殷明，医学博士药理学教授 34206836 13621816556 myin@sjtu

Shanghai Jiao Tong University

殷明，医学博士药理学教授34206836

13621816556

[email protected]

Drugs that act in the central

nervous system

1, Introduction to CNS

2, General anesthetics


Introduction to CNS

Anatomy

pathways


学习要求（在了解中枢解剖学基础上） 1 ．掌握神经元、神经胶质细胞、神经突触、血脑屏障的构成与功能。

2 ．熟悉中枢神经系统重要递质与受体的分布、生理功能及药物作用机制。

3 ．了解相关神经精神疾病的发病机制与治疗药物。



evolutionally formed last

receiving and processing information, control of sight, listening, movement, memory, wake, autonomic function…

Cortex （皮质，前称：皮层）


A group of interconnected deep brain structures, common to all mammals, and involved in olfaction, emotion, motivation, behavior, and various autonomic functions.cingulate gyrus: 扣带回； pineal ：松果

fornix: 穹窿； thalamus: 丘脑

Pituitary: 垂体； amygdala: 杏仁

Mammillary body: 乳头小体

Limbic system （边缘系统）


responsible for the regulation and coordination of complex voluntary muscular movement as well as the maintenance of posture and balance.

Cerebellum （小脑）


　　 The cerebellum has been reported to play a role in psychiatric conditions such as

　　 schizophrenia （精神分裂症）

　　 autism （自闭症）

　　 mood disorders （情感障碍）

　　 dementia （痴呆）

　　 and attention deficit hyperactivity disorder (ADHD) （多动症） ,

suggesting …


complex of structures

major divisions : thalamus and hypothalamus

functioning

• as a relay system between sensory input neurons and other parts of the brain

• as an interactive site for the central nervous and endocrine systems

working in tandem with the limbic system

Diencephalon （间脑）


thalamus


hypothalamus 下丘脑： integrative area of autonomic nerve

regulation of temperature, water balance, metabolism, blood pressure, circadian rhythm, sex activity, sleeping, etc


Shanghai Jiao Tong Universitybrain stem 脑干


tegmentum( 被盖 ), ascending reticular activating system, NTS ( 孤束核 ), area postrema( 极后区 )

regulation of sleeping, wake, eye movement, vomiting, cardiovascular and respiratory reflex

brain stem 脑干



Spinal cord 脊髓： pathways of senses and movement ；autonomic reflex…


神经元（ neuron ）


Cellular organization of the brain

1012 neurons

1014 synapses

complex networks

What is more? Glia cells 90%

神经元（ neuron ）



神经元突触联系


神经传递过程示意图

Shanghai Jiao Tong Universityneuroglial cells (glial cells or glia)

D: astrocytes E: oligodendrocyte F:Schwann cell G: microglia



Glia (Greek word = glue), not appropriate now.strocytes, oligodendrocytes, microglial cells, ependymal cells, … smaller, more in number, conducting no electrical impulses, … Functions:

• to surround neurons and hold them in place, • to supply nutrient and oxygen to neurons, • to insulate one neuron from another, and• to destroy pathogens and remove dead neurons.• More functions remain explored, for example, neurotransmission,

…

Allen NJ, Barres BA. (2009). Neuroscience: Glia - more than just brain glue. Nature. 457(7230):675-7Those who do not pay attention to glia in neuroscience research are not good neuroscientists.


neuropathway

神经通路


Mesolimbic( 中脑 -边缘 ) pathway: memory and motivating behaviors

Mesocortical( 中脑 -皮质 ) pathway: thinking and schizophrenia

Nigrostriatal( 黑质 -纹状体 ) pathway: motor control

Tuberoinfundibular( 结节 - 漏斗 ) pathway: hormones secreti

on


The synapse and synapse potentials


Shanghai Jiao Tong University pre-synaptic action potential

↓

voltage-sensitive calcium channels

↓

Ca2+ into the terminals

↓

transmitter(s) release

↓

EPSP or IPSP

Shanghai Jiao Tong University Sites of drug action in synapse transmission

1, presynaptic action potential

2, synthesis

3, storage 7, degradation

4, metabolism 8, receptor

5, release 9, ionic conductance

6, reuptake


Ach: acetylcholine

NA: norepinephrine

DA: dopamine

5-HT: serotonin; 5-hydroxytrptamine

GABA: γ-aminobutyric acid

glutamate

neurotransmitters at central synapses


opioid peptides 阿片样肽

histamine 组胺

prostaglandins 前列腺素

tackykinins 速激肽

glycine 甘氨酸

adenosine 腺苷

…


Neurotrophic factors （神经营养因子）

a family of proteins that induce the survival, development, and function of neurons.

Nerve growth factor

Brain-derived neurotrophic factor

Neurotrophin-1 ， 3 ， 4

…


Modulators 调质 : to modulate the response of a neuron to a neurotransmitter or hormone

Transmitter and modulator: action changeable sometimes

Shanghai Jiao Tong UniversityBlood-brain barrier (BBB)

1885: Paul Ehrlich: intravenous dyes in experimental organisms caused staining of all organs except the brain

1913: Edwin Goldmann put forward hypothesis that the cerebral capillaries provide anatomical basis for a physiological barrier between brain and the rest of the body

1950s: Electron microscopy demonstrated that the outermost layers of endothelial cells in brain capillaries are fused together




General anesthetics 全身麻醉药

学习要求 1. 掌握常用全身麻醉药的药理作用及临床应用。 2. 熟悉吸入麻醉药的药动学特点及全身麻醉药的作用机制；熟悉常用静脉麻醉药的作用与应用特点。 3. 了解复合麻醉的概念。


在比较有效的麻醉剂应用之前，人们怎么解决手术镇痛问题？


针灸公元前五世纪（战国时代）：扁鹊，记载中药麻醉，无从考证

公元前二世纪，华陀，麻沸散刮骨疗毒；后人认为主要系曼陀罗主要成分东莨菪碱的中枢抑制作用所致；“蒙汉药” 19 世纪中叶前，国外放血造成休克昏迷行手术；压迫肢体致发麻、冷冻止痛 19 世纪 30 年代，国外捆绑或抓住病人进行手术太监的产生：醉酒和 / 或敲头致昏后去睾丸

手术镇痛简史


1842.3.30, 美国乡村医生 Long, 洒有乙醚毛巾捂鼻，切除颈部囊肿成功。未报道。后来，“乙醚麻醉的发明者”


韦尔斯（牙医）：告诉莫顿用氧化亚氮吸入可以麻醉莫顿请教杰克逊（化学家），后者建议其用乙醚1846.10.16, Wilian T. Morton（牙医）首次在哈佛大学麻省总医院行乙醚麻醉演示，切除下颌肿瘤成功

莫顿

为争发明权：

韦尔斯自杀

莫顿晚年潦倒，死于脑出血

杰克逊罹患精神疾病

Long拒绝加入此官司


General anaesthesia: a state characterized by unconsciousness, analgesia, amnesia, skeletal muscle relaxation and loss of reflexes.

(different from just pain relieving)






Shanghai Jiao Tong UniversityGeneral anesthetics

airway→alveoli →blood →brain

airway←alveoli ←blood ←brain


Minimum alveolar concentration (MAC): concentration that prevents movement in response to skin incision in 50% of subjects studied at sea level (1 atmosphere), in 100% oxygen.


blood:gas partition coefficient:

ratio of the amount dissolved in blood to the amount in the same volume of gas in contact with that blood.

The more blood-soluble the agent (high blood-gas partition coefficient), the slower the onset of effect and the slower the patient goes to sleep

new inhaled anesthetics have low partition coefficient


肺泡内麻醉药浓度达到吸入气中麻醉药浓度 50％所需的时间

氟烷　 480±84 s

异氟烷　 210±21 s

　　七氟烷　 32±6.7 s


麻醉机

Shanghai Jiao Tong University inhaled anesthetics

enflurane （恩氟烷 ), isoflurane （异氟烷 ), desflurane （地氟烷 ), sevoflurane （七氟烷 ), nitrous oxide （氧化亚氮）

ether ( 乙醚 ), flammable and other reasons (nausea and vomiting; long induction time), no longer used clinically now


Advantages of inhaled anesthetics:

short induction period (in seconds) almost no local irritation and side effects satisfactory muscular relaxation recovery fast easy to adjust depth of anesthesia


•

Enflurane 恩氟烷


Enflurane


•

Sevoflurane


Sevoflurane (Sevorane)


Clinical uses: combined use with intravenous anesthetics for operation anesthesia


O

N N

Nitrous oxide

氧化亚氮

（笑气）

O

N

Nitric oxide

一氧化氮

（神经递质）


Shanghai Jiao Tong University Intravenous anesthetics

propofol （丙泊酚）

thiopental （硫喷妥）

midazolam （咪哒唑仑）

ketamine （氯胺酮）

etomidate （依托咪酯）

sodium oxybate （羟丁酸钠）

remifentanil （瑞芬太尼）

Shanghai Jiao Tong UniversityIntravenous anesthetics

remifentanil

瑞芬太尼

ketamine 氯胺酮

etomidate

依托咪酯


propofol ( 丙泊酚 )


thiopental sodium

（硫喷妥钠）

widely used in the middle of last century; rapid intravenous administration may lead to inhibition of breathing


ketamine 氯胺酮


NMDA antagonist

inhibition of thalamus-neocortex; blocking conduction of pain signal

excitation of limbic system

“意识与感觉的分离” rapid onset and potent

minor surgical procedures (battle field anesthetic)

与地西泮合用可提供很满意的麻醉

induction anesthesia

ketamine


Recreational use

“K 粉”、“俱乐部药”、“舞会药”

100 mg：产生自我感觉良好的 (well-being)、幻觉的、漂浮的、知觉轮换和扩张的感觉

2004.7 SFDA: 一类精神药品管理

ketamine


Clinical uses:

induction( 诱导 ) of anesthesia

minor surgical operation when used only

etomidate, propofol and remifentanil are mostly used clinically


Concepts of combined anesthesia

Preanesthetic medication 麻醉前给药

Basal anesthesia 基础麻醉

Induction of anesthesia 诱导麻醉

Combination with muscle relaxant 合用肌松药

Hypothermic anesthesia 低温麻醉

Controlled hypotension 控制性降压

Documents

殷明，医学博士 药理学教授 34206836 13621816556 myin@sjtu

殷明，医学博士药理学教授 34206836 13621816556 myin@sjtu