1. Pharmacology of the nervous system
Shi-Hong Zhang (张世红), PhD Dept. of Pharmacology, School of Medicine, Zhejiang University

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

3. Rest or digest
Fight or flight

5. Actions and classification of autonomic drugs
(1) Mimetics
- direct-acting: receptor agonists
- indirect-acting: increasing amounts and/or effects of transmitters
(2) Antagonists
- direct-acting: receptor antagonists
- indirect-acting: decreasing amounts and/or effects of transmitters

6. efferent nervous system
Pharmacology of
efferent nervous system
Cholinergic Pharmacology
Adrenergic Pharmacology

7. Cholinergic Terminal

8. Acetylcholine Release
Regulation
- by autoreceptors
ACh acting on presynaptic M2-cholinergic receptors
- by heteroreceptors
NE acting on presynaptic alpha2-adrenergic receptors
- by metabolism (extraneuronal)
乙酰胆碱激活M受体，抑制邻近交感神经末梢去甲肾上腺素的释放；而乙酰胆碱的释放也可被突触前α受体所抑制。 低血糖可抑制ACH的释放。

9. ACh inactivation Cholinesterases
Acetylcholinesterase乙酰胆碱酯酶 is located at cholinergic synapses and in erythrocytes (does not hydrolyze succinylcholine)
Pseudocholinesterase假性胆碱脂酶 (synonyms: plasmacholinesterase or butyrylcholinesterase丁酰胆碱脂酶 ) occurs mainly in plasma, liver and in glia (hydrolyzes succinylcholine)

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

11. M receptors: M2: Depression of the heart (heart rate, conduction)
M1, 3: Contraction of smooth muscles
sensitive: GI tract, bronchial, urinary bladder;
insensitive: uterine, blood vascular
M3: Exocrine glands (sensitive: sweat, tear, salivary; insensitive: GI tract);
M3: Eye (contraction of sphincter muscle of iris: miosis 缩瞳; contraction of ciliary muscle睫状肌: contraction for near vision)
M4/5分布于CNS

12. N receptors NN receptors（ N1 receptors ） NM receptors （N2 receptors ）
- Sympathetic and parasympathetic ganglia
- Adrenal medulla
NM receptors （N2 receptors ）
- The Neuromuscular Junction (NMJ) (Contraction of skeletal muscles)

13. Drug Classification 1. Cholinoceptor agonists
M, N receptor agonists: acetylcholine
M receptor agonists: pilocarpine 匹鲁卡品
N receptor agonists: nicotine
Cholinoceptor antagonists
M cholinoceptor antagonists
atropine (Antimuscarinic drugs)
N cholinoceptor antagonists
NN cholinoceptor antagonists: mecamylamine 美加明
(Ganglionic blocking drugs, rarely used)
NM cholinoceptor antagonists: succinylcholine 琥珀酰胆碱, (Neuromuscular blocking drugs) tubocurarine筒箭毒碱

14. Drug classification 3. Indirect-acting drugs:
(1) Cholinesterase inhibitors
Reversible: neostigmine 新斯的明
Irreversible: organophosphates 有机磷酸酯类
Cholinesterase reactivators: pralidoxime chloride
氯解磷定
(2) Botulinum Toxin (肉毒毒素, Botox, blocks ACh release)

15. Cholinoceptor agonists
Ach derivatives （胆碱酯类）
Natural muscarinic agonists (生物碱类M受体激动剂)
Nicotinic receptor agonists (N受体激动剂)

16. ACh Derivatives Resistant to AChE 乙酰胆碱 卡巴胆碱 醋甲胆碱 氯贝胆碱
Bond cleaved by AChE
乙酰胆碱
卡巴胆碱
乙酰胆碱中的乙酰基被氨基甲酰基取代得到卡巴胆碱，β位引入甲基得到醋甲胆碱。
醋甲胆碱
氯贝胆碱
Resistant to AChE

17. ACh Derivatives
Muscarinic agonist
Sensitivity to cholinesterase
Muscarinic activity in tissues
Atropine antagonism
Nicotinic activity
Cardio-vascular GI
Urinary bladder
Eye*
Acetylcholine
+++ ++ +
Methacholine
Carbachol -
Bethanechol 
Muscarine
Pilocarpine
Bethanechol 氯贝胆碱 is commonly used, particularly post-op for the treatment of paralytic ileus and urinary retention.

18. Natural Muscarinic Agonists
毒蕈碱
槟榔碱
毛果芸香碱
Nicotinic potency
Arecoline: areca or betal nuts (India,E. Indies)
Pilocarpine: pilocarpus (S. Amer. shrub)
Muscarine: amanita muscaria (mushroom)

19. Pilocarpine 1. Pharmacological effects and clinical uses
(1) Effects on 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 眼科 uses
Glaucoma 青光眼: narrow (closed)- or wide (open)-angle
- used for the emergency, lowering intraocular pressure
Iritis 虹膜炎: combination of miotics缩瞳药/mydriatics扩瞳药

20. (Pilocarpine)
(Atropine)

21. Circulation of aqueous humor
房水循环：睫状体上皮细胞-前房角-小梁网-巩膜静脉窦
Pilocarpine causes contraction of longitudinal fibers of the ciliary muscles

22. Glaucoma

23. Pilocarpine
(2) Promoting secretion of exocrine glands, especially in sweat, salivary and tear glands
(3) Antidote解毒剂 for atropine poisoning
2. Adverse effects: M-like syndrome

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

25. Drug Classification 1. Cholinoceptor agonists
Cholinoceptor antagonists
M cholinoceptor antagonists
atropine (Antimuscarinic drugs)
N cholinoceptor antagonists
NN cholinoceptor antagonists: mecamylamine 美加明
(Ganglionic blocking drugs, rarely used)
NM cholinoceptor antagonists: succinylcholine 琥珀酰胆碱, (Neuromuscular blocking drugs) tubocurarine筒箭毒碱

26. Muscarinic Antagonists (Antimuscarinic drugs)
2. Cholinergic antagonists
Muscarinic Antagonists (Antimuscarinic drugs)
Tertiary amines（叔铵）
Quaternary amines（季铵）
包括阿托品及类似生物碱和人工合成代用品（季铵和叔胺类）。叔胺类可经胃肠道吸收，容易进入血脑屏障；季铵类因其高极性吸收差，难透过血脑屏障。
东莨菪碱
异丙托铵
噻托溴铵

27. Atropa belladonna Datura stramonium 颠茄 曼陀罗 Datura metel Henbane Seed
天然的为左旋莨菪碱，不稳定，作用强于右旋，阿托品为消旋品。Atropa希腊神话中主管生死的女神，belladonna漂亮女人。洋金花（Datura metel）与曼陀罗花（Datura stramonium）是生物分类法中的同一属，外形十分相似。曼陀罗花所制麻醉药成为蒙汗药，主要成分是东莨菪碱。
Datura metel
Henbane Seed
洋金花
山莨菪

28. Atropine 1. Pharmacological effects
(1) Inhibition of exocrine gland secretion
salivary, sweat glands
tear, respiratory tract glands
less sensitive: GI tract glands
(2) Eye
mydriasis 瞳孔散大
rise in intraocular pressure 升高眼内压
paralysis of accommodation调节麻痹

29. (Pilocarpine)
(Atropine)

30. Atropine 1. Pharmacological effects
(3) Antispasmodic解痉 action on smooth muscle
sensitive: GI, urinary bladder (spasmodic state)
less sensitive: bile duct, urinary tract, bronchial tract
insensitive: uterus

31. Atropine Pharmacological effects
(4) Cardiovascular system: dose dependent
Lower doses: HR↓ (bradycardia); blood vessels and blood pressure: no effect
Moderate to high doses / high vagal tone: HR↑ (tachycardia); A-V conduction ↑
Large doses: cutaneous vasodilatation
(5) CNS stimulation：
sedation, memory loss, psychosis (high dose)
小剂量时先阻断末梢上的M1受体，减弱对递质释放的负反馈抑制，使Ach释放增加

32. Atropine 2. Clinical uses (1) Ophthalmology 眼科
Measurement of the refractive errors (屈光不正): children
Acute iritis or iridocyclitis: mydriatics/miotics alternatively
(2) Antispasmodic agent
GI, biliary or renal colic, enuresis遗尿
(3) Inhibition of exocrine gland secretion
Preanesthetic medication麻醉前用药
(4) Bradycardia
sinus or nodal bradycardia, A-V block
(5) Antidote for organophosphate poisoning
(6) Septic shock 感染性休克

33. Comparison of effects of several mydriatics
Drug
Concentration (%)
Mydriasis
Cycloplegia
Peak (min)
Duration (d)
Peak (h)
Atropine
1.0
30-40
7-10
1-3
7-12
Homatropine
hydrobromide
10~2.0
40-60
1-2
0.5~1
Tropicamide
0.5~1.0
20-40
0.25
0.5
< 0.25
Cyclopentolate
30-50 1
0.25-1
Eucatropine
2.0~5.0 30
1/12-1/4
(No effect)

34. Atropine 3. Adverse effects
(1) Side effects dry mouth, blurred vision, “sandy eyes” (0.5 mg)
(2) Toxicity Lethal dose: 80~130 mg (adult), 10 mg (child)
Low: xerostomia (dry mouth); anhidrosis (dry skin), tachycardia (1 mg)
Moderate: above plus mydriasis, cycloplegia (睫状肌麻痹); difficulty in speaking, swallowing & urinating; and hot, red, dry skin (2-5 mg)
High: above plus ataxia, hallucinations幻觉 & delirium谵妄; coma (10 mg)

35. Atropine 3. Adverse effects (3) Detoxication Supportive treatment
Symptomatic treatment: e.g. diazepam.
Antidote: Physostigmine or pilocarpine
(4) Contraindications
glaucoma, prostatauxe (前列腺肥大), fever

36. Scopolamine东莨菪碱 Actions and clinical uses
Peripheral effects are similar to atropine; but has stronger central effects (depression, euphoria, memory impairment, hallucination)
Pre-anesthetic medication, prevention of motion sickness, Parkinson’s disease

37. Anisodamine (654-1,2) Actions and clinical uses
Peripheral effects, similar to atropine; weak inhibition of glands; lower toxicity
Septic shock and visceral colic (relieve spasm of vascular smooth muscles)
由我国科学工作者提取自唐古特山莨菪，于1965年4月首用于临床，取名654。654-1为天然生物碱，654-2为合成品。

38. Synthesized surrogates
Tropicamide 托吡卡胺: mydriatic, cycloplegic
shorter duration (1/4 day)
Propantheline 丙胺太林，普鲁本辛
poor oral absorption and BBB penetration
antispasmodic effects in GI, treatment of peptic ulcer
Ipratropium 异丙托铵/tiotropium噻托溴铵: asthma, COPD
Benztropine 苯托品, trihexyphenidyl 苯海索: PD
Pirenzepine 哌仑西平：M1 selective, peptic ulcer, asthma

39. NN receptor antagonists (Ganglionic blocking drugs)
Acting on sympathetic and parasympathetic ganglionic cells; reducing blood pressure by inhibiting sympathetic ganglia (lack of selectivity)
Short-acting; tachyphylaxis (快速抗药反应)
Used for treatment of hypertension
Trimethaphan(咪噻芬)
Mecamylamine (美加明)

40. NM receptor antagonists (Neuromuscular blocking drugs)
Two classes:
Depolarizing: succinylcholine 琥珀酰胆碱
Non-depolarizing: drugs act as competitive antagonists
d-tubocurarine 筒箭毒碱
Note: Belong to Skeletal Muscle Relaxants. It is important to realize that muscle relaxation does not ensure unconsciousness, amnesia, or analgesia.

41. NM receptor antagonists (Neuromuscular blocking drugs )
1. Depolarizing neuromuscular blockers (Non-competitive)
(depolarizing skeletal muscle relaxants)
Act as acetylcholine (ACh) receptor agonists
the depolarized membranes remain depolarized and unresponsive to subsequent impulses (ie, they are in a state of depolarizing block).
Not metabolized by AChE
- diffuse away from the neuromuscular junction and are hydrolyzed in the plasma and liver by pseudocholinesterase (nonspecific cholinesterase, plasma cholinesterase, or butyrylcholinesterase) and elimination by kidney

42. Succinylcholine (Scoline司可林)
acetylcholine
succinylcholine
Succinylcholine is the only depolarizing agent used clinically (t1/2= 2-4 min).
Properties of actions:
initially transient fasciculations （肌束震颤）
anti-AChE agents potentiate its effects
tachyphylaxis after repeated uses
no ganglion-blocking effects at therapeutic doses
the drugs are highly polar, poor bioavailability; i.v.
as quaternary compounds, do not enter CNS
succinylcholine - rapid onset of action (30–60 s)
- short duration of action (typically less than 10 min)
as succinylcholine enters the circulation, most of it is rapidly metabolized by pseudocholinesterase into succinylmonocholine
only a small fraction of the injected dose ever reaches the neuromuscular junction
as drug serum levels fall, succinylcholine molecules diffuse away from the neuromuscular junction, limiting the duration of action.
Mechanism of Action
1.succinylcholine reacts with the nicotinic receptor to open the channel and cause depolarization of the motor end plate
2.causes an initial depolarization of the muscle membrane, often leading to fasciculations and some muscular contractions prior to inducing paralysis.
3.the depolarized membranes remain depolarized and unresponsive to subsequent impulses (ie, they are in a state of depolarizing block). (recall: excitation-concentration coupling requires end plate repolarization ("repriming") and repetitive firing to maintain muscle tension)
4.With succinylcholine a flaccid paralysis results.
5.succinylcholine has the briefest duration of action of all neuromuscular blocking drugs
6.drug of choice for terminating: laryngospasm,
endotracheal intubation,electroconvulsive shock therapy

43. Succinylcholine (Scoline)
Main pharmacological effects
Transient excitation (fasciculations), and then inhibition (relaxation)
Relax skeletal muscles in neck, limbs > face, tongue, throat; less effective on breath muscles at therapeutic doses

44. Succinylcholine (Scoline)
Clinical uses
An adjuvant in anesthesia or operation
Intubation of trachea, esophagus, etc.
Prevention of trauma during electroshock therapy （无抽搐电休克疗法）
Contraindicated in awake patients, should be used under anesthesia

45. Succinylcholine (Scoline)
Adverse effects
(1) Apnea (respiratory paralysis)
overdose or hypersensitive patients;
neostigmine potentiates the toxic effects
(2) Muscle spasm
muscular pain after operation

46. Succinylcholine (Scoline)
(3) Elevation of K+ in plasma
contraindicated in patients with a tendency of hyperkalemia
(4) Malignant hyperthermia
genetic abnormality, treated by dantrolene (Ca2+ release inhibitor)
(5) Others
rise in intraocular pressure (glaucoma);
histamine release

47. Succinylcholine (Scoline)
Drug interactions
- Thiopental （强碱性，可分解scoline）
- ChE inhibitors:
AChE inhibitors, cyclophosphamide, procaine, etc.
- Some antibiotics:
kanamycin, polymyxins, etc. (synergism in neuromuscular blocking)
Cholinesterase Inhibitors
Although cholinesterase inhibitors reverse nondepolarizing paralysis, they markedly prolong a depolarizing phase I block by two mechanisms:
- By inhibiting acetylcholinesterase, they lead to a higher ACh concentration at the nerve terminal, which intensifies depolarization.
- They also reduce the hydrolysis of succinylcholine by inhibiting pseudocholinesterase.

48. NM receptor antagonists
(Neuromuscular blocking drugs)
2. Nondepolarizing neuromuscular blockers (Competitive) (nondepolarizing skeletal muscle relaxants)
Tubocurarine (筒箭毒碱)
Reversibly bind to the nicotinic
receptor at the neuromuscular
junction (competitive antagonists)

49. Tubocurarine Effects: competitive blockade of NM receptors
Uses: adjuvant medication for anesthesia or operations, eg. tracheal intubation
Adverse effects:
Respiratory paralysis: can be reversed by neostigmine
Enhancing histamine release: BP , bronchoconstriction, salivary secretion
Blocking ganglion: BP 
Contraindications: myasthenia gravis, bronchial asthma, shock, child (< 10 y)
Therapeutic Applications:
- to obtain better muscle relaxation in surgical anesthesia.
sensation is unaffected and full anesthesia must be maintained.
- skeletal muscle relaxation facilitating tracheal intubation

50. Benzylisoquinolines（苄基异喹啉类）
Other nondepolarizing neuromuscular blockers
Benzylisoquinolines（苄基异喹啉类）
atracurium （阿曲库铵）
doxacurium（多撒库铵）
mivacurium（米库铵）
Ammonio steroids（类固醇铵类）
pancuronium （潘库铵）
vecuronium（维库铵）
pipecuronium（哌库铵）
rocuronium（罗库铵）
注射死刑：硫喷妥钠+肌松药+氯化钾

51. Drug classification 1. Cholinoceptor agonists
2. Cholinoceptor antagonists
3. Indirect-acting drugs:
Cholinesterase inhibitors
(Anticholinesterases, indirect-acting cholinomimetics)
Reversible: neostigmine 新斯的明
Irreversible: organophosphates 有机磷酸酯类
Cholinesterase reactivators: pralidoxime chloride
氯解磷定
(2) Botulinum Toxin (肉毒毒素, Botox, blocks ACh release)

52. Acetylcholinesterase (AChE) Activity

53. AChE Inhibitors
Simple alcohols with quaternary ammonium group (reversible)
Carbamic acid esters (carbamates, 氨甲酰类, slowly reversible)
C. Organophosphates (irreversible)
依酚氯铵
新斯的明
异氟磷
neostigmine
Reversible agents are used medically (glaucoma or MG)
Irreversible agents are used as pesticides or for glaucoma
毒扁豆碱

54. Acetylcholinesterase Inhibitors: Carbamates
Representative Drugs:
quaternary amine 季铵
neostigmine (新斯的明)
pyridostigmine (吡斯的明)
tertiary amine 叔胺
physostigmine (毒扁豆碱)
galantamine (加兰他敏)
rivastigmine (利斯的明)
donepezil (多奈哌齐)
quaternary amines effective in periphery only tertiary amines effective in periphery and CNS (fat-soluble)

55. Neostigmine 新斯的明 Pharmacological effects
AChE(-), ACh release↑, stimulates NMR
stronger effect on skeletal muscles
effective on GI tract and urinary bladder
more polar and can not enter CNS
relatively weak effects on CVS, glands, eye

56. Neostigmine Clinical uses
Myasthenia gravis (MG): symptomatic treatment
overdose: cholinergic crisis 胆碱能危象：大量出汗，大小便失禁，瞳孔缩小，睫状肌痉挛，心动过缓，低血压，肌无力，呼吸困难
Paralytic ileus 麻痹性肠梗阻 and urinary retention: post operative abdominal distension and urinary retention
Paroxysmal supraventricular tachycardia（rarely use）
Antidote for tubocurarine筒箭毒碱 and related drug poisoning
Glaucoma

57. Neostigmine Adverse effects
Cholinergic effects: muscarinic and nicotinic effects, treated with atropine (muscarinic)
Contraindications：
mechanical ileus（机械性肠梗阻）
urinary obstruction
bronchial asthma
poisoning of depolarizing skeletal muscle relaxants
(e.g. succinylcholine, 琥珀酰胆碱)
Nm症状导致肌无力，抽搐

58. Acetylcholinesterase Inhibitors: Reversible
Edrophonium (依酚氯铵，滕喜龙)
Rapidly absorbed;
A short duration of action (5-15min);
Used in diagnosis of myasthenia gravis;
Excess drug may provoke a cholinergic crisis, atropine is the antidote.

59. Acetylcholinesterase Inhibitors: Irreversible
Bond is hydrolyzed in binding to the enzyme
乙磷硫胆碱 梭曼
For ophthalmic use
Dichlorvos 敌敌畏
对硫磷
对氧磷
沙林梭曼塔崩：战争毒气
乐果吸收后在肝脏转化为毒性更高的氧化乐果，随胆汁储存在胆囊中。
Dimethoate 乐果
马拉硫磷
马拉氧磷

60. Organophosphates (1) Toxic symptoms Acute intoxication 急性中毒
Muscarinic symptom:
eye, exocrine glands, respiration, GI tract, urinary tract, CVS
Nicotinic symptoms:
NN: elevation of BP, increase of HR;
NM: tremor of skeletal muscles
CNS symptoms:
excitation, convulsion; depression (advanced phase)

61. Organophosphates (1) Toxic symptoms Chronic intoxication 慢性中毒
usually occupational poisoning
plasma ChE activity ↓,
weakness, restlessness, anxiety, tremor, miosis, ……

62. Organophosphates (2) Detoxication
Elimination of poison (洗胃导泻); supportive therapy
Antidotes
Atropine－antagonizing muscarinic effects; early, large dose, and repeated use
Cholinesterase reactivators－reactivation of phosphated AChE; moderate-severe patients, early use (more effective on tremor), combined with atropine
Pyraloxime methoiodide (PAM，碘解磷定)
Pralidoxime chloride (PAM-CL 氯解磷定): safer than PAM
碱性溶液+生理盐水洗胃，硫酸镁导泻；但敌百虫在碱性溶液中转化为敌敌畏，毒性更强。
对症治疗：呼吸支持、地西泮镇静、输液抗休克
阿托品化至少维持48小时，对代谢很慢的如乐果，有时可维持至20天

63. Organophosphates
Pralidoxime can restore AChE activity if administered soon after toxin exposure.
Conjugating with organophosphate by oxime group;
Conjugating with free organophasphates
解磷定对磷酰胺类如乐果有机磷中毒无效，一方面与胆碱酯酶结合牢固，另一方面乳剂为苯，合并苯中毒。

64. Summary: AchEI Applications
Pharmacological actions: Increases ACh concentrations
at cholinergic synapses, thereby increasing cholinergic activity.
glaucoma (e.g. physiostigmine毒扁豆碱, echothiophate乙磷硫胆碱 )
myasthenia gravis (e.g. Edrophonium, neostigmine, pyridostigmine )
reverse neuromuscular blockade from competitive
antagonists (neostigmine)
Alzheimer’s disease (tacrine & donepezil, galanthamine)
chemical warfare agents
insecticides

65. Botulinum Toxin 肉毒杆菌毒素
Skeletal muscle relaxants
Blocks ACh release from cholinergic terminals
Selective for ACh terminals
Results in irreversible flaccid paralysis (松弛性瘫痪) in muscles

66. Botulinum toxin inhibits ACh release by cleaving SNAP proteins
Btx, taken up into vesicles, cleaves the SNARE proteins, preventing assembly of the fusion complex and thus blocking the release of ACh.

67. Botulinum Toxin Applications
• Strabismus (斜视), blepharospasm (睑痉挛), dystonia (肌张力障碍).
• Excessive sweating
• Cosmetic procedures ( “frown lines” or “crow’s feet”鱼尾纹)
Note: effects peak at 1-2 months, can last 3-6 months.
Before
After