Pharmacology of the nervous system Shi-Hong Zhang (张世红), PhD Dept. of Pharmacology, School of Medicine, Zhejiang University shzhang713@zju.edu.cn

efferent nervous system Pharmacology of efferent nervous system Cholinergic Pharmacology Adrenergic Pharmacology

Norepinephrine (NE) or noradrenaline (NA) Adrenergic nerves most of post-ganglionic fibers of sympathetic nerves

NE synthesis in nerve terminals and turnover Catecholamine Biosynthetic Pathway

Norepinephrine and Epinephrine Synthesis in the Adrenal Medulla PNMT苯氨基乙醇N-甲基转移酶 is located in the cytosol DBH 多巴脱羧酶 is located in vesicles EPI is stored in vesicles. EPI (~80%) and NE (~20%) are released into blood NE PNMT NE EPI EPI 苯氨基乙醇N-甲基转移酶 Chromaffin cell

Norepinephrine and Epinephrine Metabolism MHPG (3-甲氧4-羟苯乙二醇): was used as an index of CNS NE turnover but generated mostly from periphery VMA(香草扁桃酸): sometimes used as an index of NE turnover Sulfate conjugates also prevalent or MHPG

Adrenergic Receptor Subtypes & G-Protein Coupled Mechanisms Phospholipase C activation, IP3 increase through Gq Mechanism: mobilize and increase intracellular free calcium Effects: primarily smooth muscle contraction 2 Adrenergic Receptors: Inhibition of adenyl cyclase through Gi proteins Mechanism: decrease intracellular cAMP levels Effects: decrease protein phosphorylation, decrease cellular function

Adrenergic Receptor Subtypes & G-Protein Coupled Mechanisms Activation of adenyl cyclase through Gs proteins Mechanism: increase intracellular cAMP levels Effects: phosphorylation of intracellular proteins, smooth muscle relaxation, cardiac muscle contraction

可乐定 去氧肾上腺素 异丙肾上腺素 q Phe:去氧肾上腺素；Clo：可乐定；Iso：异丙肾上腺素

Four Major Activators of the Adrenergic System Hypoxia - response is mainly cardiovascular: increase in heart rate & contractility (b1); vasodilation of blood vessels in muscle (b2). Hypoglycemia - response is mainly metabolic (glycogenolysis b2 and a1, gluconeogenesis b2 and a1,2, lypolysis b esp. b3, a2), but b2 vasodilation in muscle increases glucose delivery. Hypothermia - piloerection (M), peripheral vasocontraction (a1), thermogenesis (b) Hypotension – baroreceptor reflex 肝糖原的分解需要α和β2受体，脂肪分解需要α2和β受体的介导

Summary: Adrenoceptors  receptors 1 receptors: vasoconstriction: increased peripheral resistance, BP↑; contraction of radial muscle of iris: mydriasis 2 receptors: CNS, presynaptic membranes of adrenergic nerves: vasodilatation, inhibition of NE release; inhibition of insulin release

Summary: Adrenoceptors  Receptors 1 receptors: heart stimulation: contractility↑, automaticity↑, conduction↑, oxygen-consumption↑, cardiac output↑; increased lipolysis 2 receptors: bronchodilation; slight vasodilation; increased muscle and liver glycogenolysis; increased release of glucagon 3 receptors: lipolysis, thermogenesis

Drug classification 1. Direct actions on the receptors Agonists (NE, EPI, ISO, dopamine, etc) Antagonists (phentolamine, propranolol, etc) 2 Indirect actions via affecting transmitters Synthesis (L-dopa) Transport and storage (imipramine丙咪嗪, reserpine 利舍平) Release (ephedrine 麻黄碱, amphetamine 安非他明) Inactivation (MAOI)

Adrenergic agonists Dopamine CNS entry 苯乙胺 Resistant to MAO 麻黄碱 Structure-activity relationship of catecholamines and related compounds Strong efficacy COMT sensitive, short duration No entry to CNS Dopamine CNS entry Resistant to MAO 苯乙胺 1.Increaseing the size of alkyl substitutions on the amino group tends to increase b-receptor activity. 2.Without any substitution (e.g. –OH group) on the benzene ring may reduce the potency of the drug, may increase the bioavailability after oral administration and prolongs the duration of action. Furthermore, absence of –OH group tends to increase the distribution to the CNS. 3.Substitution at the alpha carbon block oxidation by monoamine oxidase (MAO). 甲基安非他明（甲基苯丙胺，冰毒）又称去氧麻黄素，可由麻黄碱加工合成。新康泰克(复方盐酸伪麻黄碱缓释胶囊 4.Substitution on the beta Carbon the drug can activate the receptor directly. Furthermore, the hydroxyl group may be important for storage of sympathomimetic amines in neural vesicles. 麻黄碱 Methamphetamine 甲基苯丙胺

Norepinephrine, Noradrenaline Pharmacological effects: 1, 2 receptor agonists (1) Vascular effects： 1：vasoconstriction (skin, renal, brain, hepatic, mesenteric, etc.), blood flow  2：inhibiting NE release (2) Blood pressure： Systolic BP , Diastolic BP (especially at larger doses)

Norepinephrine (3) Cardiac effects： weak direct stimulation (1); inhibition via reflex (in vivo) Net result: little cardiac stimulates In isolated cardiac tissue NE stimulates cardiac contractility, however, in vivo, little cardiac stimulates is noted. This is due to the increased blood pressure induces a reflex rise in vagal activity stimulating the baroreceptors. This bradycardia is sufficient to counteract the local actions of NE on heart. But the reflex compensation does not affect the positive inotropic effects of the drug.

Norepinephrine Clinical uses (limited therapeutic value) (1) Shock used in early phase of neurogenic shock: small doses and short duration (dopamine is better; replaced by Metaraminol 间羟胺，α agonist and NE releaser, weaker but longer effect) (2) Hypotension due to drug poisoning especially for chlorpromazine （氯丙嗪） (3) Hemorrhage in upper alimentary tract (上消化道) orally given after dilution Metaraminol : Acting on  receptors directly, promoting NE release indirectly；Weaker effects and longer duration than NE, weak effects on renal vessels; Used in early phase of shock, hypotension 在正常情况下，血管运动中枢不断发放冲动沿传出的交感缩血管纤维到达全身小血管，使其维持着一定的紧张性。当血管运动中枢发生抑制或传出的交感缩血管纤维被阻断时，小血管就将因紧张性的丧失而发生扩张，结果是外周血管阻力降低，大量血液淤积在微循环中，回心血量急剧减少，血压下降，引起神经源性休克（neurogenic shock）。

Norepinephrine Adverse effects (1) Ischemia and necrosis at the site of iv administration - relieved by phentolamine (酚妥拉明， 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

Phenylephrine (去氧肾上腺素) 1 receptor agonists Phenylephrine (去氧肾上腺素) Methoxamine (甲氧明) Induces reflex bradycardia, used in hypotension under anesthesia and drug poisoning, paroxysmal supraventricular tachycardia ； Phenylephrine: Mydriasis: pupillary dilator muscles, no or less effect on intraocular pressure, short-acting (for several hours); act as a nasal decongestant (鼻血管收缩药)

2 receptor agonists Clonidine可乐定 Uses: antihypertensive drug; can be administered as transdermal patch (permits continuous administration) Mechanism of action: 2 - 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 α2b receptors); dry mouth (α2 inhibit saliva secretion), sedation

2 receptor agonists Oxymetazoline (羟甲唑啉): a nasal decongestant Apraclonidine (阿可乐定): decreases intraocular pressure.

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

Concentration-dependent response in vascular smooth muscle to epinephrine 人为什么会脸红？

Epinephrine (3) Blood pressure- two phases, dose dependent Systolic BP, Diastolic BP↓(slight) , pulse pressure  (4) Respiratory system 2: dilatation of bronchial smooth muscles (Bronchodilatation) inhibition of degranulation of mast cells 1: reduces congestion and edema of bronchial mucosa (5) Gastric and bladder smooth muscles: relaxation (2) (6) Eye: intraocular pressure ↓ (α1,2) (7) Metabolic effects blood glucose  (2 and 1,2, hyperglycemia); free fatty acids  (, lipolysis)

Epinephrine (4) Respiratory 2: dilatation of bronchial smooth muscles (Bronchodilatation) inhibition of degranulation of mast cells 1: reducing congestion and edema of bronchial mucosa (5) Gastric and bladder smooth muscles: relaxation (2) (6) Eye: intraocular pressure ↓ (β desensitization, α1,2) (7) Metabolic effects blood glucose  (2 and 1,2, hyperglycemia); free fatty acids  (, lipolysis) 逼尿肌：M受体收缩，beta2受体松弛；内括约肌：M受体舒张，alpha受体收缩。外括约肌随意肌

Epinephrine Clinical uses Topical uses: Systematic uses: Adjuvant of local anesthesia Bleeding Glaucoma Systematic uses: Cardiac arrest Anaphylactic shock (过敏性休克) Acute bronchial asthma 心脏三联之一

Epinephrine Adverse effects reason: a marked elevation of BP (1) Cardiac arrhythmias (2) Hemorrhage (cerebral or subarachnoid) : reason: a marked elevation of BP (3) Central excitation: anxiety, headache... (4) Contraindications: heart diseases, hypertension, coronary arterial disease, arteriosclerosis （动脉硬化）, hyperthyroidism （甲亢）

Ephedrine 麻黄碱 Properties： CH CH NH CH2 CH NH CH3 CH3 CH3 CH3 OH Ephedrine Methamphetamine Properties： - Promoting release of NE, weak agonist effects on 1、2、1、2 receptors - chemically stable, orally effective； - less potent but longer action duration; - central stimulating: alertness , fatigue ↓, prevents sleep (adverse effects) - Tachyphylaxis (快速耐受). Methamphetamine：冰毒,脱氧麻黄碱

Ephedrine Clinical uses (1) Prevention of hypotension: anesthesia (2) Nasal decongestion: nasal drop (3) Bronchial asthma: mild, chronic cases (4) Relieving allergic disorders: urticaria 风疹, angioneurotic edema 血管神经性水肿

Dopamine Pharmacological effects: , , DA receptor agonist (1) Cardiac effects：1 receptor, weak (2) Vascular effects： DA receptor: vasodilatation of renal, mesenteric arteries (small doses); 1 receptor: vasoconstriction of skin, mesenteric/renal vessels (larger doses)

Dopamine Clinical uses Adverse effects (1) Shock cardiac and septic (感染性) shock (2) Acute renal failure combined with furosemide Adverse effects short-lived; tachycardia, arrhythmia, reduction in urine flow (renal vasoconstriction)

Isoproterenol, Isoprenaline: Pharmacological effects: 1 , 2 receptor agonist, NE releaser (1) Cardiac effects (1 receptor) (2) Vascular effects and blood pressure 2 receptor: dilatation of skeletal muscles and coronary vessels； SP , DP  or , pulse pressure  (3) Bronchodilatation (2 receptor) (4) Metabolism Promoting effects as epinephrine

Effects of catecholamines (therapeutic doses) Predominant Effects: NE :  & 1 effects EPI : 1,  2 then at higher concentrations  effects predominate ISO: 1 and  2

Isoproterenol Clinical uses Adverse effects (1) Cardiac arrest / A-V block: in emergencies (2) Shock: replaced by other sympathomimetics (due to muscular vasodilatation) (3) Bronchial asthma Adverse effects (1) Heart stimulation, arrhythmia (2) Contraindications: coronary heart disease, myocarditis 心肌炎, hyperthyroidism 心脏起搏三联：老：肾上腺素+去甲肾上腺素+异丙肾上腺素 新：肾上腺素+阿托品+利多卡因

1 receptor agonists Dobutamine （多巴酚丁胺） Heart failure (after cardiac surgery or congestive HF or acute myocardial infarction; short-term treatment) Cardiac stimulation

2 receptor agonists Terbutaline (特布他林) Uses: Bronchial asthma: dilation of bronchial smooth muscle; 2 > 1 agonist (partially selective, preferential activation of pulmonary 2 receptors by inhalation. 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) Pargyline:具有明显的降压作用，属单胺氧化酶抑制剂。其降压机理尚未完全阐明，可能由于对单胺氧化酶的抑制，使肾上腺素能神经末梢的酪胺的正常代谢发生变化，产生β-羟酪胺，后者是一种“假介质”，与去甲肾上腺素一样能被贮存、释放并与受体结合，但因引起的反应较弱，不能起到节后交感神经冲动的传导作用，以致血管舒张，血压下降。

Adrenergic Receptor Antagonists nonselective: short acting (phentolamine 酚妥拉明) long acting (phenoxybenzamine 酚苄明) selective: 1 antagonists (prazosin 哌唑嗪) 2 antagonists (yohimbine 育亨宾) β receptors antagonists: nonselective: with ISA (pindolol 吲哚洛尔) without ISA (propranolol普萘洛尔) β1 antagonists: with ISA (acebutolol 醋丁洛尔) without ISA (atenolol 阿替洛尔) /β receptor antagonists: labetalol 拉贝洛尔, carvedilol 卡维地洛

 receptor antagonists

Competitive, nonselective Phentolamine 酚妥拉明 Competitive, nonselective 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 

Clinical uses Phentolamine (1) Decrease blood pressure Hypertension from pheochromocytoma嗜铬细胞瘤 (short term use). Pre- and post-operation of pheochromocytoma • Diagnostic test for pheochromocytoma (2) Peripheral vascular diseases Acrocyanosis (手足发绀), Raynaud’s disease雷诺氏病 (3) Local vasoconstrictor extravasations (4) Improve microcirculation: shock with pulmonary edema (5) Acute myocardial infarction and obstinate congestive heart failure Major Adverse effects – postural hypotension, reflex tachycardia, arrhythmia, angina pectoris, GI reactions

Elevated Metabolic Rate 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 (a1 & ±b)

Phenoxybenzamine 酚苄明 Irreversible, nonselective (1 and 2 antagonists ) Long-acting Similar to phentolamine in actions and clinical uses

Other α antagonists 1 receptor antagonists Prazosin (哌唑嗪): treatment for hypertension, CHF Tamsulosin (坦洛新): 1A blocker, for benign prostate hypertrophy 2 receptor antagonists Yohimbine (育亨宾): for research use, ED, diabetic neuropathy Alpha 1A受体主要存在于前列腺，而alpha1B主要存在于血管。

Adrenergic Receptor Antagonists nonselective: short acting (phentolamine 酚妥拉明) long acting (phenoxybenzamine 酚苄明) selective: 1 antagonists (prazosin 哌唑嗪) 2 antagonists (yohimbine 育亨宾) β receptors antagonists: nonselective: with ISA (pindolol 吲哚洛尔) without ISA (propranolol 普萘洛尔) β1 antagonists: with ISA (acebutolol 醋丁洛尔) without ISA (atenolol 阿替洛尔) /β receptor antagonists: labetalol 拉贝洛尔, carvedilol 卡维地洛 ISA: intrinsic sympathomimetic activity

 receptor antagonists General properties: ADME First-pass elimination, especially those with high lipid solubility (eg. 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 variation Dose individualization is necessary.

 receptor antagonists Pharmacological effects 1.  receptor blockade 1) Cardiovascular effects： Depression of the heart: reduction in HR, A-V conduction, automaticity, cardiac output, oxygen consumption Hypotension: hypotensive effect in hypertensive patients

 receptor antagonists 1.  receptor blockade 2) Bronchial smooth muscles induces bronchial smooth muscle contraction in asthmatic patients 3) Metabolism lipolysis , glycogenolysis, potentiating insulin effects ~ hypoglycemia 4) Renin secretion: decrease

 receptor antagonists 2. Intrinsic sympathomimetic effects Partial agonists: e.g. pindolol, acebutolol (weaker cardiac inhibition and bronchoconstriction; cardiac stimulation in larger doses) 3. Membrane-stabilizing effects Larger doses of some drugs: quinidine-like effects, Na+ channel blockade 4. Other effects Lower intraocular pressure; Inhibit platelet aggregation; Inhibit conversion from T4 to T3

Circulation of Aqueous humor

 receptor antagonists Clinical uses (1) Arrhythmia: supraventricular, sympathetic activity  (2) Hypertension (3) Angina pectoris and myocardial infarction (4) Chronic heart failure (5) Others: hyperthyroidism, migraine, glaucoma (timolol)...

 receptor antagonists 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 receptors (4) Worsening of peripheral vascular constriction (5) Others：central depression, hypoglycemia, sexual dysfunction, etc.

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

Atenolol, Metoprolol 1receptor antagonists, no intrinsic activity atenolol : longer t1/2, once daily usually used for the treatment of hypertension

α,  receptor antagonists Labetalol, Carvedilol α, β receptor blocking, β> α usually used for treatment of hypertension, angina pectoris, moderate CHF.