Adrenergic Pharmacology Adrenergic receptor agonists Adrenergic recpeotr antagonists 张纬萍浙江大学医学院药理2012.12.3

Adrenergic PharmacologyAdrenergic Pharmacology

Adrenergic receptor agonistsAdrenergic receptor agonists Adrenergic recpeotr antagonistsAdrenergic recpeotr antagonists

张纬萍张纬萍

浙江大学医学院药理浙江大学医学院药理

2012.12.32012.12.3

NeurotransmittersNeurotransmitters• SynthesisSynthesis• StorageStorage• ReleaseRelease• InactivationInactivation

ReceptorsReceptors• ActivationActivation

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

Noradrenergic Nerve: Synthesis, storage and release of NE

Tyrosine

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: non-neuronal uptakeuptake 2: non-neuronal uptake

• Enzymatic degradationEnzymatic degradation– monoamine oxidase (MAO)monoamine oxidase (MAO)– catechol-O-methyltransferease (COMT)catechol-O-methyltransferease (COMT)

Norepinephrine and Epinephrine Synthesis 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

PNMT

NE Metabolism- Within the same cells where the amines are synthesized, and in liver- Extraneuronal O-methylation of norepinephrine and epinephrine to

metanephrines represent minor pathways of metabolism.

Act on adrenergic receptors/adrenoceptors

1

21

G-Protein Coupled Receptors

Norepinephrine (NE) release

(2 3)

low affinity for binding NE

Adrenoceptors

q

EP/NE

EP/NE

EP/Iso

1 Adrenergic Receptors:

G protein termed Gq phospholipase C activation, IP3

mechanism: mobilizes and increases intracellular free Ca2+ effects: primarily smooth muscle contraction

2 Adrenergic Receptors:

Inhibition of adenylyl cyclase (AC) 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 (2), cardiac muscle contraction (1)

Adrenergic Receptor Subtypes

& G-Protein Coupled Mechanisms

α1

postsynaptic

α2

presynaptic

β1

postsynaptic

β2

postsynaptic

blood vessels: vasoconstriction (arterioles, veins)

decreases NE release

heart: increases heart rate increases contractility increases conduction velocity

blood vessels: vasodilation lungs: bronchodilation

kidney: β1 increases renin release ( β3 increases lipolysis )

increases glycogenolysis, resulting in increase of plasma glucose levels

Adrenergic Receptor (adrenoreceptors)These are receptors activated by NE, EPI, or drugs with similar actions

3

fat cells (not NE)

The SNS Plays a Very Important Role in the Regulation of the

Cardiovascular System, which, except for the Heart, is not Innervated 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.

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

pressure variability

The SNS EnhancesSmooth Muscle Contraction

Primarily by 1 ARs,and Reduces Contraction

Primarily by 2 ARs

Mechanisms of drug actionsMechanisms of drug actions

1.1 Direct actions on the receptors1.1 Direct actions on the receptors• AgonistsAgonists• AntagonistsAntagonists

1.2 Indirect actions 1.2 Indirect actions via via affecting transmittersaffecting transmitters• Synthesis Synthesis (L-dopa)(L-dopa)• Transport and storage Transport and storage (imipramine, reserpine)(imipramine, reserpine)• Release Release (ephedrine, amphetamine)(ephedrine, amphetamine)• Inactivation Inactivation (MAOI)(MAOI)

Mechanisms of drug actionsMechanisms of drug actions

1.3 Mimetics and antagonists1.3 Mimetics and antagonists

(1) Mimetics(1) Mimetics

direct-acting:direct-acting: receptor agonists receptor agonists

indirect-acting:indirect-acting: increasing amounts and/or increasing amounts and/or

effects of transmitterseffects of transmitters

(2) Antagonists(2) Antagonists

direct-acting:direct-acting: receptor antagonists receptor antagonists

indirect-acting:indirect-acting: decreasing amounts and/or decreasing amounts and/or

effects of transmitterseffects of transmitters

Adrenoceptor agonistsAdrenoceptor agonists

(1)(1) , , receptor agonists receptor agonists • epinephrine (adrenalineepinephrine (adrenaline ，肾上腺素，肾上腺素 )) ，， dopamine dopamine

多巴胺多巴胺 , ephedrine , ephedrine 麻黄碱麻黄碱(2) (2) receptor agonists receptor agonists 112 2 receptor agonists:receptor agonists: norepinephrine norepinephrine 去甲肾上去甲肾上

腺素腺素 1 1 receptor agonists:receptor agonists: phenylephrinephenylephrine 苯肾上腺素苯肾上腺素 2 2 receptor agonists:receptor agonists: clonidine clonidine 可乐定可乐定(3) (3) receptor agonists receptor agonists ： 112 2 receptor agonists:receptor agonists: isoproterenolisoproterenol 异丙肾上腺素异丙肾上腺素 1 1 receptor agonists:receptor agonists: dobutamine dobutamine 多巴酚丁胺多巴酚丁胺 2 2 receptor agonists:receptor agonists: salbutamol salbutamol 沙丁胺醇沙丁胺醇

Drug actions and classificationDrug actions and classification

Structure-activity relationship of Structure-activity relationship of catecholamines and related compoundscatecholamines and related compounds

• Non-catecholamineNon-catecholamine

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

– Not inactivated by COMT; Not inactivated by COMT; some are poor substrate some are poor substrate for MAOfor MAO

(orally active, a prolonged (orally active, a prolonged duration of action)duration of action)

– Greater access to the CNSGreater access to the CNS

• 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

Sympathomimetic aminesSympathomimetic amines

• Direct mode Direct mode e.g. Norepinephrinee.g. Norepinephrine epinephrineepinephrine isoproterenolisoproterenol

• Indirect modeIndirect mode

• Mixed modeMixed mode e.g. ephedrinee.g. ephedrine

The mode of action The mode of action of sympathomimetic drugsof sympathomimetic drugs

– Enhances release of Enhances release of stored catecholaminesstored catecholamines

e.g. amphetaminee.g. amphetamine

– Inhibition of reuptake of Inhibition of reuptake of released catecholaminesreleased catecholamines

e.g. cocainee.g. cocaine

– Inhibition of MAOInhibition of MAO e.g. pargylinee.g. pargyline

Pharmacological effectsPharmacological effects11, , 2 , 2 , 11 , , 2 2 receptor agonistsreceptor agonists

(1) Cardiac effects(1) Cardiac effects• 11:: contractility contractility (positive inotropic), (positive inotropic), HR HR (positive chronotropic), (positive chronotropic), cardiac output cardiac output , , oxygen consumption oxygen consumption ,, inducing arrhythmiainducing arrhythmia

(2) Vascular effects (2) Vascular effects (cerebral and renal circulation)(cerebral and renal circulation)• 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: 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

(Bronchodilatation)(Bronchodilatation)• 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 (lipolysis) (lipolysis)


Effects of epinephrineEffects of epinephrine （（ therapeutic dosestherapeutic doses ））

systolic pressuresystolic pressure due to increased cardiac contractile force and a rise in cardiac output due to increased cardiac contractile force and a rise in cardiac output .diastolic pressure usually falls due to the decrease of peripheral resistance decreasing.

1 in heart, 1 in many microvessels, 2 in the vessels of skeletal muscle

(6) Smooth muscle(6) Smooth muscle• EEffects on vascular smooth muscle are of major ffects on vascular smooth muscle are of major

physiological importancephysiological importance.

• GI smooth muscle, relax (, )

• Stomach, relax

• Pyloric and ileocecal sphincters, contracted (depends on the pre-existing tone of the muscle).

• Uterine, differ upon the time

• Detrusor muscle （逼尿肌） of the bladder, contraction


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, hyperthyroidism. arteriosclerosis, hyperthyroidism. Esp. Esp. patients receiving nonselective patients receiving nonselective blockers. blockers.


NorepinephrineNorepinephrine, Noradrenaline, NE: , Noradrenaline, NE: DIRECTDIRECT

Pharmacological effectPharmacological effect11, , 2 2 receptor agonistsreceptor agonists

NE and Epi are similar potent on NE and Epi are similar potent on 11

NE has little action of NE has little action of 22

(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 norepinephrine norepinephrine

on post-synaptic on post-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 reflex reflex ((in vivoin vivo))

• Net result: little cardiac stimulatesNet result: little cardiac stimulates

NorepinephrineNorepinephrine, Noradrenaline: , Noradrenaline: DIRECTDIRECT

Effects of catecholaminesEffects of catecholamines （（ therapeutic dosestherapeutic doses ））

Predominant Effects: BPPredominant Effects: BP, peripheral resistance, peripheral resistance, HR, HR 11 receptor: vascular smooth muscle contraction receptor: vascular smooth muscle contraction 11 receptor: myocardial contraction receptor: myocardial contraction

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 ，间羟胺，间羟胺 ))

(2) Hypotension due to drug poisoning(2) Hypotension due to drug poisoning• especially for especially for chlorpromazinechlorpromazine

(3) Hemorrhage in upper alimentary tract(3) Hemorrhage in upper alimentary tract ，上消，上消化道出血化道出血

• orally given after dilution orally 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


(1) Cardiac effects(1) Cardiac effects ：： 11 receptor 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 dosessmall doses); );

11 receptor receptor ：： vasoconstriction of skin, vasoconstriction of skin,

mesenteric vessels (mesenteric vessels (larger doseslarger doses))

(3) Renal effects(3) Renal effects ：： renal renal vasodilatation; natriuretic effectsvasodilatation; natriuretic effects

Dopamine: Dopamine: DIRECTDIRECTPharmacological effects : Pharmacological effects : , , receptor, dopaminergic receptor, dopaminergic receptor agonistsreceptor agonists


(1) Shock, sever congestive failure(1) Shock, sever congestive failure• cardiac and septic shockcardiac and septic shock

(2) Acute renal failure(2) Acute renal failure• combined with furosemidecombined with furosemide

Adverse effects – Adverse effects – short-livedshort-lived• tachycardia, arrhythmia, reduction in urine tachycardia, arrhythmia, reduction in urine

flow (renal vasoconstriction)flow (renal vasoconstriction)

DopamineDopamine ，， DIRECTDIRECT

L-DOPA but not dopamine can enter brain.

(1) Cardiac effects (1) Cardiac effects ((11 receptor) receptor)

(2) Vascular effects(2) Vascular effects 2 2 receptor:receptor: dilatationdilatation of skeletal of skeletal

muscles and coronary vesselsmuscles and coronary vessels ；； SP SP ，， DP DP or or ，， pulse pulse

pressure pressure

(3) Bronchodilatation (3) Bronchodilatation ((2 2 receptor)receptor)

(4) Metabolism(4) Metabolism Promoting effects as epinephrinePromoting effects as epinephrine

IsoproterenolIsoproterenol, , Isoprenaline:Isoprenaline: DIRECT DIRECT异丙肾上腺素异丙肾上腺素11 , , 22 receptor agonists receptor agonists

Effects of catecholaminesEffects of catecholamines （（ therapeutic dosestherapeutic doses ））

Predominant Effects: HRPredominant Effects: HR, systolic BP, systolic BP, distolic BP, distolic BP, peripheral resistance , peripheral resistance

11, myocardial contraction, myocardial contraction

22, vascular dialization, vascular dialization

,, at higher concentrations at higher concentrations

Clinical usesClinical uses(1) Cardiac arrest / A-V block: (1) Cardiac arrest / A-V block: in emergenciesin emergencies

(2) Shock / Bronchial asthma: (2) Shock / Bronchial asthma: replaced by replaced by

other sympathomimeticsother sympathomimetics

Adverse effectsAdverse effects(1) Heart stimulation, arrhythmia(1) Heart stimulation, arrhythmia

(2) Contraindications:(2) Contraindications: coronary heart coronary heart

disease, myocarditis, hyperthyroidism, disease, myocarditis, hyperthyroidism,

pheochromocytoma. pheochromocytoma.

IsoproterenolIsoproterenol, Isoprenaline, Isoprenaline

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; short-term treatment)short-term treatment)

• Cardiac stimulationCardiac stimulation

(-) isomer of dobutamine is a potent agonist at (-) isomer of dobutamine is a potent agonist at 11 receptors receptors

(+)-dobutamine is a potent (+)-dobutamine is a potent 11 receptor antagonist receptor antagonist

DobutamineDobutamine:: 多巴酚丁胺多巴酚丁胺， DIRECTDIRECT

22 receptor agonists receptor agonists

Terbutaline:Terbutaline: 博利康尼，博利康尼， DIRECTDIRECT

• Uses:

BronchialBronchial asthma asthma

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

Premature LaborPremature Labor (combine with ritodrine ，羟苄羟麻黄碱 ).

• Adverse effects:

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

Terbutaline:Terbutaline: 博利康尼博利康尼间羟异丁肾上腺素

Metaproterenol间羟异丙肾上腺

Albuterol舒喘灵，沙丁胺醇

Isoetharine ， N- 异丙基乙基降肾上腺素 Pirbuterol ，吡舒喘宁吡丁醇 Bitolterol ，叔丁肾上腺素双甲苯酸酯 Fenoterol ，培罗坦克 Salmeterol ，沙美特罗 Ritodrine ，羟苄麻黄碱 Procaterol ，异丙喹喘宁


• Induces reflex bradycardia, used in Induces reflex bradycardia, used in hypotension, paroxysmal supraventricular hypotension, paroxysmal supraventricular tachycardia tachycardia ；；

• Phenylephrine: Phenylephrine: MydriasisMydriasis （瞳孔散大）（瞳孔散大） , , pupillary dilator muscles, no or less effect on pupillary dilator muscles, no or less effect on intraocular pressure, short-acting (for several intraocular pressure, short-acting (for several hours); act as a nasal decongestant hours); act as a nasal decongestant

MethoxamineMethoxamine （（伐沙克新伐沙克新）） : : DIRECT>INDIRECTDIRECT>INDIRECT PhenylephrinePhenylephrine （（苯肾上腺素苯肾上腺素）） : : DIRECT>INDIRECTDIRECT>INDIRECT


ClonidineClonidine(( 可乐定可乐定 ):): 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 （ probably on I1 receptor ） .

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

Apraclonidine, 阿拉可乐定 Brimonidine, 溴莫尼定 Guanfacine, 氯苯乙胍Guanabenz, 氯苄氨胍 Methyldopa, 甲多巴 Tizanidine, 替扎尼定

Other Other 22 receptor agonists receptor agonists

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

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 , prevents

sleep (adverse effects)sleep (adverse effects)

– Tachyphylaxis Tachyphylaxis （（快速抗药反应快速抗药反应）） ..

Ephedrine: Ephedrine: 麻黄碱，麻黄碱， MIXEDMIXED

HO

HO CH

OH

CH2 NH

CH3

CH3

NHCH

OH

CH

CH3

EpinephrineEpinephrineEphedrineEphedrine


(1) Prevention of hypotension:(1) Prevention of hypotension: anestheticsanesthetics

(2) Nasal decongestion:(2) Nasal decongestion: nasal dropnasal drop ，如感冒，如感冒(3) Bronchial asthma:(3) Bronchial asthma: mild, chronic casesmild, chronic cases

(4) Relieving allergic disorders:(4) Relieving allergic disorders: urticariaurticaria （荨麻（荨麻疹）疹） , angioneurotic edema, angioneurotic edema

Ephedrine Ephedrine

INDIRECT-acting drugs (summary)

Adrenoceptor agonistsAdrenoceptor agonists

(1)(1) receptor agonistsreceptor agonists

• epinephrine (adrenalineepinephrine (adrenaline ，肾上腺素，肾上腺素 )) ，， dopamine dopamine 多多巴胺巴胺 , ephedrine , ephedrine 麻黄碱麻黄碱

(2) (2) receptor agonists receptor agonists

112 2 receptor agonists:receptor agonists: norepinephrine norepinephrine 去甲肾上腺素去甲肾上腺素 1 1 receptor agonists:receptor agonists: phenylephrinephenylephrine 苯肾上腺素苯肾上腺素 2 2 receptor agonists:receptor agonists: clonidine clonidine 可乐定可乐定(3) (3) receptor agonists receptor agonists ： 112 2 receptor agonists:receptor agonists: isoproterenolisoproterenol 异丙肾上腺素异丙肾上腺素 1 1 receptor agonists:receptor agonists: dobutamine dobutamine 多巴酚丁胺多巴酚丁胺 2 2 receptor agonists:receptor agonists: salbutamol salbutamol 沙丁胺醇沙丁胺醇



Adrenergic Receptor Antagonists

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

Antagonists of NE at either or receptors

- competitive antagonists (reversible), blocking endogenous norepinephrine

- irreversible antagonists

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

Adrenoceptor Adrenoceptor antantagonistsagonists

（（ 11 ）） receptor antagonistsreceptor antagonists112 2 receptor antagonists:receptor antagonists:

short-acting:short-acting: phentolamine phentolamine ，酚妥拉明，酚妥拉明 long-acting:long-acting: phenoxybenzamine phenoxybenzamine ，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


Adrenoceptor Adrenoceptor 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 ，布托沙明，布托沙明

（（ 33 ）） , , receptor antagonists receptor antagonists

• labetalollabetalol ，拉替洛尔，拉替洛尔


Epinephrine reversalEpinephrine reversal

（（ adrenaline reversaladrenaline reversal ））

BP

antagonistantagonistepinephrineepinephrine epinephrineepinephrine

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

antagonists, block 5-HT release)antagonists, block 5-HT release)

PhentolaminePhentolamine

Pharmacological effectsPharmacological effects

(1) Vasodilatation(1) Vasodilatation Blocking Blocking 11 receptor: receptor: vasodilatation in both arteriolar resistance vessels and veins(2) Cardiac Stimulation (2) Cardiac Stimulation ReflexReflex ；； blocking blocking 22 receptor receptor ～～ NE release NE release (3) Cholinergic and histamine-like effects(3) Cholinergic and histamine-like effects Contraction of GI smooth muscles,Contraction of GI smooth muscles, Gastric acid secretion Gastric acid secretion


(1) (1) Hypertension from pheochromocytomaHypertension from pheochromocytoma (short term use). (short term use).

• Pre- and post-operation of pheochromocytomaPre- and post-operation of pheochromocytoma• Diagnostic test for pheochromocytomaDiagnostic test for pheochromocytoma

(2) Peripheral vascular diseases(2) Peripheral vascular diseases• Acrocyanosis, Raynaud’s diseaseAcrocyanosis, Raynaud’s disease(3) Local vasoconstrictor extravasation(3) Local vasoconstrictor extravasation

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

PhentolaminePhentolamine

Pheochromocytoma Pheochromocytoma is a rare is a rare catecholamine-secreting tumor derived catecholamine-secreting tumor derived from chromaffin cells of the adrenal from chromaffin cells of the adrenal medulla that produces excess medulla that produces excess epinephrine.epinephrine.

• Hypertension & Crises• Elevated Metabolic Rate

-heat intolerance-excessive sweating-weight loss

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

• Irreversible, nonselective ( 1 and 2 antagonists )

• Long-acting

• Similar to phentolamine in actions and clinical uses

PhenoxybenzaminePhenoxybenzamine

1 1 receptor antagonistsreceptor antagonists

PrazosinPrazosin （哌唑嗪）（哌唑嗪） : treatment for : treatment for hypertensionhypertension

Tamsulosin (Tamsulosin ( 坦索罗辛坦索罗辛 )): treatment for benign : treatment for benign prostatauxe (to relief the difficulty of prostatauxe (to relief the difficulty of urination)urination)

Terazosin Terazosin (( 特拉唑嗪特拉唑嗪 ): less potent than ): less potent than prazosin, but retains high specificity for prazosin, but retains high specificity for 11

DoxazosinDoxazosin ( ( 多沙唑嗪多沙唑嗪 ): similar as prazosin, but ): similar as prazosin, but has longer duration of action.has longer duration of action.

AlfuzosinAlfuzosin ( ( 阿夫唑嗪阿夫唑嗪 ): structure not related.): structure not related.

Adverse effects of Adverse effects of 1 1 receptor antagonistsreceptor antagonists

First-dose effect, marked hypotension,

Syncope ( 晕厥 )

ClinicallyClinically ，， these drug are used for the patient with hypertentsion and benign prostatic hyperplasia ( 良性前列腺肥大 )

22 receptor antagonists receptor antagonists

Yohimbine: for research use onlyYohimbine: for research use only

ADMEADME

• First-pass elimination,First-pass elimination,

low bioavailability: propranolollow bioavailability: propranolol （普萘洛尔）（普萘洛尔）

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

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

receptor antagonistsreceptor antagonists

Effects of an AR Antagonist

Pharmacological effectsPharmacological effects

(1) (1) receptor blockade receptor blockade

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

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

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


(1) (1) receptor blockade receptor blockade

B. Bronchial smooth muscles (B. Bronchial smooth muscles (22))

Induces bronchial smooth muscle Induces bronchial smooth muscle contraction in contraction in asthmatic patientsasthmatic patients

C. Metabolism (C. Metabolism (22 and and 33)) Lipolysis(Lipolysis( 脂解作用脂解作用 ) ) , glycogenolysis( , glycogenolysis( 糖原糖原分解分解 ) ) , classical blockers decreasing while , classical blockers decreasing while novel blockers potentiating insulin effects ~ novel blockers potentiating insulin effects ~ hypoglycemia(hypoglycemia( 低血糖低血糖 )) 。。

D. Renin secretion (D. Renin secretion (11)) Decreasing secretion of renninDecreasing secretion of rennin


(2) Intrinsic sympathomimetic effects(2) Intrinsic sympathomimetic effects Partial agonists: e.g. Partial agonists: e.g. pindolol,pindolol, acebutololacebutolol

(3) Membrane-stabilizing effects(3) Membrane-stabilizing effects Larger doses of some drugs: quinidine-like Larger doses of some drugs: quinidine-like

effects, Naeffects, Na++ channel block channel block

(4) Others(4) Others Lowering intraocular pressure;Lowering intraocular pressure;

Inhibiting platelet aggregationInhibiting platelet aggregation


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

activity activity

(2) Hypertension(2) Hypertension

(3) Angina pectoris and myocardial infarction(3) Angina pectoris and myocardial infarction 不能用于冠脉痉挛引起的心绞痛不能用于冠脉痉挛引起的心绞痛

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

(5) Others: (5) Others: hyperthyroidism, migraine, glaucomahyperthyroidism, migraine, glaucoma（（ timololtimolol ））


The Use of Beta Adrenergic Blocking Agents in Heart Failure

0 6 12 18 24

Time (weeks)

0

5

10

15

-5

-10

LVE

F %

cha

nge

Initial hemodynamic deterioration followed by reverse remodeling (decrease in EDV and ESV) with improved ventricular function over time (increased LVEF )

-Blockers Differ in Their Long-Term Effects on Mortality in HF

Bisoprolol1

Bucindolol2

Carvedilol3-5

Metoprolol tartrate6

Metoprolol succinate7

Nebivolol8

Xamoterol9

Beneficial

No effect

Beneficial

Not well studied

Beneficial

No effect

Harmful

1CIBIS II Investigators and Committees. Lancet. 1999;353:9-13. 2The BEST Investigators. N Engl J Med 2001; 344:1659-1667. 3Colucci WS, et al. Circulation 1996;94:2800-2806. 4Packer M, et al. N Engl J Med 2001;344:1651-1658. 5The CAPRICORN Investigators. Lancet. 2001;357:1385-1390. 6Waagstein F, et al. Lancet. 1993;342:1441-1446. 7MERIT-HF Study Group. Lancet. 1999;353:2001-2007. 8SENIORS Study Group. Eur Heart J. 2005; 26:215-225. 9The Xamoterol in Severe heart Failure Study Group. Lancet. 1990;336:1-6.

Adverse effectsAdverse effects

(1) Heart depression: (1) Heart depression: contraindicated in heart contraindicated in heart failure, severe A-V block, sinus bradycardiafailure, severe A-V block, sinus bradycardia

(2) Worsening of asthma: (2) Worsening of asthma: contraindicated in contraindicated in bronchial asthmatic patientsbronchial asthmatic patients

(3) Withdrawal syndrome(3) Withdrawal syndrome ：： up-regulation of the up-regulation of the receptorsreceptors

(4) Worsening of peripheral vascular constriction(4) Worsening of peripheral vascular constriction

(5) Others(5) Others ：： central depression, hypoglycemia,central depression, hypoglycemia, etc.etc.


• 11, , 2 2 receptor blocking receptor blocking

• no intrinsic activityno intrinsic activity

• first-elimination after oral first-elimination after oral administration, individual variation of administration, individual variation of bioavailabilitybioavailability

PropranololPropranolol

TimololTimolol• For treatment of glaucoma (wide-angle)For treatment of glaucoma (wide-angle)

11receptor antagonists, no intrinsic receptor antagonists, no intrinsic

activityactivity

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

• Usually used for treatment of Usually used for treatment of hypertensionhypertension

Atenolol, MetoprololAtenolol, Metoprolol

1 blocker Ca2+ blocker Antioxidation1 blocker

NO

NO, 2 agonist,

受体阻断剂的药理学特性

α, α, receptor antagonists receptor antagonists

• α, β receptor blocking, β> αα, β receptor blocking, β> α

• usually used for treatment of usually used for treatment of

hypertensionhypertension

LabetalolLabetalol

summaryAgonist Receptor

specificityTherapeutic uses Side

effects

epinephrine 1, 2

1, 2

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

increase duration of action

norepinephrine 1, 2

(1)

• shock

isoproterenol 1, 2 • Asthma• As cardiac stimulant

dopamine Dopaminergic,

• Shock,• Congestive heart

failure

dobutamine 1 • Heart failure

summaryAgonist Receptor

specificityTherapeutic uses

ephedrine CNS

•asthma•as a nasal decongestant

Metaraminol •Shock•hypotension

Phenylephrine 1 •supraventricular tachycardia •glaucoma•as a nasal decongestant

Methoxamien 1 •supraventricular tachycardia

Clonidine •hypertension

SalbutemolTerbutalineRitodrinealbuterol

•Asthma•Premature labor

summaryAntagonist Receptor

specificityTherapeutic uses

PhentolaminePhenoxybenz

-amine

1 • pheochromocytoma• Peripheral vascular diseases• Local vasoconstrictor

extravasation

Prazosin 1 • hypertension

Propranolol 1 • Hypertension• Glaucoma• Migraine• Hyperthyroidism• Angina pectoris• Myocardial infarction

Timolol 1 • Glaucoma • hypertension

AtenololMetoprolol

1 • hypertension

Labetalol • hypertension

1. Hypotension （低血压）• 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 (1 AR agonists).

2. Shock （休克）

3. Cardiogenic Shock （心源性休克）

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

• Usually associated with hypotension.

• Use of 1-adrenergic agonists to increase peripheral vascular resistance, and 1-adrenergic agonists to improve cardiac function.

• Massive myocardial infarction.

• Stimulation of cardiac 1-adrenergic receptors is needed: isoproterenol, norepinephrine, epinephrine, dobutamine, dopamine.

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

4. Local Vascular Effects （局部的血管变化）- 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 （过敏反应）

5. Nasal Decongestion （鼻腔充血）- 1-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 （哮喘）- 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 （早产）- 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 Agonists AR Agonists

1. Pheochromocytoma （肾上腺嗜铬细胞瘤）2. Hypertension （高血压）

3. Heart Failure （心功能衰竭）

- 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 Antagonists AR Antagonists

Documents

Adrenergic Pharmacology Adrenergic receptor agonists Adrenergic recpeotr antagonists 张纬萍浙江大学医学院药理2012.12.3