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5987531.ppt
1. Pharmacology of efferent
nervous system
Shi-Hong Zhang (张世红), PhD
Dept. of Pharmacology,
School of Medicine, Zhejiang University
shzhang713@zju.edu.cn
7. Sympathetic stimulation causes:
• 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 （蠕动） 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 of the GI tract
9.
10. Organization of the nervous system
Sympathetic
Nervous System
Peripheral
Nervous
System (PNS)
Central
Nervous
System (CNS)
Efferent
Division
Afferent
Division
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.
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. • Choline Uptake→
• ACh Synthesis
Choline + AcCoA → ACh
ChAT
• ACh Storage
• ACh Release
• ACh Effects
- Postsynaptic
- Presynaptic
• ACh inactivation
ACh → Choline + Acetate
AChE
Cholinergic Terminal
16. Regulation
- by autoreceptors
ACh acting on presynaptic m2-cholinergic receptors
- by heteroreceptors
NE acting on presynaptic alpha2-adrenergic receptors
- by metabolism (extraneuronal)
Acetylcholine Release
17. ACh inactivation
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)
20. • 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, tear, salivary;
insensitive: GI tract);
• Eye (contraction of sphincter muscle of iris: miosis;
contraction of ciliary muscle睫状肌: contraction for
near vision)
M receptors:
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. • NN receptors（ N1 receptors ）
- Sympathetic and parasympathetic ganglia
- Adrenal medulla
• NM receptors （N2 receptors ）
- The Neuromuscular Junction (NMJ)
(Contraction of skeletal muscles)
N receptors
23. • 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
N receptors : Ligand-gated Ion Channels
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 many autoimmune diseases, stress can make the
symptoms worse
• Treatment is to potentiate cholinergic signaling and to
remove the antibodies (blood dialysis)
27. 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新斯的明
Irreversible: organophosphates 有机磷酸酯类
Cholinesterase reactivators: pralidoxime iodide
碘解磷定
Drug classification
28. 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 (Botox, blocks ACh release)
Drug classification
33. • Poisoning causes muscarinic
overstimulation：
- salivation, lacrimation, visual
disturbances;
- abdominal colic and diarrhea
- bronchospasm and bradycardia
- hypotension; shock
• Treatment is with atropine
Atropa belladonna
Amanita muscaria
“Food” Poisoning
颠茄
伞形毒蕈
34. (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 眼科 uses
Glaucoma 青光眼: narrow (closed)- or wide (open)-angles
used for the emergency lowering of intraocular pressure
Iritis: miotics缩瞳药/mydriatics扩瞳药
Pilocarpine
37. Glaucoma
• Open-angle glaucoma：
disease of the aging eye -
increased intraocular
pressure, degeneration of
the optic head, and
restricted visual field
• 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: increase aqueous outflow by
contraction of the ciliary muscle to increase tone
and alignment of the trabecular network
40. （2） Promoting secretion of exocrine glands,
especially in sweat, salivary and tear glands
• Systemic use
Antidote解毒剂 for atropine poisoning
• Adverse effects
M-like syndrome
Pilocarpine
41. 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.
N receptor agonists:
Nicotine
42. 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 新斯的明
Irreversible: organophosphates 有机磷酸酯类
Cholinesterase reactivators: pralidoxime iodide
碘解磷定
Drug classification
44. A. Competitive (reversible)
B. Carbamates (氨甲酰类slowly reversible)
C. Organophosphates (irreversible)
AChE Inhibitors
neostigmine
These agents are
reversible and are
used medically
(glaucoma or MG)
These agents are
irreversible and
are used as
pesticides or for
glaucoma
毒扁豆碱
新斯的明
依酚氯铵
45. 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.
Other reversible ACHEI: tacrine 他克林, donepezil 多奈哌齐
46. Acetylcholinesterase Inhibitors: Carbamates
Inhibitory Effects are slowly
reversible
Representative Drugs
neostigmine (quaternary amine 季铵)
pyridostigmine (quaternary amine)
physiostigmine (tertiary amine 叔胺)
quaternary amines effective in periphery only
tertiary amines effective in periphery and CNS
（fat-soluble）
47. 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
Neostigmine 新斯的明
48. Clinical uses
1. Myasthenia gravis: 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
2. Paralytic ileus 麻痹性肠梗阻urinary retention: post operative
abdominal distension and urinary retention
3. Paroxysmal superventricular tachycardia（rarely use）
4. Antidote for tubocurarine ( 筒 箭 毒 碱 ) and related drug
poisoning
5. Glaucoma
Neostigmine
52. 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.
54. (2) Detoxication
• Elimination of poison; 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 （氯解磷定）: safer than PAM
– Obidoxime chloride（双复磷）: two active oxime
groups
Organophosphates
56. Why isn’t this ACHEI pesticide neurotoxic to humans?
Insects and mammals metabolize the ‘prodrug’ differently
Mammals – esterase activity: hydrolyzes the molecule into
inactive metabolites
Insects - P450 metabolism: P-S bond converted to P-O bond:
now, the molecule, malaoxon, is an active inhibitor
Malathion马拉硫磷
67. 3. Adverse effects
(3) Detoxication
Supportive treatment
Symptomatic treatment: e.g. diazepam for CNS
symptoms.
Antidote: Physostigmine or pilocarpine
(4) Contraindications
glaucoma, prostatauxe 前列腺肥大, fever
Atropine
68. • 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
Scopolamine东莨菪碱
69. Anisodamine (654-1,2)
• Actions and clinical uses
– Peripheral effects, similar to atropine; lower
toxicity
– Septic shock and visceral colic (relieve
spasm of vascular smooth muscles)
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?
74. • 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)
NN receptor antagonists
(Ganglionic blocking drugs)
75. • 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.
NM receptor antagonists
(Neuromuscular blocking drugs )
76. 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
NM receptor antagonists
(Neuromuscular blocking drugs )
77. Succinylcholine (Scoline司可林)
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
acetylcholine
succinylcholine
78. • 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
Succinylcholine (Scoline)
79. • 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
Succinylcholine (Scoline)
80. • Adverse effects
(1) Apnea (respiratory paralysis)
overdose or hypersensitive patients;
neostigmine potentiates the toxic effects
(2) Muscle spasm
muscular pain after operation
Succinylcholine (Scoline)
81. (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
Succinylcholine (Scoline)
82. 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
83. • 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)
Succinylcholine (Scoline)
84. 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)
NM receptor antagonists
(Neuromuscular blocking drugs)
85. • 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)
Tubocurarine
87. 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
89. 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
90. Applications
• Strabismus (lack of parallelism of eyes 斜视), blepharospasm
(eyelid spasm), dystonia (abnormal tonicity).
• Excessive sweating
• Cosmetic procedures ( “frown lines” or “crow’s feet”鱼尾纹)
Note: effects can last for ~3-6 months.
Botulinum Toxin
