1. Adrenergic Pharmacology
Shi-Hong Zhang (张世红), PhD Dept. of Pharmacology, School of Medicine, Zhejiang University

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

3. Biosynthesis of Catecholamines

4. Norepinephrine synthesis in nerve terminals and turnover

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

6. Norepinephrine and Epinephrine Metabolism
MOPGAL (3-甲氧-4-羟苯乙二醇), VMA(香草扁桃酸) and their sulfate conjugates: used as indices of NE turnover
Aldehyde reductase: 醛还原酶
or MHPG

7. Adrenergic Receptor Subtypes & G-Protein Coupled Mechanisms
Gq coupled, phospholipase C (PLC) - IP3 pathway, mobilize and increase intracellular free calcium
Effects: primarily smooth muscle contraction
2 Adrenergic Receptors:
Gi coupled, inhibition of adenyl cyclase (AC), decrease intracellular cAMP levels
Effects: decrease protein phosphorylation
β （β1-3）Adrenergic Receptors:
Gs coupled, activate AC, increase intracellular cAMP levels
Effects: phosphorylation of intracellular proteins

8. Adrenoceptors  receptors
1 receptors: vasoconstriction (BP↑), contraction of radial muscle of iris (mydriasis)
2 receptors: vasoconstriction, inhibition of NE release; inhibition of insulin release

9. Adrenoceptors  Receptors
1 receptors: heart stimulation: contractility↑, automaticity↑, conduction↑, oxygen-consumption↑, cardiac output↑; increased lipolysis脂肪分解
2 receptors: bronchodilation; slight vasodilation; increased muscle and liver glycogenolysis肝糖分解; increased release of glucagon胰高血糖素
3 receptors: lipolysis, thermogenesis产热

10. 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), b2-mediated vasodilation in muscle increases glucose delivery.
Hypothermia - piloerection (a1), 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

11. Drug classification 1. Direct-acting agents 2. Indirect-acting agents
Agonists (NE, EPI, ISO, dopamine, ephedrine 麻黄碱, etc)
Antagonists (phentolamine 酚妥拉明, propranolol 普萘洛尔, etc)
2. Indirect-acting agents
Synthesis (L-dopa)
Transport and storage (imipramine丙咪嗪, reserpine 利舍平)
Release (ephedrine, amphetamine 安非他明)
Inactivation (MAOI)

12. Adrenergic agonists Strong efficacy COMT sensitive Short duration
Structure-activity relationship of
catecholamines and related compounds 
Dopamine 2 β 3 1 4 6 5
CNS entry
去甲肾上腺素
肾上腺素
异丙肾上腺素
苯乙胺
Phenethylamine
Strong efficacy
COMT sensitive
Short duration
No entry to CNS
Resistant to MAO
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。泰诺等感冒药含有麻黄碱，可以作为冰毒合成的原料
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.
Ephedrine麻黄碱
儿茶酚
Affinity for  receptors increases as group on amine nitrogen gets larger
Methamphetamine甲基苯丙胺

13. Norepinephrine, Noradrenaline
Pharmacological effects:
1, 2 receptor agonist
(1) Vascular effects：
1: Vasoconstriction (skin, renal, brain, hepatic, mesenteric, etc.), blood flow , systolic BP , diastolic BP (esp. at larger doses.
2: presynaptic action, inhibits NE release.

14. Norepinephrine (2) Cardiac effects：
Weak direct stimulation (1); weak increase of heart contractility and inhibition of HR via reflex (in vivo)
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.exec

15. 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, with weaker but longer effect)
(2) Hypotension due to drug poisoning
especially for chlorpromazine氯丙嗪 overdose
(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）。

16. Norepinephrine Adverse effects
(1) Ischemia and necrosis at the site of iv infusion
- relieved by phentolamine (酚妥拉明， receptor antagonist)
(2) Acute renal failure
- avoid larger doses and longer duration; monitor urinary volume
(3) Contraindication
- hypertension, arteriosclerosis, heart diseases, severe urinary volume , microcirculation disorders

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

18. 2 receptor agonists Oxymetazoline (羟甲唑啉): a nasal decongestant
Apraclonidine (阿可乐定): decreases intraocular pressure.

19. 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

20. 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
: vasoconstriction (skin, mucous, viscera), especially at large doses
2: vasodilatation, especially in skeletal muscle and coronary vessels

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

22. Epinephrine (3) Blood pressure- two phases, dose dependent
Systolic BP, diastolic BP↓(slight) , pulse pressure 
Epinephrine
Epinephrine reversal
10 g/min

23. Epinephrine (4) Bronchial smooth muscles
2: dilates bronchial smooth muscles
inhibits degranulation of mast cells
1: reduces 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)
膀胱平滑肌（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
外括约肌为随意肌

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

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

26. 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 (large doses)

27. Dopamine Clinical uses Adverse effects (1) Shock
cardiac and septic (感染性) shock
(2) Acute renal failure
combined with furosemide呋塞米
Adverse effects
Tachycardia, arrhythmia, reduction in urine flow (renal vasoconstriction)

28. Ephedrine 麻黄碱 Properties：CH CH NH
CH2 CH NH
CH3
CH3
CH3
CH3 OH
Ephedrine麻黄碱
Methamphetamine甲基苯丙胺
Properties：
- promotes release of NE, weak agonist effects on 1、2、1、2 receptors
- chemically stable, orally effective；
- less potent but longer action duration than Epi;
- central stimulating: alertness , fatigue ↓, sleeplessness
- tachyphylaxis (快速耐受).
Methamphetamine：冰毒,脱氧麻黄碱

29. Ephedrine Clinical uses
(1) Prevention of hypotension during anesthesia
(2) Nasal decongestion: nasal drop
(3) Bronchial asthma: mild, chronic cases
(4) Relief of allergic disorders: urticaria 风疹, angioneurotic edema

30. Isoproterenol, Isoprenaline
Pharmacological effects:
1 , 2 receptor agonist
(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

31. Effects of NE, EPI, ISO and DA (therapeutic doses) on cardiovascular indices
静脉滴注，除多巴胺为500 ug/min外，其余均为10 ug/min

32. 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

33. 1 receptor agonists Dobutamine （多巴酚丁胺） Cardiac stimulation
Used for heart failure (after cardiac surgery or congestive HF or acute myocardial infarction; short-term treatment)

34. 2 receptor agonists Salbutamol (沙丁胺醇) 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).

35. Adrenoceptor Agonists
α1, α2 Receptor agonists (norepinephrine)
α1 Receptor agonists (phenylephrine)
α2 Receptor agonists (clonidine)
α, β agonists (epinephrine, dopamine, ephedrine)
β agonists
β1, β2 Receptor agonists (isoprenaline)
β1 Receptor agonists (dobutamine)
β2 Receptor agonists (salbutamol)

36. Adrenoceptor 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 antagonists:
nonselective: with ISA (pindolol 吲哚洛尔)
without ISA (propranolol普萘洛尔)
β1 antagonists: atenolol 阿替洛尔, metoprolol美托洛尔
/β antagonists: with ISA (labetalol 拉贝洛尔)
without ISA (carvedilol 卡维地洛)
ISA: intrinsic sympathomimetic activity

37.  Antagonists
Adrenaline reversal

38. 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; blockade of 2 receptor promotes NE release
(3) Cholinergic and histamine-like effects
Contraction of GI smooth muscles,
Gastric acid secretion 

39. Clinical uses Phentolamine Major Adverse effects
(1) Decrease blood pressure
- Hypertension from drugs
- Pheochromocytoma嗜铬细胞瘤 (short term use) : diagnostic test, peri-surgery uses
(2) Peripheral vascular diseases
- Acrocyanosis (手足发绀), Raynaud’s disease雷诺氏病
(3) Local NE extravasations
(4) Shock: improves microcirculation
(5) Acute myocardial infarction and obstinate congestive heart failure
(6) Drug-induced hypertension
Major Adverse effects
Postural hypotension, reflex tachycardia, arrhythmia, angina pectoris, GI reactions, peptic ulcer

40. 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)

41. Phenoxybenzamine 酚苄明 Irreversible, nonselective (1 and 2)
Strong effect, slow but long action (up to 3~4 days)
Similar to phentolamine in actions and clinical uses
酚苄明进入体内先环化，再与受体形成牢固的共价键，故作用缓慢而持久。

42. Other α antagonists 1 antagonists
Prazosin (哌唑嗪): treatment for hypertension, CHF
Tamsulosin (坦洛新): 1A blocker, for benign prostate hypertrophy
2 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。

43. Adrenoceptor 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 antagonists:
nonselective: with ISA (pindolol 吲哚洛尔)
without ISA (propranolol普萘洛尔)
β1 antagonists: atenolol 阿替洛尔, metoprolol美托洛尔
/β antagonists: with ISA (labetalol 拉贝洛尔)
without ISA (carvedilol 卡维地洛)
ISA: intrinsic sympathomimetic activity

45.  antagonists General properties: ADME
Bioavailability: depends on lipid solubility, absorption, first-pass elimination.
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.

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

47.  antagonists 1.  blockade 2) Bronchial smooth muscles
induces bronchial smooth muscle contraction in asthmatic patients
3) Metabolism
lipolysis , VLDL and TG , HDL
glycogenolysis,– hypoglycemia (esp. after insulin)
T4-T3 turnover, T3 sensitivity
4) Renin secretion: decrease

48.  antagonists 2. Intrinsic sympathomimetic action (ISA)
Partial agonists: e.g. pindolol, acebutolol, labetalol, weaker cardiac inhibition and bronchoconstriction, weak vasodilatation/cardiac stimulation at larger doses
3. Membrane-stabilizing effect
At larger doses of some drugs: local anesthetic-like effects, Na+ channel blockade
4. Lower intraocular pressure

49. Circulation of Aqueous humor

50.  antagonists Clinical uses
(1) Arrhythmia: tachycardia associated with sympathetic activity  , ischemia, and cardiac glycosides强心苷.
(2) Hypertension
(3) Angina pectoris and myocardial infarction
(4) Chronic heart failure: mild to moderate CHF (carvedilol, metoprolol, bisoprolol), + cardiac glycosides when necessary
(5) Others: hyperthyroidism, tremor, migraine, glaucoma (timolol噻吗洛尔)

51.  antagonists Adverse effects
(1) Heart depression: contraindicated in heart failure, severe A-V block, sinus bradycardia
(2) Worsening asthma: esp. non-selective agents, contraindicated in bronchial asthmatic patients
(3) Rebound phenomenon: up-regulation of receptors
(4) Worsening peripheral vascular constriction: more  occupation of endogenous catecholamine
(5) Others: central depression, hypoglycemia, sexual dysfunction, etc.