1. Pharmacology for Autonomic Drugs Shi-Hong Zhang (张世红), PhD Dept
Pharmacology for Autonomic Drugs Shi-Hong Zhang (张世红), PhD Dept. of Pharmacology, School of Medicine, Zhejiang University

2. Organization of the nervous system Nervous System Peripheral Nervous
System (PNS)
Central
Nervous
System (CNS)
Organization
of the nervous system

3. Peripheral
Nervous
System (PNS)
Efferent
Division
Afferent
Division
Autonomic
System (ANS)
Somatic
System
Parasympathetic
Sympathetic
Enteric

4. 交感中枢：脊髓胸腰段灰质侧角+迷走神经脑干核团
副交感中枢：三叉神经、迷走神经、舌咽神经、舌咽神经的脑部核团

6. The Enteric Nervous System (+SNS/PSNS)
A highly simplified diagram of the intestinal wall and some of the circuitry of the enteric nervous system (ENS). The ENS receives input from both the sympathetic and the parasympathetic systems and sends afferent impulses to sympathetic ganglia and to the central nervous system. Many transmitter or neuromodulator substances have been identified in the ENS; see Table 6–1. ACh, acetylcholine; AC, absorptive cell; CM, circular muscle layer; EC, enterochromaffin cell; EN, excitatory neuron; EPAN, extrinsic primary afferent neuron; 5HT, serotonin; IN, inhibitory neuron; IPAN, intrinsic primary afferent neuron; LM, longitudinal muscle layer; MP, myenteric plexus; NE, norepinephrine; NP, neuropeptides; SC, secretory cell; SMP, submucosal plexus.
The Enteric Nervous System (+SNS/PSNS)

7. The release of noradrenalin 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

8. 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 （蠕动）of the GI tract

10. 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

11. Neurotransmitters
Synthesis
Storage
Release
Degradation
Receptors
Activation

12. Drug actions and classification
Autonomic drugs: mimetics and antagonists
(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

13. Cholinergic Pharmacology
Adrenergic Pharmacology

14. CASE STUDY
In mid-afternoon, a coworker brings 43-year-old JM to the emergency department because he is unable to continue picking vegetables. His gait is unsteady and he walks with support from his colleague. JM has difficulty speaking and swallowing, his vision is blurred, and his eyes are filled with tears. His coworker notes that JM was working in a field that had been sprayed early in the morning with a material that had the odor of sulfur. Within 3 hours after starting his work, JM complained of tightness in his chest that made breathing difficult, and he called for help before becoming disoriented.

15. Cholinergic Terminal Choline Uptake→ ACh Synthesis ACh Storage
Choline + AcCoA → ACh
ChAT
ACh Storage
ACh Release
ACh Effects
- Postsynaptic
- Presynaptic
ACh inactivation
ACh → Choline + Acetate
AChE

16. 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。

17. Cholinesterases
Acetylcholinesterase is located at cholinergic synapses and in erythrocytes (does not hydrolyze succinylcholine)
Pseudocholinesterase (synonyms: plasmacholinesterase or butyrylcholinesterase丁酰胆碱脂酶 ) occurs mainly in plasma, liver and in glia (hydrolyzes succinylcholine)

18. 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

19. M receptors : G-protein Coupled
Muscarinic Receptor Signaling Pathways
平滑肌：M1,3,5
心肌：M2//4

20. M receptors: Depression of the heart (heart rate, conduction)
Contraction of smooth muscles (sensitive: GI tract, bronchial, urinary bladder; insensitive: uterine, blood vascular)
Exocrine glands (sensitive: sweat, tears, salivary; insensitive: GI tract);
Eye (contraction of sphincter muscle of iris: miosis; contraction of ciliary muscle: contraction for near vision)

21. Cholinergic Vasodilation
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

22. 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)

23. 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

24. Ganglionic Neurotransmission
N = Nicotinic AChR
M = Muscarinic AChR
EPSP = Excitatory Postsynaptic Potential
IPSP = Inhibitory Postsynaptic Potential

25. The Neuromuscular Junction (NMJ)B

26. Myasthenia Gravis 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)

27. 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
Cholinesterase reactivators: pralidoxime iodide

28. Drug classification 2 Cholinergic antagonists
(1) Cholinoceptor antagonists
M cholinoceptor antagonists
atropine (Antimuscarinic drugs)
N cholinoceptor antagonists
NN cholinoceptor antagonists: mecamylamine
(Ganglionic blocking drugs, rarely used)
NM cholinoceptor antagonists: succinylcholine
(Neuromuscular blocking drugs )
(2) Botulinum Toxin (blocks ACh release)

29. Cholinomimetics Direct-acting drugs
Ach derivatives （胆碱酯类）
Natural Muscarinic agonists (生物碱类M受体激动剂)
N受体激动剂

30. Bond cleaved by AChE
乙酰胆碱
卡巴胆碱
醋甲胆碱
氯贝胆碱
AChE resistant

31. ACh Derivatives
Bethanechol is most commonly used, particularly post-op for the treatment of paralytic ileus and urinary retention

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

33. “Food” Poisoning Poisoning causes muscarinic overstimulation：
- salivation, lacrimation, visual disturbances;
- abdominal colic and diarrhea
- bronchospasm and bradycardia
- hypotension; shock
Treatment is with atropine
Amanita muscaria
伞形毒蕈
Atropa belladonna 颠茄

34. Pilocarpine (1) Eyes Miosis: contraction of sphincter muscle of iris
Lowing intraocular pressure: enlarging angle of anterior chamber, increasing drainage of aqueous humor
Spasm of accommodation: contraction of ciliary muscle, contraction for near vision
Ophthalmological uses
Glaucoma: narrow (closed)- or wide (open)-angles
used for the emergency lowering of intraocular pressure
Iritis: miotics缩瞳药/mydriatics扩瞳药

35. Circulation of aqueous humor

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

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

38. Glaucoma Glaucoma management involves lowering IOP by
- Decreasing aqueous production by the ciliary
body
- Increasing aqueous outflow through the
trabecular meshwork and uveal outflow paths

39. pilocarpine: parasympathomimetics
increase aqueous outflow by contraction of the ciliary muscle to increase tone and alignment of the trabecular network

40. Pilocarpine
（2） Promoting secretion of exocrine glands, especially in sweat, salivary and tear glands
Systemic use
Antidote for atropine poisoning
Adverse effects
M -like syndrome

41. 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.

43. 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
Cholinesterase reactivators: pralidoxime iodide

44. Acetylcholinesterase (AChE) Activity

45. These agents are reversible and are used medically (glaucoma or MG)
Cholinomimetics- Indirect Agents:
AChE Inhibitors
A. Competitive (reversible)
B. Carbamates (氨甲酰类slowly reversible)
C. Organophosphates (irreversible)
依酚氯铵
新斯的明
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

46. Acetylcholinesterase Inhibitors: Reversible
Edrophonium
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.

47. Acetylcholinesterase Inhibitors: Carbamates
Inhibitory Effects are slowly reversible
Representative Drugs
neostigmine (quaternary amine)
pyridostigmine (quaternary amine) physiostigmine (tertiary amine)
quaternary amines effective in periphery only
tertiary amines effective in periphery and CNS
（fat-soluble）

48. Neostigmine Pharmacological effects
AChE(-), ACh release↑, 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

49. Neostigmine Clinical uses Myasthenia gravis: symptomatic treatment
overdose: cholinergic crisis
Paralytic ileus and bladder: post operative abdominal distension and urinary retention
Paroxysmal superventricular tachycardia（rarely use）
Antidote for tubocurarine (筒箭毒碱) and related drug poisoning
Glaucoma
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

50. Neostigmine Adverse effects
Cholinergic effects: muscarinic and nicotinic effects, treated with atropine (muscarinic)
Contraindications：
mechanical ileus（肠梗阻）
urinary obstruction
bronchial asthma
poisoning of depolarizing skeletal muscle relaxants
(e.g. succinylcholine, 琥珀酰胆碱)

51. 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
Dimethoate 乐果
马拉硫磷
马拉氧磷

52. Organophosphates
Pralidoxime can restore AChE activity if administered soon after toxin exposure.
Conjugating with organophosphate by oxime group;
Conjugating with free organophasphates

53. Organophosphates (1) Toxic symptoms Acute intoxication
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)

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

55. 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 methoiodide (PAM)
Pralidoxime chloride: safer than PAM
Obidoxime chloride: two active oxime groups

56. Why isn’t this ACHEI pesticide neurotoxic to humans?
Malathion
Insects and mammals metabolize the ‘prodrug’ differently
Insects - P450 metabolism: P-S bond converted to P-O bond: now, the molecule, malaoxon, is an active inhibitor
Mammals – esterase activity: hydrolyzes the molecule into inactive metabolites

57. 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)
chemical warfare agents
insecticides

58. Drug classification 2 Cholinergic antagonists
(1) Cholinoceptor antagonists
M cholinoceptor antagonists
atropine (Antimuscarinic drugs)
N cholinoceptor antagonists
NN cholinoceptor antagonists: mecamylamine
(Ganglionic blocking drugs, rarely used)
NM cholinoceptor antagonists: succinylcholine
(Neuromuscular blocking drugs )
Botulinum Toxin (blocks ACh release)

59. Muscarinic Antagonists (Antimuscarinic drugs)
Tertiary amines（叔铵）
Quaternary amines（季铵）
异丙托铵
噻托溴铵

60. Atropa belladonna Datura stramonium 颠茄 曼陀罗 Datura sp. Henbane Seed 洋金花
山莨菪

61. Atropine 1. Pharmacological effects
(1) Inhibition of exocrine gland secretion
salivary, sweat glands
tear, respiratory tract glands
relatively ineffective: GI tract
(2) Eye
mydriasis (瞳孔散大)
rise in intraocular pressure
paralysis of accommodation

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

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

64. Atropine Pharmacological effects
(4) Cardiovascular System: dose dependent
Lower therapeutic doses: HR↓(bradycardia); Blood vessels and blood pressure: no effect
Moderate to high therapeutic doses / high vagal tone: HR↑ (tachycardia); A-V conduction ↑
Larger doses: cutaneous vasodilatation
(5) CNS stimulation
sedation, memory loss, psychosis (high dose)

65. Atropine 2. Clinical uses (1) Ophthalmology
Measurement of the refractive errors (屈光不正): children
Acute iritis or iridocyclitis: mydriatics/miotics
(2) Antispasmodic agent
GI, biliary or renal colic, enuresis
(3) Inhibiting exocrine gland secretion
Preanesthetic medication
(4) Bradycardia
sinus or nodal bradycardia, A-V block
(5) Antidote for organophosphate poisoning

66. Atropine 3. Adverse effects
(1) Side effects dry mouth, blurred vision, “sandy eyes”
(2) toxicity Lethal dose: 80~130 mg (adult), 10 mg (child)
Low: xerostomia (dry mouth); anhidrosis (Dry skin), tachycardia
Moderate: above plus mydriasis, cycloplegia (睫状肌麻痹); difficulty speaking, swallowing & urinating; and hot, red, dry skin
High: above plus ataxia, hallucinations & delirium; coma (i.e. CNS symptoms)

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

68. Scopolamine Actions and clinical uses
Peripheral effects are similar to atropine; but has stronger central effects (depression)
Pre-anesthetic medication, prevention of motion sickness, Parkinson’s disease

69. Anisodamine (654-1,2) Actions and clinical uses
Peripheral effects, similar to atropine; lower toxicity
Septic shock and visceral colic

70. Other antagonists Propantheline (丙胺太林，普鲁本辛)
poor absorption (po) and BBB penetration
antispasmodic effects in GI, treatment of peptic ulcer disease
Tropicamide (托吡卡胺): mydriatics, cycloplegic
shorter duration (1/4 day)
Examination of eyes
Ipratropium (异丙托铵): asthma
Benztropine (苯托品): Parkinson’s disease
Pirenzepine (哌仑西平)：M1 selective, peptic ulcer, asthma

71. CASE STUDY
JH, a 63-year-old architect, complains of urinary symptoms to his family physician. He has hypertension and the last 8 years, he has been adequately managed with a thiazide diuretic and an angiotensin-converting enzyme inhibitor. During the same period, JH developed the signs of benign prostatic hypertrophy, which eventually required prostatectomy to relieve symptoms. He now complains that he has an increased urge to urinate as well as urinary frequency, and this has disrupted the pattern of his daily life. What do you suspect is the cause of JH’s problem? What information would you gather to confirm your diagnosis? What treatment steps would you initiate?

72. Nicotinic receptor antagonists

73. NN receptor antagonists (Ganglionic blocking drugs)
Acting on sympathetic and parasympathetic ganglionic cells; reducing blood pressure by inhibiting sympathetic ganglia ( have been abandoned for clinical use, due to their 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)

74. NM receptor antagonists (Neuromuscular blocking drugs )
Two classes:
Non-depolarizing: drugs act as competitive antagonists
Depolarizing: succinylcholine
Note: Belong to Skeletal Muscle Relaxants. It is important to realize that muscle relaxation does not ensure unconsciousness, amnesia, or analgesia.

75. 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

76. Succinylcholine (Scoline)
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 potentiates their 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

77. 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

78. 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 use under anesthesia

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

80. 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

81. Genetic Variation: Effects on Duration of Action of Succinylcholine
duration of action is prolonged by high doses or by abnormal metabolism. The latter may result from hypothermia (decreases the rate of hydrolysis), low pseudocholinesterase levels, or a genetically aberrant enzyme.
Low pseudocholinesterase levels generally produce only modest prolongation of succinylcholine's actions (2-20 min).
One in 50 patients has one normal and one abnormal (atypical) pseudocholinesterase gene, resulting in a slightly prolonged block (20-30 min).
Even fewer (1 in 3000) patients have two abnormal genes (homozygous atypical) that produce an enzyme with little or no affinity for succinylcholine and have a very long blockade (e.g., 4-8 h) following administration of succinylcholine.
Scoline apnea

82. 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.

83. 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)
(note: curare rarely used)

84. Tubocurarine Effects: competitive blockade of NM receptors
Uses: adjuvant treatment of 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

85. 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）

86. Botulinum Toxin (肉毒杆菌毒素)
Skeletal Muscle Relaxants
blocks ACh release from cholinergic terminals
selective for ACh terminals
- irreversible; Botox acts as a protease that cleaves specific proteins involved in exocytosis, results in flaccid paralysis (松弛性瘫痪) in muscles;

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

88. Botulinum Toxin
an anaerobic bacillus, clostridium botulinum can multiply in preserved food
it synthesizes a protein that can be absorbed (pinocytosis or transport?) from the GI tract to reach the systemic circulation
penetrates tissues to reach cholinergic nerve terminals
then, it is uptaken (pinocytosis) and internalized in vesicles whose lumen becomes acidified
- the low pH of the vesicles splits the inactive molecule into 2 active enzymes that have proteolysis functions

89. Botulinum Toxin Applications
• Strabismus (lack of parallelism of eyes), blepharospasm (eyelid spasm), dystonia (abnormal tonicity).
• Excessive sweating
• Cosmetic procedures ( “frown lines” or “crow’s feet”)
Note: effects can last for ~3-6 months.