藥理學(xué)教程課件：中樞神經(jīng)系統(tǒng)藥理學(xué)概論(五年制)

1、中樞神經(jīng)系統(tǒng)藥理學(xué)概論GENERAL PRINCIPLES OF CENTRAL NERVOUS SYSTEM第三篇Cognitive processing Motor processing Parkinsons diseasememoryAlzheimers diseaseEmotional processing Sensory processing therapeutic effects adverse reaction (mechanism of effect)drug-protein（receptors; ion channels; enzymes cell signal transd

2、uctionNeurotransmitterReceptorsSignal TransductionFunctionAcetylcholineMuscarinicM1, M3, M5IP3, DAG, iCa2+Excitatory; role in arousal and consciousness, memory consolidationM2, M4cAMP, gK+, gCa2+Inhibitory; autoreceptor and heteroreceptor, decreases NT releaseNicotinicgNa+, gCa2+Excitatory; increase

3、s NT release, role in nicotine dependenceMechanism of action of ionotropic receptors. Ionotropic receptors directly open ion channels (ionotropic receptors are themselves ion channels). The example is the nicotinic ACh receptor. This is a transmembrane protein (A) consisting of five nonidentical sub

4、units (B), each one passing right through the membrane. The subunits surround a pore (C) that selectively allows certain ions through when it is opened by a ligand (D).Amino AcidsGABAGABAAgCl-Inhibitory (major); ligand-gated ion channel site of action of sedative-hypnotics, alcohol, general anesthet

5、icsGABABcAMP, gK+, gCa2+Inhibitory; modulates motor neuron excitabilityGlutamateNMDA, AMPA, KAgNa+, gCa2+Excitatory (major); roles in LTP (memory), excitotoxicity of neuronsmGlu1, mGlu5IP3, DAG, iCa2+Excitatory; memory consolidation, neuronal excitationmGlu2-mGlu4, mGlu6-mGlu8cAMP, gK+, gCa2+Inhibit

6、ory; role in thalamic sensory processingReceptor sites for GABA, benzodiazepines, barbiturates, and ethanol on the GABAA chloride ion channel. The GABAA chloride ion channel is a protein complex pentameric form that has varying combinations of , , and subunits. GABA binds to a site near the junction

7、 of and subunits, and this causes conformational changes that open the chloride ion channel and lead to neuronal membrane hyperpolarization. Biogenic AminesDopamineD1, D5cAMP, PKAExcitatory; basal ganglia function, memory and performanceD2, D3, D4cAMP, gK+, gCa2+Inhibitory; decreases dopamine releas

8、e, reduces firing of neuronsNorepinephrine1IP3, DAG, iCa2+Excitatory; autonomic nuclei in brain stem2cAMP, gK+, gCa2+Inhibitory; sympathetic outflow from CNS; decreases pain transmission1, 2cAMP, PKAExcitatory; cortex, limbic system, nucleus accumbensSignal transduction with a G protein-coupled rece

9、ptor. (A) A typical G protein-coupled receptor contains a ligand-binding site on the external surface of the plasma membrane and a G protein-binding site on the internal surface. In the inactive state, GDP is bound to the G subunit of the G protein. (B) and (C) When the agonist (Ag) binds to the rec

10、eptor, GTP binds to the G protein and causes the dissociation of GDP. (D) Activation of the G subunit by GTP causes the dissociation of the G and G subunits. (E) The G subunit is then able to activate AC and thereby stimulate the conversion of ATP to cAMP. (F) GTP hydrolysis, catalyzed by G subunit

11、GTPase, leads to reassociation of the G and the G and G subunits.Serotonin (5-HT)*5-HT1cAMP, gK+, gCa2+Inhibitory; role in anxiety and depression5-HT2IP3, DAG, iCa2+Excitatory; widespread distribution, role in antipsychotic action5-HT3gNa+, gCa2+Excitatory; mediate fast neuronal transmission in neoc

12、ortex; presynaptic modulation of NT release5-HT4cAMP, PKAExcitatory; role in cognitive processes, anxietyHistamineH1IP3, DAG, iCa2+Excitatory; increases NT release, role in arousal, anxietyH2cAMP, PKAExcitatory; located in hippocampus, amygdala and basal gangliaH3 cAMP, gK+, gCa2+Inhibitory; autorec

13、eptor and heteroreceptor, decreases NT releaseNeuropeptidesOpioid peptidesMu, delta, kappa cAMP, gK+, gCa2+Inhibitory; analgesic role in sensory processing, role in drug dependence for opioids and other substancesDelirium is a general term that refers to disorders of cognitive processing, and one of

14、 the manifestations of schizophrenia is impaired cognitive processing. Drugs that affect cognitive processing include antipsychotics, CNS stimulants and sedative-hypnotics. Cognitive processing occurs in prefrontal cortical structures, where sensory information is integrated with past experience and

15、 interpreted in a manner that can result in thoughts and behavioral action. Cognitive processing utilizes memory and is influenced by emotions. At the same time, emotions are largely derived from past experience and cognition. Cognitive processing also encompasses abstract reasoning and forethought,

16、 which are processes that do not necessarily result in motor expression but can influence emotional processing and future acts. Memory is the ability to recall events and integrate them into cognitive processing, emotional processing, and ongoing motor activities. One form of memory, called procedur

17、al memory, is used to recall a set of practiced motor actions (e.g., riding a bicycle or typing on a keyboard) and it involves the interaction of limbic structures, the cerebellum, and the basal ganglia. Another form of memory, called declarative memory, involves thoughts and associations that may b

18、e used to determine future actions. For example, remembering that touching a hot stove is painful may keep a child from playing near the stove in the future, and remembering that a family members birthday is approaching may trigger activities such as planning a dinner party. Declarative memory invol

19、ves neuronal tracts in the hippocampus, amygdala, thalamus, and neocortex. Dementia is a term used to describe a number of memory disorders, including Alzheimers disease. The involvement of the basal ganglia in procedural memory may explain why some patients with Parkinsons disease have difficulties

20、 with practiced motor actions. Drugs that affect memory include the cholinesterase inhibitors and CNS depressants such as the benzodiazepines Emotional processing is responsible for the generation of emotions such as anger, anxiety, fear, happiness, love, and sadness. These emotions represent the co

21、nscious perception of neuronal activity originating in the limbic system. Emotions contribute to a state of mental preparedness for anticipated future activities. For example, anxiety contributes to a state of heightened vigilance, which may amplify the response to a future stimulus or event. Disord

22、ers in which emotional processing is defective include anxiety states, mood disorders, and schizophrenia. Drugs that affect emotional processing in the limbic system include anxiolytic (antianxiety) drugs, antidepressants, antipsychotics, CNS stimulants, opioids, and all drugs that produce drug depe

23、ndence. Hence, most CNS drugs have some effect on emotional processing. Sensory processing involves neuronal tracts that perceive external stimuli and transmit that information to the brain. These include the sensory systems responsible for vision, hearing, olfaction, touch, and pain.Disorders in wh

24、ich sensory processing is defective include sleep disorders, chronic pain syndromes, and disorders of the special senses such as blindness, deafness, and taste and olfactory dysfunction. Among the drugs that affect sensory processing are antidepressants, local and general anesthetics, opioid analges

25、ics, and sedative-hypnotics. Motor processing refers to the neuronal activity that enables body movement. Disturbances in motor processing occur in Parkinsons disease, Huntingtons disease, and a variety of degenerative and demyelinating neuron disorders. Drugs that affect motor processing include an

26、tiparkinsonian drugs, CNS stimulants, muscle relaxants, and sedative-hypnotics. 心臟疾病遞質(zhì)的合成、儲(chǔ)存、釋放和滅活突觸后遞質(zhì)受體中樞神經(jīng)興奮心臟疾病欣快、失眠、不安、幻覺(jué)、妄想、躁狂、驚厥等中樞神經(jīng)系統(tǒng)藥理學(xué)特點(diǎn)興奮性遞質(zhì)釋放增多或激動(dòng)興奮性受體中樞神經(jīng)系統(tǒng)藥物的作用機(jī)制與 特點(diǎn)中樞神經(jīng)系統(tǒng)藥物作用的選擇性中樞神經(jīng)抑制鎮(zhèn)靜、抑郁、睡眠、昏迷抑制性遞質(zhì)釋放增多或激動(dòng)抑制性受體Sites of CNS Drug ActionProcessMechanismDrug ExampleMajor UseNT synthes

27、isIncrease synthesis of NT by precursor loadingLevodopa(左旋多巴)ParkinsonismNT storageBlock transport of NT into vesiclesReserpine(利血平)HypertensionNT releaseIncrease NT releaseMethylphenidate(利他林)Attention deficit-hyperactivity disorderNT reuptakeBlock reuptake of NTFluoxetine(氟西汀)DepressionNT degradat

28、ionBlock NT degradation enzymeTacrine(他克林)Alzheimers diseaseReceptor activationAgonist activity at receptorMorphine(嗎啡)Pain statesReceptor blockadeAntagonist activity at receptorClozapine(氯氮平)SchizophreniaSignal transductionBlock formation of second messengersLithium(鋰)Bipolar disorderNeuronal condu

29、ctionBlock axonal action potentialsLidocaine(利多卡因)Local anesthesiaCNS = central nervous system; NT = neurotransmitter. Disorder or IndicationDrug Group/ClassNeurodegenerative DisordersParkinsons diseaseDopamine A-enhancing compoundsAlzheimers diseaseAcetylcholinesterase inhibitorsNMDA receptor antag

30、onistsPsychiatric DisordersPsychotic disorders (schizophrenia)Typical and atypical antipsychoticsMajor depressionAntidepressantsBipolar disorderMood stabilizers, anticonvulsants, atypical antipsychoticsAnxietyAnxiolyticsSleep disordersAnxiolytics and sleep-promoting drugsAnorexia nervosa and bulimia

31、 nervosaAntidepressants, antipsychoticsAnorexia/cachexiaCorticosteroids, progestational agentsObesityAppetite suppressants, fat absorption inhibitorsNeurological DisordersSeizuresAnticonvulsantsMajor Neuropsychiatric Disorders and Classes of Drugs Used for Treatment鎮(zhèn)靜催眠藥中樞神經(jīng)系統(tǒng)藥理抗癲癇藥抗驚厥藥抗精神失常藥鎮(zhèn)痛藥解熱鎮(zhèn)痛

32、抗炎藥抗帕金森病藥Sedative-Hypnotic DrugsAntiepilepsy and Antieclampsia DrugsDrugs for Neurodegenerative DiseasesDrugs for Psychiatric DisordersAntipyretic-analgesic and antiinflammatory drugsAnalgesics第九章鎮(zhèn)靜催眠抗焦慮藥Sedative-Hypnotic and antianxiety DrugsSedative-hypnotic drugs are among the most widely used ph

33、armaceutical agents in the world21concept是指對(duì)中樞神經(jīng)系統(tǒng)具有普遍抑制作用,能夠引起鎮(zhèn)靜、催眠、抗焦慮的藥物鎮(zhèn)靜藥(sedatives):催眠藥(hypnotics): 能緩和激動(dòng), 消除躁動(dòng), 恢復(fù)安靜情緒的藥物能促進(jìn)和維持近似生理睡眠的藥物抗焦慮藥(antianxiety drugs):能緩解焦慮、緊張的藥物 表現(xiàn)：肌肉松馳、血壓、心率、呼吸 多夢(mèng)，伴有眼球快速轉(zhuǎn)動(dòng) 功能：記憶智力恢復(fù) 入睡： NREMS （80分120分） REMS （20分30分） NREMS ，成人一夜交替46次。 非快動(dòng)眼睡眠（NREMS ） 快動(dòng)眼睡眠（REMS ）表現(xiàn)：

34、閉目、瞳孔縮小，呼吸、循環(huán) 功能穩(wěn)定，無(wú)眼球快速轉(zhuǎn)動(dòng)分期：1期(思睡)、2期(淺睡) 3期、4期(慢波睡眠, 夜驚夜游)功能：促進(jìn)生長(zhǎng)、恢復(fù)體力 生理睡眠巴比妥類巴比妥類苯二氮類+- 劑量: 小 中 較大 大 過(guò)量 作用: 抗焦慮 鎮(zhèn)靜催眠 抗驚厥 麻醉 呼吸肌麻痹 長(zhǎng)期、反復(fù)使用耐受性和依賴性藥物作用特點(diǎn) 苯二氮類巴比妥類其它藥物分類安全性較高，即使大劑量也不會(huì)出現(xiàn)麻醉和中樞麻痹與苯二類相比安全性較差水合氯醛目前應(yīng)用較少。新型藥物;佐匹克隆,扎來(lái)普隆(tolerance)(dependence) Dose-response curves of barbiturates and benzodi

35、azepines. The barbiturates exhibit a linear dose-response effect, which progresses from sedation to respiratory depression, coma, and death. Benzodiazepines exhibit a ceiling effect, which precludes severe CNS depression following oral administration of these drugs. Intravenous administration of ben

36、zodiazepines can produce anesthesia and mild respiratory depression. 苯二氮類 (benzodiazepines, BZ or BDZ)地西泮 (diazepam, 安定)氯氮 (chlordiazepoxide，利眠寧)氟西泮 (flurazepam,氟安定)硝西泮 (nitrazepam ,硝基安定)艾司唑侖 （estazolam, 舒樂(lè)安定）奧沙西泮 (oxazepam，去甲羥安定) 三唑侖 (triazolam)1,4-苯并二氮卓的衍生物是20世紀(jì)60年代后相繼問(wèn)世的一類具有鎮(zhèn)靜、催眠及抗焦慮等作用的藥物 P.O 吸收

37、快、完全 血漿蛋白結(jié)合率高 肝藥酶 去甲地西泮（仍有活性） 肝腸循環(huán) 部分 作用時(shí)間 膽汁 少量 排出 胎盤、乳汁 脂溶性高弱堿性藥 Pharmacokinetics地西泮（diazepam, 安定,valium） 1. 抗焦慮: 小于鎮(zhèn)靜劑量時(shí)即有良好的抗焦慮作用, 可 顯著改善緊張、焦慮、激動(dòng)和失眠等癥狀, 主要用于焦慮癥。 2. 鎮(zhèn)靜催眠: 小劑量鎮(zhèn)靜，大劑量催眠。明顯縮短入睡時(shí) 間，顯著延長(zhǎng)睡眠持續(xù)時(shí)間，減少覺(jué)醒次數(shù)。 用于失眠癥。Effects and indications明顯縮短非快動(dòng)眼睡眠的慢波睡眠期，減少夜驚或夜游癥；對(duì)快動(dòng)眼睡眠影響較小;停藥反跳較輕；治療指數(shù)高，對(duì)呼吸影響

38、小，安全范圍較大；依賴性、戒斷癥狀較輕；對(duì)肝藥酶幾無(wú)誘導(dǎo)作用；一般副作用較輕，不引起麻醉。characters3. 抗驚厥和抗癲癇: 有很強(qiáng)的抗驚厥作用, 用于輔助治療破傷 風(fēng)、子癇、小兒高熱及藥物中毒性驚厥。 治療癲癇持續(xù)狀態(tài)的首選藥(iv安定)。4. 中樞性肌松作用: 肌松，降低肌張力?？捎糜诰徑庵袠猩窠?jīng) 病變及局部病變引起的肌肉強(qiáng)直或肌肉 痙攣。 較小劑量：抑制腦干網(wǎng)狀結(jié)構(gòu)下行系統(tǒng)易化神經(jīng)元 較大劑量：增強(qiáng)脊髓神經(jīng)元的突觸前抑制GABA-A受體是由,亞單位組成的離子通道。GABA與亞單位結(jié)合，使氯離子的內(nèi)流增加，使膜電位變?yōu)槌?jí)化，產(chǎn)生突觸后膜抑制效應(yīng)。GABA-A受體上存在苯二氮 卓類

39、、巴比妥類的結(jié)合位點(diǎn)，分別在亞基和亞基，它們?cè)鰪?qiáng)內(nèi)源性的GABA作用，產(chǎn)生抑制效應(yīng)，從而發(fā)揮其鎮(zhèn)靜、催眠、抗焦慮、中樞性肌松和抗驚厥作用。苯二氮卓類增加氯離子通道開(kāi)放頻率巴比妥類 延長(zhǎng)氯離子通道開(kāi)放時(shí)間mechanismdifference口服毒性小, 安全范圍大, 連續(xù)用藥可出現(xiàn)頭昏、嗜睡、乏力等。大劑量偶致視力模糊、震顫、皮疹、白細(xì)胞減少等。靜注過(guò)量可致昏迷和呼吸抑制。耐受性、習(xí)慣性和成癮性 大劑量應(yīng)用時(shí)可產(chǎn)生。Adverse reaction 地西泮（diazepam,安定） 口服吸收快，半衰期較長(zhǎng)，其代謝物仍有活性， 故作用持久。 艾司唑侖（estazolam，舒樂(lè)安定） 口服吸收快，

40、入睡迅速，維持5-8h，副作用少，臨床使用較多。 氟西泮（flurazepam，氟安定） 起效快，作用強(qiáng)而持久，反復(fù)應(yīng)用可有蓄積， 主要用于短期催眠，嚴(yán)重抑郁癥，肝腎疾患 不宜用。 三唑侖（triazolam，三唑安定） 作用快、強(qiáng)、短；催眠時(shí)后遺作用少， 但易有反跳性失眠等。Commonly used preparation 巴比妥酸C5位上進(jìn)行取代而得的一組中樞抑制藥 第二節(jié) 巴比妥類（Barbiturates）分類藥物長(zhǎng)效中效短效超短效苯巴比妥戊巴比妥司可巴比妥硫噴妥脂溶性低高蛋白結(jié)合率低高顯效慢快維持時(shí)間長(zhǎng)短代謝部分肝主肝主肝全肝Pharmacokinetics 1.鎮(zhèn)靜催眠: 縮短入

41、睡時(shí)間, 延長(zhǎng)睡眠時(shí)間，減少覺(jué)醒次數(shù)。 縮短快動(dòng)眼睡眠，久用停藥易發(fā)生反跳現(xiàn)象。 2.抗驚厥、抗癲癇: 大劑量時(shí)有抗驚厥作用, 用于小兒高熱, 破傷風(fēng)、子癇、腦膜炎、腦炎及中樞興奮藥中毒 引起的驚厥。苯巴比妥可用于治療癲癇大發(fā)作及 癲癇持續(xù)狀態(tài)。Effects and indications 3. 麻醉及麻醉前給藥: 硫噴妥鈉作靜脈麻醉或誘導(dǎo)麻醉用; 苯巴比妥或戊巴比妥可作為麻醉前 給藥, 以消除患者手術(shù)前的精神緊張。4. 增強(qiáng)中樞抑制藥的作用：與解熱鎮(zhèn)痛藥合用，增強(qiáng)后者的 鎮(zhèn)痛作用。激動(dòng)GABA受體,延長(zhǎng)Cl-通道開(kāi)放時(shí)間，增強(qiáng)Cl-內(nèi)流mechanism1. 后遺作用: 服用催眠劑量后，

42、次晨可出現(xiàn)頭暈、無(wú)力 困倦、惡心、嘔吐等后遺癥狀, 服用較小劑 量可減少。 2. 耐受性：短期內(nèi)反復(fù)用藥可引起藥效降低，需加大劑量 才能維持原來(lái)的效應(yīng)。 3. 依賴性: 長(zhǎng)期應(yīng)用可產(chǎn)生精神依賴性和軀體依賴性，停 藥后出現(xiàn)戒斷癥狀: 失眠、興奮、焦慮、震顫、 流涕, 甚至驚厥。 4. 急性中毒：昏迷、血壓下降、呼吸抑制等，處理原則洗 胃、給氧、堿化尿液、升壓及中樞興奮藥。Adverse reaction作用/藥物苯二氮類巴比妥類抗焦慮(小于鎮(zhèn)靜劑量)有無(wú)鎮(zhèn)靜催眠有有抗驚厥、抗癲癇有有中樞肌松作用有無(wú)大劑量產(chǎn)生麻醉作用無(wú)有肝藥酶誘導(dǎo)作用無(wú)有安全范圍大小依賴性、戒斷癥狀輕重鎮(zhèn)靜催眠藥最常用其它用途c

43、omparation第十章抗癲癇藥及抗驚厥藥Antiepilepsy and Antieclampsia Drugs西安交通大學(xué)基礎(chǔ)醫(yī)學(xué)院藥理學(xué)系 周筠 癲癇是一種突發(fā)性、短暫性和反復(fù)發(fā)作性大腦功能失調(diào)性疾病。 癲癇是一種腦局部病灶神經(jīng)元細(xì)胞異常過(guò)度放電并向周圍擴(kuò)散而引起的大腦功能短暫失調(diào)綜合征。 突發(fā)性及反復(fù)發(fā)作性為其發(fā)作特點(diǎn)，抽搐或意識(shí)障礙為其主要表現(xiàn)。 concept黃帝內(nèi)經(jīng)中對(duì)癲癇二字有過(guò)確切的定義，“癲”即癲狂，表示發(fā)作時(shí)的意識(shí)障礙；“癇”即抽搐，表示發(fā)作時(shí)的痙攣狀態(tài)。病因分型原發(fā)性癲癇繼發(fā)性癲癇臨床癥狀分型局限性發(fā)作全身性發(fā)作復(fù)合性局限性發(fā)作（精神運(yùn)動(dòng)性發(fā)作）單純局限性發(fā)作 無(wú)意識(shí)

44、障礙局限性發(fā)作繼發(fā)全身強(qiáng)直-陣攣性發(fā)作失神性發(fā)作（小發(fā)作）非典型失神性發(fā)作肌陣攣性發(fā)作癲癇持續(xù)狀態(tài)強(qiáng)直-陣攣性發(fā)作(大發(fā)作)癲癇分型意識(shí)障礙意識(shí)喪失Patterns on electroencephalogram (EEG) in the normal state and during seizures. The locations of seizure foci are shown as shaded areas on the cerebral hemispheres. (A) In the normal state, the EEG shows asynchronous alpha (8-

45、12 Hz) and beta (12-30 Hz) rhythms originating in the cortex of the frontal (F), temporal (T), and occipital (O) lobes. (B) During a partial seizure, synchronous discharges are observed in various areas of the brain. In this example, they are seen in the left frontal and left temporal lobes, but the

46、y are not seen in other lobes. (C) During a generalized tonic-clonic seizure, the tonic phase is characterized by low-frequency and high-amplitude waves, whereas the clonic phase shows synchronous oscillations. (D) During a generalized absence seizure, a synchronous 3-Hz spike-and-wave pattern is se

47、en throughout the cortex.Neuronal mechanisms underlying seizures. In this example, a seizure is caused by the synchronous discharge of a group of neurons (focus) in the cortex. Activation of NMDA receptors increases calcium influx and nitric oxide synthesis. Nitric oxide then diffuses to the presyna

48、ptic neuron and increases the release of glutamate via formation of cyclic guanosine monophosphate. Increased excitatory glutamate neurotransmission leads to long-term potentiation. Long-term potentiation is believed to facilitate a depolarization shift, characterized by prolonged depolarizations wi

49、th spikelets. The depolarization shift can cause adjacent neurons to discharge synchronously and thereby precipitate a seizure.防治癲癇的主要方法是長(zhǎng)期服用抗癲癇藥控制癥狀抗癲癇的作用方式有兩種:A、直接抑制病灶神經(jīng)元的異常放電。B、防止病灶異常放電的擴(kuò)散。機(jī)制:1. 增強(qiáng)腦內(nèi)GABA-A受體功能2.抑制電壓依賴性鈉離子通道3. 抑制T-型電壓依賴型鈣離子通道 苯妥英鈉 苯巴比妥 卡馬西平(酰胺咪嗪) 丙戊酸鈉 乙琥胺 地西泮常用的抗癲癇藥物：苯妥英鈉 （sodium

50、phenytoin，大侖丁 dilantin ）1. 阻滯Na+通道，減少Na+內(nèi)流2. 抑制Ca2+通道，抑制Ca2+內(nèi)流3. 抑制強(qiáng)直后增強(qiáng)PTP(posttetanic potentiation)的形成4. 抑制鈣調(diào)素激酶的活性，影響突觸傳遞功能阻止癲癇病灶異常放電向正常腦組織的擴(kuò)散膜穩(wěn)定作用1. 抗癲癇: 強(qiáng)直陣攣性發(fā)作為首選藥 精神運(yùn)動(dòng)性發(fā)作有效 失神性發(fā)作無(wú)效2. 治療周圍神經(jīng)痛: 三叉神經(jīng)、舌咽神經(jīng)及坐骨神經(jīng)痛3. 抗心律失常: 強(qiáng)心苷過(guò)量中毒所致心律失常的首選藥Effects and indications 1. 局部刺激: 強(qiáng)堿性, 對(duì)胃腸道有刺激, 飯后服。 2.牙齦增生:

51、 多見(jiàn)于青少年和兒童, 長(zhǎng)期服用者發(fā)生率 20%, 膠原組織增生。 3. 神經(jīng)系統(tǒng)反應(yīng): 血藥濃度大于20ug/ml出現(xiàn)眼球震顫, 復(fù)視等，嚴(yán)重者共濟(jì)失調(diào)、精神錯(cuò)亂。 4. 血液及造血系統(tǒng): 長(zhǎng)期服用可致葉酸缺乏, 發(fā)生巨幼紅 細(xì)胞性貧血, 應(yīng)定期檢查血象。 5. 其他： 誘導(dǎo)肝藥酶，加速VitD代謝 , 骨軟化癥adverse reaction DrugEffects on Ion FluxEffects on GABAEffects on GlutamateCarbamazepine (卡馬西平)Blocks voltage-sensitive sodium channels-Diazep

52、am (安定)-Enhances GABA-mediated chloride flux-Ethosuximide (乙琥胺)Blocks T-type calcium channels-Phenobarbital (苯巴比妥)-Enhances GABA-mediated chloride flux-Phenytoin (苯妥英鈉)Blocks voltage-sensitive sodium channels-Primidone (撲米酮)Possibly blocks voltage-sensitive sodium channelsEnhances GABA-mediated chlo

53、ride flux-Valproate (丙戊酸鈉)Possibly blocks voltage-sensitive sodium channels and T-type calcium channelsIncreases GABA synthesis and inhibits GABA degradationPossibly decreases glutamate synthesisMechanisms of Antiepileptic Drugs藥物強(qiáng)直陣攣性發(fā)作(大發(fā)作)單純局限性發(fā)作復(fù)合性局限性發(fā)作(精神運(yùn)動(dòng)性發(fā)作)失神性發(fā)作(小發(fā)作)肌陣攣性發(fā)作癲癇持續(xù)狀態(tài)苯妥英鈉+*+（靜注）卡

54、馬西平+*丙戊酸鈉 +*乙琥胺+*苯巴比妥+*+撲米酮+地西泮+*氯硝西泮+注：“+”表示有效，“*”表示首選 驚厥是中樞神經(jīng)過(guò)度興奮所致, 表現(xiàn)為全身骨骼肌不自主的強(qiáng)烈收縮, 呈強(qiáng)直性或陣攣性抽搐。 常用藥物：巴比妥類、水合氯醛、地西泮（iv） 硫酸鎂 (magnesium sulfate) 口服： 導(dǎo)瀉、利膽 注射： 中樞抑制 骨骼肌松弛 血管擴(kuò)張抗驚厥藥Antieclampsia Drugs抗帕金森病和治療阿爾茨海默病藥Drugs for Neurodegenerative Diseases西安交通大學(xué)基礎(chǔ)醫(yī)學(xué)院藥理學(xué)系 周筠Muhammad Ali, the greatest boxe

55、r 4月11日是“世界帕金森病日”從1997年開(kāi)始，每年的4月11日被確定為“世界帕金森病日”（4月11日是帕金森病的發(fā)現(xiàn)者英國(guó)內(nèi)科醫(yī)生詹姆斯帕金森博士的生日）拳王阿里在一九九六年亞特蘭大奧運(yùn)會(huì)上的精彩瞬間阿里在61場(chǎng)職業(yè)拳賽中勝出56場(chǎng)，更3度登上世界拳王寶座，贏得“最偉大拳王”美譽(yù)第十三章 抗帕金森病藥 帕金森氏病 (Parkinsons disease, PD)又稱震顫麻痹（paralysis agitans） ：慢性進(jìn)行性運(yùn)動(dòng)障礙，屬錐 體外系疾病。多老年人發(fā)病。 1817年，英國(guó)醫(yī)生James Parkinson 首次描述 1953年，肯定病變部位在黑質(zhì)和紋狀體 1960年，發(fā)現(xiàn)與黑

56、質(zhì)紋狀體中DA含量顯著降低 1961年，用L-Dopa治療取得良好的效果 典型臨床癥狀： 靜止震顫、肌肉僵直、運(yùn)動(dòng)遲緩、 姿勢(shì)不穩(wěn), 嚴(yán)重者可伴有記憶障礙和癡呆 藥物分類：擬多巴胺藥和中樞抗膽堿藥 病因?qū)W說(shuō)：多巴胺缺失學(xué)說(shuō) 興奮性神經(jīng)毒性學(xué)說(shuō) 氧化自由基學(xué)說(shuō) 線粒體功能障礙學(xué)說(shuō)擬多巴胺類藥物 左旋多巴 （levodopa, L-dopa） 由酪氨酸羥化而來(lái)，是體內(nèi)合成NA的中間物 吸收： 口服吸收容易 代謝： 排泄：腎臟多巴脫羧酶多巴胺不良反應(yīng)1%原形中樞左旋多巴卡比多巴抑制 Pharmacokinetics 抗帕金森病: 被黑質(zhì)多巴胺能神經(jīng)元攝取，脫羧為多 巴胺補(bǔ)充遞質(zhì), 用于治療帕金森氏病

57、。 特點(diǎn)： 起效慢，藥后23周, 最大療效16個(gè)月 肌肉僵直、運(yùn)動(dòng)困難好，震顫差 輕癥較好，重癥較差，治療效果與殘存神經(jīng)元 數(shù)量有關(guān)。 對(duì)其他原因引起的帕金森綜合征有效。 對(duì)氯丙嗪引起的錐體外系反應(yīng)無(wú)效 Effects and indications 消化道癥狀：80% 與CTZ有關(guān)。 心血管反應(yīng)：體位性低血壓、心律失常 神經(jīng)系統(tǒng)：不自主異常運(yùn)動(dòng) “開(kāi)-關(guān)”現(xiàn)象（on-off phenomena） 精神癥狀 ：興奮，焦慮等（DA過(guò)度興奮中腦-邊緣系統(tǒng) DA受體） 1. 維生素B6：多巴脫羧酶輔酶，增強(qiáng)外周脫羧酶活性 2. 抗精神病藥：阻斷DA受體adverse reaction drug interactionsMechanisms of dopaminergic drugs used in the treatment of Parkinsons disease. Levodopa is transported across the gut wall and the blood-brain barrier and is converted to dopamine in striatal neurons. Carbi