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

Neurotransmitters Synthesis Synthesis Storage Storage Release Release Inactivation InactivationReceptors Activation Activation Brain stem or spinal cord Pre-ganglionicneuron Ganglionic transmitter Post-ganglionicneuron Neuroeffector transmitter Effector organ Efferent 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) Uptake Uptake neurotransmitter transporters – uptake 1: neuronal uptake – uptake 2: non-neuronal uptake Enzymatic degradation Enzymatic degradation – monoamine oxidase (MAO) – 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 NE PNMT NE 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1  22 11 G-Protein Coupled Receptors Norepinephrine (NE) release (2(2 3)3) low affinity for binding NE

Adrenoceptors

q EP/NE EP/Iso

 1 Adrenergic Receptors: G protein termed G q phospholipase C activation, IP 3  mechanism: mobilizes and increases intracellular free Ca 2+  effects: primarily smooth muscle contraction  2 Adrenergic Receptors: Inhibition of adenylyl cyclase (AC) through G i proteins  mechanism: decreases intracellular cAMP levels  effects: decreased protein phosphorylation, decreased cellular function  Adrenergic Receptors: Activation of adenylyl cyclase through G s 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

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 M 2 R) 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 Enhances Smooth Muscle Contraction Primarily by  1 ARs, and Reduces Contraction Primarily by  2 ARs

Mechanisms of drug actions 1.1 Direct actions on the receptors AgonistsAgonists AntagonistsAntagonists 1.2 Indirect actions via affecting transmitters Synthesis (L-dopa)Synthesis (L-dopa) Transport and storage (imipramine, reserpine)Transport and storage (imipramine, reserpine) Release (ephedrine, amphetamine)Release (ephedrine, amphetamine) Inactivation (MAOI)Inactivation (MAOI)

Mechanisms of drug actions 1.3 Mimetics and antagonists (1) Mimetics (1) Mimetics direct-acting: receptor agonists direct-acting: receptor agonists indirect-acting: increasing amounts and/or indirect-acting: increasing amounts and/or effects of transmitters effects of transmitters (2) Antagonists (2) Antagonists direct-acting: receptor antagonists direct-acting: receptor antagonists indirect-acting: decreasing amounts and/or indirect-acting: decreasing amounts and/or effects of transmitters effects of transmitters

Adrenoceptor agonists Adrenoceptor agonists (1) ,  receptor agonists epinephrine (adrenaline ，肾上腺素 ) ， dopamine 多 巴胺, ephedrine 麻黄碱epinephrine (adrenaline ，肾上腺素 ) ， dopamine 多 巴胺, ephedrine 麻黄碱 (2)  receptor agonists  1  2 receptor agonists:norepinephrine 去甲肾上 腺素  1  2 receptor agonists: norepinephrine 去甲肾上 腺素  1 receptor agonists:phenylephrine 苯肾上腺素  1 receptor agonists: phenylephrine 苯肾上腺素  2 receptor agonists:clonidine 可乐定  2 receptor agonists: clonidine 可乐定 (3)  receptor agonists (3)  receptor agonists ：  1  2 receptor agonists: isoproterenol 异丙肾上腺素  1  2 receptor agonists: isoproterenol 异丙肾上腺素  1 receptor agonists: dobutamine 多巴酚丁胺  1 receptor agonists: dobutamine 多巴酚丁胺  2 receptor agonists: salbutamol 沙丁胺醇  2 receptor agonists: salbutamol 沙丁胺醇 Drug actions and classification

Structure-activity relationship of catecholamines and related compounds

Non-catecholamineNon-catecholamine –Indirect-acting by causing the release of stored catecholamine. –Not inactivated by COMT; some are poor substrate for MAO (orally active, a prolonged duration of action) (orally active, a prolonged duration of action) –Greater access to the CNS CatecholamineCatecholamine –High potency in activating  or  receptors –Rapid inactivation by COMT and by MAO –Poor penetration into the CNS Sympathomimetic amines

Direct modeDirect mode e.g. Norepinephrine e.g. Norepinephrine epinephrine epinephrine isoproterenol isoproterenol Indirect modeIndirect mode Mixed modeMixed mode e.g. ephedrine e.g. ephedrine The mode of action of sympathomimetic drugs –Enhances release of stored catecholamines e.g. amphetamine e.g. amphetamine –Inhibition of reuptake of released catecholamines e.g. cocaine e.g. cocaine –Inhibition of MAO e.g. pargyline e.g. pargyline

Pharmacological effects  1,  2,  1,  2 receptor agonists (1) Cardiac effects  1 : contractility  (positive inotropic),  1 : contractility  (positive inotropic), HR  (positive chronotropic), HR  (positive chronotropic), cardiac output , cardiac output , oxygen consumption , oxygen consumption , inducing arrhythmia inducing arrhythmia (2) Vascular effects (cerebral and renal circulation)  1 ： vasoconstriction (skin, mucous, viscera),  1 ： vasoconstriction (skin, mucous, viscera), especially at larger doses especially at larger doses  2 ： vasodilatation of skeletal muscles  2 ： vasodilatation of skeletal muscles and coronary vessels and coronary vessels Epinephrine, Adrenaline : DIRECT

Concentration-dependent response in vascular smooth muscle to epinephrine Predominant Effects low [EPI] β 2 > α high [EPI] α > β 2

(3) Blood pressure Systolic BP , Diastolic BP ↓(slight) Systolic BP , Diastolic BP ↓(slight) (4) Respiratory  2 ： dilatation of bronchial smooth muscles  2 ： dilatation of bronchial smooth muscles (Bronchodilatation) (Bronchodilatation)  1 ： reducing congestion and edema of  1 ： reducing congestion and edema of bronchial mucosa bronchial mucosa (5) Metabolic effects blood glucose  (hyperglycemia); blood glucose  (hyperglycemia); free fatty acids  (lipolysis) free fatty acids  (lipolysis) Epinephrine, Adrenaline : DIRECT

Effects of epinephrine （ therapeutic doses ） systolic pressure due to increased cardiac contractile force and a rise in cardiac output systolic pressure 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 Effects on vascular smooth muscle are of major physiological importanceEffects on vascular smooth muscle are of major physiological 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 Epinephrine, Adrenaline : DIRECT

Clinical uses Systematic uses: Cardiac arrest Anaphylactic shock Acute bronchial asthma Topical uses: Adjuvant of local anesthesia Bleeding Epinephrine, Adrenaline : DIRECT

Adverse effects (1) Cardiac arrhythmias (2) Hemorrhage (cerebral or subarachnoid) : reason: a marked elevation of BP reason: a marked elevation of BP (3) Central excitation ： anxiety, headache... (4) Contraindications: heart diseases, hypertension, coronary arterial disease, arteriosclerosis, hyperthyroidism. Esp. patients receiving nonselective  blockers. Epinephrine, Adrenaline : DIRECT

Norepinephrine, Noradrenaline, NE: DIRECT Pharmacological effect  1,  2 receptor agonists NE and Epi are similar potent on  1 NE has little action of  2 (1) Vascular effects ：  1 ： vasoconstriction (skin, renal, brain,  1 ： vasoconstriction (skin, renal, brain, hepatic, mesenteric, etc.), blood flow  hepatic, mesenteric, etc.), blood flow   2 ： inhibiting NE release

Actions of norepinephrine on post-synaptic (  1 ) and pre- synaptic (  2 ) receptors

(2) Blood pressure ： Systolic BP , Diastolic BP  (especially at larger doses)Systolic BP , Diastolic BP  (especially at larger doses) (3) Cardiac effects ： Weak direct stimulation (  1 ); inhibition via reflex(in vivo)Weak direct stimulation (  1 ); inhibition via reflex (in vivo) Net result: little cardiac stimulatesNet result: little cardiac stimulates Norepinephrine, Noradrenaline: DIRECT

Effects of catecholamines （ therapeutic doses ） Predominant Effects: BP , peripheral resistance , HR    1 receptor: vascular smooth muscle contraction   1 receptor: myocardial contraction

Clinical uses (limited therapeutic value) (1) Shock used in early phase of some types of shock: small doses and shorter durationused in early phase of some types of shock: small doses and shorter duration (dopamine is better; replaced by Metaraminol ，间羟胺 ) (dopamine is better; replaced by Metaraminol ，间羟胺 ) (2) Hypotension due to drug poisoning especially for chlorpromazineespecially for chlorpromazine (3) Hemorrhage in upper alimentary tract ，上消化 道出血 orally given after dilutionorally given after dilution Norepinephrine, Noradrenaline: DIRECT

Adverse effects (1) Ischemia and necrosis at the site of iv administrationrelieved by filtrating the area with phentolamine (  receptor antagonist) (1) Ischemia and necrosis at the site of iv administration relieved by filtrating the area with phentolamine (  receptor antagonist) (2) Acute renal failure avoiding larger doses and longer duration; monitoring urinary volume (3) Contraindication hypertension, arteriosclerosis, heart diseases, severe urinary volume , microcirculation disorders Norepinephrine, Noradrenaline: DIRECT

(1) Cardiac effects ：  1 receptor, weak (2) Vascular effects ： DA receptor ： vasodilatation of renal and mesenteric arteries, blood flow  (small doses);  1 receptor ： vasoconstriction of skin, mesenteric vessels (larger doses) (3) Renal effects ： renal vasodilatation; natriuretic effects Dopamine: DIRECT Pharmacological effects : ,  receptor, dopaminergic receptor agonists

Clinical uses (1) Shock, sever congestive failure cardiac and septic shockcardiac and septic shock (2) Acute renal failure combined with furosemidecombined with furosemide Adverse effects – short-lived tachycardia, arrhythmia, reduction in urine flow (renal vasoconstriction)tachycardia, arrhythmia, reduction in urine flow (renal vasoconstriction) Dopamine ， DIRECT L-DOPA but not dopamine can enter brain.

(1) Cardiac effects (  1 receptor) (2) Vascular effects  2 receptor: dilatation of skeletal muscles and coronary vessels ；  2 receptor: dilatation of skeletal muscles and coronary vessels ； SP  ， DP  or  ， pulse pressure  SP  ， DP  or  ， pulse pressure  (3) Bronchodilatation (  2 receptor) (4) Metabolism Promoting effects as epinephrine Promoting effects as epinephrine Isoproterenol, Isoprenaline: DIRECT 异丙肾上腺素  1,  2 receptor agonists

Effects of catecholamines （ therapeutic doses ） Predominant Effects: HR , systolic BP , distolic BP , peripheral resistance   1, myocardial contraction  2, vascular dialization , at higher concentrations

Clinical uses (1) Cardiac arrest / A-V block: in emergencies (2) Shock / Bronchial asthma: replaced by other sympathomimetics other sympathomimetics Adverse effects (1) Heart stimulation, arrhythmia (2) Contraindications: coronary heart disease, myocarditis, hyperthyroidism, disease, myocarditis, hyperthyroidism, pheochromocytoma. pheochromocytoma. Isoproterenol, Isoprenaline

 1 receptor agonists Heart failure (after cardiac surgery or congestive HF or acute myocardial infarction; short-term treatment)Heart failure (after cardiac surgery or congestive HF or acute myocardial infarction; short-term treatment) Cardiac stimulationCardiac stimulation (-) isomer of dobutamine is a potent agonist at  1 receptors (-) isomer of dobutamine is a potent agonist at  1 receptors (+)-dobutamine is a potent  1 receptor antagonist (+)-dobutamine is a potent  1 receptor antagonist Dobutamine: 多巴酚丁胺 DIRECT Dobutamine: 多巴酚丁胺， DIRECT

 2 receptor agonists Terbutaline: 博利康尼， DIRECT Uses: Bronchial asthma Bronchial asthma Dilation of bronchial smooth muscle;  2 >  1 agonist (partially selective): preferential activation of pulmonary  2 receptors by inhalation. Premature Labor Premature 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: 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  2 receptor agonists

Induces reflex bradycardia, used in hypotension, paroxysmal supraventricular tachycardia ；Induces reflex bradycardia, used in hypotension, paroxysmal supraventricular tachycardia ； Phenylephrine: Mydriasis （瞳孔散大）, pupillary dilator muscles, no or less effect on intraocular pressure, short-acting (for several hours); act as a nasal decongestantPhenylephrine: Mydriasis （瞳孔散大）, pupillary dilator muscles, no or less effect on intraocular pressure, short-acting (for several hours); act as a nasal decongestant Methoxamine （伐沙克新） : DIRECT>INDIRECT Methoxamine （伐沙克新 ） : DIRECT>INDIRECT Phenylephrine （苯肾上腺素） : DIRECT>INDIRECT Phenylephrine （苯肾上腺素 ） : DIRECT>INDIRECT  1 receptor agonists

Clonidine( 可乐定 ): DIRECT  2 receptor agonists Uses: antihypertensive drug; can be administered as transdermal patch (permits continuous administration) Mechanism of action : α 2 -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  2 receptor agonists

Promoting the release of NE, weak agonist effectson  1 、  2 、  1 、  2 receptorsPromoting the release of NE, weak agonist effects on  1 、  2 、  1 、  2 receptors Properties ： –chemically stable, orally effective ； –less potent but longer action duration; –central stimulating: alertness , fatigue ↓, prevents sleep (adverse effects) –Tachyphylaxis （ 快速抗药反应 ）. Ephedrine: 麻黄碱， MIXED Epinephrine Ephedrine

Clinical uses (1) Prevention of hypotension: anesthetics (2) Nasal decongestion: nasal drop ，如感冒 (3) Bronchial asthma: mild, chronic cases (4) Relieving allergic disorders: urticaria （荨麻 疹）, angioneurotic edema 疹）, angioneurotic edema Ephedrine

INDIRECT -acting drugs (summary)

Adrenoceptor agonists Adrenoceptor agonists (1)  receptor agonists epinephrine (adrenaline ，肾上腺素 ) ， dopamine 多巴 胺, ephedrine 麻黄碱epinephrine (adrenaline ，肾上腺素 ) ， dopamine 多巴 胺, ephedrine 麻黄碱 (2)  receptor agonists  1  2 receptor agonists:norepinephrine 去甲肾上腺素  1  2 receptor agonists: norepinephrine 去甲肾上腺素  1 receptor agonists:phenylephrine 苯肾上腺素  1 receptor agonists: phenylephrine 苯肾上腺素  2 receptor agonists:clonidine 可乐定  2 receptor agonists: clonidine 可乐定 (3)  receptor agonists (3)  receptor agonists ：  1  2 receptor agonists: isoproterenol 异丙肾上腺素  1  2 receptor agonists: isoproterenol 异丙肾上腺素  1 receptor agonists: dobutamine 多巴酚丁胺  1 receptor agonists: dobutamine 多巴酚丁胺  2 receptor agonists: salbutamol 沙丁胺醇  2 receptor agonists: salbutamol 沙丁胺醇 Drug actions and classification

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 antagonists （ 1 ）  receptor antagonists  1  2 receptor antagonists:  1  2 receptor antagonists: short-acting: phentolamine ，酚妥拉明 short-acting: phentolamine ，酚妥拉明 long-acting: phenoxybenzamine ，酚苄明 long-acting: phenoxybenzamine ，酚苄明  1 receptor antagonists: razosin ， 哌唑嗪  1 receptor antagonists: prazosin ， 哌唑嗪  2 receptor antagonists: ohimbine ， 育亨宾  2 receptor antagonists: yohimbine ， 育亨宾 Drug actions and classification

Adrenoceptor antagonists （ 2 ）  receptor antagonists  1  2 receptor antagonists: propranolol ， 普萘洛尔  1  2 receptor antagonists: propranolol ， 普萘洛尔  1 receptor antagonists: atenolol ，阿替洛尔  1 receptor antagonists: atenolol ，阿替洛尔  2 receptor antagonists: butoxamine ，布托沙明  2 receptor antagonists: butoxamine ，布托沙明 （ 3 ） ,  receptor antagonists labetalol ，拉替洛尔 labetalol ，拉替洛尔 Drug actions and classification

Epinephrine reversal （ adrenaline reversal ） BP  antagonist  antagonist epinephrine epinephrine

competitive, (  1,  2 receptor antagonists, block 5-HT release)competitive, nonselective (  1,  2 receptor antagonists, block 5-HT release) Phentolamine Pharmacological effects (1) Vasodilatation Blocking  1 receptor: Blocking  1 receptor: vasodilatation in both arteriolar resistance vessels and veins (2) Cardiac Stimulation Reflex ； blocking  2 receptor ～ NE release  Reflex ； blocking  2 receptor ～ NE release  (3) Cholinergic and histamine-like effects Contraction of GI smooth muscles, Contraction of GI smooth muscles, Gastric acid secretion  Gastric acid secretion 

Clinical uses (1) Hypertension from pheochromocytoma (short term use). Pre- and post-operation of pheochromocytoma Pre- and post-operation of pheochromocytoma Diagnostic test for pheochromocytoma (2) Peripheral vascular diseases Acrocyanosis, Raynaud’s disease Acrocyanosis, Raynaud’s disease (3) Local vasoconstrictor extravasation Major Adverse effects arrhythmia, angina pectoris, Major Adverse effects – postural hypotension, reflex tachycardia, arrhythmia, angina pectoris, GI reactions Phentolamine

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

 1 receptor antagonists Prazosin （哌唑嗪） : treatment for hypertension Tamsulosin ( 坦索罗辛 ): treatment for benign prostatauxe (to relief the difficulty of urination) Terazosin ( 特拉唑嗪 ): less potent than prazosin, but retains high specificity for  1 Doxazosin ( 多沙唑嗪 ): similar as prazosin, but has longer duration of action. Alfuzosin ( 阿夫唑嗪 ): structure not related.

Adverse effects of  1 receptor antagonists First-dose effect, marked hypotension, Syncope ( 晕厥 ) Clinically ， Clinically ， these drug are used for the patient with hypertentsion and benign prostatic hyperplasia ( 良性前列腺肥大 )  2 receptor antagonists Yohimbine: for research use only

ADME First-pass elimination,First-pass elimination, low bioavailability: propranolol （普萘洛尔） low bioavailability: propranolol （普萘洛尔） Hepatic metabolism and renal excretion, hepatic and renal functions alter the effects of the drugs and result in large individual variationHepatic metabolism and renal excretion, hepatic and renal functions alter the effects of the drugs and result in large individual variation So, dose individualization is necessary.So, dose individualization is necessary.  receptor antagonists

Effects of an  AR Antagonist

Pharmacological effects (1)  receptor blockade A. Cardiovascular effects ： Depressing heart: reduction in HR, A-V conduction, automaticity, cardiac output, oxygen consumption Depressing heart: reduction in HR, A-V conduction, automaticity, cardiac output, oxygen consumption Hypotension: peripheral blood flow , hypertensive effects in hypertensive patients Hypotension: peripheral blood flow , hypertensive effects in hypertensive patients  receptor antagonists

(1)  receptor blockade B. Bronchial smooth muscles (  2 ) Induces bronchial smooth muscle contraction in asthmatic patients Induces bronchial smooth muscle contraction in asthmatic patients C. Metabolism (  2 and  3 ) Lipolysis( 脂解作用 ) , glycogenolysis( 糖原 分解 ) , classical blockers decreasing while novel blockers potentiating insulin effects ~ hypoglycemia( 低血糖 ) 。 Lipolysis( 脂解作用 ) , glycogenolysis( 糖原 分解 ) , classical blockers decreasing while novel blockers potentiating insulin effects ~ hypoglycemia( 低血糖 ) 。 D. Renin secretion (  1 ) Decreasing secretion of rennin Decreasing secretion of rennin  receptor antagonists

(2) Intrinsic sympathomimetic effects Partial agonists: e.g. pindolol, acebutolol Partial agonists: e.g. pindolol, acebutolol (3) Membrane-stabilizing effects Larger doses of some drugs: quinidine-like Larger doses of some drugs: quinidine-like effects, Na + channel block effects, Na + channel block (4) Others Lowering intraocular pressure; Lowering intraocular pressure; Inhibiting platelet aggregation Inhibiting platelet aggregation  receptor antagonists

Clinical uses (1) Arrhythmia ： supraventricular, sympathetic activity  (2) Hypertension (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 (5) Others: hyperthyroidism, migraine, glaucoma （ timolol ）  receptor antagonists

The Use of Beta Adrenergic Blocking Agents in Heart Failure Time (weeks) LVEF % change 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 Bisoprolol 1 Bucindolol 2 Carvedilol 3-5 Metoprolol tartrate 6 Metoprolol succinate 7 Nebivolol 8 Xamoterol 9 Beneficial No effect Beneficial Not well studied Beneficial No effect Harmful 1 CIBIS II Investigators and Committees. Lancet. 1999;353: The BEST Investigators. N Engl J Med 2001; 344: Colucci WS, et al. Circulation 1996;94: Packer M, et al. N Engl J Med 2001;344: The CAPRICORN Investigators. Lancet. 2001;357: Waagstein F, et al. Lancet. 1993;342: MERIT-HF Study Group. Lancet. 1999;353: SENIORS Study Group. Eur Heart J. 2005; 26: The Xamoterol in Severe heart Failure Study Group. Lancet. 1990;336:1-6.

Adverse effects (1) Heart depression: contraindicated in heart failure, severe A-V block, sinus bradycardia (2) Worsening of asthma: contraindicated in bronchial asthmatic patients (3) Withdrawal syndrome ： up-regulation of the receptors (4) Worsening of peripheral vascular constriction (5) Others ： central depression, hypoglycemia, etc.  receptor antagonists

 1,  2 receptor blocking  1,  2 receptor blocking no intrinsic activity no intrinsic activity first-elimination after oral administration, individual variation of bioavailability first-elimination after oral administration, individual variation of bioavailability Propranolol Propranolol Timolol For treatment of glaucoma (wide-angle)For treatment of glaucoma (wide-angle)

 1 receptor antagonists, no intrinsic activity  1 receptor antagonists, no intrinsic activity Atenolol : longer t 1/2, once dailyAtenolol : longer t 1/2, once daily Usually used for treatment of hypertensionUsually used for treatment of hypertension Atenolol, Metoprolol Atenolol, Metoprolol

 1 blocker Ca 2+ blocker Antioxidation  1 blocker  NO  NO,  2 agonist,  受体阻断剂的药理学特性

α,  receptor antagonists α, β receptor blocking, β> α α, β receptor blocking, β> α usually used for treatment of usually used for treatment of hypertension hypertension Labetalol

summary AgonistReceptor specificity Therapeutic usesSide 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 dopamineDopaminergic ,  Shock, Congestive heart failure dobutamine  Heart failure

summary AgonistReceptor specificity Therapeutic uses ephedrine  CNS asthma as a nasal decongestant Metaraminol  Shock hypotension Phenylephrine  supraventricular tachycardia glaucoma as a nasal decongestant Methoxamien  supraventricular tachycardia Clonidine  hypertension Salbutemol Terbutaline Ritodrine albuterol  Asthma Premature labor

summary AntagonistReceptor specificity Therapeutic uses Phentolamine Phenoxybenz -amine     pheochromocytoma Peripheral vascular diseases Local vasoconstrictor extravasation Prazosin  hypertension Propranolol     Hypertension Glaucoma Migraine Hyperthyroidism Angina pectoris Myocardial infarction Timolol     Glaucoma hypertension Atenolol Metoprolol  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 (   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   -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  1 (±  ) 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） -   -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  1 (±  ) 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  2 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  1 &  AR Antagonists