传出神经系统药理浙江大学医学院药理学系卢韵碧 [email protected]. Nervous System Organization of the nervous system

传出神经系统药理传出神经系统药理浙江大学医学院浙江大学医学院

药理学系药理学系卢韵碧卢韵碧

[email protected]@zju.edu.cn

Nervous SystemNervous System

Organization of the nervous systemOrganization of the nervous system


PeripheralPeripheralNervousNervous

System (PNS)System (PNS)

CentralCentralNervousNervous

System (CNS)System (CNS)







EfferentEfferentDivisionDivision

AfferentAfferentDivisionDivision









SomaticSomaticSystemSystem










AutonomicAutonomicSystem (ANS)System (ANS)



SympatheticSympathetic










ParasympatheticParasympathetic

(Enteric)(Enteric)

The Enteric Nervous System (+SNS/PSNS)The Enteric Nervous System (+SNS/PSNS)


SympatheticSympathetic










ParasympatheticParasympathetic

(Enteric)(Enteric)

Drugs that produce their primary therapeutic effect by mimicking or altering the functions of autonomic nervous system are called autonomic drugs.

NeurotransmittersNeurotransmitters

ReceptorsReceptors

Brain stem or Brain stem or spinal cordspinal cord

Pre-ganglionic Pre-ganglionic neuronneuron

Ganglionic transmitterGanglionic transmitter

Post-ganglionic Post-ganglionic neuronneuron

Neuroeffector transmitterNeuroeffector transmitter

Effector organEffector organ

Efferent neurons of ANSEfferent neurons of ANS

drugs

The NeuronThe neuron is the basic unit of the nervous system that permits integration of information and transmits this info to other cells

1) The dendrites receive info from other neurons (or sensory endings)

2) The cell body integrates the dendritic input and determines whether an action potential is fired

3) The axon is the cable that transmits the action potential

4) The synaptic terminal is where the action potential is converted into neurotransmitter release that is sensed by the postsynaptic cell

The Synapse: Part I• The synapse converts the The synapse converts the

electrical signals of action electrical signals of action potentials into the potentials into the chemical signals of chemical signals of neurotransmitter (NT) neurotransmitter (NT) release.release.

• NTs are packaged at high NTs are packaged at high concentration in synaptic concentration in synaptic vesicles via transporters.vesicles via transporters.

• Action potential Action potential depolarization of the depolarization of the terminal activates voltage-terminal activates voltage-dependent Cadependent Ca++++ channels, channels, causing an influx of Cacausing an influx of Ca++++..

The Synapse: Part II

• CaCa++++ influx interacts with influx interacts with synaptic vesicle proteins synaptic vesicle proteins called SNAREs to promote called SNAREs to promote fusion between these fusion between these proteins in the synaptic proteins in the synaptic vesicles and the plasma vesicles and the plasma membrane, fusing the two membrane, fusing the two membranes.membranes.

• Release of NT activates Release of NT activates postsynaptic and postsynaptic and presynaptic ion channels presynaptic ion channels and GPCRs.and GPCRs.

SNAREs

GPCR

NT (ligand)-gated Ion Channel

The release of norepinephrine (sympathetic stimulation) has

the following effects

• stimulates heartbeat • raises blood pressure • dilates the pupils • dilates the trachea and bronchi • stimulates the conversion of liver glycogen into gluc

ose • shunts blood away from the skin and viscera to the s

keletal 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

NeurotransmittersNeurotransmitters•SynthesisSynthesis•StorageStorage•ReleaseRelease•InactivationInactivation

ReceptorsReceptors•ActivationActivation








Drug actions Drug actions and classificationand classification

Drug actions and classificationDrug actions and classification1.1. Mechanisms of drug actions Mechanisms of drug actions1.1 Direct actions on the receptors1.1 Direct actions on the receptors

• AgonistAgonist• Blocker / AntagonistBlocker / Antagonist

1.2 Indirect actions 1.2 Indirect actions via via affecting transmittersaffecting transmitters• Synthesis Synthesis • Transport and storageTransport and storage• Release Release • InactivationInactivation

1.3 Mimetics (1.3 Mimetics ( 拟似药拟似药 ) and antagonists) and antagonists (1) Mimetics(1) Mimetics• direct-acting:direct-acting: receptor agonists receptor agonists• indirect-acting:indirect-acting: increasing amounts and/or effects of transmitters increasing amounts and/or effects of transmitters

(2) Antagonists(2) Antagonists• direct-acting:direct-acting: receptor antagonists receptor antagonists• indirect-acting:indirect-acting: decreasing amounts and/or effects of transmitters decreasing amounts and/or effects of transmitters

Cholinergic Cholinergic PharmacologyPharmacologyAdrenergic PharmacologyAdrenergic Pharmacology

Cholinergic Cholinergic PharmacologyPharmacologyAdrenergic PharmacologyAdrenergic Pharmacology

NeurotransmittersNeurotransmitters•SynthesisSynthesis•StorageStorage•ReleaseRelease•InactivationInactivation

ReceptorsReceptors•ActivationActivation








1.1. Choline UptakeCholine Uptake

2.2. ACh SynthesisACh SynthesisCholine acetyltransferase(ChACholine acetyltransferase(ChA

T)T)Choline + AcCoA → ACh Choline + AcCoA → ACh ChATChAT

3.3. ACh StorageACh Storage

4.4. ACh ReleaseACh Release

5.5. ACh EffectsACh Effectsa)a) PostsynapticPostsynapticb)b) PresynapticPresynaptic

6.6. ACh MetabolismACh MetabolismAcetylcholinesterase(AChE)Acetylcholinesterase(AChE) AChACh → Choline + Acetate→ Choline + Acetate AChEAChE

Cholinergic TerminalCholinergic Terminal

RegulationRegulation

- by autoreceptors- by autoreceptorsACh acting on presynaptic ACh acting on presynaptic MM22-cholinergic receptors-cholinergic receptors

- by heteroreceptors- by heteroreceptorsNE acting on presynaptic NE acting on presynaptic 22-adrenergic receptors-adrenergic receptors

- by metabolism (extraneuronal)- by metabolism (extraneuronal)

Acetylcholine Releaseby exocytosis

Cholinesterases

AcetylcholinesteraseAcetylcholinesterase is located at cholinergic synapses is located at cholinergic synapses and in erythrocytes and in erythrocytes (does not (does not hydrolyze succinylcholine)hydrolyze succinylcholine)

PseudocholinesterasePseudocholinesterase ((synonyms: plasmacholinesterase synonyms: plasmacholinesterase or butyrylcholinesterase)or butyrylcholinesterase) occurs mainly in plasma, liver occurs mainly in plasma, liver and in glia and in glia ((hydrolyzes succinylcholine)hydrolyzes succinylcholine)

Cholinergic ReceptorsCholinergic Receptors (cholinoceptors, acetylcholine receptors)(cholinoceptors, acetylcholine receptors)

• Muscarinic receptors (M receptors)Muscarinic receptors (M receptors) MM1, 3, 51, 3, 5 ; M ; M2, 42, 4

G-protein Coupled End Organs

• Nicotinic receptors (N receptors)Nicotinic receptors (N receptors) NNNN (N (N11) receptors; N) receptors; NMM(N(N2 2 )) receptorsreceptors Ligand-gated Ion Channels NMJ & Ganglia

Cholinergic Cholinergic PharmacologyPharmacology

M receptors : M receptors : G-protein CoupG-protein Coupledled

MuscarinicMuscarinicReceptorReceptorSignalingSignalingPathwaysPathways

SmoothMusclecontraction

cAMP↓

Heart rate↓

• Depression of the heart Depression of the heart (heart rate, conducti(heart rate, conduction)on)

• 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, salisweat, tears, salivary; vary; insensitive: insensitive: GI tract);GI tract);

• Eye Eye (contraction of sphincter muscle of iris: (contraction of sphincter muscle of iris: mimiosisosis; contraction of ciliary muscle: ; contraction of ciliary muscle: contraction contraction for near visionfor near vision))

• CNSCNS

M receptors : end organs and effect of activationM receptors : end organs and effect of activation

Cholinergic VasodilationCholinergic 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

• NNNN receptors receptors （（ 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

N receptors : N receptors : Ligand-gated Ion ChannelsLigand-gated Ion Channels

• At the NMJ, At the NMJ, N receptorsN receptors Pentameric with four Pentameric with four types of subunits, two types of subunits, two subunits bind ACh for subunits bind ACh for ligand gatingligand gating

• All other All other nAChRs, nAChRs, including those including those at the at the peripheral peripheral ganglia, have 2 ganglia, have 2 ’s and 3 ’s and 3 ’s’s

The Neuromuscular The Neuromuscular

Junction (NMJ)Junction (NMJ)

AA BB

MMyasthenia yasthenia GGravisravis

• This means “serious disorder the NMJ”This means “serious disorder the NMJ”

• This is an autoimmune diseaseThis is an autoimmune disease

• Antibodies against the Antibodies against the subunit of the nAChR subunit of the nAChR

• The ability of ACh to activate the nAChRs is blocThe ability of ACh to activate the nAChRs is blocked by the antibodiesked by the antibodies

• As for many autoimmune diseases, stress can mAs for many autoimmune diseases, stress can make the symptoms worseake the symptoms worse

• Treatment is to potentiate cholinergic signaling aTreatment is to potentiate cholinergic signaling and to remove the antibodies (blood dialysis)nd to remove the antibodies (blood dialysis)

1 Cholinomimetics (1 Cholinomimetics (Parasympathomimetics))(1) Direct-acting drugs: Cholinoceptor agonists(1) Direct-acting drugs: Cholinoceptor agonists• 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-acting drugs: Cholinesterase inhibitors (2) Indirect-acting drugs: Cholinesterase inhibitors (Anticholinesterases)(Anticholinesterases)

• Reversible:Reversible: neostigmineneostigmine• Irreversible:Irreversible: organophosphatesorganophosphates

Drug classificationDrug classification

1 Cholinomimetics (1 Cholinomimetics (Parasympathomimetics))(1) Direct-acting drugs: Cholinoceptor agonists(1) Direct-acting drugs: Cholinoceptor agonists• 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-acting drugs: Cholinesterase inhibitors (2) Indirect-acting drugs: Cholinesterase inhibitors (Anticholinesterases)(Anticholinesterases)



Cholinomimetics:Cholinomimetics:Direct-acting drugsDirect-acting drugs

AChEAChEResistantResistant

AChAChDerivativesDerivatives Bond cle

aved by AChE

乙酰胆碱

醋甲胆碱

贝胆碱

卡巴胆碱

ACh DerivativesACh Derivatives

BethanecholBethanechol is most commonly used, is most commonly used, particularly post-op for the treatment of particularly post-op for the treatment of paralytic ileus and urinary retentionparalytic ileus and urinary retention

Natural Muscarinic AgonistsNatural Muscarinic Agonists

(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, lacrimation, visual disturbances;- abdominal colic and diarrhea- bronchospasm and bradycardia- hypotension; shock

• Treatment is with atropine

Atropa belladonna => atropineAmanita muscaria => muscarine

““Food” PoisoningFood” Poisoning

pilocarpinepilocarpine

miosismiosis

near sightnear sight

spasm of spasm of accommodationaccommodation

PilocarpinePilocarpine ：： ParasympatheticParasympathetic Effects & Therapeutic Uses Effects & Therapeutic Uses（（ 11 ）） EyesEyes • Miosis (Miosis ( 缩瞳缩瞳 ): ): contraction of sphincter muscle of iris• Lowing intraocular pressure:Lowing intraocular pressure: enlarging angle of anterior chamber, increasin

g drainage of aqueous humor• Spasm of accommodation (Spasm of accommodation ( 调节痉挛调节痉挛 ): ): contraction of ciliary muscle, contract

ion for near vision

• Ophthalmological usesOphthalmological uses Glaucoma:Glaucoma: narrow (closed)- narrow (closed)- oror wide (open)-angleswide (open)-angles it is the drug of choice in the emergency lowering of intraocular pressureit is the drug of choice in the emergency lowering of intraocular pressure Iritis:Iritis: miotics/mydriaticsmiotics/mydriatics

Muscarinic AgonistsMuscarinic Agonists

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

GlaucomaGlaucoma

• Glaucoma management involves lowering IOP by

- Decreasing aqueous production by the ciliary body

- Increasing aqueous outflow through the trabecular meshwork and uveal outflow paths

• pilocarpine: parasympathomimetics

increase aqueous outflow by contraction of the ciliary muscle to increase tone and alignment of the trabecular network

Pilocarpine Increase Aqueous Pilocarpine Increase Aqueous Humor OutflowHumor Outflow

PilocarpinePilocarpine

（（ 22 ）） Promoting secretion of exocrine glanPromoting secretion of exocrine glan

ds, ds, especially in sweat, salivary and tear glaespecially in sweat, salivary and tear gla

ndsnds

• Systemic useSystemic use

AntidoteAntidote for atropine poisoning for atropine poisoning

Muscarinic Agents:Muscarinic Agents: Parasympathetic Effects & Parasympathetic Effects &

Therapeutic UsesTherapeutic Uses

- - 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 & motility and 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

1 Cholinomimetics 1 Cholinomimetics (1) Direct-acting drugs: Cholinoceptor agonists(1) Direct-acting drugs: Cholinoceptor agonists• M, N receptor agonists: M, N receptor agonists: acetylcholineacetylcholine• M receptor agonists: pilocarpineM receptor agonists: pilocarpine• N receptor agonists: nicotineN receptor agonists: nicotine

(2) Indirect-acting drugs: Cholinesterase inhibitors (2) Indirect-acting drugs: Cholinesterase inhibitors (Anti-cholinesterases)(Anti-cholinesterases)



Cholinergic antagonistsCholinergic antagonists ：： Cholinesterase reactivatorsCholinesterase reactivators ppralidoxime iodideralidoxime iodide

Cholinomimetics-Cholinomimetics- Indirect Agents: Indirect Agents: AChE InhibitorsAChE Inhibitors

Acetylcholinesterase (AChE) Activity

Ach 与 AchE 复合物

乙酰化 AchE

胆碱酯酶

胆碱

A. Edrophonium (reversible, competitive)

B. Carbamates ( 氨甲酰类， slowly reversible)

C. Organophosphates (irreversible)

Cholinomimetics-Cholinomimetics- Indirect Agents: Indirect Agents: AChE InhibitorsAChE Inhibitors

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

Acetylcholinesterase Inhibitors: Reversible

Edrophonium chloride ( 依酚氯铵，氯化腾喜龙 )

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 (quaternary amine ，新斯的明 ) physostigmine (tertiary amine ，毒扁豆碱 ) pyridostigmine (quaternary amine ，吡啶斯的明 )

quaternary amines effective in periphery onlytertiary amines effective in periphery and CNS（ fat-soluble ）


neostigmine (quaternary amine) – Pharmacological effects Pharmacological effects • AChE(-), ACh releaseAChE(-), ACh release↑↑, 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: symptomatic treatment, overdose: cholinergic crisis• Paralytic ileus and bladder: Paralytic ileus and bladder: post operative abdominal distension and urinary retentio

n (术后腹气胀和尿储留 )• Paroxysmal superventricular tachycardiaParoxysmal superventricular tachycardia （（ rarely userarely use ））• Antidote for tubocurarine and related drug poisoningAntidote for tubocurarine and related drug poisoning

neostigmine (quaternary amine) – Adverse effectsAdverse effects• Cholinergic effects: Cholinergic effects: muscarinic and nicotinic effects, muscarinic and nicotinic effects,

treated with atropine (muscarinic)treated with atropine (muscarinic)

• ContraindicationsContraindications ：： mechanical ileusmechanical ileus

urinary obstructionurinary obstruction

bronchial asthmabronchial asthma

poisoning of depolarizing skeletal muscle relaxantspoisoning of depolarizing skeletal muscle relaxants

(e.g. succinylcholine(e.g. succinylcholine ，琥珀胆碱，琥珀胆碱 ) )


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

Acetylcholinesterase Inhibitors: Organophosphates

Effects of Organophosphates are irreversible (covalent bond formation)

Pralidoxime ( 解磷定 ) can restore AChE activity if administered soon after toxin exposure.

•Conjugating with organoConjugating with organophosphate by oxime group; phosphate by oxime group;

•Conjugating with free organoConjugating with free organophosphatesphosphates

(1) Toxic symptoms(1) Toxic symptoms– Acute intoxicationAcute intoxication• Muscarinic symptomsMuscarinic symptoms eye, exocrine glands, respiration, GI teye, exocrine glands, respiration, GI t

ract, urinary tract, CVSract, urinary tract, CVS

• Nicotinic symptomsNicotinic symptoms NNNN: : elevation of BP, increase of HR;elevation of BP, increase of HR; NN22: :

tremor of skeletal musclestremor of skeletal muscles• CNS symptomsCNS symptoms excitation, convulsion; depression (advanceexcitation, convulsion; depression (advance

d phase)d phase)– Chronic intoxicationChronic intoxication• usually occupational poisoningusually occupational poisoning• plasma ChE activity plasma ChE activity ↓,↓,• weakness, restlessness, anxiety, tremor, miosis, ……weakness, restlessness, anxiety, tremor, miosis, ……


(2) Detoxication(2) Detoxication

•Elimination of poison; Supportive therapyElimination of poison; Supportive therapy•AntidotesAntidotes

AtropineAtropine －－ antagonizing muscarinic effects; antagonizing muscarinic effects; early, larearly, larger dose, and repeated useger dose, and repeated use

Cholinesterase reactivatorsCholinesterase reactivators －－ reactivation of phosphreactivation of phosphorylated AChE; orylated AChE; moderate-severe patients, early use (mormoderate-severe patients, early use (more effective on tremor), combined with atropinee effective on tremor), combined with atropine– Pyraloxime methoiodide (PAM)Pyraloxime methoiodide (PAM)– Pralidoxime chloride: Pralidoxime chloride: saver than PAMsaver than PAM– Obidoxime chloride: Obidoxime chloride: two active oxime groupstwo active oxime groups


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 organophosphate inhibitor

Malathion ，马拉硫磷

glaucoma (e.g. physiostigmine, echothiophate )

myasthenia gravis (e.g. edrophonium, neostigmine, pyridosti

gmine )

reverse neuromuscular blockade from competitive antagonists (neostigmine)

Alzheimer’s disease (tacrine他克林 & donepezil多奈哌齐 )

chemical warfare agents

insecticides

Summary: ACHEI Applications

Pharmacological Actions: Increases ACh concentrations at cholinergic synapses, thereby increasing cholinergic activity.

2 Cholinergic antagonists2 Cholinergic antagonists

(1) Cholinoceptor antagonists(1) Cholinoceptor antagonists

• M cholinoceptor antagonistsM cholinoceptor antagonists– atropine (atropine (Antimuscarinic drugs))

• N cholinoceptor antagonistsN cholinoceptor antagonists– NNN N cholinoceptor antagonists:cholinoceptor antagonists: mecamylaminemecamylamine

((Ganglionic Blocking drugs, rarely used))– NNM M cholinoceptor antagonists:cholinoceptor antagonists: succinylcholinesuccinylcholine

((Neuromuscular Blocking drugs ))

• Botulinum Toxin Botulinum Toxin ((blocks ACh release))


Muscarinic Antagonists (Antimuscarinic drugs)

Tertiary amines Quaternary amines

阿托品

异丙托品

东莨菪碱

1.1. Pharmacological effectsPharmacological effects

(1) (1) IOP , mydriasis (IOP , mydriasis ( 扩瞳扩瞳 ), paralysis of accommodation ), paralysis of accommodation (( 调节麻痹调节麻痹 ))

AtropineAtropine

atropineatropine

• mydriasismydriasis

• paralysis of paralysis of accommodationaccommodation

far sightfar sight

intraocular pressureintraocular pressure

pilocarpinepilocarpine

atropineatropine

miosismiosis

mydriasismydriasis

paralysis of paralysis of accommodationaccommodation

near sightnear sight

spasm of spasm of accommodationaccommodation

far sightfar sight

1. 1. Pharmacological effectsPharmacological effects(2)(2) Antispasmodic action on smooth muscle(Antispasmodic 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, bronchial tra bile duct, urinary tract, bronchial tra

ctct• insensitive:insensitive: uterus uterus

(3) (3) Inhibition of exocrine gland secretion Inhibition of exocrine gland secretion • 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 • Lower therapeutic doses:Lower therapeutic doses: HR↓ HR↓(bradycardia);(bradycardia); Blood veBlood ve

ssels and blood pressure:ssels and blood pressure: no effectno effect• Moderate to high therapeutic doses / high vagal tone: Moderate to high therapeutic doses / high vagal tone:

HRHR↑ ↑ (tachycardia);(tachycardia); A-V conduction ↑ A-V conduction ↑• Larger doses:Larger doses: cutaneous vasodilatation cutaneous vasodilatation

(5) CNS stimulation(5) CNS stimulation

• sedation, memory loss, psychosis (high dose)(high dose)

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 ↓

Moderate to high Moderate to high therapeutic dosestherapeutic doses ::Block Post-synaptic M2 receptor → HR↑

Regulation of K+ Channels

↓Heart rate ↓

2. 2. Clinical usesClinical uses(1) Ophthalmology(1) Ophthalmology• Measurement of the refractive errors:Measurement of the refractive errors: children children• Acute iritisAcute iritis 虹膜炎虹膜炎 or iridocyclitisor iridocyclitis 虹膜睫状体炎虹膜睫状体炎 :: mydriatic mydriatic

s / miotics s / miotics （（ to prevent synechia/adhesion to prevent synechia/adhesion 虹膜粘连虹膜粘连））(2) Antispasmodic agent(2) Antispasmodic agent ：： Anisodamine(Anisodamine( 山莨菪碱山莨菪碱 ))• GI, biliary or renal colic, enuresisGI, biliary or renal colic, enuresis

(3) Inhibiting exocrine gland secretion(3) Inhibiting exocrine gland secretion • Preanesthetic medicationPreanesthetic medication

(4) Bradyarrhythmia(4) Bradyarrhythmia • sinus or nodal bradycardia, atrioventricularsinus or nodal bradycardia, atrioventricular (A-V)(A-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, “sandy eyes”dry mouth, blurred vision, “sandy eyes”

(2) toxicity (2) toxicity Lethal dose: 80~130 mg (adult), 10 mg (child)Lethal dose: 80~130 mg (adult), 10 mg (child)• LowLow: xerostomia (: xerostomia (dry mouthdry mouth); anhidrosis (d); anhidrosis (dry skinry skin), tachycardiad), tachycardiad• ModerateModerate: above plus mydriasis, cycloplegia; difficulty on speaking, swallowi: above plus mydriasis, cycloplegia; difficulty on speaking, swallowi

ng & urinating; and hot, red, dry skinng & urinating; and hot, red, dry skin• HighHigh: above plus ataxia, hallucinations & delirium; coma (i.e. CNS symptoms): above plus ataxia, hallucinations & delirium; coma (i.e. CNS symptoms)

(3) Detoxication (3) Detoxication • Symptomatic treatment: e.g. diazepam (Symptomatic treatment: e.g. diazepam ( 安定安定 ).).• Physostigmine or pilocarpinePhysostigmine or pilocarpine

(4) Contraindications(4) Contraindications• glaucoma, prostatauxe (glaucoma, prostatauxe ( 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 central effects (depression)but has stronger central effects (depression)

– Pre-anesthetic medication, prevention of Pre-anesthetic medication, prevention of motion sickness, Parkinson’s diseasemotion sickness, Parkinson’s disease

ScopolamineScopolamine

• Propantheline Propantheline (( 普鲁本辛普鲁本辛 )) – poor absorption (po) and BBB penetrationpoor absorption (po) and BBB penetration– antispasmodicantispasmodic effects in GI, treatment of peptic ulcer effects in GI, treatment of peptic ulcer

diseasedisease• Tropicamide Tropicamide (( 托吡卡胺托吡卡胺 ):): mydriatics mydriatics (( 扩瞳剂扩瞳剂 )), cyclople, cyclople

gic gic (( 睫状肌麻痹剂睫状肌麻痹剂 ))– shorter duration (1/4 day) shorter duration (1/4 day) – Examination of eyesExamination of eyes• Ipratropium Ipratropium (( 异丙阿托品异丙阿托品 )): : asthmaasthma• Benztropine Benztropine (( 苯扎托品苯扎托品 ):): Parkinson’s diseaseParkinson’s disease

othersothers

Nicotinic receptor Nicotinic receptor antagonistsantagonists

• Acting on sympathetic and parasympathetic gaActing on sympathetic and parasympathetic ganglionic cells; reducing blood pressure by inhibnglionic cells; reducing blood pressure by inhibiting sympathetic ganglia ( have been abandoneiting sympathetic ganglia ( have been abandoned for clinical use, due to their lack of selectivity) d for clinical use, due to their lack of selectivity)

• Short-acting; tachyphylaxis (Short-acting; tachyphylaxis ( 快速耐受快速耐受 ))

• Used for treatment of hypertensionUsed for treatment of hypertension ─ trimethaphan (trimethaphan ( 樟磺咪芬樟磺咪芬 ))– mecamylamine (mecamylamine ( 美卡拉明美卡拉明 ))

NNNN receptor antagonists receptor antagonists((Ganglionic Blocking drugs ，神经节阻滞药 ))

• Two classes:

Non-depolarizing ( 非除极化型 ): drugs act as competitive antagonists

Depolarizing( 除极化型 ): 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 ((Neuromus

cular Blocking drugs, 神经肌肉阻滞药 ))

1. 1. Depolarizing neuromuscular blockers (Depolarizing neuromuscular blockers (Non-competitive))• (depolarizing skeletal muscle relaxants(depolarizing skeletal muscle relaxants ，，去极化型肌松去极化型肌松

药药 ))

• act as acetylcholine (ACh) receptor agonists– the depolarized membranes remain depolarized and unresponsive t

o subsequent impulses (ie, they are in a state of depolarizing block).

• not metabolized by AChE- they diffuse away from the neuromuscular junction and are hydrolyz

ed 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))

SuccinylcholineSuccinylcholine, , ScolineScoline

Succinylcholine is the only depolarizing agent used clinically (t1/2= 2-4 min).

Properties of actions:Properties of actions:• initially transient fasciculations (initially transient fasciculations ( 肌束震颤肌束震颤 ))• anti-AChE potentiates their effectsanti-AChE potentiates their effects• tachyphylaxis after repeated usestachyphylaxis after repeated uses• no ganglion-blocking effects at therapeutic dosesno ganglion-blocking effects at therapeutic doses• the drugs are highly polar, poor bioavailability; i.v. the drugs are highly polar, poor bioavailability; i.v. • as quaternary compounds. . .do not enter CNSas quaternary compounds. . .do not enter CNS

acetylcholineacetylcholine succinylcholinesuccinylcholine

• Main pharmacological effectsMain pharmacological effects

– Transient Transient excitation (fasciculations),excitation (fasciculations), and t and then hen inhibition (relaxation)inhibition (relaxation)

– Relax Relax Skeletal MusclesSkeletal Muscles in in neck, limbs > faneck, limbs > face, tongue, throat; less effective on breath ce, tongue, throat; less effective on breath muscles at therapeutic dosesmuscles at therapeutic doses


• 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


• Adverse effectsAdverse effects

(1) Apnea (respiratory paralysis)(1) Apnea (respiratory paralysis) 窒息窒息• overdose or overdose or hypersensitive patientshypersensitive patients;;

• neostigmine potentiates the toxic effectsneostigmine potentiates the toxic effects

(2) Muscle spasm (2) Muscle spasm • muscular pain after operationmuscular pain after operation

(because of transient fasciculations)(because of transient fasciculations)


(3) Elevation of K(3) Elevation of K++ in plasma in plasma• contraindicatedcontraindicated in patients with a tendency in patients with a tendency

of hyperkalemia (burn injury, massive traumof hyperkalemia (burn injury, massive trauma, neurological disorders)a, neurological disorders)

(4) Malignant hyperthermia(4) Malignant hyperthermia• genetic abnormalitygenetic abnormality

(5) Others(5) Others• rise in intraocular pressure (glaucoma);rise in intraocular pressure (glaucoma);• histamine release histamine release


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

• Of the recognized abnormal pseudocholinesterase genes, the dibucaine-resistant (variant) gene, which displays 1/100 of normal affinity for succinylcholine, is the most common.

• Therefore, adequacy of pseudocholinesterase can be determined in the laboratory quantitatively in units per liter (a minor factor) and qualitatively by dibucaine number.

• "Dibucaine number" test identifies patients with abnormal plasma cholinesterase

– Dibucaine is an amide local anesthetic that inhibits wild type plasma cholinesterase by 80%; however, it inhibits atypical enzyme by only 20%.

– The percentage of inhibition of pseudocholinesterase activity is termed the dibucaine number. The dibucaine number is proportional to pseudocholinesterase function and independent of the amount of enzyme

• If dibucaine number equals 80: normal cholinesterase

• If dibucaine number equals 20: homozygous for atypical cholinesterase

• Drug interactionsDrug interactions

– ThiopentalThiopental

– ChE inhibitors: ChE inhibitors:

AChE inhibitors, cyclophosphamide(AChE inhibitors, cyclophosphamide( 环磷酰环磷酰胺胺 ), procaine (), procaine ( 普鲁卡因普鲁卡因 ), ), etcetc..

– Some antibiotics:Some antibiotics: kanamycin (kanamycin ( 卡那霉素卡那霉素 ), polymyxins (), polymyxins ( 多粘菌素多粘菌素 ), ), ee

tc.tc. (synergism in neuromuscular blocking) (synergism in neuromuscular blocking)


2. 2. Nondepolarizing neuromuscular blockers Nondepolarizing neuromuscular blockers ((Competitive )

• (nondepolarizing skeletal muscle relaxants)(nondepolarizing skeletal muscle relaxants)

Tubocurarine Tubocurarine (( 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 receptors receptors

Uses:Uses: adjuvant treatment of anesthesia or operationsadjuvant treatment of anesthesia or operations

Adverse effects:Adverse effects:• Respiratory paralysis: Respiratory paralysis: can be reversed by neostigminecan be reversed by neostigmine

• Enhancing histamine release: Enhancing histamine release: BP BP , hypotension, broncho, hypotension, bronchoconstriction, salivary secretionconstriction, salivary secretion

• Blocking ganglion: Blocking ganglion: BP BP

• Contraindications: Contraindications: myasthenia gravis, bronchial asthma, smyasthenia gravis, bronchial asthma, shock, child (< 10 y)hock, child (< 10 y)

Drug interactionsDrug interactions• Similar to these of scolineSimilar to these of scoline

TubocurarineTubocurarine

• Benzylisoquinolines Benzylisoquinolines • Atracurium(Atracurium( 阿曲库铵 ) ) • Doxacurium(Doxacurium( 多多库氯铵 ))• Mivacurium(Mivacurium( 咪库铵 ))

• Ammonio steroidsAmmonio steroids• Pancuronium(Pancuronium( 潘库铵 ) ) • Vecuronium(Vecuronium( 维库铵 ))• Pipecuronium(Pipecuronium( 哌哌库铵 ) ) • Rocuronium(Rocuronium( 罗库铵 ))

Other nondepolarizing neuromOther nondepolarizing neuromuscular blockersuscular 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)

2 Cholinergic antagonists2 Cholinergic antagonists

(1) Cholinoceptor antagonists(1) Cholinoceptor antagonists

• M cholinoceptor antagonistsM cholinoceptor antagonists– atropine (atropine (Antimuscarinic drugs))

• N cholinoceptor antagonistsN cholinoceptor antagonists– NNN N cholinoceptor antagonists:cholinoceptor antagonists: mecamylaminemecamylamine

((Ganglionic Blocking drugs, rarely used))– NNM M cholinoceptor antagonists:cholinoceptor antagonists: succinylcholinesuccinylcholine

((Neuromuscular Blocking drugs ))

• Botulinum Toxin Botulinum Toxin ((blocks ACh release))


BotulinumBotulinum ToxinToxin

- 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 in muscles; (can also be used for excessive sweating, tension/migraine)

Acts by cleaving SNARE proteins → inhibits ACh release

Amazing Details on Botulinum Toxin

. . How does it do it. . . .?

- 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

• Strabismus ( 斜视， lack of parallelism of eyes), blepharospasm ( 眼睑痉挛， eyelid spasm), dystonia ( 肌张力失常， abnormal tonicity).

• Excessive sweating• Cosmetic procedures ( “frown lines” or “crow’s feet”)

Note: effects can last for ~3-6 months.

LA Times

Botulinum Toxin Applications

Documents

传出神经系统药理 浙江大学医学院 药理学系 卢韵碧 [email protected]. Nervous System Organization of the nervous system

传出神经系统药理浙江大学医学院药理学系卢韵碧 [email protected]. Nervous System Organization of the nervous system