Transcript N receptor agonists

Autonomic Pharmacology
张纬萍
浙江大学医学院药理
[email protected]
2013.10.11
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
Nervous System
神经系统
Nervous System
Peripheral
Nervous
System (PNS)
神经系统
Central
Nervous
System (CNS)
Nervous System
Peripheral
Nervous
System (PNS)
Efferent
Division
神经系统
Central
Nervous
System (CNS)
Afferent
Division
Nervous System
Peripheral
Nervous
System (PNS)
Efferent
Division
Central
Nervous
System (CNS)
Afferent
Division
Somatic motor
Nervous System
神经系统
Nervous System
Peripheral
Nervous
System (PNS)
Efferent
Division
Central
Nervous
System (CNS)
Afferent
Division
Autonomic nervous
System (ANS)
神经系统
Somatic motor
Nervous System
Nervous System
Peripheral
Nervous
System (PNS)
Efferent
Division
Central
Nervous
System (CNS)
Afferent
Division
Autonomic nervous
System (ANS)
Somatic motor
Nervous System
Parasympathetic副交感
Sympathetic 交感
Enteric 肠神经系统
神经系统
交感和副交感神经系统
thoracolumbar
craniosacral
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
Absorptive cell
吸收细胞
Enterochromaffin cell
肠噬铬细胞
The Enteric Nervous System肠神经系统 (+SNS/PSNS)
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
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
Nervous System
Peripheral
Nervous
System (PNS)
Central
Nervous
System (CNS)
Drugs that produce their primary
therapeutic effect by mimicking or
Efferent
Division
Afferent
Division
altering the functions of autonomic
nervous system are called
autonomic drugs.
Autonomic nervous
System (ANS)
Somatic motor
Nervous System
Parasympathetic
Sympathetic
(Enteric)
神经系统
Neurotransmitters
drugs
Receptors
Neurotransmitters
•Synthesis
•Storage
•Release
•Inactivation
Receptors
•Activation
Neurotransmitters
Mimetics
Indirect actions




Synthesis
Transport and storage
Release
Inactivation
 Direct-acting: receptor agonists
 Indirect-acting: increasing
amounts and/or effects of
transmitters
drugs
Direct actions
Agonists激动剂
Antagonists
拮抗剂
Receptors
Antagonists
 Direct-acting: receptor
antagonists
 Indirect-acting: decreasing
amounts and/or effects of
transmitters
Neurotransmitters
Mimetics
Indirect actions




Synthesis
Transport and storage
Release
Inactivation
 Direct-acting: receptor agonists
 Indirect-acting: increasing
amounts and/or effects of
transmitters
drugs
Direct actions
Agonists激动剂
Antagonists
拮抗剂
Receptors
Antagonists
 Direct-acting: receptor
antagonists
 Indirect-acting: decreasing
amounts and/or effects of
transmitters
Cholinergic Pharmacology
Adrenergic Pharmacology
Cholinergic Terminal
1. Choline Uptake
2. ACh Synthesis
Choline acetyltransferase(ChAT)
Choline + AcCoA → ACh
ChAT
3. ACh Storage
4. ACh Release
5. ACh Effects
a) Postsynaptic
b) Presynaptic
6. ACh Metabolism
Acetylcholinesterase(AChE)
ACh → Choline + Acetate
AChE
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)
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)
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
M receptors :
G-protein
Coupled
Muscarinic
Receptor
Signaling
Pathways
Smooth
Muscle
contraction
cAMP↓
(first,
second,
third messenger)
Heart rate↓
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
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
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
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)
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
The Neuromuscular
Junction (NMJ)
A
B
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)
Drug classification
ACh
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
Cholinomimetics:
Direct-acting drugs
ACh
Derivatives
Bond
cleaved
by AChE
卡巴胆碱
乙酰胆碱
氯贝胆碱
乙酰甲胆碱
AChE
Resistant
Cholinomimetics:
Direct-acting drugs
Bethanechol is most commonly used, particularly postoperation for the treatment of paralytic ileus（麻痹性肠梗
阻） and urinary retention（尿储留）
Natural Muscarinic Agonists
槟榔碱
areca or betal nuts
(India,E. Indies)
匹鲁卡品
毛果云香硷
pilocarpus
(S. Amer. shrub)
毒蕈碱
amanita muscaria
(mushroom)
(Most to least nicotinic)
“Food” Poisoning
Amanita muscaria => muscarine
Pilocarpus=> Pilocarpine
Atropa belladonna => atropine
Deadly Nightshade, 癫茄
Areca nuts=> Arecoline
“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
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）
light
巩膜窦
小梁网
睫状肌
睫状体上皮细胞
paralysis of
accommodation
Ciliary muscle
(dilation)
Canal of Schlemm
mydriasis
zonule
posterior
chamber
Anterior
chamber
lens
far sight
atropine
spasm of
accommodation
iris
悬韧带
miosis
zonule
Anterior
chamber
Ciliary muscle
(contraction)
near sight
pilocarpine
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
Medical Conditions of the Eye
• Cataracts - Clouding of the lens
• Glaucoma - Loss of peripheral or “side” vision
Medical Conditions of the Eye
• Macular Degeneration - Loss of central or
“straight ahead” vision
• Diabetic Retinopathy - Blurring of central
vision to blindness
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
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
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
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
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.
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
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
CholinomimeticsIndirect Agents:
AChE Inhibitors
Acetylcholinesterase (AChE) Activity
酯解部位
阴离子部位
水解
乙酰化AChE
胆碱
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
These agents are
reversible and are
used medically
(glaucoma or MG)
氨甲酰酚羟基
异氟磷
neostigmine
毒扁豆碱
These agents are
irreversible and
are used as
pesticides or for
glaucoma
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.
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 amine)
二甲氨基甲酰化AChE
quaternary amines effective in periphery only
tertiary amines effective in periphery and CNS
（fat-soluble）
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
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
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)
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。
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
Acetylcholinesterase Inhibitors:
Irreversible
Bond is hydrolyzed
in binding to the
enzyme
乙膦硫胆碱
梭曼
For ophthalmic use
对硫磷
These agents are
used as
pesticides or for
glaucoma.
马拉硫磷
Acetylcholinesterase Inhibitors:
Organophosphates
异氟磷
老化
解磷定
Effects of
Organophosphates are
irreversible (covalent
bond formation)
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
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, ……
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
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
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
See you next Class!