2. Chapter 9 Central and Peripheral Sympatholytic ( 抗交感神经药物 ) and Vasodilators ( 血管扩张药 )

3. 2 血压的调节

4. Central and Peripheral Sympatholytics and Vasodilators Brain Ganglion 神经节 Increase rhythms of the heart arterial contraction Neurotransmitter Increase Blood pressure

5. 1, Centrally Acting Sympatholytics 567 Clonidine Guanabenz Guanfacine 可乐定 胍那苄 胍法辛

6. Mechanism of action   2 adernoceptors (  肾上腺素  2 受体， CNS ) related to sedation, bradycardia( 心动过 缓 ) and mental depression.  I 1 Imidazoline receptors ( I 1 咪唑啉受体 )  Agonists: Inhibition of sympathetic output

7. Specific Drug 1 3 569 Clonidine Hydrochloride 盐酸可乐定 2-(2,6-Dichlorophenylamino) imidazolidine hydrochloride

8. Physicochemical Properties  White crystal powder  Soluble in water, ethanol ； Insoluble in chloroform and ether;

9. Metabolism 40~60%, unchanged drug, renal route T 1/2 =6-20 hrs, bid T 1/2 =18-41 hrs, impaired renal function ob> 90% Conjugation, 10-20%

10. Therapeutic Applications  Mild to moderate hypertension  Sever cancer pain （ opioid receptor ） (combination with opiates)

11. Adverse Effects  Sedation; dry mouth(50%);  Withdrawal syndromes （戒断综合征） : headache, tremors( 颤抖 ), constipation, mental depression   2 adernoceptors (  肾上腺素受体 ) > imidazoline I 1 receptor

12. Moxonidine 莫索尼定, 0.2-0.4mg, qd 40-50% unchanged excreted in the urine unmetabolized -OH, - COOH

13. Rilmenidine 1-3mg, T1/2=8h BA>95% Excreted unchangde in the urine 利美尼定 Imidazoline I 1 receptor: reduced the adverse effects

14. 2, Ganglion blockers （ 神经节 阻断剂 ）  General structure ： amine with huge size group ；  Mecamylamine 美加明  Side effects limited its application

15. 3. Adrenergic Neuron （神经元） Blocking Agents （作用于神经末梢 的药物） brain ganglion Increase Rhythms of the heart arterial contraction neurotransmitter  肾上腺素能阻断剂 Increase Blood pressure

16. Reserpine 利舍平  an old drug ， isolated from the root of Rauwolfid serpentina ( 印度萝芙 ) ， 1918

17. Structure of Reserpine Indole alkaloid

18. Physicalchemical Properties  Soluble in organic agents ， mp.264- 265˚C ； alkalescence( 弱碱性 )

19. Chemical stability hv/ heat Hydrolysis oxidation ， Y-G-B

20. Pharmacokinetics  Peak blood concentration: 2h  The full effects: 2-3 weeks  Phase I Reaction （第一阶段血浆清除率） 4.5h; Phase II Reaction 11.3 day;  Feces : >60%, urine 10%

21. Therapeutic Application  Mild to moderate hypertension  CNS side effects ( 长期使用引起抑郁症，鼻塞、 腹泻 )  Schizophrenic （精神分裂） disorders  Rarely used.

22. 4. Arterial Vasodilators brain ganglion Increase Rhythms of the heart arterial contraction neurotransmitter Increase Blood pressure

23. α 1 adrenergic antagonists  α 1 adrenergic receptor— mediated contraction of arterial and venous smooth muscle ；  α 2 adrenergic receptor( peripheral ) — mediated decrease rhythm of the heart  α adrenergic antagonists  α 1 adrenergic antagonists ， 1960

24. Phentolamine flush Acid stomach increase rhythm of the heart 酚妥拉明

25.  1 Adrenergic blockers Prazosin 哌唑嗪 1-(4-amino-6,7-dimethoxy-2-quinazolin)-4-(2-furancarbonyl) piperazine hydrochloride 1 4 564

26. Character White crystal powder; Partly soluble in ethnol; Insoluble in water

27. Metabolism Ob 45-65%, T 1/2 =2-3hrs, Duration of action=4-6hrs, bid or tid

28. Indictions  A step 1 drug  Moderate to severe hypertension  Advantageous for older men with BPH( 前列腺 增生 )

29. Hydralazine 肼屈嗪 1-Phthalazinone Hydrazone 1- 肼基 -2 ， 3- 二氮杂萘 574

30. Hydralazine  yellow crystal ， mp.172-173 。 C  Be soluble in acetic acid and acidic water

31. Metabolism -COCH3 -OH, conjugation Acetylation phenotype 2-4h, 8h in some patients with slow acetylators

32. Indications  Moderate to severe hypertension as a step 2 or 3 drug therapy  Be used when the drug cannot be given orally and when blood pressure must be lowered immediately

33. Central and Peripheral Sympatholytics and Vasodilators brain ganglion Increase Rhythms of the heart arterial contraction neurotransmitter Increase Blood pressure

34. 5,β Receptor blockers  Adrenaline

35. β Receptor blockers  β 1 R(Heart) —contraction of smooth muscle ;increase rhythms of the heart  β 2 R (bronchia and vascular)—dilation （） 扩张血管（沙丁胺醇）  Heart: β 1 : β 2 =5:1  Lung: β 1 : β 2 =3:7

36. β Receptor blockers  1 ） β adrenergic receptor blockers ；  2 ） β 1 adrenergic receptor blockers ；  3 ）  /β adrenergic receptor blockers ；

37. βadrenergic receptor blockers 1950s Dichloroisoproterenol (DIC) 二氯特诺 Agonist-antagonist Origin of β-adrenergic antagonists

38. Pronethalol 丙萘洛尔 A clinical candidate was introduced in 1962 Be withdrawn in 1963 because of tumor induction in animal test

39. Aryloxypropanolamine  Propranolol About 9 β-blockers are in the Top 200 prescription drugs Aryl ring Secondary amine Secondary alcohol

40. Propranolol Hydrochloride  盐酸普萘洛尔 1-isopropylamino-3-(1-naphthyloxy)- 2-propanol hydrochloride 心得安 萘心安

41. Propranolol Hydrochloride  Be soluble in water ， insoluble in ether, benzene  Mp.161-165 ℃  Mp.93-94 ℃ HCI

42. Propranolol Hydrochloride  Unstable in acidic solution

43. Metabolism  Oxidation in liver, T 1/2 =3-5hrs -OH Oxidation,M

44. Synthesis of Propranolol Hydrochloride

45. Indications  Angina, arrhythmias, hypertension  Side effects: depression( 易透过血 脑屏障，产生中枢反 应 )  Asthma( 哮喘, 支气管 痉挛；抑制心脏 )

46. Nadolol 纳多洛尔

47. Esmolol 308 艾司洛尔 T 1/2 = 8 mins Used during surgery Reduced adverse effects

48. R&D  Soft drugs( 软药 ) are active analogs of a lead compound that are deactivated in a predictable and controllable way after having achieved their therapeutic effect  Hard drugs are metabolized difficultly and have a long duration of action 564

49.  1 – Selective blockers  Drugs with greater affinity for the  1 - receptors of the heart than for  2 -receptors in other tissues  4-substituted phenyloxypropanolamines

50.  1 blockers  Metoprolol Tartrate  美托洛尔 酒石酸盐 1-[4-(2-methoxyethyl)phenoxy]-3-(1-methylethyl)amino]- 2-propanol L-(+)-tartrate

51. Metablism  Oxidation and dealkylation, T1/2=3-7 hrs

52. metabolism dealkylation Oxidation

53. Therapeutic application  Less side effect( 降低呼吸系统的副作用 )  Used in the treatment of hypertension

54. Atenolol  阿替洛尔 308  P=0.008, Less affection on CNS, cleared by the kidney  Used in the treatment of hypertension,angina,

55.  /  Receptor blocker 柳胺苄心安 Labetalol 拉贝洛尔 Phenylethanolamine Aryl ring Ethanol Second amino

56. Labetalol Widely used in the trearment of hypertension, angina, arrhythmias

57. Dilevalol 地来洛尔 R,R  Receptor blocker Be withdrawal from market because of hepatic toxicity

58. Structure-activity Relationship Mimic adrenaline

59. SAR  Ar----aryl rings : benzene,naphthalene ect. ；  4-substituted phenyloxypropanolamines selectively inhibited  1 -receptors  Lipophilic drugs/liver; hydrophilic agents/kidney

60. SAR  Side chain: isopropane

61. SAR  Aryloxypropanlamines arylethanolamines S absolute configuration R absolute configuration

62. Objects  To master SAR of  adrenergic receptor blockers  To master the structure, name and metabolism of Clonidine, Reserpine,Prazosin, Propranolol, Metoprolol.  To master the definition of soft drug and hard drug ；