传出神经系统药理 -...
Transcript of 传出神经系统药理 -...
传出神经系统药理传出神经系统药理(I)(I)
YunYun--Bi Lu, PhDBi Lu, PhD卢韵碧卢韵碧
Dept. of Pharmacology Dept. of Pharmacology School of Medicine, Zhejiang UniversitySchool of Medicine, Zhejiang University
[email protected]@zju.edu.cn
1、传出神经系统简介
2、胆碱能神经系统药理
(1)胆碱受体激动药
(2)胆碱酯酶抑制药
(3)胆碱受体阻断药
3、肾上腺素能神经系统药理
(1)肾上腺素受体激动药
(2)肾上腺素受体阻断药
Organization of the nervous systemOrganization of the nervous system
Nervous SystemNervous System
PeripheralPeripheralNervousNervous
System (PNS)System (PNS)
CentralCentralNervousNervous
System (CNS)System (CNS)
Organization of the nervous systemOrganization of the nervous system
Nervous SystemNervous System
PeripheralPeripheralNervousNervous
System (PNS)System (PNS)
CentralCentralNervousNervous
System (CNS)System (CNS)
EfferentEfferentDivisionDivision
AfferentAfferentDivisionDivision
SomaticSomaticSystemSystem
Organization of the nervous systemOrganization of the nervous system
Nervous SystemNervous System
PeripheralPeripheralNervousNervous
System (PNS)System (PNS)
CentralCentralNervousNervous
System (CNS)System (CNS)
EfferentEfferentDivisionDivision
AfferentAfferentDivisionDivision
AutonomicAutonomicSystem (ANS)System (ANS)
SomaticSomaticSystemSystem
Organization of the nervous systemOrganization of the nervous system
SympatheticSympathetic
Nervous SystemNervous System
PeripheralPeripheralNervousNervous
System (PNS)System (PNS)
CentralCentralNervousNervous
System (CNS)System (CNS)
EfferentEfferentDivisionDivision
AfferentAfferentDivisionDivision
AutonomicAutonomicSystem (ANS)System (ANS)((自主自主))
SomaticSomaticSystemSystem((运动运动))
ParasympatheticParasympathetic
(Enteric)(Enteric)
The Enteric Nervous System (+SNS/PSNS)The Enteric Nervous System (+SNS/PSNS)
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Organization of the nervous systemOrganization of the nervous system
SympatheticSympathetic
Nervous SystemNervous System
PeripheralPeripheralNervousNervous
System (PNS)System (PNS)
CentralCentralNervousNervous
System (CNS)System (CNS)
EfferentEfferentDivisionDivision
AfferentAfferentDivisionDivision
AutonomicAutonomicSystem (ANS)System (ANS)((自主自主))
SomaticSomaticSystemSystem((运动运动))
ParasympatheticParasympathetic
(Enteric)(Enteric)
Drugs that produce their primary therapeutic effect by mimicking (模拟)or altering (改变)the functions of autonomic nervous system are called autonomic drugs.
The Neuron The Synapse
SNAREs
GPCR
NT (ligand)-gated Ion Channel
The Synapse
Thoracic and lumbarThoracic and lumbarSacral region and MedullaSacral region and Medulla
EffectorEffector organorgan
PostPost--ganglionicganglionic neuronneuron
PrePre--ganglionicganglionic neuronneuron
GangliaGanglia
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Thoracic and lumbarThoracic and lumbarSacral region and MedullaSacral region and Medulla
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The release of norepinephrine (sympathetic stimulation) has the following effects
• stimulates heartbeat • raises blood pressure • dilates the pupils (瞳孔)• dilates the trachea and bronchi • stimulates the conversion of liver glycogen into
glucose • shunts blood away from the skin and viscera(内脏) to
the skeletal muscles, brain, and heart • inhibits peristalsis(蠕动) 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 (瞳孔)• increased blood flow to the skin and viscera (内脏)• Peristalsis(蠕动) of the GI tract
NeurotransmittersNeurotransmitters
ReceptorsReceptors
Efferent neurons of ANSEfferent neurons of ANS
drugs
NeurotransmittersNeurotransmitters••Synthesis (Synthesis (合成合成))••Storage(Storage(贮存贮存))••Release(Release(释放释放))••Inactivation(Inactivation(灭活灭活))ReceptorsReceptors••Activation (Activation (激活激活))
Drug actions Drug actions and classificationand classification
Efferent neurons of ANSEfferent neurons of ANS
Drug actions and classificationDrug actions and classification1.1. Mechanisms of drug actionsMechanisms of drug actions1.1 Direct actions on the receptors1.1 Direct actions on the receptors•• AgonistsAgonists•• AntagonistsAntagonists1.2 Indirect actions 1.2 Indirect actions via via affecting transmittersaffecting transmitters•• Synthesis Synthesis •• Transport and storageTransport and storage•• Release Release •• InactivationInactivation1.3 1.3 MimeticsMimetics(拟似药)(拟似药) and antagonistsand antagonists(拮抗剂)(拮抗剂)
(1) (1) MimeticsMimetics•• directdirect--acting:acting: receptor agonistsreceptor agonists•• indirectindirect--acting:acting: increasing amounts and/or effects of transmittersincreasing amounts and/or effects of transmitters
(2) Antagonists(2) Antagonists•• directdirect--acting:acting: receptor antagonistsreceptor antagonists•• indirectindirect--acting:acting: decreasing amounts and/or effects of transmittersdecreasing amounts and/or effects of transmitters
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Cholinergic PharmacologyCholinergic PharmacologyAdrenergic PharmacologyAdrenergic Pharmacology
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Cholinergic PharmacologyCholinergic PharmacologyAdrenergic PharmacologyAdrenergic Pharmacology
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NeurotransmittersNeurotransmitters••SynthesisSynthesis••StorageStorage••ReleaseRelease••InactivationInactivationReceptorsReceptors••ActivationActivation
Efferent neurons of ANSEfferent neurons of ANS
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1.1. CholineCholine UptakeUptake2.2. AChACh SynthesisSynthesisCholineCholine acetyltransferase(ChATacetyltransferase(ChAT))CholineCholine + + AcCoAAcCoA →→ AChACh
ChATChAT((胆碱乙酰转移酶胆碱乙酰转移酶))
3.3. AChACh StorageStorage4.4. AChACh ReleaseRelease5.5. AChACh EffectsEffects
a)a) PostsynapticPostsynapticb)b) PresynapticPresynaptic
6.6. AChACh MetabolismMetabolismAcetylcholinesterase(AChEAcetylcholinesterase(AChE))
AChACh →→ CholineCholine + Acetate+ AcetateAChEAChE((乙酰胆碱酯酶乙酰胆碱酯酶))
Cholinergic TerminalCholinergic Terminal
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RegulationRegulation
-- by by autoreceptorsautoreceptorsAChACh acting on acting on presynapticpresynaptic MM22--cholinergic receptorscholinergic receptors
-- by by heteroreceptorsheteroreceptorsNE acting on NE acting on presynapticpresynaptic 22--adrenergic receptorsadrenergic receptors
-- by metabolism (by metabolism (extraneuronalextraneuronal))
Acetylcholine Releaseby exocytosis
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Cholinesterases
AcetylcholinesteraseAcetylcholinesterase((乙酰胆碱酯酶乙酰胆碱酯酶)) is located at cholinergic is located at cholinergic synapses and in erythrocytes synapses and in erythrocytes (does (does not hydrolyzenot hydrolyzesuccinylcholinesuccinylcholine琥珀胆碱琥珀胆碱))
PseudocholinesterasePseudocholinesterase((假性胆碱酯酶假性胆碱酯酶)) ((synonyms: synonyms: plasmacholinesteraseplasmacholinesterase or or butyrylcholinesterasebutyrylcholinesterase丁酰胆碱酯酶丁酰胆碱酯酶))occurs mainly in plasma, liver and in occurs mainly in plasma, liver and in gliaglia ((hydrolyzeshydrolyzessuccinylcholinesuccinylcholine))
Cholinergic ReceptorsCholinergic Receptors((cholinoceptorscholinoceptors, acetylcholine receptors), acetylcholine receptors)
•• MuscarinicMuscarinic receptors (M receptors)receptors (M receptors)MM1, 3, 51, 3, 5 ; M; M2, 42, 4G-protein Coupled End Organs
•• Nicotinic receptors (N receptors)Nicotinic receptors (N receptors)NNNN (N(N11) receptors; N) receptors; NMM(N(N2 2 )) receptorsreceptorsLigand-gated Ion ChannelsNMJ & Ganglia
Cholinergic PharmacologyCholinergic Pharmacology
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M receptors : M receptors : GG--protein protein CoupledCoupled
MuscarinicMuscarinicReceptorReceptorSignalingSignalingPathwaysPathways
SmoothMusclecontraction
cAMP↓
Heart rate↓
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•• Depression of the heart Depression of the heart (heart rate, (heart rate, conduction)conduction)
•• Contraction of smooth muscles Contraction of smooth muscles (sensitive:sensitive:GI tract, bronchial, urinary bladder;GI tract, bronchial, urinary bladder; insensitive:insensitive:uterine, blood vascular) uterine, blood vascular) Mostly smooth muscle contraction - heart being the main exception
•• Exocrine glandsExocrine glands (sensitive: sensitive: sweat, tears, sweat, tears, salivary; salivary; insensitive: insensitive: GI tract);GI tract);
•• Eye Eye (contraction of sphincter muscle of iris: (contraction of sphincter muscle of iris: miosismiosis; contraction of ; contraction of ciliaryciliary muscle: muscle: contraction for near visioncontraction for near vision))
•• CNSCNS
M receptors : end organs and effect of activationM receptors : end organs and effect of activation
Cholinergic Cholinergic VasodilationVasodilation
• 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) inthe endothelium
• In the absence of the endothelium, a small amount of vasoconstriction is observed
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•• NNNN receptorsreceptors(( NN11 receptors receptors ))•• Sympathetic and parasympathetic gangliaSympathetic and parasympathetic ganglia•• Adrenal medullaAdrenal medulla
•• NNMM receptors receptors ((NN2 2 receptors receptors ))•• The Neuromuscular Junction (NMJ) The Neuromuscular Junction (NMJ)
(Contraction of skeletal muscles)(Contraction of skeletal muscles)
N receptors : subtypes and locationN receptors : subtypes and location
The Neuromuscular The Neuromuscular Junction (NMJ)Junction (NMJ)
AA BB
N receptors : N receptors : LigandLigand--gated Ion Channelsgated Ion Channels
•• At the NMJ, At the NMJ, N receptorsN receptorsPentamericPentameric with four with four types of subunits, two types of subunits, two subunits bind subunits bind AChACh for for ligandligand gatinggating
•• All other All other nAChRsnAChRs, , including those including those at the at the peripheral peripheral ganglia, have 2 ganglia, have 2 ’’ss and 3 and 3 ’’ss
MMyasthenia yasthenia GGravisravis(重症肌无力)(重症肌无力)
•• This means This means ““serious disorder the NMJserious disorder the NMJ””
•• This is an autoimmune diseaseThis is an autoimmune disease
•• Antibodies against the Antibodies against the subunit of the subunit of the nAChRnAChR
•• The ability of The ability of AChACh to activate the to activate the nAChRsnAChRs is is blocked by the antibodiesblocked by the antibodies
•• As for many autoimmune diseases, stress can As for many autoimmune diseases, stress can make the symptoms worsemake the symptoms worse
•• Treatment is to potentiate cholinergic signaling Treatment is to potentiate cholinergic signaling and to remove the antibodies (blood dialysis)and to remove the antibodies (blood dialysis)
1 1 CholinomimeticsCholinomimetics ((Parasympathomimetics))(1) Direct(1) Direct--acting drugs: acting drugs: CholinoceptorCholinoceptor agonistsagonists•• M, N receptor agonists:M, N receptor agonists: acetylcholineacetylcholine(乙酰胆碱)(乙酰胆碱)
•• M receptor agonists:M receptor agonists: pilocarpinepilocarpine(毛果芸香碱)(毛果芸香碱)
•• N receptor agonists:N receptor agonists: nicotinenicotine(烟碱)(烟碱)
(2) Indirect(2) Indirect--acting drugs: Cholinesterase inhibitors acting drugs: Cholinesterase inhibitors ((AnticholinesterasesAnticholinesterases))
•• Reversible:Reversible: neostigmineneostigmine (新斯的明)(新斯的明)
•• Irreversible:Irreversible: organophosphates organophosphates (有机磷脂类)(有机磷脂类)
Drug classificationDrug classification☺
1 1 CholinomimeticsCholinomimetics ((Parasympathomimetics))(1) Direct(1) Direct--acting drugs: acting drugs: CholinoceptorCholinoceptor agonistsagonists•• M, N receptor agonists: acetylcholineM, N receptor agonists: acetylcholine•• M receptor agonists:M receptor agonists: pilocarpinepilocarpine•• N receptor agonists: nicotineN receptor agonists: nicotine(2) Indirect(2) Indirect--acting drugs: Cholinesterase inhibitors acting drugs: Cholinesterase inhibitors
((AnticholinesterasesAnticholinesterases))•• Reversible:Reversible: neostigmineneostigmine•• Irreversible:Irreversible: organophosphatesorganophosphates
Drug classificationDrug classification☺☺
CholinomimeticsCholinomimetics::DirectDirect--acting drugsacting drugs
AChEAChEResistantResistant
AChAChDerivativesDerivatives
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AChACh DerivativesDerivatives
BethanecholBethanechol(贝胆碱)(贝胆碱) is most commonly is most commonly used, particularly postused, particularly post--op for the op for the treatment of paralytic treatment of paralytic ileusileus and urinary and urinary retention.retention.
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Natural Natural MuscarinicMuscarinic AgonistsAgonists
(Most to least nicotinic)(Most to least nicotinic)
• Muscarine: amanita muscaria (mushroom)• Pilocarpine: pilocarpus (S. Amer. shrub)• Arecoline: areca or betal nuts (India,E. Indies)
• Poisoning causes muscarinic overstimulation- salivation(流涎), lacrimation(流泪), visual disturbances;- abdominal colic and diarrhea- bronchospasm and bradycardia- hypotension; shock
• Treatment is with atropine (阿托品)
Atropa belladonna => atropineAmanita muscaria => muscarine
““FoodFood”” PoisoningPoisoning略
MuscarinicMuscarinic Agonists:Agonists:Parasympathetic Effects & Parasympathetic Effects &
Therapeutic UsesTherapeutic UsesPilocarpinePilocarpine (毛果芸香碱,匹鲁卡品)(毛果芸香碱,匹鲁卡品)
((11))EyesEyes•• MiosisMiosis(缩瞳)(缩瞳)::•• Lowing intraocular pressure Lowing intraocular pressure (减低眼内压)(减低眼内压) ::
•• Spasm of accommodationSpasm of accommodation(调节痉挛)(调节痉挛): :
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((11))EyesEyes•• MiosisMiosis: : contraction of sphincter muscle of iris•• Lowing intraocular pressure:Lowing intraocular pressure: enlarging angle of anterior
chamber, increasing drainage of aqueous humor (房水)•• Spasm of accommodation: Spasm of accommodation: contraction of ciliary muscle,
contraction for near vision
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pilocarpinepilocarpine
pilocarpinepilocarpine
miosismiosis
near sightnear sight
spasm of spasm of accommodationaccommodation
irisiris
Anterior Anterior chamberchamber
CiliaryCiliary musclemuscle(contraction)(contraction)
zonulezonule
atropineatropinelenslens
mydriasismydriasis
paralysis of paralysis of accommodationaccommodation
far sightfar sightAnterior Anterior chamberchamber
zonulezonuleCanal of Canal of SchlemmSchlemm
posteriorposteriorchamberchamber
CiliaryCiliary musclemuscle(dilation)(dilation)
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Circulation of Aqueous humorCirculation of Aqueous humor
Glaucoma(青光眼)• 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
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Normal Glaucoma
field of vision
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GlaucomaGlaucoma• Glaucoma management involves lowering IOP by
- Decreasing aqueous production by the ciliarybody
- Increasing aqueous outflow through the trabecular meshwork and uveal outflow paths
• pilocarpine: parasympathomimeticsincrease aqueous outflow by 1)contraction of the ciliary muscle to increase tone 2)alignment of the trabecular network
PilocarpinePilocarpine Increase Aqueous Increase Aqueous Humor OutflowHumor Outflow
MuscarinicMuscarinic Agonists:Agonists:Parasympathetic Effects & Parasympathetic Effects &
Therapeutic UsesTherapeutic UsesPilocarpinePilocarpine((11))EyesEyes•• MiosisMiosis: : contraction of sphincter muscle of iris•• Lowing intraocular pressure:Lowing intraocular pressure: enlarging angle of anterior
chamber, increasing drainage of aqueous humor•• Spasm of accommodation: Spasm of accommodation: contraction of ciliary muscle,
contraction for near vision
•• Ophthalmological usesOphthalmological usesGlaucoma:Glaucoma: narrow (closed)narrow (closed)-- oror wide (open)wide (open)--anglesanglesit is the drug of choice it is the drug of choice in the emergencyin the emergency lowering of intraocular pressurelowering of intraocular pressureIritisIritis:: miotics/mydriaticsmiotics/mydriatics ((缩瞳药缩瞳药//扩瞳药扩瞳药))
PilocarpinePilocarpine((22)) Promoting secretion of exocrine Promoting secretion of exocrine
glands, glands, especially in sweat, salivary and especially in sweat, salivary and tear glands (tear glands (如:口腔干燥如:口腔干燥))
•• Systemic useSystemic useAntidote(Antidote(解毒药解毒药)) for atropine poisoning for atropine poisoning
MuscarinicMuscarinic Agents:Agents:Parasympathetic Effects & Parasympathetic Effects &
Therapeutic UsesTherapeutic Uses
1 1 CholinomimeticsCholinomimetics ((Parasympathomimetics))(1) Direct(1) Direct--acting drugs: acting drugs: CholinoceptorCholinoceptor agonistsagonists•• M, N receptor agonists: M, N receptor agonists: acetylcholineacetylcholine•• M receptor agonists: M receptor agonists: pilocarpinepilocarpine•• N receptor agonists:N receptor agonists: nicotinenicotine(2) Indirect(2) Indirect--acting drugs: Cholinesterase inhibitors acting drugs: Cholinesterase inhibitors
((AnticholinesterasesAnticholinesterases))•• Reversible: Reversible: neostigmineneostigmine•• Irreversible: organophosphatesIrreversible: organophosphates
Drug classificationDrug classification
-- actions at ganglia, NMJ, brain
Actions are complex and frequently unpredictable, because of the variety of neuroeffector sites and becausenicotine both stimulates and desensitizes effectors. Nicotine typically will affect the
Periphery: HR, BP, GI tone & motilityand also
CNS: stimulation, tremors, respiration, emetic effects
The addictive power of cigarettes is directly related to their nicotine content.
N receptor agonists:N receptor agonists:NicotineNicotine略
CholinomimeticsCholinomimetics--Indirect Agents: Indirect Agents: AChEAChE InhibitorsInhibitors
1 1 CholinomimeticsCholinomimetics(1) Direct(1) Direct--acting drugs: acting drugs: CholinoceptorCholinoceptor agonistsagonists•• M, N receptor agonists: M, N receptor agonists: acetylcholineacetylcholine•• M receptor agonists: M receptor agonists: pilocarpinepilocarpine•• N receptor agonists: nicotineN receptor agonists: nicotine(2) Indirect(2) Indirect--acting drugs: Cholinesterase inhibitors acting drugs: Cholinesterase inhibitors
((AnticholinesterasesAnticholinesterases))•• Reversible:Reversible: neostigmineneostigmine (新斯的明)(新斯的明)
•• Irreversible:Irreversible: organophosphates organophosphates (有机磷酸酯类)(有机磷酸酯类)
Drug classificationDrug classification
1 1 CholinomimeticsCholinomimetics(1) Direct(1) Direct--acting drugs: acting drugs: CholinoceptorCholinoceptor agonistsagonists•• M, N receptor agonists: M, N receptor agonists: acetylcholineacetylcholine•• M receptor agonists: M receptor agonists: pilocarpinepilocarpine•• N receptor agonists: nicotineN receptor agonists: nicotine(2) Indirect(2) Indirect--acting drugs: Cholinesterase inhibitors acting drugs: Cholinesterase inhibitors
((AnticholinesterasesAnticholinesterases))•• Reversible:Reversible: neostigmineneostigmine•• Irreversible:Irreversible: organophosphatesorganophosphates
Drug classificationDrug classification
Cholinergic antagonistsCholinergic antagonists:: Cholinesterase Cholinesterase reactivatorsreactivators ppralidoximeralidoxime iodide iodide (碘解磷定)(碘解磷定)
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Acetylcholinesterase (AChE) Activity
6×105 Ach per minute
胆碱酯酶
乙酸
酯解部位
Ach与AchE复合物
阴离子部位
乙酰化AchE
胆碱
A. Edrophonium (reversible, competitive)
B. Carbamates (slowly reversible)
C. Organophosphates (irreversible)
CholinomimeticsCholinomimetics-- Indirect Agents: Indirect Agents: AChEAChE InhibitorsInhibitors
neostigmineThese agents are These agents are reversible and are reversible and are
used medically used medically (glaucoma or MG)(glaucoma or MG)
These agents are These agents are irirreversible and reversible and
are used as are used as pesticides or for pesticides or for
glaucomaglaucoma
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Acetylcholinesterase Inhibitors:Reversible
Edrophonium chloride (依酚氯铵,滕喜隆)
Rapidly absorbed; A short duration of action (5-15min);Competitive (reversible)
Used in diagnosis of myastheniagravis (重症肌无力).
Excess drug may provoke a cholinergic crisis(胆碱能危象), Atropine is the antidote.
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Acetylcholinesterase Inhibitors: Carbamates
Inhibitory Effects are slowly reversible
Representative Drugsneostigmine (新斯的明)physostigmine (毒扁豆碱)pyridostigmine (吡斯的明)
氨甲酰基转到丝氨酸羧基
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Acetylcholinesterase Inhibitors: Carbamates
Inhibitory Effects are slowly reversible
Representative Drugsneostigmine (quaternary amine)physostigmine (tertiary amine)pyridostigmine (quaternary amine)
quaternary amines effective in periphery onlytertiary amines effective in periphery and CNS(fat-soluble)
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neostigmine (quaternary amine) –– Pharmacological effectsPharmacological effects•• AChEAChE((--), ), AChACh releaserelease↑↑, stimulating N, stimulating NMMRR•• stronger effect on skeletal muscles stronger effect on skeletal muscles •• effective on GI tract and on urinary bladder effective on GI tract and on urinary bladder •• more polar and can not enter CNSmore polar and can not enter CNS•• relatively ineffective on CVS, glands, eyerelatively ineffective on CVS, glands, eye–– Clinical usesClinical uses•• Myasthenia gravis(Myasthenia gravis(重症肌无力重症肌无力):): symptomatic treatment,
overdose: cholinergic crisis•• Paralytic Paralytic ileusileus and bladder: and bladder: post operative abdominal
distension(术后腹气胀) and urinary retention(尿储留)•• Paroxysmal Paroxysmal superventricularsuperventricular tachycardia(tachycardia(阵发性室上性阵发性室上性
心动过速心动过速))•• Antidote for Antidote for tubocurarinetubocurarine((筒箭毒碱筒箭毒碱)) and related drug and related drug
poisoningpoisoning
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neostigmine (quaternary amine) –– Adverse effectsAdverse effects•• Cholinergic effects: Cholinergic effects: muscarinicmuscarinic and nicotinic effects, and nicotinic effects,
treated with atropine (treated with atropine (muscarinicmuscarinic))
•• ContraindicationsContraindications::mechanical mechanical ileusileus (机械性肠梗阻)(机械性肠梗阻)
urinary obstruction urinary obstruction (尿路梗阻)(尿路梗阻)
bronchial asthma bronchial asthma (支气管哮喘)(支气管哮喘)
poisoning of depolarizing skeletal muscle relaxants poisoning of depolarizing skeletal muscle relaxants ((去极化型肌松药去极化型肌松药)) (e.g. (e.g. succinylcholinesuccinylcholine 琥珀胆碱琥珀胆碱) )
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Other reversible AChE inhibitors
Pyridostigmine 吡斯的明
•• Similar as Similar as neostigmineneostigmine, slow but longer duration, slow but longer duration
Physostigmine毒扁豆碱•• Stronger than Stronger than neostigmineneostigmine•• No direct action on M and N receptorNo direct action on M and N receptor•• Can enter CNS, Can enter CNS, 先兴奋后抑制先兴奋后抑制
•• Stimulate N receptor of sympathetic nervous node Stimulate N receptor of sympathetic nervous node complex effects on cardiovascular systemcomplex effects on cardiovascular system
•• Stimulate N receptor of skeletal muscle Stimulate N receptor of skeletal muscle 肌束震颤肌束震颤
•• 主要用于急性青光眼,抗胆碱药中毒,但其本身的毒性较主要用于急性青光眼,抗胆碱药中毒,但其本身的毒性较大。大。
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Other reversible AChE inhibitors
Galanthamine加兰他敏
•• Similar as Similar as neostigmineneostigmine, can enter CNS and treat for , can enter CNS and treat for ADAD
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
These agents are used as
pesticides or for glaucoma.
Acetylcholinesterase Inhibitors: Irreversible
Bond is hydrolyzed in binding to the enzyme
For ophthalmic useFor ophthalmic use((乙硫磷乙硫磷))
((马拉硫磷马拉硫磷))
((对硫磷对硫磷))
((梭曼梭曼))
(1) Toxic symptoms(1) Toxic symptoms–– Acute intoxicationAcute intoxication•• MuscarinicMuscarinic symptomssymptoms eye, exocrine glands, eye, exocrine glands,
respiration, GI tract, urinary tract, CVSrespiration, GI tract, urinary tract, CVS•• Nicotinic symptomsNicotinic symptoms NNNN: : elevation of BP, increase of elevation of BP, increase of
HR;HR; NN22: : tremor of skeletal musclestremor of skeletal muscles•• CNS symptomsCNS symptoms excitation, convulsion; depression excitation, convulsion; depression
(advanced phase)(advanced phase)–– Chronic intoxicationChronic intoxication•• usually occupational poisoningusually occupational poisoning•• plasma plasma ChEChE activity activity ↓↓,,•• weakness, restlessness, anxiety, tremor, weakness, restlessness, anxiety, tremor, miosismiosis, , …………
Acetylcholinesterase Inhibitors: Organophosphates
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(2) (2) DetoxicationDetoxication
••Elimination of poison; Supportive therapyElimination of poison; Supportive therapy••AntidotesAntidotes
AtropineAtropine--antagonizing antagonizing muscarinicmuscarinic effects; effects; early, early, larger dose, and repeated uselarger dose, and repeated use
Cholinesterase Cholinesterase reactivatorsreactivators--reactivation of reactivation of phosphorylatedphosphorylated AChEAChE; ; moderatemoderate--severe patients, early severe patients, early use (more effective on tremor), combined with atropineuse (more effective on tremor), combined with atropine–– PyraloximePyraloxime methoiodidemethoiodide (PAM(PAM,碘解磷定,碘解磷定))–– PralidoximePralidoxime chloride(chloride(氯解磷定氯解磷定): ): saver than PAMsaver than PAM–– ObidoximeObidoxime chloride: chloride: two active two active oximeoxime groups(groups(肟基肟基))
Acetylcholinesterase Inhibitors: Organophosphates
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Acetylcholinesterase Inhibitors: Organophosphates
Effects of Organophosphates are irreversible (covalent bond formation)
Pralidoxime(碘解磷定) can restore AChE activity if administered soon aftertoxin exposure.
••Conjugating with Conjugating with organophosphate organophosphate by by oximeoximegroup ; group ;
••Conjugating with Conjugating with free free organophasphatesorganophasphates
异氟磷
解磷定
单烷氧基磷酰化AChE老化
有机磷转到-NOH
磷酰化
glaucoma (e.g. physiostigmine, Echothiophate )
myasthenia gravis (e.g. Edrophonium, neostigmine, pyridostigmine )
reverse neuromuscular blockade from competitiveantagonists (neostigmine)
Alzheimer’s disease (tacrine & donepezil)
chemical warfare agents
insecticides
Summary: ACHEI ApplicationsPharmacological Actions: Increases ACh concentrations at cholinergic synapses, thereby increasing cholinergic activity.
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Summary
CholinomimeticsCholinomimetics ((Parasympathomimetics))(1) Direct(1) Direct--acting drugs: acting drugs: CholinoceptorCholinoceptor agonistsagonists
M, N receptor agonists: M, N receptor agonists: acetylcholineacetylcholineM receptor agonists: M receptor agonists: pilocarpinepilocarpineN receptor agonists: nicotineN receptor agonists: nicotine
(2) Indirect(2) Indirect--acting drugs: acting drugs: AChEAChE inhibitorsinhibitorsReversible: Reversible: neostigmineneostigmineIrreversible: organophosphatesIrreversible: organophosphatesCholinesterase Cholinesterase reactivatorsreactivators::PAMPAM
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2 Cholinergic antagonists2 Cholinergic antagonists(1) (1) CholinoceptorCholinoceptor antagonistsantagonists•• M M cholinoceptorcholinoceptor antagonistsantagonists
–– atropine (atropine (Antimuscarinic drugs, 阿托品))
•• N N cholinoceptorcholinoceptor antagonistsantagonists–– NNN N cholinoceptorcholinoceptor antagonists:antagonists: mecamylaminemecamylamine
((Ganglionic Blocking drugs, rarely used, 美卡拉明))–– NNM M cholinoceptorcholinoceptor antagonists:antagonists: succinylcholinesuccinylcholine
((Neuromuscular Blocking drugs, 琥珀胆碱 ))
•• BotulinumBotulinum Toxin Toxin ((blocks ACh release))
Drug classificationDrug classification☺
NM
NNNN
MM
2 Cholinergic antagonists2 Cholinergic antagonists(1) (1) CholinoceptorCholinoceptor antagonistsantagonists•• M M cholinoceptorcholinoceptor antagonistsantagonists
–– atropine (atropine (Antimuscarinic drugs))
•• N N cholinoceptorcholinoceptor antagonistsantagonists–– NNN N cholinoceptorcholinoceptor antagonists: antagonists: mecamylaminemecamylamine
((Ganglionic Blocking drugs, rarely used))–– NNM M cholinoceptorcholinoceptor antagonists:antagonists: succinylcholinesuccinylcholine
((Neuromuscular Blocking drugs ))
•• BotulinumBotulinum Toxin Toxin ((blocks ACh release))
Drug classificationDrug classification略
Muscarinic Antagonists (Antimuscarinic drugs)
Tertiary amines Quaternary amines
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pilocarpinepilocarpine
atropineatropine
near sightnear sight
(1) Eye (1) Eye ••intraocular pressureintraocular pressure•升高眼内压
••intraocular pressure intraocular pressure
•• 调节麻痹调节麻痹
•• 扩瞳扩瞳
pilocarpinepilocarpine
atropineatropinelenslens
miosismiosis
•• mydriasismydriasis
•• paralysis of paralysis of accommodationaccommodation
near sightnear sight
••spasm of spasm of accommodationaccommodation
far sightfar sight
irisiris
Anterior Anterior chamberchamber
CiliaryCiliary musclemuscle(contraction)(contraction)
zonulezonule
Anterior Anterior chamberchamber
zonulezonuleCanal of Canal of SchlemmSchlemm
posteriorposteriorchamberchamber
CiliaryCiliary musclemuscle(relaxation)(relaxation)
(1) Eye (1) Eye ••intraocular pressureintraocular pressure•升高眼内压
••intraocular pressure intraocular pressure
•• 调节麻痹调节麻痹
•• 扩瞳扩瞳
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1. 1. Pharmacological effectsPharmacological effects(2)(2) Antispasmodic action on smooth muscleAntispasmodic action on smooth muscle
((解痉解痉) ) •• sensitive:sensitive: GI, urinary bladder (spasmodic state)GI, urinary bladder (spasmodic state)•• relatively insensitive:relatively insensitive: bile duct, urinary tract, bile duct, urinary tract,
bronchial tractbronchial tract•• insensitive:insensitive: uterusuterus
(3) (3) Inhibition of exocrine gland secretion Inhibition of exocrine gland secretion ((抑制腺体分泌抑制腺体分泌) )
•• salivary, sweat glandssalivary, sweat glands•• tear, respiratory tract glandstear, respiratory tract glands•• relatively ineffective: GI tractrelatively ineffective: GI tract
AtropineAtropine☺☺
1.1. Pharmacological effectsPharmacological effects(4) Cardiovascular System: dose dependent((4) Cardiovascular System: dose dependent(剂量剂量
依赖的依赖的))•• Lower therapeutic doses:Lower therapeutic doses: HRHR↓↓(bradycardia(bradycardia心动过缓心动过缓););
Blood vessels and blood pressure:Blood vessels and blood pressure: no effectno effect•• Moderate to high therapeutic doses / high Moderate to high therapeutic doses / high vagalvagal tone: tone:
HRHR↑↑ (tachycardia(tachycardia心动过速心动过速);); AA--V conduction V conduction ↑↑•• Larger doses:Larger doses: cutaneouscutaneous vasodilatation (vasodilatation (皮肤血管扩张皮肤血管扩张))(5) CNS stimulation(5) CNS stimulation• Sedation(镇静), memory loss(失忆), psychosis (high (high
dosedose,精神失常,精神失常))
AtropineAtropine☺☺
Lower therapeutic doses:Lower therapeutic doses:Block Pre-synaptic M1 receptor →Ach release↑→activate Post-synaptic M2 receptor → HR↓
Regulation of K+ Channels
↓Heart rate ↓
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Moderate to high Moderate to high therapeutic dosestherapeutic doses ::Block Post-synaptic M2 receptor → HR↑
Regulation of K+ Channels
↓Heart rate ↓
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2. 2. Clinical usesClinical uses(1) Ophthalmology(1) Ophthalmology•• Measurement of the refractive errors:Measurement of the refractive errors: childrenchildren•• Acute Acute iritisiritis or or iridocyclitisiridocyclitis:: mydriatics/mioticsmydriatics/miotics (( to to
prevent prevent synechiasynechia/adhesion/adhesion虹膜与晶状体粘连)虹膜与晶状体粘连)
(2) Antispasmodic agent(2) Antispasmodic agent ((解痉剂解痉剂))•• GI, GI, biliarybiliary or renal colic, enuresis(or renal colic, enuresis(遗尿遗尿))
(3) Inhibiting exocrine gland secretion(3) Inhibiting exocrine gland secretion•• PreanestheticPreanesthetic medication (medication (全身麻醉前给药全身麻醉前给药))(4) (4) BradyarrhythmiaBradyarrhythmia (缓慢性心律失常)•• sinus or nodal sinus or nodal bradycardiabradycardia, , atrioventricularatrioventricular (A(A--V)V) blockblock
(5) Antidote for organophosphate poisoning(5) Antidote for organophosphate poisoning
AtropineAtropine☺☺
3. 3. Adverse effectsAdverse effects(1) Side effects (1) Side effects dry mouth, blurred vision, dry mouth, blurred vision, ““sandy eyessandy eyes””
(2) toxicity (2) toxicity Lethal dose: 80~130 mg (adult), 10 mg (child)Lethal dose: 80~130 mg (adult), 10 mg (child)•• LowLow: : xerostomiaxerostomia ((dry mouthdry mouth); ); anhidrosisanhidrosis (d(dry skinry skin), tachycardia), tachycardia•• ModerateModerate: above plus : above plus mydriasismydriasis, , cycloplegiacycloplegia((睫状肌麻痹睫状肌麻痹); difficulty on ); difficulty on
speaking, swallowing & urinating; and hot, red, dry skinspeaking, swallowing & urinating; and hot, red, dry skin•• HighHigh: above plus ataxia(: above plus ataxia(共济失调共济失调), hallucinations(), hallucinations(幻觉幻觉) & delirium() & delirium(谵妄谵妄); );
comacoma昏迷昏迷 (i.e. CNS symptoms)(i.e. CNS symptoms)
(3) (3) DetoxicationDetoxication•• Symptomatic treatment: e.g. diazepam (Symptomatic treatment: e.g. diazepam (安定安定))•• PhysostigminePhysostigmine((毒扁豆碱毒扁豆碱) or ) or pilocarpinepilocarpine
(4) Contraindications(4) Contraindications•• glaucoma(glaucoma(青光眼青光眼), ), prostatauxeprostatauxe((前列腺肥大前列腺肥大), fever), fever
AtropineAtropine☺☺
•• Actions and clinical usesActions and clinical uses
–– Peripheral effects are similar to atropine; Peripheral effects are similar to atropine; but has stronger but has stronger central effectscentral effects (depression)(depression)
–– PrePre--anesthetic medication, anesthetic medication, prevention of prevention of motion sicknessmotion sickness, Parkinson, Parkinson’’s diseases disease
Scopolamine Scopolamine ((东莨菪碱东莨菪碱))☺
•• Actions and clinical usesActions and clinical uses
–– 654, 654654, 654--22:解痉,抗感染性休克治疗:解痉,抗感染性休克治疗
–– Weaker action than atropine, lower toxicityWeaker action than atropine, lower toxicity
AnisodamineAnisodamine ((山莨菪碱山莨菪碱))☺
Synthetic or semiSynthetic or semi--synthetic synthetic mydriaticsmydriatics
•• HomatropineHomatropine 后马托品后马托品
•• TropicamideTropicamide 托吡卡胺托吡卡胺
•• CyclopentolateCyclopentolate 环喷托酯环喷托酯
•• EucatropineEucatropine 尤卡托品尤卡托品
Lower side effect and shorter Lower side effect and shorter duration for duration for mydriasismydriasis
othersothers
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Synthetic antiSynthetic anti--spasm agentsspasm agents
IpratropiumIpratropium ((异丙托溴胺异丙托溴胺)): : asthmaasthmaScopolamine Scopolamine methylbromidemethylbromide ((溴甲东莨菪碱溴甲东莨菪碱)): : GIGIHomatropineHomatropine methylbromidemethylbromide ((溴甲后马托品溴甲后马托品)): : GI and coughGI and coughMepenzolateMepenzolate bromide (bromide (溴化甲哌佐酯溴化甲哌佐酯): GI): GIPropanthelinePropantheline ((普鲁本辛普鲁本辛) ) –– poor absorption (poor absorption (popo) and BBB penetration) and BBB penetration–– antispasmodic effects in GI, treatment of antispasmodic effects in GI, treatment of
peptic ulcer diseasepeptic ulcer disease
othersothers
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Selective MSelective M--receptor antagonistsreceptor antagonists
•• PirenzepinePirenzepine 哌仑西平哌仑西平::MM11 and Mand M44
•• TelenzepineTelenzepine 替仑西平替仑西平::more selective to more selective to MM11
ulcerulcer•• TripitamineTripitamine:: MM22 and Mand M33 selectiveselective•• DarifenacinDarifenacin 达非那新达非那新
othersothers
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2 Cholinergic antagonists2 Cholinergic antagonists(1) (1) CholinoceptorCholinoceptor antagonistsantagonists•• M M cholinoceptorcholinoceptor antagonistsantagonists
–– atropine (atropine (Antimuscarinic drugs))
•• N N cholinoceptorcholinoceptor antagonistsantagonists–– NNN N cholinoceptorcholinoceptor antagonists:antagonists: mecamylaminemecamylamine
((Ganglionic Blocking drugs, rarely used))–– NNM M cholinoceptorcholinoceptor antagonists:antagonists: succinylcholinesuccinylcholine
((Neuromuscular Blocking drugs ))
•• BotulinumBotulinum Toxin Toxin ((blocks ACh release))
Drug classificationDrug classification
•• Acting on sympathetic and parasympathetic Acting on sympathetic and parasympathetic ganglionicganglionic cells; reducing blood pressure by cells; reducing blood pressure by inhibiting sympathetic ganglia ( have been inhibiting sympathetic ganglia ( have been abandoned for clinical use, due to their lack abandoned for clinical use, due to their lack of selectivity) of selectivity)
•• ShortShort--acting; acting; tachyphylaxistachyphylaxis ((快速耐受快速耐受))
•• Used for treatment of hypertensionUsed for treatment of hypertension── TrimetaphanTrimetaphan ((樟磺咪芬樟磺咪芬))–– MecamylamineMecamylamine ((美卡拉明美卡拉明))
NNNN receptor antagonistsreceptor antagonists((Ganglionic Blocking drugs))
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• Two classes:
Non-depolarizing: drugs act as competitive antagonists
Depolarizing: succinylcholine (琥珀胆碱)
Note: Belong to Skeletal Muscle Relaxants. It is important to realize that muscle relaxation does not ensure unconsciousness, amnesia, or analgesia.
NNMM receptor antagonists receptor antagonists ((Neuromuscular Blocking drugs ))
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1. 1. Depolarizing neuromuscular blockers (Depolarizing neuromuscular blockers (Non-competitive))•• (depolarizing skeletal muscle relaxants)(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- they 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
NNMM receptor antagonists receptor antagonists ((Neuromuscular Blocking drugs ))
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SuccinylcholineSuccinylcholine, , ScolineScoline
Succinylcholine is the only depolarizing agent used clinically(t1/2= 2-4 min).
Properties of actions:Properties of actions:•• initially transient fasciculationsinitially transient fasciculations ((肌束震颤肌束震颤))•• antianti--AChE potentiates their effectsAChE potentiates their effects•• tachyphylaxis after repeated usestachyphylaxis after repeated uses•• no ganglionno ganglion--blocking effects at therapeutic dosesblocking effects at therapeutic doses•• the drugs are highly polar, poor bioavailability; the drugs are highly polar, poor bioavailability; i.vi.v. . •• as quaternary compounds. . .do not enter CNSas quaternary compounds. . .do not enter CNS
acetylcholineacetylcholinesuccinylcholinesuccinylcholine
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•• Main pharmacological effectsMain pharmacological effects–– Transient Transient excitation (excitation (fasciculationsfasciculations),), and then and then
inhibition (relaxation)inhibition (relaxation)
SuccinylcholineSuccinylcholine, , ScolineScoline
–– Relax Relax Skeletal MusclesSkeletal Muscles inin neck, limbs > face, neck, limbs > face, tongue, throat; less effective on breath muscles tongue, throat; less effective on breath muscles at therapeutic dosesat therapeutic doses
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•• Clinical usesClinical uses–– An adjuvant in anesthesia or operationAn adjuvant in anesthesia or operation–– Intubation of Intubation of trachea, esophagus, trachea, esophagus, etc.etc.–– Prevention of trauma during electroshock therapyPrevention of trauma during electroshock therapy
–– ContraindicatedContraindicated in awake patients, should use in awake patients, should use under anesthesiaunder anesthesia
SuccinylcholineSuccinylcholine, , ScolineScoline☺
•• Adverse effectsAdverse effects
(1) Apnea(1) Apnea窒息窒息 (respiratory paralysis)(respiratory paralysis)•• overdose or overdose or hypersensitive patientshypersensitive patients;;•• neostigmineneostigmine potentiates the toxic effectspotentiates the toxic effects
(2) Muscle spasm (2) Muscle spasm •• muscular pain after operationmuscular pain after operation(because of transient (because of transient fasciculationsfasciculations))
SuccinylcholineSuccinylcholine, , ScolineScoline☺
(3) Elevation of K(3) Elevation of K++ in plasmain plasma•• contraindicatedcontraindicated in patients with a tendency of in patients with a tendency of
hyperkalemiahyperkalemia (burn injury, massive trauma, (burn injury, massive trauma, neurological disorders)neurological disorders)
(4) Malignant hyperthermia (4) Malignant hyperthermia 恶性高热恶性高热((treatment: rapidly cooling the patient and administration of dantrolene 丹曲林)
•• genetic abnormalitygenetic abnormality
(5) Others(5) Others•• rise in intraocular pressure (glaucoma);rise in intraocular pressure (glaucoma);•• histamine release histamine release
SuccinylcholineSuccinylcholine, , ScolineScoline☺
Genetic Variation: Effects on Duration of Action of Succinylcholine
• The duration of action is prolonged by high doses or by abnormal metabolism. The latter may result from hypothermia, low pseudocholinesterase levels, or a genetically aberrant enzyme. (hypothermia decreases the rate of hydrolysis)
• 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: mechanical ventilation
•• Drug interactionsDrug interactions
–– ChEChE inhibitors: inhibitors: AChEAChE inhibitors, inhibitors, cyclophosphamidecyclophosphamide ((环磷环磷
酰胺酰胺), procaine(), procaine(普鲁卡因普鲁卡因), ), etcetc..
–– Some antibiotics:Some antibiotics:kanamycinkanamycin((卡那霉素卡那霉素), ), polymyxinspolymyxins((多粘菌素多粘菌素), ), etc.etc. (synergism in neuromuscular (synergism in neuromuscular blocking) blocking)
SuccinylcholineSuccinylcholine, , ScolineScoline
2. 2. NondepolarizingNondepolarizing neuromuscular blockers neuromuscular blockers ((Competitive )
•• ((nondepolarizingnondepolarizing skeletal muscle relaxants)skeletal muscle relaxants)
TubocurarineTubocurarine ((筒箭毒碱筒箭毒碱))Reversibly bind to the nicotinicReversibly bind to the nicotinicreceptor at the neuromuscularreceptor at the neuromuscularjunction (competitive antagonists) junction (competitive antagonists)
(note: curare rarely used)
Effects:Effects: competitive blockade of competitive blockade of NNMM receptorsreceptors
Uses:Uses: adjuvant treatment of anesthesia or operationsadjuvant treatment of anesthesia or operationsAdverse effects:Adverse effects:•• Respiratory paralysis: Respiratory paralysis: can be reversed by can be reversed by neostigmineneostigmine
•• Enhancing histamine release: Enhancing histamine release: BP BP , hypotension, , hypotension, bronchoconstrictionbronchoconstriction, salivary secretion, salivary secretion
•• Blocking ganglion: Blocking ganglion: BP BP
•• Contraindications: Contraindications: myasthenia gravis, bronchial myasthenia gravis, bronchial asthma, shock, child (< 10 y)asthma, shock, child (< 10 y)
Drug interactionsDrug interactions•• Similar to these of Similar to these of scolinescoline
TubocurarineTubocurarine☺
TubocurarineTubocurarine ((筒箭毒碱筒箭毒碱)) SuccinylcholineSuccinylcholine ((琥珀胆碱琥珀胆碱))
眼部肌肉,四肢、颈部、躯干、肋间肌、膈肌
颈部肌肉、肩胛、腹部、四肢
AChE抑制剂减轻其作用 AChE抑制剂增强其作用
有肌束颤动无肌束颤动
非竞争性的竞争性的
窒息解救:AChE抑制剂或呼吸机 窒息解救:呼吸机
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•• BenzylisoquinolinesBenzylisoquinolines•• atracuriumatracurium•• doxacuriumdoxacurium•• mivacuriummivacurium•• AmmonioAmmonio steroidssteroids•• pancuroniumpancuronium•• vecuroniumvecuronium•• pipecuroniumpipecuronium•• rocuroniumrocuronium
Other Other nondepolarizingnondepolarizingneuromuscular blockersneuromuscular blockers
It is important to realize that neuromuscular junction blocking agents produce paralysis, not anesthesia.
In other words, muscle relaxation does not ensure unconsciousness, amnesia, or analgesia.
(note: currently used NMJ blockers differ in time of onset and clinical duration : pancuronium>atracurium>rocuronium)
BotulinumBotulinum ToxinToxin肉毒毒素肉毒毒素
- 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 (松弛性麻痹) in muscles; (can also be used for excessive sweating, tension/migraine)
Acts by cleaving SNARE proteins →inhibits ACh release
• 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.
Botulinum Toxin Applications
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