Y n un--bi Lu, Bi Lu, PhD Dept of. Pharmacology School of Medicine, Zhejiang University
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1 传出神经系统药理 Yun-Bi Lu, PhD 卢韵碧 Dept. of Pharmacology School of Medicine, Zhejiang University
2 Cholinergic i Pharmacology Adrenergic Pharmacology
3 3 肾上腺素能神经系统药理 (1) 肾上腺素受体激动药 (2) 肾上腺素受体阻断药
4
5 Neurotransmitters Synthesis y ( 合成 ) Storage( 贮存 ) Release( 释放 ) Inactivation( 灭活 ) Receptors Activation ( 激活 ) Drug actions and classification Efferent neurons of ANS
6 Noradrenergic Nerve: Synthesis, storage and release of NE Tyrosine ( 酪氨酸 ) L-DOPA tyrosine hydroxylase y (TH)* 酪氨酸羟化酶 DOPA decarboxylase 多巴脱羧酶 dopamine (DA) 多巴胺 dopamine beta-hydroxylase (DBH) norepinephrine (NE) Uptake neurotransmitter transporters uptake 1: neuronal uptake uptake 2: non-neuronal neuronal uptake Enzymatic degradation monoamine oxidase (MAO) catechol-o-methyltransferease (COMT)
7 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. PNMT NE NE EPI EPI Chromaffin cell ( 肾上腺嗜铬细胞 ) EPI disposition: metabolism by COMT, MAO, sulfation, uptake into NE terminals 苯乙醇胺氮位甲基转移酶
8 Norepinephrine (NE) release receptor binding (reversible) Adrenergic Receptors/Adrenoceptors receptor activation signal transduction ( 2 3 ) low affinity for binding NE response G-Protein Coupled Receptors
9 略 EP/NE EP/NE q
10 Adrenergic Receptor Subtypes & G-Protein Coupled Mechanisms 1 Adrenergic Receptors: G protein termed G q phospholipase C activation, IP 3 mechanism: mobilizes and increases intracellular free calcium 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 l cyclase through h G s proteins mechanism: increases intracellular camp levels effects: phosphorylation of intracellular proteins smooth muscle relaxation ( 2), cardiac muscle contraction ( 1)
11 Adrenergic Receptor (adrenoreceptors) 略 These are receptors activated by NE, EPI, or drugs with similar actions G q G i G s G s α 1 postsynaptic α 2 presynaptic β 1 postsynaptic β 2 postsynaptic blood vessels: vasoconstriction (arterioles, veins) decreases NE release heart: increases heart rate increases contractility increases conduction velocity blood vessels: vasodilation lungs: bronchodilation kidney: increases β 1 increases renin release glycogenolysis, resulting in increase (β 3 increases lipolysis l i ) of plasma glucose levels 3 fat cells (not NE)
12 Summary: Adrenoceptors (adrenergic receptors) receptors 1 receptors: (vasoconstriction: increased peripheral resistance, BP ; contraction of radial muscle of fii iris: mydriasis) di i 2 receptors: (CNS, presynaptic membranes of adrenergic nerves: vasodilatation, inhibition of NE release; inhibition of insulin release)
13 Summary: Adrenoceptors (adrenergic receptors) receptors 1 receptors (contractility 心收缩, automaticity 自律性, conduction 心传导, oxygen-consumption 氧耗, cardiac output 心输出量 : heart stimulation; increased lipolysis 脂解作用 ) 2 receptors (relaxation of bronchial smooth muscles: bronchodilation 支气管扩张 ; slight vasodilation 血管舒张 ; increased muscle and liver glycogenolysis 糖原分解 ; increased release of glucagon 胰高血糖素 ) 3 receptors (lipolysis, thermogenesis 生热作用 )
14 Adrenoceptors
15 Concentration-dependent response in vascular smooth muscle to epinephrine Predominant Effects low [EPI] β2 > α high [EPI] α > β2 肾上腺素对血管的作用取决于各器官血管平滑肌上 α β2 受体的分布密度和给药剂量大小
16 Structure-activity relationship( ( 构效关系 ) of catecholamines and related compounds For activation of receptor -receptor activity 去甲肾上腺素肾上腺素异丙肾上腺素 Bioavailability of oral admin. Duration. CNS distribution Resistance to MAO 苯乙胺 Block MAO uptake-1 Catecholamine Non-Catecholamine 麻黄碱
17 The mode of action of sympathomimetic drugs Direct mode e.g. Norepinephrine epinephrine isoproterenol Indirect mode Enhances release of stored catecholamines e.g. amphetamine( 安非他命 安非他命 ) Inhibition of reuptake of released catecholamines e.g. cocaine( 可卡因 ) Inhibition of MAO e.g. pargyline( 优降宁 优降宁 ) Mixed mode e.g. ephedrine ( 麻黄碱 麻黄碱 )
18 Mechanisms of drug actions 1.1 Direct actions on the receptors Agonists Antagonists 1.2 Indirect actions via affecting transmitters Synthesis (L-dopa) Transport and storage (imipramine, reserpine) Release (ephedrine, amphetamine) Inactivation (MAOI) 1.3 Mimetics and antagonists (1) Mimetics 拟肾上腺素药, 拟交感胺类 direct-acting: receptor agonists indirect-acting: increasing amounts and/or effects of transmitters (2) Antagonists direct-acting: receptor antagonists indirect-acting: decreasing amounts and/or effects of transmitters
19 Drug actions and classification Adrenoceptor agonists (1) receptor agonists 1 2 receptor agonists: norepinephrine( 去甲肾上腺素 ) 1 receptor agonists: phenylephrine( p 去氧肾上腺素 ) 2 receptor agonists: clonidine( 可乐定 ) (2), receptor agonists epinephrine (adrenaline 肾上腺素 ),dopamine( 多巴胺 ), ephedrine( 麻黄碱 ) (3) receptor agonists: 1 2 receptor agonists: isoproterenol( 异丙肾上腺素 ) 1 receptor agonists: dobutamine ( 多巴酚丁胺 ) 2 receptor agonists: salbutamol( 沙丁胺醇 )
20 Norepinephrine,, Noradrenaline ( 去甲肾上腺素 ): DIRECT Pharmacological effect 1, 2 receptor agonists (1) Vascular effects: 1 :vasoconstriction (skin, renal, brain, hepatic, mesenteric, etc.), blood flow 2 :inhibiting NE release
21 Actions of norepinephrine p on post-synaptic synaptic ( 1 ) and pre- synaptic ( 2 ) receptors
22 Norepinephrine,, Noradrenaline (2) Blood pressure: Systolic BP,, Diastolic BP (especially ( p y at larger doses) (3) Cardiac effects: weak direct stimulation ( 1 ); inhibition via reflex (in vivo) Net result: little cardiac stimulates
23 Effects of catecholamines (therapeutic doses) 略 Predominant Effects: NE : & 1 effects 1
24 Norepinephrine,, Noradrenaline Clinical uses (1) Shock uses (limited therapeutic value) used in early phase of some types of shock: small doses and shorter duration (dopamine is better; replaced by Metaraminol 间羟胺 ) (2) Hypotension due to drug poisoning especially for chlorpromazine( 氯丙嗪 ) (3) Hemorrhage in upper alimentary tract orally given after dilution
25 Norepinephrine, p, Noradrenaline Adverse effects (1) Ischemia and necrosis at the site of iv administration relieved by filtrating the area with phentolamine ( 酚妥拉明, receptor antagonist) (2) Acute renal failure avoiding larger doses and longer duration; monitoring i urinary volume (3) Contraindication hypertension, arteriosclerosis, heart diseases, severe urinary volume,, microcirculation disorders
26 Metaraminol 间羟胺 Acting on receptors directly irectly, promoting NE release indirectly; Weaker effects and longer duration than NE, Weak effects on renal vessels; Used in early phase of shock, hypotension
27 1 1 receptor agonists 略 Methoxamine( 甲氧明 ), Phenylephrine( 去氧 肾上腺素 ): DIRECT>INDIRECT Induces reflex bradycardia, used in hypotension, paroxysmal supraventricular tachycardia, via reflex (in vivo) ; Phenylephrine: Mydriasis( 扩瞳 ), pupillary dilator muscles, no or less effect on intraocular pressure, short-acting (for several hours); act as a nasal decongestant
28 2 receptor agonists 略 Clonidine( 可乐定 可乐定 ): ): DIRECT 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
29 Drug actions and classification Adrenoceptor agonists (1) receptor agonists 1 2 receptor agonists: norepinephrine( 去甲肾上腺素 ) 1 receptor agonists: phenylephrine( p 去氧肾上腺素 ) 2 receptor agonists: clonidine( 可乐定 ) (2), receptor agonists epinephrine (adrenaline 肾上腺素 ),dopamine( 多巴胺 ), ephedrine( 麻黄碱 ) (3) receptor agonists: 1 2 receptor agonists: isoproterenol( 异丙肾上腺素 ) 1 receptor agonists: dobutamine ( 多巴酚丁胺 ) 2 receptor agonists: salbutamol( 沙丁胺醇 )
30 Epinephrine, Adrenaline( 肾上腺素 ): DIRECT Pharmacological effects 1, 2, 1, 2 receptor agonists (1) Cardiac effects 1 : contractility (positive inotropic), HR (positive chronotropic), cardiac output t, oxygen consumption, inducing arrhythmia (2) Vascular effects 1 :vasoconstriction ti ti (skin, mucous, viscera), especially at larger doses 2 :vasodilatation of skeletal muscles and coronary vessels
31 Epinephrine, p Adrenaline ( 肾上腺素 (3) Blood pressure 肾上腺素 ) Systolic BP( 收缩压 ), Diastolic BP( 舒张压 ) (slight) (4) Respiratory 2 :dilatation of bronchial smooth muscles 2 (Bronchodilatation) 1 :reducing congestion and edema of bronchial mucosa (5) Metabolic effects blood glucose (hyperglycemia); free fatty acids (lipolysis)
32 Effects of catecholamines (therapeutic doses) 略 antagonist Predominant Effects: NE : & 1 effects EPI : 1, 2 then at higher concentrations effects predominate
33 Clinical uses Epinephrine, Adrenaline Topical uses( 局部用药 ): Adjuvant of local anesthesia ( 与局麻药配伍 ) 局部止血 Systematic uses: Cardiac arrest ( 心脏骤停 ) Anaphylactic shock ( 过敏性休克 ) Acute bronchial asthma ( 支气管哮喘急性发作 )
34 Adverse effects Epinephrine, p Adrenaline (1) Cardiac arrhythmias ( 心律失常 ) (2) Hemorrhage 出血 (cerebral or subarachnoid) : reason: a marked elevation of BP (3) Central excitation:anxiety, ti anxiety, headache... (4) Contraindications: heart diseases, hypertension, coronary arterial disease, arteriosclerosis( 动脉硬化 ), hyperthyroidism( 甲亢 )
35 Dopamine( 多巴胺 多巴胺 ): DIRECT Pharmacological effects :, receptor, dopaminergic receptor agonists (1) Cardiac effects: 1 receptor, weak (2) Vascular effects: DA receptor:vasodilatation of renal and mesenteric arteries, blood flow (small doses); 1 1 receptor:vasoconstriction of skin, mesenteric vessels (larger doses) (3) Renal effects:renal vasodilatation; natriuretic effects
36 Clinical uses (1) Shock Dopamine cardiac and septic shock (2) Acute renal failure combined with furosemide ( 呋塞米, 速尿 ) Adverse effects short short-lived tachycardia( 心动过速 ), arrhythmia( 心律失常 ), reduction in urine flow (renal vasoconstriction)
37 Ephedrine( p ( 麻黄碱 麻黄碱 ): ): MIXED CH OH CH CH3 Ephedrine NH CH3 HO HO CH OH CH2 Epinephrine i Promoting release of NE, weak agonist effects on receptors Properties: chemically stable, orally effective; less potent but longer action duration; central stimulating: alertness, fatigue, prevents sleep (adverse effects) Tachyphylaxis ( 快速耐受性 ). NH CH3
38 Clinical uses Ephedrine (1) Prevention of hypotension: anesthetics (2) Nasal decongestion: nasal drop (3) Bronchial asthma: mild, chronic cases (4) Relieving allergic disorders: urticaria( 荨麻疹 ), angioneurotic edema( 血管神经性水肿 )
39 Drug actions and classification Adrenoceptor agonists (1) receptor agonists 1 2 receptor agonists: norepinephrine( 去甲肾上腺素 ) 1 receptor agonists: phenylephrine( p 去氧肾上腺素 ) 2 receptor agonists: clonidine( 可乐定 ) (2), receptor agonists epinephrine (adrenaline 肾上腺素 ),dopamine( 多巴胺 ), ephedrine( 麻黄碱 ) (3) receptor agonists: 1 2 receptor agonists: isoproterenol( 异丙肾上腺素 ) 1 receptor agonists: dobutamine ( 多巴酚丁胺 ) 2 receptor agonists: salbutamol( 沙丁胺醇 )
40 Isoproterenol,, Isoprenaline ( 异丙肾上腺素 ): DIRECT Pharmacological effects : 1 1, 2 2 receptor agonists (1) Cardiac effects ( 1 receptor) (2) Vascular effects and blood pressure e 2 receptor: dilatation of skeletal muscles and coronary vessels; SP, DP or, pulse pressure( 脉压 ) (3) Bronchodilatation ( 2 receptor) (4) Metabolism Promoting effects as epinephrine
41 Effects of catecholamines (therapeutic doses) 略 Predominant Effects: NE : & 1 effects EPI : 1, 2 then at higher concentrations effects predominate ISO: 1 and 2
42 Isoproterenol,, Isoprenaline Clinical uses (1)Cardiac arrest /A-V block: in emergencies (2)Shock / Bronchial asthma: replaced sympathomimetics Adverse effects (1) Heart stimulation, arrhythmia replaced by other (2) Contraindications: coronary heart disease, myocarditis, hyperthyroidism, pheochromocytoma.
43 1 receptor agonists Dobutamine( 多巴酚丁胺 多巴酚丁胺 ): ): DIRECT Heart failure (after cardiac surgery or congestive HF or acute myocardial infarction; short-term term treatment) Cardiac stimulation
44 2 receptor agonists Terbutaline( 特布他林 ): DIRECT Uses: Bronchial asthma dilation of bronchial smooth muscle; 2 > 1 agonist (partially selective): preferential activation of pulmonary 2 receptors by inhalation. Use: Premature Labor ( 早产,combine with ritodrine 利托君 ). Adverse effects: headache, cardiac stimulation and skeletal muscle fine tremor ( 2 receptors on presynaptic motor terminals; their activation enhances ACh release).
45 Drug actions and classification 略 3
46 Drug actions and classification Adrenoceptor antagonists agonists (1) receptor antagonists 1 2 receptor antagonists: short-acting: phentolamine ( 酚妥拉明 ) long-acting acting: phenoxybenzamine( 酚苄明 ) 1 receptor antagonists: prazosin( 哌唑嗪 ) 2 receptor antagonists: t yohimbine( 育亨宾 育亨宾 )
47 Drug actions and classification Adrenoceptor antagonists agonists (2) receptor antagonists 1 2 receptor antagonists: propranolol( 普萘洛尔 ) 1 receptor antagonists: atenolol ( 阿替洛尔 ) 2 receptor antagonists: butoxamine( 布他沙明 ) (3), receptor antagonists labetalol( 拉贝洛尔 )
48 ,
49 epinephrine e antagonist epinephrine BP Epinephrine reversal 肾上腺素作用的翻转 (adrenaline reversal)
50 Phentolamine ( 酚妥拉明 ) competitive, nonselective ( 1, 2 receptor antagonists) Pharmacological effects (1) Vasodilatation Blocking 1 receptor: vasodilation in both arteriolar resistance vessels and veins (2) Cardiac Stimulation Reflex;blocking 2 receptor ~NE release (3) Cholinergic and histamine-like effects Contraction of GI smooth muscles, Gastric acid secretion CH3 HO N CH2 N H N
51 Clinical uses Phentolamine (1) Hypertension from pheochromocytoma h ( 肾上腺嗜铬细胞瘤,short term use). pre- and post-operation operation of pheochromocytoma Diagnostic test for pheochromocytoma (2) Peripheral vascular diseases Acrocyanosis ( 肢端发绀 ) Raynaud s disease ( 雷诺综合征 ) (3) Local vasoconstrictor extravasation Major Adverse effects Postural hypotension, reflex tachycardia, yp, y, arrhythmia, angina pectoris, GI reactions
52 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 & ± )
53 Phentolamine Clinical uses (1) Hypertension from pheochromocytoma (short term use). pre- pe and post-operation operation o of pheochromocytoma o ocyto Diagnostic test for pheochromocytoma (2) Peripheral vascular diseases Acrocyanosis ( 肢端发绀 ) Raynaud s disease ( 雷诺综合征 ) (3) Local vasoconstrictor extravasation( 局部血管收缩剂外漏 ) Major Adverse effects Postural hypotension, reflex tachycardia, arrhythmia, angina pectoris, GI reactions
54 Phenoxybenzamine ( 酚苄明 酚苄明 ) Irreversible, nonselective ( 1 and 2 antagonists ) Long-acting Similar to phentolamine in actions and clinical uses 竞争性 非竞争性
55 1 receptor antagonists prazosin ( 哌唑嗪 ) treatment for hypertension tamsulosin ( 坦洛新 ) treatment for benign prostatauxe ( 良性前列腺增生,to relief the difficulty of urination) 2 receptor antagonists yohimbine ( 育亨宾 ) for research use only
56 receptor antagonists ADME First-pass elimination, low bioavailability: propranolol Hepatic metabolism and renal excretion, hepatic and renal functions alter the effects of the drugs and result in large individual dua variation at So, dose individualization is necessary.
57 receptor antagonists Pharmacological effects (1) receptor blockade A. Cardiovascular effects: Depressing heart: reduction in HR, A-V conduction, automaticity, cardiac output, oxygen consumption Hypotension: peripheral blood flow, hypotensive e effects ects in hypertensive e patients
58 receptor antagonists (1) receptor blockade B. Bronchial smooth muscles induces bronchial smooth muscle contraction in asthmatic patients C. Metabolism Lipolysis, glycogenolysis insulin effects ~ hypoglycemia, potentiating D. Renin secretion decreasing secretion of renin
59 receptor antagonists (2) Intrinsic i sympathomimetic ti effects( 内在拟交感活性 ) Partial agonists: e.g. pindolol ( 吲哚洛尔 ), acebutolol ( 醋丁洛尔 ) (3) Membrane-stabilizing effects Larger doses of some drugs: quinidine- like effects, Na + channel block (4) Others Lowering intraocular pressure; Inhibiting platelet aggregation g
60 receptor antagonists Clinical uses (1) Arrhythmia:sympathetic activity (2) Hypertension (3) Angina pectoris and myocardial infarction (4) Chronic heart failure (5) Others: hyperthyroidism, migraine( 偏头痛 ), glaucoma (timolol 噻吗洛尔 ), anxiety, tremor...
61 Circulation of Aqueous humor
62 receptor antagonists Adverse effects (1) Heart depression: contraindicated in heart failure, severe A-V block, sinus bradycardia di (2) Worsening of asthma: contraindicated t d in bronchial asthmatic patients (3) Withdrawal syndrome( 反跳现象 ): up-regulation of the receptors (4) Worsening of peripheral vascular constriction (5) Others : central depression, hypoglycemia( 低血糖 ), etc.
63 Propranolol ( 普萘洛尔 1, 2 receptor blocking no intrinsic activity 普萘洛尔 ) first-elimination after oral administration, individual variation of bioavailability Timolol ( 噻吗洛尔 ) For treatment of glaucoma (wide-angle)
64 Atenolol( l l( 阿替洛尔 阿替洛尔 ), Metoprolol( 美托洛尔 美托洛尔 ) 1 receptor antagonists, no intrinsic activity atenolol : longer t 1/2, once daily usually used for treatment of hypertension
65 α, receptor antagonists Labetalol ( 拉贝洛尔 ) α, β receptor blocking, β> α usually used for treatment of hypertension
66 受体阻断剂的药理学特性 略 NO, 2 agonist 1 blocker Ca 2+ blocker Antioxidation id 1 blocker NO
67 略
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