1. Autonomic Pharmacology 张纬萍 浙江大学医学院药理 weiping601@zju.edu.cn

2. 第一次课的内容
1、传出神经系统简介
2、胆碱能神经系统
（1）胆碱受体激动药
（2）胆碱酯酶抑制药

3. Nervous System
神经系统

4. Nervous System
Peripheral
Nervous
System (PNS)
Central
System (CNS)
神经系统

5. Nervous System
Peripheral
Nervous
System (PNS)
Central
System (CNS)
Efferent
Division
Afferent
神经系统

6. Nervous System
Peripheral
Nervous
System (PNS)
Central
System (CNS)
Efferent
Division
Afferent
Somatic motor
神经系统

7. Nervous System
Peripheral
Nervous
System (PNS)
Central
Nervous
System (CNS)
Efferent
Division
Afferent
Division
Autonomic nervous
System (ANS)
Somatic motor
Nervous System
神经系统

8. Sympathetic 交感
Nervous System
Peripheral
Nervous
System (PNS)
Central
System (CNS)
Efferent
Division
Afferent
Parasympathetic副交感
Enteric 肠神经系统
Autonomic nervous
System (ANS)
Somatic motor
Nervous System
神经系统

9. 交感和副交感神经系统

10. thoracolumbar
craniosacral

11. The Enteric Nervous System肠神经系统 (+SNS/PSNS)
longitudinal muscle layer
纵行肌
Myenteric plexus
肌间神经丛
Circular muscle layer
环行肌
Submucosal plexus
粘膜下神经丛
Secretory cell
分泌细胞
Enterochromaffin cell
肠噬铬细胞
Absorptive cell
吸收细胞
The Enteric Nervous System肠神经系统 (+SNS/PSNS)

13. The release of noradrenaline has the following effects
stimulates heartbeat
raises blood pressure
dilates the pupils
dilates the trachea and bronchi
stimulates the conversion of liver glycogen into glucose
shunts blood away from the skin and viscera to the skeletal muscles, brain, and heart
inhibits peristalsis in the gastrointestinal (GI) tract
inhibits contraction of the bladder and rectum

14. Parasympathetic stimulation causes
slowing down of the heartbeat
lowering of blood pressure
constriction of the pupils
increased blood flow to the skin and viscera
peristalsis of the GI tract

15. Peripheral Nervous System (PNS) Central System (CNS)
Sympathetic
Nervous System
Peripheral
Nervous
System (PNS)
Central
System (CNS)
Efferent
Division
Afferent
Parasympathetic
(Enteric)
Drugs that produce their primary therapeutic effect by mimicking or altering the functions of autonomic nervous system are called autonomic drugs.
Autonomic nervous
System (ANS)
Somatic motor
Nervous System
神经系统

16. Neurotransmitters Receptors
drugs
Neurotransmitters
Synthesis
Storage
Release
Inactivation
Receptors
Activation

17. Neurotransmitters Receptors
Indirect actions
Mimetics
Synthesis
Transport and storage
Release
Inactivation
Direct-acting: receptor agonists
Indirect-acting: increasing amounts and/or effects of transmitters
drugs
Direct actions
Antagonists
Agonists激动剂
Direct-acting: receptor
antagonists
Indirect-acting: decreasing amounts and/or effects of transmitters
Antagonists
拮抗剂
Receptors

18. Neurotransmitters Receptors
Indirect actions
Mimetics
Synthesis
Transport and storage
Release
Inactivation
Direct-acting: receptor agonists
Indirect-acting: increasing amounts and/or effects of transmitters
drugs
Direct actions
Antagonists
Agonists激动剂
Direct-acting: receptor
antagonists
Indirect-acting: decreasing amounts and/or effects of transmitters
Antagonists
拮抗剂
Receptors

19. Cholinergic Pharmacology
Adrenergic Pharmacology

20. Cholinergic Terminal Choline Uptake ACh Synthesis ACh Storage
Choline acetyltransferase(ChAT)
Choline + AcCoA → ACh
ChAT
ACh Storage
ACh Release
ACh Effects
Postsynaptic
Presynaptic
ACh Metabolism
Acetylcholinesterase(AChE)
ACh → Choline + Acetate
AChE

21. Acetylcholine Release
by exocytosis
Regulation
- by auto-receptors
ACh acting on presynaptic M2-cholinergic receptors
- by hetero-receptors
NE acting on presynaptic a2-adrenergic receptors
- by metabolism (extra-neuronal)

22. Cholinesterases
胆碱酯酶
Acetylcholinesterase is located at cholinergic synapses and in erythrocytes (does not hydrolyze succinylcholine)
Pseudocholinesterase (假性胆碱酯酶，synonyms: plasma cholinesterase or butyrylcholinesterase丁酰胆碱酯酶) exists mainly in plasma, liver and in glia (hydrolyzes succinylcholine)
AChE主要存在于突触间隙、胆碱能神经元、红细胞，水解ACh
BChE主要存在于血浆，水解其他胆碱脂类

23. Cholinergic Receptors
(cholinoceptors, acetylcholine receptors)
Muscarinic receptors (M receptors)
M1, 3, 5 ; M2, 4
G-protein Coupled
End Organs
Nicotinic receptors (N receptors)
NN (N1) receptors; NM(N2 ) receptors
Ligand-gated Ion Channels
NMJ & Ganglia

24. M receptors : G-protein Coupled
Smooth
Muscle
contraction
cAMP↓
Heart rate↓
M receptors : G-protein Coupled
Muscarinic Receptor Signaling Pathways
(first,
second,
third messenger)

25. M receptors : end organs and effect of activation
血管平滑肌：收缩或舒张
The response of an isolated blood vessel to ACh depends on whether the endothelium is intact (unrubbed) or missing
When the endothelium is present, ACh causes smooth muscle relaxation by stimulating the production of nitric oxide (NO) in the endothelium
In the absence of the endothelium, a small amount of vasoconstriction is observed ——Fred Murad, 1998

26. M receptors : end organs and effect of activation
心脏：Depression of the heart
— 负性肌力：NE释放
— 负性频率：open K+ channel，depolarization
— 负性传导：AV node and Purkinje fibers
— 缩短心房不应期：  AP duration

27. M receptors : end organs and effect of activation
平滑肌：收缩(sensitive: GI tract, bronchial, urinary bladder; insensitive: uterine, blood vascular) Mostly smooth muscle contraction - heart being the main exception
外分泌腺：sensitive: sweat, tears, salivary; insensitive: GI tract;
Eye (contraction of sphincter muscle of iris: miosis缩瞳; contraction of ciliary muscle睫状肌 收缩: contraction for near vision)
CNS: activation，yet ACh can hardly pass BBB

28. N receptors : subtypes and location
NN receptors（ N1 receptors ）
Sympathetic and parasympathetic ganglia
Adrenal medulla
NM receptors （N2 receptors ）
The Neuromuscular Junction (NMJ)
(Contraction of skeletal muscles)

29. Ligand-gated Ion Channels
N receptors :
Ligand-gated Ion Channels
At the NMJ, N receptors Pentameric with four types of subunits, two a subunits bind ACh for ligand gating
All other nAChRs, including those at the peripheral ganglia, have 2 a’s and 3 b’s

30. The Neuromuscular Junction (NMJ)B
The Neuromuscular Junction (NMJ)

31. Myasthenia Gravis重症肌无力
This means “serious disorder the NMJ”
This is an autoimmune disease
Antibodies against the a subunit of the nAChR
The ability of ACh to activate the nAChRs is blocked by the antibodies
As for many autoimmune diseases, stress can make the symptoms worse
Treatment is to potentiate cholinergic signaling and to remove the antibodies (blood dialysis)

32. Drug classification ACh M- and N- Receptors drugs
Indirect actions
Cholinesterase inhibitors (Anticholinesterases)
Reversible: neostigmine
新斯的明
Irreversible: organophosphates
drugs
Direct actions
Cholinoceptor agonists
M, N receptor agonists:
acetylcholine，乙酰胆碱
M receptor agonists:
pilocarpine，匹鲁卡品
N receptor agonists:
nicotine，尼古丁
Cholinergic antagonists
M- and N- Receptors

33. Cholinomimetics: Direct-acting drugs
ACh Derivatives
Bond cleaved by AChE
卡巴胆碱
乙酰胆碱
Poor perfusion of visceral organs and rapid hydrolysis by plasma butyrylcholinesterase limit access of systemically administered ACh to visceral muscarinic receptors. Parasympathetic sacral innervation causes detrusor muscle contraction, increased voiding pressure, and ureter peristalsis, but for similar reasons these responses are not evident with administered ACh.
氯贝胆碱
AChE Resistant
乙酰甲胆碱

34. Cholinomimetics: Direct-acting drugs
Bethanechol is most commonly used, particularly post-operation for the treatment of paralytic ileus（麻痹性肠梗阻） and urinary retention（尿储留）

35. Natural Muscarinic Agonists
匹鲁卡品
毛果云香硷
毒蕈碱
槟榔碱
areca or betal nuts
(India,E. Indies)
pilocarpus
(S. Amer. shrub)
amanita muscaria
(mushroom)
(Most to least nicotinic)

36. “Food” Poisoning Amanita muscaria => muscarine
Atropa belladonna => atropine
Deadly Nightshade, 癫茄
Pilocarpus=> Pilocarpine
Areca nuts=> Arecoline

37. “Food” Poisoning
Poisoning causes muscarinic overstimulation or blocking (for belladonna only)
- salivation, lacrimation(流泪), visual
disturbances;
- abdominal colic and diarrhea
- bronchospasm and bradycardia
- hypotension; shock
Treatment is with atropine

38. Muscarinic Agonists: Parasympathetic Effects & Therapeutic Uses
Pilocarpine
（1）Eyes
Miosis(缩瞳): contraction of sphincter muscle of iris
Lowing intraocular pressure: enlarging angle of anterior chamber, increasing drainage of aqueous humor
Spasm of accommodation(调节痉挛): contraction of ciliary muscle, contraction for near vision
Ophthalmological uses
Glaucoma(青光眼): (concentration ≤ 2%)
narrow (closed)- or wide (open)-angles
it is the drug of choice in the emergency lowering of intraocular pressure
Iritis (虹膜炎): miotics（缩瞳）/mydriatics（扩瞳）

39. light
巩膜窦
小梁网
睫状体上皮细胞
睫状肌

40. atropine pilocarpine 悬韧带 lens miosis mydriasis paralysis of
accommodation
near sight
spasm of
far sight
iris
Anterior
chamber
Ciliary muscle
(contraction)
zonule
Canal of Schlemm
posterior
(dilation)
悬韧带

41. Glaucoma
Disease of the aging eye - increased intraocular pressure (IOP), degeneration of the optic head, and restricted visual field typify primary open-angle glaucoma
obstruction of the aqueous drainage leads to elevated IOP, and may result in glaucomatous damage to the optic nerve

42. Medical Conditions of the Eye
Cataracts - Clouding of the lens
Glaucoma - Loss of peripheral or “side” vision

43. Medical Conditions of the Eye
Macular Degeneration - Loss of central or “straight ahead” vision
Diabetic Retinopathy - Blurring of central vision to blindness

44. Glaucoma Glaucoma management involves lowering IOP by
- Decreasing aqueous production by the ciliary
body
- Increasing aqueous outflow through the
trabecular meshwork (小梁网) and uveal outflow
paths（房水排出通道）
- Neuroprotection

45. Pilocarpine Increase Aqueous Humor Outflow
pilocarpine: parasympathomimetics
increase aqueous outflow by contraction of the ciliary muscle to increase tone and alignment of the trabecular network

46. Muscarinic Agents: Parasympathetic Effects & Therapeutic Uses
Pilocarpine
(2) Promoting secretion of exocrine glands,
especially in sweat, salivary and tear glands
(3) Gastrointestinal tract: increasing tone and motility
(4) Urinary tract: contraction of bladder and relax for
external sphincter muscles
(5) Respiratory system: bronchoconstriction and
secretion
(5) CNS: cortical arousal or activation

47. Muscarinic Agents: Parasympathetic Effects & Therapeutic Uses
Other use
(1) Gastrointestinal disorders, like gastroparesis
(2) Urinary bladder disorders, urinary retention
(3) Xerostomia（口腔干燥）,
(4) Antidote for atropine poisoning

48. N receptor agonists: Nicotine
- actions at ganglia, NMJ, brain
Actions are complex and frequently
unpredictable, because of the variety
of neuroeffector sites and because
nicotine both stimulates and desensitizes effectors. Nicotine typically will affect the：
Periphery: HR, BP,  GI tone & motility
and also
CNS: stimulation, tremors, respiration, emetic effects
The addictive power of cigarettes is directly related to their nicotine content.
可用于戒烟

49. Drug classification 1 Cholinomimetics(Parasympathomimetics)
(1) Direct-acting drugs: Cholinoceptor agonists
M, N receptor agonists: acetylcholine
M receptor agonists: pilocarpine
N receptor agonists: nicotine
(2) Indirect-acting drugs: Cholinesterase inhibitors (Anticholinesterases)
Reversible: neostigmine
Irreversible: organophosphates

50. Drug classification 1 Cholinomimetics
(1) Direct-acting drugs: Cholinoceptor agonists
M, N receptor agonists: acetylcholine
M receptor agonists: pilocarpine
N receptor agonists: nicotine
(2) Indirect-acting drugs: Cholinesterase inhibitors (Anticholinesterases)
Reversible: neostigmine
Irreversible: organophosphates
Cholinergic antagonists： Cholinesterase reactivators pralidoxime iodide

51. Cholinomimetics- Indirect Agents:
AChE Inhibitors

52. Acetylcholinesterase (AChE) Activity
酯解部位
阴离子部位 水解
Ach季胺阳离子头与阴离子部位结合
羰基碳与酯解部位的Ser结合
酯键断裂
乙酰化AChE 胆碱

53. These agents are reversible and are used medically (glaucoma or MG)
Cholinomimetics- Indirect Agents:
AChE Inhibitors
A. Edrophonium依酚氯铵 (reversible, competitive)
B. Carbamates 氨甲酰类(slowly reversible)
C. Organophosphates 有机磷类(irreversible)
新斯的明
依酚氯铵
异氟磷
依酚氯铵主要是非共价结合，还有他克林（tacrine）、多奈派齐（donepezil），后两者对AChE的亲和力高，脂溶性强，易进入中枢
氨甲酰酚羟基
neostigmine
These agents are irreversible and are used as pesticides or for glaucoma
These agents are reversible and are used medically (glaucoma or MG)
毒扁豆碱

54. Acetylcholinesterase Inhibitors: Reversible
Edrophonium 依酚氯铵
Rapidly absorbed;
A short duration of action (5-15min);
Competitive (reversible)
Used in diagnosis of myasthenia gravis.
Excess drug may provoke a cholinergic
crisis, Atropine is the antidote.
或者判断治疗过程中抗AChE的药量是否不足OR过量；

55. Acetylcholinesterase Inhibitors: Carbamates
Inhibitory Effects are slowly reversible
Representative Drugs
neostigmine 新斯的明
(quaternary amine)
physiostigmine 毒扁豆碱
(tertiary amine)
pyridostigmine吡斯的明
quaternary amines effective in periphery only
tertiary amines effective in periphery and CNS
（fat-soluble）
二甲氨基甲酰化AChE

56. Acetylcholinesterase Inhibitors: Carbamates
neostigmine (quaternary amine)
Pharmacological effects
AChE(-), Ach ↑, directly stimulating NMR
stronger effect on skeletal muscles
effective on GI tract and urinary bladder
more polar and can not enter CNS
relatively ineffective on CVS, glands, eye

57. Acetylcholinesterase Inhibitors: Carbamates
neostigmine (quaternary amine)
Clinical uses
Myasthenia gravis: symptomatic treatment, overdose: cholinergic crisis
Paralytic ileus and bladder: post operative abdominal distension and urinary retention
Paroxysmal superventricular tachycardia（阵发性室上速）
Antidote for tubocurarine （筒箭毒碱） and related drug poisoning

58. Acetylcholinesterase Inhibitors: Carbamates
neostigmine (quaternary amine)
Adverse effects
Cholinergic effects: muscarinic and nicotinic effects, treated with atropine (muscarinic)
Contraindications：
mechanical ileus 机械性肠梗阻
urinary obstruction 泌尿道梗阻
bronchial asthma 支气管哮喘
poisoning of depolarizing skeletal muscle relaxants
(e.g. succinylcholine琥珀胆碱)

59. Other reversible AChE inhibitors
Pyridostigmine吡斯的明
Similar as neostigmine, slow but longer duration
Physostigmine毒扁豆碱
Stronger than neostigmine
No direct action on M and N receptor
Can enter CNS, 先兴奋后抑制
Stimulate N receptor of sympathetic nervous node  complex effects on cardiovascular system
Stimulate N receptor of skeletal muscle  肌束震颤
主要用于急性青光眼，抗胆碱药中毒，但其本身的毒性较大。

60. Other reversible AChE inhibitors
Galanthamine加兰他敏
Similar as neostigmine, can enter CNS and treat for AD
Dihydrogalanthamine二氢加兰他敏
Ambenonium chloride安贝氯胺
Demecarium bromide地美溴铵
Distigmine bomide溴地斯的明
Eseridine依舍立定
Eptastigmine依斯的明

61. Acetylcholinesterase Inhibitors: Irreversible
Bond is hydrolyzed in binding to the enzyme
对硫磷
马拉硫磷
乙膦硫胆碱 梭曼
For ophthalmic use
These agents are used as pesticides or for glaucoma.

62. Acetylcholinesterase Inhibitors: Organophosphates
Effects of Organophosphates are irreversible (covalent bond formation)
异氟磷 老化
单烷氧基磷酰化AChE
Pralidoxime(碘解磷定) can restore AChE activity if administered soon after toxin exposure.
Conjugating with organophosphate by oxime group;
Conjugating with free organophasphates
解磷定

63. Acetylcholinesterase Inhibitors: Organophosphates
(1) Toxic symptoms
Acute intoxication
Muscarinic symptoms eye, exocrine glands, respiration, GI tract, urinary tract, CVS
Nicotinic symptoms NN: elevation of BP, increase of HR; N2: tremor of skeletal muscles
CNS symptoms excitation, convulsion(抽搐); depression (advanced phase)
Chronic intoxication
usually occupational poisoning
plasma ChE activity ↓,神经衰弱症候群
weakness, restlessness, anxiety, tremor, miosis, ……

64. Acetylcholinesterase Inhibitors: Organophosphates
(2) Detoxication
Elimination of poison; Supportive therapy
Antidotes
Atropine－antagonizing muscarinic effects; early, larger dose, and repeated use
Cholinesterase reactivators－reactivation of phosphated AChE; moderate-severe patients, early use (More effective on tremor), combined with atropine
Pyraloxime chloride (氯解磷定)：saver than PAM
Pralidoxime iodide (PAM) (碘解磷定)
Obidoxime chloride(双复磷): two active oxime groups
碘解磷定：最早的AChE复活药，但不稳定，对内吸磷、马拉硫磷和对硫磷有些，对敌百虫、敌敌畏等较差，对乐果无效；
双复磷：有两个污基，作用较强，较持久，易进入BBB，对M、N、CNS症状均有效

65. ACHEI Applications
Pharmacological Actions: Increases ACh concentrations
at cholinergic synapses, thereby increasing cholinergic activity.
glaucoma (e.g. physiostigmine毒扁豆碱)
myasthenia gravis (e.g. Edrophonium依酚氯胺, neostigmine新斯的明, pyridostigmine 吡斯的明)
reverse neuromuscular blockade from competitive
antagonists (neostigmine)
Alzheimer’s disease (tacrine他克林 & donepezil多奈派齐)
chemical warfare agents
insecticides

66. Summary Cholinomimetics (Parasympathomimetics)
(1) Direct-acting drugs: Cholinoceptor agonists
M, N receptor agonists: acetylcholine
M receptor agonists: pilocarpine
N receptor agonists: nicotine
(2) Indirect-acting drugs: AChE inhibitors
Reversible: neostigmine
Irreversible: organophosphates
Cholinesterase reactivators：PAM

67. See you next Class!