁螺环酮）（丁螺环酮）5-HT5-HT1A 1A receptor receptor selective selective partial partial agonist, agonist, lowering lowering 5-5-HT releaseHT releaseF
37、ewer sedative, hypnotic, memory-deficient effectsFewer sedative, hypnotic, memory-deficient effectsNo No cross cross tolerance tolerance to to benzodiazepines, benzodiazepines, and and less less potential of dependencepotential of dependenceSchizophrenia(精神分裂症) Neurological Disorder - impairs abilit
38、y to perceive, understand & interpret the environmentImpaired social and occupational functionBehavioral Syndrome predictable or notEtiology and biology remain unclear- familial tendency, DA and other neurotransmittersHistory early dementia, unremitting bad courseSigns & SymptomslPositive symptomsDe
39、lusions ( (妄想妄想) ) - fixed false belief outside cultural norm (bizarre vs. non bizarre)Hallucinations ( (幻觉幻觉) ) - perceptual (hearing), have no outside source “Like my voice”Not an illusion (a mistaken perception for which there is an actual external stimulus) Disorganization ( (思维紊乱思维紊乱) ) - patte
40、rn of speech or behavior, making up words without a meaning (neologisms) lNegative symptomsAffective flatteningAvolition / Amotivation (decreased motivation)Autistic(孤独) behaviors (social withdrawal )Anhedonia (inability to experience pleasure )Ambivalence (coexistence of opposing attitudes or feeli
41、ngs，矛盾心态) Anosognosia (疾病感缺失) (impaired awareness of illness )Signs & Symptoms1. Phenothiazines1. Phenothiazines（吩噻嗪类）（吩噻嗪类）（吩噻嗪类）（吩噻嗪类）Chlorpromazine 氯丙嗪氯丙嗪氯丙嗪氯丙嗪 perphenazine perphenazine 奋乃静；奋乃静；奋乃静；奋乃静； fluphenazine fluphenazine 氟奋乃静氟奋乃静氟奋乃静氟奋乃静 trifluoperazine trifluoperazine 三氟拉嗪；三氟拉嗪；三氟拉嗪；三氟拉
42、嗪；thioridazine thioridazine 硫利达嗪硫利达嗪硫利达嗪硫利达嗪2. Thioxanthenes (2. Thioxanthenes (硫杂蒽类硫杂蒽类硫杂蒽类硫杂蒽类) )Chlorprothixene 氯普噻吨（泰尔登）氯普噻吨（泰尔登）3. Butyrophenones3. Butyrophenones（丁酰苯类）（丁酰苯类）（丁酰苯类）（丁酰苯类）Haloperidol 氟哌啶醇氟哌啶醇Droperidol 氟哌利多（氟哌啶）氟哌利多（氟哌啶）Classified according to chemical structuresD. Antipsychotic
43、drugsTypical antipsychotic drugs are dopamine DTypical antipsychotic drugs are dopamine D2 2 receptor antagonists receptor antagonists TypicalOthersOthers PenfluridolPenfluridol 五氟利多五氟利多五氟利多五氟利多 Longer duration of action, taking once weeklyLonger duration of action, taking once weekly SulprideSulpri
44、de 舒必利舒必利舒必利舒必利 selectively acts on mesolimbic Dselectively acts on mesolimbic D2 2 receptors receptors few extrapyramidal reactions few extrapyramidal reactions ClozapineClozapine 氯氮平氯氮平氯氮平氯氮平 Blocking DBlocking D4 4 and 5-HT receptors and 5-HT receptors RisperidoneRisperidone 利培酮利培酮利培酮利培酮 Blocking
45、 Blocking D D2 2 and 5-and 5-HTHT2 2 receptors receptorsActions of some Actions of some secondary generation secondary generation drugsdrugs AtypicalD. Antipsychotic drugsHigh potencyLow potency螺环哌啶酮螺环哌啶酮 苯哌利多苯哌利多 三氟哌啶醇三氟哌啶醇 氟哌利多氟哌利多 普马嗪普马嗪 D. Antipsychotic drugsThe dopamine hypothesis of schizophre
46、niaThe serotonin hypothesis of schizophreniaThe glutamate hypothesis of schizophreniaPhenothiazines（吩噻嗪类）（吩噻嗪类）（吩噻嗪类）（吩噻嗪类）Chlorpromazine 氯丙嗪氯丙嗪氯丙嗪氯丙嗪D. Antipsychotic drugs1. 1. Pharmacological effectsPharmacological effects(1)(1)Central effects:Central effects:Blocking central DBlocking central D2
47、2 dopamine receptors dopamine receptorsa) Antipsychotic effects (neuroleptic effects)a) Antipsychotic effects (neuroleptic effects) for treatment of for treatment of schizophreniaschizophrenia controlling excitation and then hallucinations (weeks to controlling excitation and then hallucinations (we
48、eks to months)months)b) Antiemetic effects(b) Antiemetic effects(镇吐作用镇吐作用镇吐作用镇吐作用) ) inhibiting inhibiting chemoreceptor trigger zonechemoreceptor trigger zone (CTZ) dopaminergic (CTZ) dopaminergic functionfunctionc) Poikilothermic effects (c) Poikilothermic effects (体温调节作用体温调节作用体温调节作用体温调节作用) ) hypo
49、thermic anesthesiahypothermic anesthesia artificial hibernation ( artificial hibernation (人工冬眠人工冬眠人工冬眠人工冬眠) )d) Extrapyramidal effectsd) Extrapyramidal effects primary adverse effectsprimary adverse effectse) Potentiating the effects of central depressantse) Potentiating the effects of central depre
50、ssants sedative-hypnotics, analgesics, general anesthetics, ethanol sedative-hypnotics, analgesics, general anesthetics, ethanolD. Antipsychotic drugs(2) Autonomic nervous system effects(2) Autonomic nervous system effectsa) Hypotensive effectsa) Hypotensive effects receptor blockade, receptor block
51、ade, postural hypotensionpostural hypotensionb) Anticholinergic effectsb) Anticholinergic effects dry dry mouth, mouth, constipation, constipation, blurred blurred vision, vision, urinary urinary retention, etc.retention, etc.(3) Endocrine effects(3) Endocrine effects prolactin prolactin ACTH, growt
52、h hormone ACTH, growth hormone D. Antipsychotic drugs2. Clinical uses(1) Treatment of schizophrenia(1) Treatment of schizophrenia(2) Treatments of emesis and hiccough(2) Treatments of emesis and hiccough used forused for emesis emesis （止吐）（止吐）（止吐）（止吐） andand hiccoughhiccough（呃逆）（呃逆）（呃逆）（呃逆） but inef
53、fective on motion sicknessbut ineffective on motion sickness(3) Hypothermic anesthesia (3) Hypothermic anesthesia (combined with lowering room combined with lowering room temperaturetemperature) ) and artificial hibernation ( and artificial hibernation (combined with combined with Pethidine Pethidin
54、e 哌替啶哌替啶哌替啶哌替啶 and promethazineand promethazine异丙嗪异丙嗪异丙嗪异丙嗪) ) D. Antipsychotic drugs3. Adverse effects(1) Side effects(1) Side effects CeCentral ntral depressiondepression Peripheral Peripheral effects:effects: postural postural hypotensionhypotension, , dry dry mouth, mouth, and and other other ef
55、fects effects resulting resulting from from muscarinic and muscarinic and receptor blockade receptor blockadeD. Antipsychotic drugs(2) Extrapyramidal effects(2) Extrapyramidal effectsDue to DA receptor block: a) Parkinsonism a) Parkinsonism b) Akathisia ( b) Akathisia (静坐不能静坐不能静坐不能静坐不能) ) c) Acute d
56、ystonia ( c) Acute dystonia (急性肌张力障碍急性肌张力障碍急性肌张力障碍急性肌张力障碍) ) attenuated by central muscarinic antagonistsattenuated by central muscarinic antagonistsDue to supersensitive to DA: Tardive dyskinesiaTardive dyskinesia ( (迟发性运动障碍迟发性运动障碍迟发性运动障碍迟发性运动障碍) )D. Antipsychotic drugs(3) Other central reactions(3
57、) Other central reactions neuroleptic maglinant syndrome neuroleptic maglinant syndrome ( (神经阻滞药恶神经阻滞药恶神经阻滞药恶神经阻滞药恶性综合征）性综合征）性综合征）性综合征） psychotic reactions psychotic reactions ( (药源性精神异常药源性精神异常药源性精神异常药源性精神异常) ) epilepsy and convulsion: lowering seizure epilepsy and convulsion: lowering seizure thres
58、holdthreshold(4) Allergic and hemological reactions(4) Allergic and hemological reactions skin reactions, leukopenia, skin reactions, leukopenia, obstructive obstructive jaundice, jaundice, liver damageliver damageD. Antipsychotic drugs(5) CVS reactions (5) CVS reactions arrhythmiaarrhythmia hypoten
59、sion: treated by hypotension: treated by receptor agonists receptor agonists sudden death (elderly with CVS diseases) sudden death (elderly with CVS diseases)(6) Endocrine reactions(6) Endocrine reactions hyperplasia of mammary glands ( hyperplasia of mammary glands (乳腺增生乳腺增生乳腺增生乳腺增生), ), galactorrh
60、ea (galactorrhea (溢乳溢乳溢乳溢乳), amenorrhea (), amenorrhea (闭经闭经闭经闭经 ), ), child growth retard( child growth retard(生长抑制生长抑制生长抑制生长抑制) )D. Antipsychotic drugs(6) Acute intoxication(6) Acute intoxication severe CNS depression, coma, severe hypotensionsevere CNS depression, coma, severe hypotension(7) Cont
61、raindications(7) Contraindications epilepsy epilepsy coma coma elderly with CVS disorders elderly with CVS disorders severe hepatic and renal dysfunction severe hepatic and renal dysfunctionD. Antipsychotic drugsOther phenothiazinesperphenazine 奋乃静奋乃静奋乃静奋乃静fluphenazine 氟奋乃静氟奋乃静氟奋乃静氟奋乃静trifluoperazin
62、e 三氟拉嗪三氟拉嗪三氟拉嗪三氟拉嗪thioridazine 硫利达嗪硫利达嗪硫利达嗪硫利达嗪more potent therapeutic effects and extrapyramidal effectsD. Antipsychotic drugsThioxanthenes ( (硫杂蒽类硫杂蒽类硫杂蒽类硫杂蒽类) )Chlorprothixene 氯普噻吨（泰尔登）氯普噻吨（泰尔登）氯普噻吨（泰尔登）氯普噻吨（泰尔登）Used for the patients with symptoms of Used for the patients with symptoms of depress
63、iondepression and and anxietyanxietyD. Antipsychotic drugsButyrophenones（丁酰苯类）（丁酰苯类）（丁酰苯类）（丁酰苯类）Haloperidol 氟哌啶醇氟哌啶醇氟哌啶醇氟哌啶醇Droperidol 氟哌利多（氟哌啶）氟哌利多（氟哌啶）氟哌利多（氟哌啶）氟哌利多（氟哌啶）Combined with fentanyl: neuroleptanalgesianeuroleptanalgesia（神神神神经经经经安定安定安定安定 镇痛镇痛镇痛镇痛 麻醉术）麻醉术）麻醉术）麻醉术）D. Antipsychotic drugsOthe
64、rsPenfluridol Penfluridol 五氟利多五氟利多五氟利多五氟利多 Longer duration of action, taking once weeklyLonger duration of action, taking once weeklySulpride 舒必利舒必利舒必利舒必利 selectively acts on mesolimbic Dselectively acts on mesolimbic D2 2 receptors receptors few extrapyramidal reactions few extrapyramidal reactions
65、 Clozapine 氯氮平氯氮平氯氮平氯氮平 Blocking DBlocking D4 4 and 5-HT receptors and 5-HT receptors Risperidone 利培酮利培酮利培酮利培酮 Blocking Blocking D D2 2 and 5-and 5-HTHT2 2 receptors receptorsD. Antipsychotic drugs局部麻醉药局部麻醉药Local Anesthetics (LAs)Definition: drugs that cause loss of sensation without loss of conscio
66、usnessReversibly block nerve conductionAct on every type of nerve fiberAlso act on cardiac muscle, skeletal muscle and the brainNo structural damage to the nerve cell可卡因可卡因普鲁卡因普鲁卡因丁卡因丁卡因苯佐卡因苯佐卡因all are weak basesBH+ B + H+Structural Classes: Esters and Amides利多卡因利多卡因甲哌卡因甲哌卡因布比卡因布比卡因布比卡因布比卡因丙胺卡因丙胺卡因U
67、se-dependent BlockadeActions of LAsIonic gradient and resting membrane potential are unchangedDecrease the amplitude of the action potentialSlow the rate of depolarizationIncrease the firing thresholdSlow impulse conductionProlong the refractory periodCNS Toxicity Correlation between potency and sei
68、zure thresholdlBupivacaine2 ug/mllLidocaine10 ug/mlCardiovascular ToxicityAttributable to their direct effect on cardiac muscleContractilitylNegative inotropic effect that is dose-related and correlates with potencylInterference with calcium signaling mechanismsAutomaticitylNegative chronotropic eff
69、ectRhythmicity and ConductivitylVentricular arrhythmiasAbsorption (injected or topical)- affected by vascularity (血供血供)- presence of additional vasoconstrictor (血管收缩剂血管收缩剂)- Duration prolonged by vasoconstrictor (epinephrine) - localizes agent to site of action - contraindicated in extremities(末梢部位末
70、梢部位)- Systemic Toxic Effects: CNS, cardiovascular PharmacokineticsAlpha phase (快速吸收相快速吸收相) rapidly redistributed to well-perfused tissuesBeta phase (再分布相再分布相) distribution to less perfused or slowly equili ibrating tissuesGamma phase (消除相消除相) clearance representing metabolism and excretionDistributi
71、on- LAs bind in the blood to a1-glycoprotein and albuminPharmacokineticsUses of local anesthesia / Modes of Administration Topical local (surface) anesthesia(表面麻醉表面麻醉): for eye, ear, nose, and throat procedures and for cosmetic surgeryInfiltration anesthesia (浸润麻醉浸润麻醉): local injection around the re
72、gion to be operated.Conduction anesthesia (传导麻醉传导麻醉): local injection around the peripheral nerve trunk Epidural ansthesia (硬膜下麻醉硬膜下麻醉): local injection into the epidural space Subarachnoid anesthesia (蛛网膜下腔麻醉蛛网膜下腔麻醉): or Spinal anesthesia (脊髓麻醉，腰麻脊髓麻醉，腰麻): local injection into the cerebrospinal flu
73、id in subarachnoid cavityAdverse reactionsToxicity: CNS, CVSAllergic ReactionsuMetabolite of “ester” LAslPara-aminobenzoic acidlAllergenuAllergy to “amide” LAs is extremely rareLidocaineOne of the most widely used local anestheticsRapid onset, medium durationAlso available in ointment（软膏）（软膏）, jelly
74、（凝胶）（凝胶）, and aerosol（喷雾剂）（喷雾剂）Other uses: anti-arrhythmicEutectic Mixture of Local Anesthetic (EMLA)Contains lidocaine (2.5%), prilocaine (丙胺卡因 2.5%), emulsifier乳化剂乳化剂, thickener增稠剂增稠剂, distilled water(a eutectic mixture has a melting point below room temperature and therefore both local anesthetic
75、s exist as a liquid oil rather than as crystals) Must be applied one hour prior to procedure全身性麻醉剂全身性麻醉剂WHAT IS General ANESTHESIA ?Anesthesia is necessary for some diagnostic, therapeutic, and surgical interventionThe physiologic state induced by general anesthetics typically includes analgesia, am
76、nesia, loss of consciousness, inhibition of sensory and autonomic reflexes, and skeletal muscle relaxation.Types of General Anesthesia : Inhaled Anesthetics (gases or “vapors”) Intravenous Anesthetics (be given intravenously).Inhaled anesthetics(吸入麻醉药吸入麻醉药)Many different, apparently unrelated molecu
77、les produce general anesthesia inert gases, simple inorganic & organic compounds, more complex organic compoundsCharacteristics rapid onset, rapid reversibility, relationship between lipid solubility & potencyStages of anesthesia (ether)Stage I: analgesia sensory block in spinal cordStage II: parado
78、xical excitation due to loss of some inhibitory tone and direct stimulation of excitatory transmission Stage III: surgical anesthesia block of the ascending reticular activating systemStage IV: failure cardiovascular and respiratory collapse due to inhibitionSigns for anesthetic depthTachycardiaHype
79、rtension Eyelid reflexLacrimationSwallowingLaryngospasmMovementTOO LIGHTTOO DEEP Hypotension Organ failureGas at room temperatureDiethyl Ether(乙醚乙醚)Volatile liquids at room temperatureHalothane(氟烷氟烷)Isoflurane(异氟醚异氟醚)Desflurane(地氟醚地氟醚)Inhaled anesthetic delivery systemVaporizing the anesthetic liqui
80、dGas flowmetersMaskHigher blood solubility is shown as a larger blood boxHigher solubility means gas rapidly moves into blood, but concentration that reaches brain increases more slowlyBlood:gas partition coefficient:an index for solubilityBrain:Blood Partition CoefficientMAC minimum alveolar anesth
81、etic concentrationMAC is the anesthetic concentration that produces immobility in 50% of patients exposed to a noxious stimulus.Addition of MACFactors that alter MACIncrease MAC Being young, hyperthermia, chronic ETOH, CNS stimulants, hyperthyroidismDecrease MAC Old age, hypothermia, acute ETOH, CNS
82、 depressant drugs including narcotics & benzodiazepines General characteristicsAnalgesia weak except for nitrous oxidePotency high, except for nitrous oxideMuscle Relaxation some, but weakAirway irritation desflurane (地氟醚地氟醚) worst, sevoflurane (七氟烷七氟烷) best toleratedPrimary effect on conductive tis
83、sue inhibitoryPrimary effect on smooth muscle relaxationEffects on brainTransition to unconsciousness 0.4 MAC O2 consumption but Cerebral Blood Flow means potential injury with brain tumors/head injury ( pressure)Effects on ventilation Respiratory Rate; Tidal Volume Ventilation; PaCO2; Hypoxia RiskL
84、iver toxicity“Halothane Hepatitis”Incidence post Halothane 0.003%Symptoms fever, anorexia(胃口不好胃口不好), nausea & vomiting that occur 2 - 5 days post-opBlood eosinophilia; altered liver functionRare liver failure & deathMalignant hyperthermiaHypermetabolic syndrome hyperthermia, CO2, tachycardia, cyanos
85、is, muscle rigidityTriggered by halogenated anesthetics & depolarizing muscle relaxantsFamilial relationship, i.e. genetic heterogeneitylmutation in Ca2+ reuptakeIncidence, 1/14,000 anesthesia (0.01%)Specific Treatment Dantrolene (inhibit Ca2+ release from the sarcoplasmic reticulum)Nitrous oxide to
86、xicityBone Marrow Depression megaloblastic, inhibition of B12 dependant enzymesPeripheral neuropathyExpansion of closed air spaces bowel obstruction, pneumothorax, bullous emphysema, middle ear obstruction, pneumocephalusCNS injury adults & neonatesNITROUS OXIDE KILLS NEURONS IN THE YOUNG AND THE OL
87、DDeveloping rat brainExposure to a combination including nitrous, isoflurane & midazolamPersistent learning deficitsEarly apoptosisEarly apoptosisLate apoptosisLate apoptosiscontrolexposedIntravenous Anesthetics(静脉麻醉药静脉麻醉药)Usually activate GABAA receptors硫喷妥硫喷妥异丙酚异丙酚依托咪酯依托咪酯氯胺酮氯胺酮咪达唑仑咪达唑仑Redistribution of thiopental after an intravenous bolus administration硫喷妥硫喷妥Combination of Anesthetics (复合麻醉)PremedicationBasal anesthesiaInduction of anesthesiaskeletal muscle relaxantsNeuroleptanesthesia (NLA,神经安定镇痛术)See you next class!
