autonomic pharmacology -...

Autonomic Autonomic PharmacologyPharmacology

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

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)

thoracolumbarthoracolumbarcraniosacralcraniosacral


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.

The NeuronThe neuron is the basic unit of the nervous system that permits integration of information and transmits this info to other cells1) The dendrites receive info from

other neurons (or sensory endings)

2) The cell body integrates the dendritic input and determines whether an axon 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.

•• NTsNTs are packaged at high 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 voltageterminal 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

NeurotransmittersNeurotransmitters

ReceptorsReceptors

Brain stem or Brain stem or spinal cordspinal cord

PrePre--ganglionicganglionicneuronneuron

GanglionicGanglionic transmittertransmitter

PostPost--ganglionicganglionicneuronneuron

NeuroeffectorNeuroeffector transmittertransmitter

EffectorEffector organorganEfferent neurons of ANSEfferent neurons of ANS

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

NeurotransmittersNeurotransmitters

ReceptorsReceptors







drugs

NeurotransmittersNeurotransmitters••SynthesisSynthesis••StorageStorage••ReleaseRelease••InactivationInactivationReceptorsReceptors••ActivationActivation







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 and antagonistsand antagonists

(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

Cholinergic Cholinergic PharmacologyPharmacologyAdrenergic PharmacologyAdrenergic Pharmacology

1.1. Choline UptakeCholine Uptake2.2. ACh SynthesisACh SynthesisCholineCholine acetyltransferase(ChATacetyltransferase(ChAT))CholineCholine + + AcCoAAcCoA →→ AChACh

ChATChAT

3.3. ACh StorageACh Storage4.4. AChACh ReleaseRelease5.5. ACh EffectsACh Effects

a)a) PostsynapticPostsynapticb)b) PresynapticPresynaptic

6.6. AChACh MetabolismMetabolismAcetylcholinesterase(AChEAcetylcholinesterase(AChE))

AChACh →→ CholineCholine + Acetate+ AcetateAChEAChE

Cholinergic TerminalCholinergic Terminal

RegulationRegulation

-- by autoreceptorsby autoreceptorsACh acting on presynaptic ACh acting on presynaptic MM22--cholinergic receptorscholinergic receptors

-- by heteroreceptorsby heteroreceptorsNE acting on presynaptic NE acting on presynaptic 22--adrenergic receptorsadrenergic 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 hydrolyze succinylcholinesuccinylcholine))

PseudocholinesterasePseudocholinesterase ((synonyms: synonyms: plasmacholinesteraseplasmacholinesteraseor butyrylcholinesterase)or butyrylcholinesterase) occurs mainly in plasma, liver occurs mainly in plasma, liver and in and in gliaglia ((hydrolyzes hydrolyzes succinylcholinesuccinylcholine))

Ganglionic Neurotransmission

N = Nicotinic AChRM = Muscarinic AChR

EPSP = Excitatory Postsynaptic PotentialIPSP = Inhibitory Postsynaptic Potential

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

M receptors : M receptors : GG--protein protein CoupledCoupled

MuscarinicMuscarinicReceptorReceptorSignalingSignalingPathwaysPathways

SmoothMusclecontraction

cAMP↓

Heart rate↓

•• 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 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) inthe endothelium

• In the absence of the endothelium, a small amount of vasoconstriction is observed

•• 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

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

The Neuromuscular The Neuromuscular Junction (NMJ)Junction (NMJ)

AA BB

MMyasthenia yasthenia GGravisravis•• 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 ACh to activate the The ability of ACh 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(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:Irreversible: organophosphatesorganophosphates

Drug classificationDrug classification

CholinomimeticsCholinomimetics::DirectDirect--acting drugsacting drugs

AChEAChEResistantResistant

AChAChDerivativesDerivatives Bond

cleaved by AChE

乙酰胆碱

乙酰甲胆碱

卡巴胆碱

氯贝胆碱

ACh DerivativesACh Derivatives

BethanecholBethanechol is most commonly used, is most commonly used, particularly postparticularly post--op for the treatment of op for the treatment of paralytic paralytic ileusileus and urinary retentionand urinary retention

Natural Muscarinic AgonistsNatural Muscarinic Agonists

(Most to least nicotinic)(Most to least nicotinic)

• Muscarine(毒蕈碱): amanita muscaria (mushroom)• Pilocarpine (毛果芸香碱): pilocarpus (S. Amer. shrub)• Arecoline (槟榔碱): : areca or betal nuts (India,E.

Indies)

• Poisoning causes muscarinic overstimulation- salivation, lacrimation(流泪), visual disturbances;- abdominal colic and diarrhea- bronchospasm and bradycardia- hypotension; shock

• Treatment is with atropine

Atropa belladonna => atropineAmanita muscaria => muscarine

““FoodFood”” PoisoningPoisoning

Muscarinic Agonists:Muscarinic Agonists:Parasympathetic Effects & Parasympathetic Effects &

Therapeutic UsesTherapeutic UsesPilocarpinePilocarpine（（11））EyesEyes•• MiosisMiosis((缩瞳缩瞳): ): 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(调节痉挛调节痉挛): ): contraction of

ciliary muscle, contraction for near vision

•• Ophthalmological usesOphthalmological usesGlaucoma(Glaucoma(青光眼青光眼):):narrow (closed)narrow (closed)-- oror wide (open)wide (open)--anglesanglesit is the drug of choice in the emergency lowering of intraoculait is the drug of choice in the emergency lowering of intraocular pressurer pressureIritisIritis:: miotics/mydriaticsmiotics/mydriatics

pilocarpinepilocarpine

atropineatropinelenslens

miosismiosis

mydriasismydriasis

paralysis of paralysis of accommodationaccommodation

near sightnear sight

sspasm of pasm of accommodationaccommodation

far sightfar sight

irisiris

Anterior Anterior chamberchamber

CiliaryCiliary musclemuscle(contraction)(contraction)

zonulezonule


zonulezonuleCanal of Canal of SchlemmSchlemm

posteriorposteriorchamberchamber

CiliaryCiliary musclemuscle(dilation)(dilation)

Circulation of Aqueous humorCirculation of Aqueous humor

Glaucoma• Disease of the aging eye -

increased intraocular pressure, degeneration of the optic head, and restricted visual field typify primary open-angle glaucoma

• obstruction of the aqueous drainage leads to elevated intraocular pressure (IOP), and may result in glaucomatous damage to the optic nerve

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

PilocarpinePilocarpine Increase Aqueous Increase Aqueous Humor OutflowHumor Outflow

PilocarpinePilocarpine（（22）） Promoting secretion of exocrine glands, Promoting secretion of exocrine glands,

especially in sweat, salivary and tear glandsespecially in sweat, salivary and tear glands•• 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 & 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

1 1 Cholinomimetics(Cholinomimetics(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


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


Cholinergic antagonistsCholinergic antagonists：： Cholinesterase Cholinesterase reactivatorsreactivators ppralidoximeralidoxime iodideiodide

CholinomimeticsCholinomimetics--Indirect Agents: Indirect Agents: AChEAChE InhibitorsInhibitors

Acetylcholinesterase (AChE) Activity

A. Edrophonium依酚氯铵 (reversible, competitive)

B. Carbamates 氨甲酰类(slowly reversible)

C. Organophosphates 有机磷类(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

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 cholinergiccrisis, Atropine is the antidote.

Acetylcholinesterase Inhibitors: Carbamates

Inhibitory Effects are slowly reversible

Representative Drugsneostigmine 新斯的明(quaternary amine)physiostigmine 毒扁豆碱(tertiary amine)pyridostigmine吡斯的明(quaternary amine)

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

Acetylcholinesterase Inhibitors: Carbamatesneostigmine (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 urinary bladder effective on GI tract and 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 Paralytic ileusileus and bladder: and bladder: post operative abdominal

distension and urinary retention•• Paroxysmal Paroxysmal superventricularsuperventricular tachycardiatachycardia（阵发性室上速）（阵发性室上速）

•• Antidote for Antidote for tubocurarinetubocurarine and related drug poisoningand related drug poisoning

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 ileusileusurinary obstructionurinary obstructionbronchial asthmabronchial asthmapoisoning of depolarizing skeletal muscle relaxantspoisoning of depolarizing skeletal muscle relaxants(e.g. (e.g. succinylcholinesuccinylcholine) )

Acetylcholinesterase Inhibitors: Carbamates

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

对硫磷

马拉硫磷

乙膦硫胆碱梭曼

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 by organophosphate by oximeoximegroup; group;

••Conjugating with free Conjugating with free organophasphatesorganophasphates

(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(excitation, convulsion( 抽搐抽搐 ); );

depression (advanced phase)depression (advanced phase)–– Chronic intoxicationChronic intoxication•• usually occupational poisoningusually occupational poisoning•• plasma plasma ChEChE activity activity ↓↓,,•• weakness, restlessness, anxiety, tremor, weakness, restlessness, anxiety, tremor, miosismiosis, , …………


(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 phosphatedphosphated AChEAChE; ; moderatemoderate--severe patients, early use severe patients, early use (More effective on tremor), combined with atropine(More effective on tremor), combined with atropine–– PyraloximePyraloxime methoiodidemethoiodide((氯解磷定氯解磷定))：：saver than PAMsaver than PAM–– PralidoximePralidoxime chloride (PAM)chloride (PAM)–– ObidoximeObidoxime chloride(chloride(双复磷双复磷): ): two active two active oximeoxime groupsgroups


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

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.

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))


Muscarinic Antagonists (Antimuscarinic drugs)

Tertiary amines Quaternary amines

阿托品

东莨菪碱

异丙托溴铵

1. 1. Pharmacological effectsPharmacological effects

AtropineAtropine

pilocarpinepilocarpine

atropineatropinelenslens

miosismiosis

•• mydriasismydriasis

•• paralysis of paralysis of accommodationaccommodation

near sightnear sight

sspasm of pasm of accommodationaccommodation

far sightfar sight

irisiris


CiliaryCiliary musclemuscle(contraction)(contraction)

zonulezonule


zonulezonuleCanal of Canal of SchlemmSchlemm

posteriorposteriorchamberchamber

CiliaryCiliary musclemuscle(relaxation)(relaxation)

(1) Eye (1) Eye ••intraocular pressureintraocular pressure

1. 1. Pharmacological effectsPharmacological effects(2)(2) Antispasmodic action on smooth muscleAntispasmodic action on smooth muscle•• 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 •• 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: HRHR↓↓(bradycardia(bradycardia);); Blood Blood

vessels and blood pressure: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); AA--V conduction V conduction ↑↑•• Larger doses:Larger doses: cutaneouscutaneous vasodilatationvasodilatation(5) CNS stimulation(5) CNS stimulation• sedation, memory loss, psychosis (high dose)(high dose)

AtropineAtropine

2. 2. Clinical usesClinical uses(1) Ophthalmology(1) Ophthalmology•• Measurement of the refractive errors(Measurement of the refractive errors(验光验光):): childrenchildren•• Acute Acute iritisiritis or or iridocyclitisiridocyclitis:: mydriatics/mioticsmydriatics/miotics （（ to to

prevent prevent synechiasynechia/adhesion/adhesion））

(2) Antispasmodic agent(2) Antispasmodic agent•• 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 medicationmedication(4) (4) BradyarrhythmiaBradyarrhythmia•• sinus or nodal sinus or nodal bradycardiabradycardia, A, A--V blockV block(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), ), tachycardiadtachycardiad•• 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); );

coma (i.e. CNS symptoms)coma (i.e. CNS symptoms)

(3) (3) DetoxicationDetoxication•• Symptomatic treatment: e.g. diazepam.Symptomatic treatment: e.g. diazepam.•• PhysostigminePhysostigmine or or pilocarpinepilocarpine

(4) Contraindications(4) Contraindications•• glaucoma, glaucoma, prostatauxeprostatauxe, 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)

–– PrePre--anesthetic medication, prevention of anesthetic medication, prevention of motion sickness, Parkinsonmotion sickness, Parkinson’’s diseases disease

ScopolamineScopolamine

•• PropanthelinePropantheline ((普鲁本辛普鲁本辛))

–– poor absorption (poor absorption (popo) and BBB penetration) and BBB penetration–– antispasmodicantispasmodic effects in GI, treatment of effects in GI, treatment of

peptic ulcer diseasepeptic ulcer disease•• TropicamideTropicamide ((托吡卡胺托吡卡胺)) : : mydriaticsmydriatics, ,

cycloplegiccycloplegic ((睫状肌麻痹睫状肌麻痹))–– shorter duration (1/4 day) shorter duration (1/4 day) –– Examination of eyesExamination of eyes•• IpratropiumIpratropium ((异丙托溴胺异丙托溴胺)): : asthmaasthma•• BenztropineBenztropine: : ParkinsonParkinson’’s diseases disease

othersothers

Nicotinic receptor Nicotinic receptor antagonistsantagonists

•• 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

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

NNNN receptor antagonistsreceptor antagonists((Ganglionic Blocking drugs))

• 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 ))

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 ))

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•• 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

•• Main pharmacological effectsMain pharmacological effects

–– Transient Transient excitation (excitation (fasciculationsfasciculations肌束震肌束震颤颤),), and then and then inhibition (relaxation)inhibition (relaxation)

–– Relax Relax Skeletal MusclesSkeletal Muscles inin neck, limbs > neck, limbs > face, tongue, throat; less effective on face, tongue, throat; less effective on breath muscles at therapeutic dosesbreath muscles 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)•• overdose or overdose or hypersensitive patientshypersensitive patients;;•• neostigmineneostigmine potentiates the toxic effectspotentiates the toxic effects

(2) (2) FasciculationsFasciculations 肌束震颤肌束震颤

•• muscular pain after operationmuscular pain after operation(because of transient (because of transient fasciculationsfasciculations))


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

of of hyperkalemiahyperkalemia (burn injury, massive (burn injury, massive trauma, neurological disorders)trauma, 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 pseudocholinesteraseactivity is termed the dibucaine number. The dibucainenumber 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

–– Thiopental (Thiopental (硫喷妥硫喷妥))

–– 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((多粘菌多粘菌素素 ), ), etc.etc. (synergism in neuromuscular (synergism in neuromuscular blocking) blocking)


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

•• BenzylisoquinolinesBenzylisoquinolines((苄基异喹啉类苄基异喹啉类 ) )

•• AtracuriumAtracurium((阿曲库铵阿曲库铵) ) •• DoxacuriumDoxacurium((多库氯铵多库氯铵))•• MivacuriumMivacurium((咪库铵咪库铵))•• AmmonioAmmonio steroidssteroids•• PancuroniumPancuronium((潘库铵潘库铵) ) •• VecuroniumVecuronium((维库铵维库铵))•• PipecuroniumPipecuronium((派库铵派库铵) ) •• RocuroniumRocuronium((罗库铵罗库铵))

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

- 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 (lack of parallelism of eyes，斜视), blepharospasm (eyelid spasm), dystonia (abnormal tonicity，肌张力障碍).

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

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

LA Times

Botulinum Toxin Applications

Cholinergic PharmacologyCholinergic PharmacologyAdrenergic PharmacologyAdrenergic Pharmacology

Parasympathetic NSParasympathetic NS

EYEEYEContraction of iris sphincter muscle(pupil dilates)Contraction of ciliary muscle(lens accommodates for near vision)LacrimalLacrimal glandglandStimulates tearsSalivary glandSalivary glandCopious, water secretionTrachea and bronchiolesTrachea and bronchiolesConstricts, increase secretionHeartHeartrate↓contractility ↓

GastrointestinalGastrointestinalMuscle motility & tone ↑UUretersreters and bladderand bladderContraction of detrusorRelaxation of trigone &sphincter GenitaliaGenitalia--malemaleStimulates erection

Sympathetic NSSympathetic NS

EYEEYEcontraction of iris radial muscle (pupil dilates)contraction of ciliary muscle(lens accommodates for near vision)Salivary glandSalivary glandcopious, water secretionTrachea and bronchiolesTrachea and bronchiolesdilatesHeartHeartrate↑contractility ↑

Blood vesselsBlood vesselsdilatation (Skeletal muscle) constriction (skin,mucus, membranes & splanchin area) GastrointestinalGastrointestinalmuscle motility & tone ↓contraction of sphinctersUretersUreters and bladderand bladderrelaxes detrusorcontraction of trigone &sphincterGenitaliaGenitalia--femalefemaleRelaxation of uterus

NeurotransmittersNeurotransmitters••SynthesisSynthesis••StorageStorage••ReleaseRelease••InactivationInactivationReceptorsReceptors••ActivationActivation







Drug actions Drug actions and classificationand classification

Noradrenergic Nerve: Synthesis, storage and release of NETyrosine

tyrosine hydroxylase (TH)

L-DOPA

DOPA decarboxylase

dopamine (DA)

dopamine beta-hydroxylase (DBH)

norepinephrine (NE)

•• UptakeUptakeneurotransmitter transportersneurotransmitter transporters–– uptake 1: neuronal uptakeuptake 1: neuronal uptake–– uptake 2: nonuptake 2: non--neuronal uptakeneuronal uptake

•• Enzymatic degradationEnzymatic degradation–– monoamine monoamine oxidaseoxidase (MAO)(MAO)–– catecholcatechol--OO--methyltransfereasemethyltransferease

(COMT)(COMT)

Regulation of NE Synthesis and Turnover

Tyrosine hydroxylase (TH) activity is rate limiting

TH activity inhibited by NE product

TH activity modulated by presynapticautoreceptors

- alpha2 receptors can reduce NE release- beta2 receptors can increase NE release

Presynaptic heteroreceptors can modulate NE release

- ACh can reduce NE release

TH activity increases or decreases to maintain steady-state levels of norepinephrine.

The above processes contribute to regulation of steady-state NE levels (rate of synthesis = rate of output) Catecholamine

Biosynthetic Pathway

Norepinephrine and EpinephrineSynthesis in the Adrenal Medulla

- NE is stored in vesicles- DBH is located in vesicles - PNMT is located in the cytosol . - EPI is stored in vesicles- EPI (~80%) and NE (~20%) released into blood

- These hormones bind adrenergic receptors on target cells, inducing the same effects as direct sympathetic nervous stimulation.

Chromaffin cell

NEPNMT

NE EPI

EPI

EPI disposition: metabolism by COMT, MAO,sulfation, uptake into NE terminals

NE Metabolism- takes place within the same cells where the amines are synthesized, and in liver

- Extraneuronal O-methylation of norepinephrine and epinephrine to metanephrines(尿甲氧基肾上腺素 ) represent minor pathways of metabolism.

MHPG: was used as an index of CNS NE turnoverbut generated mostly from periphery

VMA: sometimes used as an index of NE turnover

Sulfate conjugatesalso prevalent

Adrenergic Receptors/Adrenoceptors

1

21

G-Protein Coupled Receptors

Norepinephrine(NE) release

signal transduction

response

receptor binding (reversible)

receptor activation

(2 3)low affinity for binding NE

1 Adrenergic Receptors:G protein termed Gq phospholipase C activation, IP3

mechanism: mobilizes and increases intracellular free calcium effects: primarily smooth muscle contraction

2 Adrenergic Receptors: Inhibition of adenylyl cyclase through Gi proteins

mechanism: decreases intracellular cAMP levels effects: decreased protein phosphorylation, decreased cellular function

Adrenergic Receptors: Activation of adenylyl cyclase through Gs proteins

mechanism: increases intracellular cAMP levels effects: phosphorylation of intracellular proteins smooth muscle relaxation, cardiac muscle contraction

Adrenergic Receptor Subtypes& G-Protein Coupled Mechanisms

The SNS Plays a Very Important Role in the

Regulation of the Cardiovascular System, which,

except for the Heart, is notInnervated by the PSNS

SNS Regulation of Cardiac Function

• The SNS innervates the entire heart while the PSNS only innervates the S-A and A-V nodes.

• Neural modulation of heart rate occurs in part through enhancement (NE via 1 ARs) or reduction (ACh via M2R) of pacemaker activity, which is directly stimulated by elevated cAMP levels.

• The SNS via 1 ARs also increases the force of contraction. Both heart rate and contractile force contribute to cardiac output.

The SNS EnhancesSmooth Muscle Contraction

Primarily by 1 ARs,and Reduces Contraction

Primarily by 2 ARs

SNS Regulation of Blood Pressure• Acute loss of SNS function lowers blood pressure• Chronic loss of SNS function greatly increases blood

pressure variability

Four Major Activators of the Adrenergic System

1- Hypoglycemia2- Hypothermia3- Hypoxia4- Hypotension

• Hypoxia - response is mainly cardiovascular: 1 receptors via SNS NE increase heart rate & contractility, resulting in greater cardiac output; 2 receptors via adrenal Epivasodilate blood vessels in muscle, increasing oxygen delivery, and mediate bronchodilation to facilitate oxygen intake.

• Hypoglycemia - response is mainly metabolic (next slides), but 2 vasodilation in muscle increases glucose (as well as oxygen) delivery.

Response toHypoglycemia(insulin injection)

The release of E (and to a lesser

extent NE) by the adrenal is in direct response to falling

blood glucose levels

Insu

lin in

ject

ion

Glycogenolysis (糖原分解)

• The brain and muscle must have glucose• The main sites of glycogenolysis are the

liver and muscle• Glycogen is broken down by glycogen

phosphorylase• This enzyme is activated by both PKA and

PKC through stimulation of 2 and 1adrenergic receptors, respectively

Gluconeogenesis(糖异生)• The liver and kidney are the key sites• Substrates: lactate (from muscle) and glycerol

(from fat)• Several enzymes in the pathway are activated

by PKC through 1 stimulation• Both glycogenolysis & gluconeogenesis are

indirectly stimulated by facilitating release of glucagon (2) & inhibiting release of insulin (2)

Lipolysis (脂解作用)• Lipases are stimulated by (esp. 3) receptors

Energy Mobilization by Epinephrine

Response to Hypothermia:1 - Piloerection2 - Peripheral vasoconstriction3 - Thermogenesis

-Brown fat a) activationb) proliferation

Peripheral Vasoconstriction

• To reduce heat loss, vasoconstriction occurs peripherally

• Lower temperatures increase the affinity of the 2 receptors, which are located on the peripheral vasculature, for NE & E

• This leads to constriction of the peripheral vasculature

Other SNS Functions

2 relaxationSmooth muscleDigestionGut2 inhibition& Secretion

of vasDeferens1 contractionSmooth muscleEjaculationVas

capsuleblood cells1 contractionSplenic circulatingSpleen

muscle(piloerection)1 contractionPiloerectorRaised hairSkin

smooth musclethe airway2 relaxationBronchialDilation ofLung

of irispupils 1 contractionRadial muscleDilation ofEye

MechanismMediatorEffect

receptorsreceptors•• 1 1 receptors:receptors:

(vasoconstriction: increased peripheral (vasoconstriction: increased peripheral resistance, resistance, BPBP↑↑; contraction of radial muscle ; contraction of radial muscle of iris: of iris: mydriasismydriasis))

•• 2 2 receptors:receptors:(CNS, (CNS, presynapticpresynaptic membranes of adrenergic membranes of adrenergic nerves: nerves: vasodilatation, inhibition of NE release; vasodilatation, inhibition of NE release; inhibition of insulin release)inhibition of insulin release)

Summary:Summary:AdrenoceptorsAdrenoceptors (adrenergic receptors)(adrenergic receptors)

receptorsreceptors

•• 1 1 receptors receptors (contractility(contractility↑↑, automaticity, automaticity↑↑, , conductionconduction↑↑, oxygen, oxygen--consumptionconsumption↑↑, cardiac , cardiac outputoutput↑↑: : heart stimulationheart stimulation; increased ; increased lipolysislipolysis))

•• 2 2 receptors receptors (relaxation of bronchial smooth (relaxation of bronchial smooth muscles: muscles: bronchodilationbronchodilation; slight ; slight vasodilationvasodilation; ; increased muscle and liver increased muscle and liver glycogenolysisglycogenolysis; increased ; increased release of glucagon)release of glucagon)

•• 3 3 receptors receptors ((lipolysislipolysis, , thermogenesisthermogenesis))

Summary:Summary:AdrenoceptorsAdrenoceptors (adrenergic receptors)(adrenergic receptors)

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 (L(L--dopa)dopa)•• Transport and storage Transport and storage ((imipramineimipramine, , reserpinereserpine))•• Release Release ((ephedrine, amphetamine)ephedrine, amphetamine)•• Inactivation Inactivation (MAOI)(MAOI)1.3 1.3 MimeticsMimetics and antagonistsand antagonists

(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

StructureStructure--activity relationship of activity relationship of catecholaminescatecholamines and related compoundsand related compounds

•• NonNon--catecholaminecatecholamine

–– IndirectIndirect--acting by acting by causing the release of causing the release of stored catecholamine.stored catecholamine.

–– Not inactivated by Not inactivated by COMT; some are poor COMT; some are poor substrate for MAOsubstrate for MAO(orally active, a (orally active, a prolonged duration of prolonged duration of action)action)

–– Greater access to the Greater access to the CNSCNS

•• CatecholamineCatecholamine

–– High potency in High potency in activating activating or or receptorsreceptors

–– Rapid inactivation by Rapid inactivation by COMT and by MAOCOMT and by MAO

–– Poor penetration into the Poor penetration into the CNSCNS

SSympathomimeticympathomimetic aminesamines

•• Direct mode Direct mode e.g. e.g. NorepinephrineNorepinephrine

epinephrineepinephrineisoproterenolisoproterenol

•• Indirect modeIndirect mode

•• Mixed modeMixed modee.g. ephedrinee.g. ephedrine

The mode of action The mode of action of of sympathomimeticsympathomimetic drugsdrugs

–– Enhances release of Enhances release of stored stored catecholaminescatecholaminese.g. amphetaminee.g. amphetamine

–– Inhibition of reuptake of Inhibition of reuptake of released released catecholaminescatecholaminese.g. cocainee.g. cocaine

–– Inhibition of MAOInhibition of MAOe.g. e.g. pargylinepargyline

Adrenoceptors

AdrenoceptorAdrenoceptor agonistsagonists(1)(1) , , receptor agonistsreceptor agonists•• epinephrine (adrenaline)epinephrine (adrenaline)，，dopamine, dopamine,

ephedrineephedrine(2) (2) receptor agonists receptor agonists •• 112 2 receptor agonists:receptor agonists: norepinephrinenorepinephrine•• 1 1 receptor agonists:receptor agonists: phenylephrinephenylephrine•• 2 2 receptor agonists:receptor agonists: clonidineclonidine(3) (3) receptor agonistsreceptor agonists：•• 112 2 receptor agonists:receptor agonists: isoproterenolisoproterenol•• 1 1 receptor agonists:receptor agonists: dobutaminedobutamine•• 2 2 receptor agonists:receptor agonists: salbutenolsalbutenol

Drug actions and classificationDrug actions and classification

Pharmacological effectsPharmacological effects11, , 2 , 2 , 11 , , 2 2 receptor agonistsreceptor agonists(1) Cardiac effects(1) Cardiac effects•• 11:: contractility contractility (positive (positive inotropicinotropic),),

HR HR (positive (positive chronotropicchronotropic), ), cardiac output cardiac output , , oxygen consumption oxygen consumption ,,inducing arrhythmiainducing arrhythmia

(2) Vascular effects(2) Vascular effects•• 11：：vasoconstriction (skin, mucous, viscera),vasoconstriction (skin, mucous, viscera),

especially at larger dosesespecially at larger doses•• 22：：vasodilatation of skeletal muscles vasodilatation of skeletal muscles

and coronary vesselsand coronary vessels

Epinephrine,Epinephrine, Adrenaline Adrenaline ((肾上腺素肾上腺素)): DIRECT: DIRECT

Concentration-dependent response in vascular smooth muscle to epinephrine

Predominant Effectslow [EPI] β2 > αhigh [EPI] α > β2

(3) Blood pressure(3) Blood pressure•• Systolic BP Systolic BP , Diastolic BP , Diastolic BP ↓↓(slight)(slight)(4) Respiratory(4) Respiratory•• 22：：dilatation of bronchial smooth muscles dilatation of bronchial smooth muscles

((BronchodilatationBronchodilatation))•• 11：：reducing congestion and edema of reducing congestion and edema of

bronchial mucosabronchial mucosa

(5) Metabolic effects (5) Metabolic effects •• blood glucose blood glucose (hyperglycemia)(hyperglycemia); ;

free fatty acids free fatty acids ((lipolysislipolysis))

Epinephrine,Epinephrine, AdrenalineAdrenaline

Effects of Effects of catecholaminescatecholamines（（therapeutic dosestherapeutic doses））

Predominant Effects:Predominant Effects:NE :NE : & & 11 effectseffectsEPI :EPI : 11, , 22 then at higher concentrations then at higher concentrations effects predominateeffects predominateISO: ISO: 11 and and 22

Clinical usesClinical uses

Systematic uses:Systematic uses:

Cardiac arrestCardiac arrest

Anaphylactic shockAnaphylactic shock

Acute bronchial asthmaAcute bronchial asthma

Topical uses:Topical uses:

Adjuvant of Adjuvant of local anesthesialocal anesthesia

BleedingBleeding


Adverse effectsAdverse effects

(1) Cardiac arrhythmias(1) Cardiac arrhythmias

(2) Hemorrhage (2) Hemorrhage (cerebral or subarachnoid)(cerebral or subarachnoid) : :

reason: a marked elevation of BPreason: a marked elevation of BP

(3) Central excitation(3) Central excitation：：anxiety, headache...anxiety, headache...

(4) Contraindications: (4) Contraindications: heart diseases, heart diseases, hypertension, coronary arterial disease, hypertension, coronary arterial disease, arteriosclerosis, hyperthyroidismarteriosclerosis, hyperthyroidism


(1) Cardiac effects(1) Cardiac effects：：1 receptor1 receptor, weak, weak(2) Vascular effects(2) Vascular effects：：

DA receptorDA receptor：：vasodilatation of renal vasodilatation of renal and mesenteric arteries , blood flow and mesenteric arteries , blood flow (small doses); (small doses);

1 receptor1 receptor：：vasoconstriction of vasoconstriction of skin, mesenteric vessels (larger doses)skin, mesenteric vessels (larger doses)(3) Renal effects(3) Renal effects：：renal vasodilatation; renal vasodilatation; natriureticnatriuretic effectseffects

Dopamine (Dopamine (多巴胺多巴胺): ): DIRECTDIRECT

Pharmacological effects : Pharmacological effects : , , receptor, receptor, ddopaminergicopaminergicreceptor receptor agonistsagonists

Clinical usesClinical uses(1) Shock(1) Shock•• cardiac and septic shockcardiac and septic shock(2) Acute renal failure(2) Acute renal failure•• combined with combined with furosemidefurosemide

Adverse effects Adverse effects –– shortshort--livedlived•• tachycardia, arrhythmia, reduction in urine tachycardia, arrhythmia, reduction in urine

flow (renal vasoconstriction)flow (renal vasoconstriction)

DopamineDopamine

•• Promoting release of NE, weak agonist effectsPromoting release of NE, weak agonist effects on on 11、、22、、11、、22 receptorsreceptors

PropertiesProperties：：–– chemically stable, orally effectivechemically stable, orally effective；；–– less potent but longer action duration;less potent but longer action duration;–– central stimulating: central stimulating: alertness alertness , fatigue , fatigue ↓↓, ,

prevents sleepprevents sleep (adverse effects)(adverse effects)–– TachyphylaxisTachyphylaxis ((快速耐受快速耐受).).

Ephedrine Ephedrine ((麻黄碱麻黄碱):): MIXEDMIXED

HO

HO CH

OH

CH2 NH

CH3CH3

NHCH

OH

CH

CH3

EpinephrineEpinephrineEphedrineEphedrine

Clinical usesClinical uses(1) Prevention of hypotension:(1) Prevention of hypotension: anestheticsanesthetics

(2) Nasal decongestion:(2) Nasal decongestion: nasal dropnasal drop

(3) Bronchial asthma:(3) Bronchial asthma: mild, chronic casesmild, chronic cases

(4) Relieving allergic disorders:(4) Relieving allergic disorders: urticariaurticaria ((风疹风疹), ), angioneuroticangioneurotic edemaedema

Ephedrine Ephedrine

NorepinephrineNorepinephrine, , NoradrenalineNoradrenaline

((去甲肾上腺素去甲肾上腺素): ): DIRECTDIRECT

Pharmacological effectPharmacological effect11, , 2 2 receptor agonistsreceptor agonists

(1) Vascular effects(1) Vascular effects：：11：：vasoconstriction (skin, renal, brain, vasoconstriction (skin, renal, brain,

hepatic, mesenteric, hepatic, mesenteric, etcetc.), blood flow .), blood flow 22：：inhibiting NE releaseinhibiting NE release

Actions of Actions of norepinephrinenorepinephrine

on poston post--synaptic synaptic ((11) and pre) and pre--synaptic (synaptic (2 2 ) )

receptorsreceptors

(2) Blood pressure(2) Blood pressure：：•• Systolic BP Systolic BP , Diastolic BP , Diastolic BP (especially (especially

at larger doses) at larger doses) (3) Cardiac effects(3) Cardiac effects：：• weak direct stimulation (weak direct stimulation (11); inhibition ); inhibition

viavia reflexreflex ((in vivoin vivo))•• Net result: little cardiac stimulatesNet result: little cardiac stimulates


Clinical uses Clinical uses ((limitedlimited therapeutic value)therapeutic value)

(1) Shock(1) Shock•• used in early phase of some types of shock: used in early phase of some types of shock:

small doses and shorter duration small doses and shorter duration ((dopaminedopamine is better; replaced by is better; replaced by MetaraminolMetaraminol间间羟胺羟胺))

(2) Hypotension due to drug poisoning(2) Hypotension due to drug poisoning•• especially for especially for chlorpromazine chlorpromazine ((氯丙嗪氯丙嗪))(3) Hemorrhage in upper alimentary tract(3) Hemorrhage in upper alimentary tract•• orally given after dilutionorally given after dilution


Adverse effectsAdverse effects(1) Ischemia and necrosis at the site of (1) Ischemia and necrosis at the site of iviv

administrationadministration relieved by filtrating the area relieved by filtrating the area with with phentolaminephentolamine (( receptor antagonist)receptor antagonist)

(2) Acute renal failure(2) Acute renal failure avoiding larger doses avoiding larger doses and longer duration; monitoring urinary and longer duration; monitoring urinary volumevolume

(3) Contraindication(3) Contraindication hypertension, hypertension, arteriosclerosis, heart diseases, severe arteriosclerosis, heart diseases, severe urinary volume urinary volume , microcirculation disorders, microcirculation disorders


•• Induces reflex Induces reflex bradycardiabradycardia, used in hypotension, , used in hypotension, paroxysmal paroxysmal supraventricularsupraventricular tachycardia tachycardia ；；

•• PhenylephrinePhenylephrine:: MydriasisMydriasis, , pupillarypupillary dilator dilator muscles, no or less effect on intraocular muscles, no or less effect on intraocular pressure, shortpressure, short--acting (for several hours); acting (for several hours); act as a nasal decongestant act as a nasal decongestant

MethoxamineMethoxamine甲氧明甲氧明: : DIRECT>INDIRECTDIRECT>INDIRECT

PhenylephrinePhenylephrine去氧肾上腺素去氧肾上腺素:: DIRECT>INDIRECTDIRECT>INDIRECT

1 receptor agonists1 receptor agonists

•• ClonidineClonidine: : DIRECTDIRECT– Uses: antihypertensive drug; can be administered as

transdermal patch (permits continuous administration)

– Mechanism of action : – α2 - adrenergic partial agonist; actions

predominantly in CNS – lowers blood pressure by inhibiting sympathetic

vasomotor tone

– Adverse effects: (iv administration may result in transient increase in blood pressure (activation of post-synaptic receptors); dry mouth, sedation

22 receptor agonistsreceptor agonists

(1) Cardiac effects (1) Cardiac effects ((11 receptor)receptor)(2) Vascular effects and blood (2) Vascular effects and blood

pressurepressure2 2 receptor:receptor: dilatation of skeletal dilatation of skeletal muscles and coronary vesselsmuscles and coronary vessels；；

SP SP ，， DP DP or or ，， pulse pulse pressure pressure

(3) (3) BronchodilatationBronchodilatation ((2 2 receptor)receptor)(4) Metabolism(4) Metabolism

Promoting effects as epinephrinePromoting effects as epinephrine

IsoproterenolIsoproterenol, , IsoprenalineIsoprenaline异丙肾上腺素异丙肾上腺素:: DIRECTDIRECTPharmacological effects : Pharmacological effects : 1 , 1 , 2 receptor agonists2 receptor agonists

Clinical usesClinical uses(1)Cardiac arrest / A(1)Cardiac arrest / A--V block: V block: in emergenciesin emergencies(2)Shock / Bronchial asthma: (2)Shock / Bronchial asthma: replaced by other replaced by other

sympathomimeticssympathomimetics

Adverse effectsAdverse effects(1) Heart stimulation, arrhythmia(1) Heart stimulation, arrhythmia(2) Contraindications:(2) Contraindications: coronary heart coronary heart

disease, disease, myocarditismyocarditis, hyperthyroidism, hyperthyroidism……

IsoproterenolIsoproterenol, , IsoprenalineIsoprenaline

1 1 receptor agonistsreceptor agonists

•• Heart failure Heart failure (after cardiac surgery or (after cardiac surgery or congestive HF or acute myocardial infarction; congestive HF or acute myocardial infarction; shortshort--term treatment)term treatment)

•• Cardiac stimulationCardiac stimulation

DobutamineDobutamine ((多巴酚丁胺多巴酚丁胺):): DIRECTDIRECT

22 receptor agonistsreceptor agonists

TerbutalineTerbutaline ((特布他林特布他林)):: DIRECTDIRECT

• Uses: BronchialBronchial asthmaasthmadilation of bronchial smooth muscle; 2 > 1 agonist (partially selective): preferential activation of pulmonary 2 receptors by inhalation.

Use: Premature Labor (with ritodrine).

• Adverse effects: headache, cardiac stimulation and skeletal muscle fine tremor (2 receptors on presynaptic motor terminals; their activation enhances ACh release).

INDIRECT-acting drugs (summary)

Adrenergic Receptor Antagonists

antagonists of NE at either or receptors.

- competitive antagonists (reversible), blocking endogenous norepinephrine

- irreversible antagonists

Antagonist characteristics:- receptor occupancy (binding affinity) - no receptor activation (no efficacy)

- nonselective and selective drugs available for both the or receptors.

AdrenoceptorAdrenoceptor antantagonistsagonists（（11）） receptor antagonistsreceptor antagonists•• 112 2 receptor antagonists:receptor antagonists:

shortshort--acting:acting: phentolaminephentolamine（酚妥拉明）（酚妥拉明）

longlong--acting:acting: phenoxybenzaminephenoxybenzamine（酚苄明）（酚苄明）

•• 1 1 receptor antagonists:receptor antagonists: prazosinrazosin（哌唑嗪）（哌唑嗪）

•• 2 2 receptor antagonists:receptor antagonists: yohimbineohimbine（育亨宾）（育亨宾）


AdrenoceptorAdrenoceptor antantagonistsagonists（（22）） receptor antagonistsreceptor antagonists•• 112 2 receptor antagonists:receptor antagonists: propranololpropranolol （普萘洛尔）（普萘洛尔）

•• 1 1 receptor antagonists:receptor antagonists: atenololatenolol（阿替洛尔）（阿替洛尔）

•• 2 2 receptor antagonists:receptor antagonists: butoxaminebutoxamine（布他沙明）（布他沙明）

（（33））, , receptor antagonistsreceptor antagonists•• labetalollabetalol（拉贝洛尔）（拉贝洛尔）


Epinephrine reversalEpinephrine reversal

（（adrenaline reversaladrenaline reversal））

BP

antagonistantagonistepinephrineepinephrine epinephrineepinephrine

•• competitive, competitive, nonselective ((11, , 2 2 receptor receptor antagonists)antagonists)

PhentolaminePhentolamine （酚妥拉明）（酚妥拉明）

N

NCH3

HO

N CH2

HPharmacological effectsPharmacological effects

(1) Vasodilatation(1) VasodilatationBlocking Blocking 1 receptor: 1 receptor: vasodilation in both arteriolar

resistance vessels and veins(2) Cardiac Stimulation (2) Cardiac Stimulation ReflexReflex；；blocking blocking 2 receptor 2 receptor ～～NE release NE release (3) Cholinergic and histamine(3) Cholinergic and histamine--like effectslike effectsContraction of GI smooth muscles,Contraction of GI smooth muscles,Gastric acid secretion Gastric acid secretion

Clinical usesClinical uses(1) (1) • Hypertension from Hypertension from pheochromocytomapheochromocytoma

(short term use). (short term use). •• prepre-- and postand post--operation of operation of

pheochromocytomapheochromocytoma• Diagnostic test for Diagnostic test for pheochromocytomapheochromocytoma(2) Peripheral vascular diseases(2) Peripheral vascular diseases•• AcrocyanosisAcrocyanosis, , RaynaudRaynaud’’ss diseasedisease(3) Local vasoconstrictor (3) Local vasoconstrictor extravasationextravasation

Major Adverse effectsMajor Adverse effects– postural hypotension, reflex tachycardia, arrhythmia, angina pectoris, arrhythmia, angina pectoris, GI reactions

PhentolaminePhentolamine

PheochromocytomaPheochromocytoma is a rare is a rare catecholaminecatecholamine--secreting tumor derived secreting tumor derived from from chromaffinchromaffin cells of the adrenal cells of the adrenal medulla that produces excess epinephrine.medulla that produces excess epinephrine.

• Hypertension & Crises• Elevated Metabolic Rate

-heat intolerance-excessive sweating-weight loss

• Temporarily manage with -adrenergic antagonists (1 & ±)

Pheochromocytoma

• Irreversible, nonselective ( 1 and 2antagonists )

• Long-acting• Similar to

phentolamine in actions and clinical uses

PhenoxybenzaminePhenoxybenzamine （酚苄明）（酚苄明）

1 1 receptor antagonistsreceptor antagonists•• prazosinprazosintreatment for hypertensiontreatment for hypertension

22 receptor antagonistsreceptor antagonists• yohimbineyohimbinefor research use onlyfor research use only

ADMEADME•• FirstFirst--pass elimination,pass elimination,

low bioavailability: low bioavailability: propranololpropranolol

•• Hepatic metabolism and renal excretion, Hepatic metabolism and renal excretion, hepatic and renal functions alter the hepatic and renal functions alter the effects of the drugs and result in large effects of the drugs and result in large individual variationindividual variation

•• So, So, dose individualizationdose individualization is necessary.is necessary.

receptor antagonistsreceptor antagonists

Effects of an AR Antagonist

Pharmacological effectsPharmacological effects

(1) (1) receptor blockadereceptor blockade

A. Cardiovascular effectsA. Cardiovascular effects：：• Depressing heart: Depressing heart: reduction in HR, Areduction in HR, A--V V

conduction, automaticity, cardiac output, conduction, automaticity, cardiac output, oxygen consumptionoxygen consumption

•• Hypotension:Hypotension: peripheral blood flow peripheral blood flow , , hypotensivehypotensive effects in hypertensive effects in hypertensive patientspatients


(1) (1) receptor blockadereceptor blockadeB. Bronchial smooth musclesB. Bronchial smooth muscles•• induces bronchial smooth muscle contraction induces bronchial smooth muscle contraction

in asthmatic patientsin asthmatic patients

C. MetabolismC. Metabolism•• lipolysislipolysis , , glycogenolysisglycogenolysis , potentiating , potentiating

insulin effects ~ hypoglycemiainsulin effects ~ hypoglycemia

D. D. ReninRenin secretionsecretion•• decreasing secretion of decreasing secretion of reninrenin


(2) Intrinsic (2) Intrinsic sympathomimeticsympathomimetic effectseffects•• Partial agonists: Partial agonists: e.g. e.g. pindololpindolol,, acebutololacebutolol

(3) Membrane(3) Membrane--stabilizing effectsstabilizing effects•• Larger doses of some drugs: Larger doses of some drugs: quinidinequinidine--like like

effects, Naeffects, Na++ channel blockchannel block

(4) Others(4) Others•• Lowering intraocular pressure;Lowering intraocular pressure;•• Inhibiting platelet aggregationInhibiting platelet aggregation


Circulation of Aqueous humorCirculation of Aqueous humor

Clinical usesClinical uses(1) Arrhythmia(1) Arrhythmia：：supraventricularsupraventricular, sympathetic , sympathetic

activity activity

(2) Hypertension(2) Hypertension

(3) Angina pectoris and myocardial infarction(3) Angina pectoris and myocardial infarction

(4) Chronic heart failure(4) Chronic heart failure

(5) Others: (5) Others: hyperthyroidism, migraine headache, hyperthyroidism, migraine headache, glaucomaglaucoma（（timololtimolol））......


Adverse effectsAdverse effects(1) Heart depression: (1) Heart depression: contraindicated in heart contraindicated in heart

failure, severe Afailure, severe A--V block, sinus V block, sinus bradycardiabradycardia(2) Worsening of asthma: (2) Worsening of asthma: contraindicated in contraindicated in

bronchial asthmatic patientsbronchial asthmatic patients(3) Withdrawal syndrome(3) Withdrawal syndrome：：upup--regulation of the regulation of the

receptorsreceptors(4) Worsening of peripheral vascular (4) Worsening of peripheral vascular

constrictionconstriction(5) Others(5) Others：：central depression, hypoglycemia,central depression, hypoglycemia,

etc.etc.


•• 11, , 2 2 receptor blockingreceptor blocking•• no intrinsic activityno intrinsic activity•• firstfirst--elimination after oral administration, elimination after oral administration,

individual variation of bioavailabilityindividual variation of bioavailability

PropranololPropranolol （普萘洛尔）（普萘洛尔）

TimololTimolol （噻吗洛尔）（噻吗洛尔）•• For treatment of glaucoma (wideFor treatment of glaucoma (wide--angle)angle)

•• 11receptor antagonists, no receptor antagonists, no intrinsic activityintrinsic activity

••

•• atenololatenolol : longer t: longer t1/21/2, once daily, once daily

•• usually used for treatment of usually used for treatment of hypertensionhypertension

AtenololAtenolol （阿替洛尔）（阿替洛尔）MetoprololMetoprolol（美托洛尔）（美托洛尔）

αα, , receptor antagonistsreceptor antagonists

•• αα, , ββ receptor blocking, receptor blocking, ββ> > αα•• usually used for treatment of usually used for treatment of

hypertensionhypertension

LabetalolLabetalol （拉贝洛尔）（拉贝洛尔）

summary

• Heart failure

• Shock,• Congestive heart

failure

• Asthma• As cardiac stimulant

• shock

• Acute asthma,• anaphylactic shock,• in local anesthetics

to increase duration of action

Therapeutic uses

dobutamine

Dopaminergic,

dopamine

1,2isoproterenol

1,21)

norepinephrine

1,21,2

epinephrine

Adverse effects/

contraindications

Receptorspecificity

Agonist

summary

•Asthma•Premature labor

•hypertension

•supraventriculartachycardia

•supraventriculartachycardia •glaucoma•as a nasal decongestant

•Shock•hypotension

•asthma•as a nasal decongestant

Therapeutic uses

SalbutemolTerbutalineRitodrinealbuterol

Clonidine

Methoxamien

Phenylephrine

Metaraminol

CNS

ephedrine

Adverse effects/contraindications

Receptor specificity

Agonist

summary

• hypertension

• hypertension

• Glaucoma • hypertension

• Hypertension• Glaucoma• Migraine• Hyperthyroidism• Angina pectoris• Myocardial infarction

• hypertension

• pheochromocytoma• Peripheral vascular diseases• Local vasoconstrictor

extravasation

Therapeutic uses

labetalol

AtenololMetoprolol

timolol

propranololprazosin

PhentolaminePhenoxybenz-

amine

Adverse effects/contraindications

Receptorspecificity

Antagonist

1. Hypotension-To preserve adequate blood perfusion to heart, brain or kidneys in cases of hemorrhage, overdose of antihypertensive drugs or spinal cord injuries.

-Short duration of treatment: NE, phenylephrine, methoxamine, ephedrine ( AR agonists).

2. Shock

3. Cardiogenic Shock

-Inadequate perfusion to tissues as a consequence of hypovolemia, cardiac failure, or altered vascular resistance.

-Usually associated with hypotension.

-Use of -adrenergic agonists to increase peripheral vascular resistance, and -adrenergic agonists to improve cardiac function.

-Massive myocardial infarction.

-Stimulation of cardiac -adrenergic receptors is needed: isoproterenol, norepinephrine, epinephrine, dobutamine, dopamine.

Therapeutic Uses of Therapeutic Uses of 11 ((±±) AR Agonists) AR Agonists

4. Local Vascular Effects-Reduction of regional blood flow in surgery (nose, throat, larynx) to improve visualization by limiting hemorrhage.

-Epinephrine retards the absorption of local anesthetics and increases the duration of anesthesia (vasoconstrictor effect of epinephrine)

6. Allergic Reactions

5. Nasal Decongestion--Adrenergic agonists are used as nasal decongestants.

-These drugs decrease the volume of the nasal mucosa and therefore reduce the resistance to airflow.

-Oxymetazoline, phenylephrine and ephedrine are commonly used.

-Epinephrine (s.c.) is used in acute hypersensitivity reactions.

-Activation of -adrenergic receptors on mast cells suppresses the release of histamine and leukotrienes.

Therapeutic Uses of Therapeutic Uses of 11 ((±±) AR Agonists) AR Agonists

1. Asthma

-Asthma is a condition of overreactive airways. Asthma attacks can make it very difficult to breath because of excess bronchoconstriction.

- AR agonists such as albuterol, metaproterenol and terbutaline are used.

-The drugs are administered by inhalation and are absorbed slowly, limiting their systemic side effects, and selectivity reduces cardiac stimulation.

2. Premature Labor-When labor occurs prematurely (before 37 weeks), it is a risk to the fetus.

- AR agonists relax the smooth muscle of the uterus and help prevent premature delivery. The goal is to reach at least 37 weeks when the fetal lungs have matured.

Therapeutic Uses of Therapeutic Uses of 22 AR AgonistsAR Agonists

1. Pheochromocytoma

2. Hypertension

3. Heart Failure

-While not commonly used anymore, 1 blockers can be use to treat hypertension.

-Somewhat more common is the use of blockers. These work centrally(the most important effect – the mechanism is not completely understood) and peripherally (decrease heart rate some).

-After a myocardial infarction, the SNS will be activated to increase the cardiac output from the remaining good heart tissue. This is good in the short-term, but long-term changes lead to cardiac hypertrophy and failure.

-Ironically, blockers reduce the incidence of sudden death from heart failure.

Therapeutic Uses of Therapeutic Uses of 11 & & AR AntagonistsAR Antagonists

Other Important Catecholamine DrugsOther Important Catecholamine Drugs•• TH Inhibitor TH Inhibitor –– --methylmethyl--pp--tyrosinetyrosine•• DBH Inhibitors DBH Inhibitors –– (no good selective ones)(no good selective ones)•• VMAT Inhibitors VMAT Inhibitors –– reserpinereserpine & amphetamine& amphetamine•• False Transmitters False Transmitters –– tyraminetyramine &&

--methylmethyl--DOPA ( DOPA ( --methylmethyl--NE)NE)•• MAO Inhibitors MAO Inhibitors –– pargylinepargyline (nonselective),(nonselective),

chlorgylinechlorgyline (MAOA), (MAOA), deprenyldeprenyl (MAOB)(MAOB)•• NET Inhibitors NET Inhibitors –– desipraminedesipramine, , reboxetinereboxetine•• Neurotoxin Neurotoxin –– 66--hydroxydopamine, DSPhydroxydopamine, DSP--44

autonomic pharmacology -...

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