1 Chapter 4 Circulatory System Agents

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3 Overview Cardiovascular disease is the first cause of death in developed countries. About 1/3-1/4 of 3000 new drugs in developing in the world. Angina （心绞痛）, cardiac arrhythmias ( 心律失常）, hypertension （高血压）, hyperlipidemias （高血脂）, and disorders of blood coagulation （凝血）

4 Pathogenesis ( 发病机制 ) Central nervous system action Nerve ending release chemomitter ( 化学递质 ) Affect coherent receptor, enzyme and ion channel Lipoprotein metabolism Generation of thrombocyte ( 血小板 ) Various kinds of endogenous regulatory factor

5 Outline 1. β-Adrenergic Blocking Agents 2. Calcium Channel Blockers 3. Sodium and Potassium Channel Blockers 4. Angiotensin Converting Enzyme Inhibitors and Angiotensin Ⅱ Receptor Antagonists Propranolol “-lol” series Nifedipine “ -dipine ” І a 、 І b and І c Captopril “ -pril ” Losartan “ -sartan ” Angina ( 绞痛 ) Arrhythmias ( 心率失常 ) Hypertension

6 Outline 5. NO Donor Drugs 6. Cardiac Agents 7. Lipid Regulators 8. Antithrombotic Drugs Nitroglycerin Digoxin Lovastatin “ -tatin ” Congestive heart failure ( C H F, 充血性心力衰竭 ) Angina pectoris ( 心绞痛 ) Hyperlipidemia Disorders of blood coagulation Clopidogrel

7 Section 1 β-Adrenergic Block Agents ( 肾上腺能 β- 受体阻滞剂 )

8 Request and Purpose To master the structure, chemical name, physico-chemical property, metabolism in vivo, clinical application and synthetic route of propranolol hydrochloride ( 盐酸 普萘洛尔 ). To be familiar with metoprolol tartrate ( 酒石酸美托洛尔 ). To get information of practolol ( 普拉洛尔 ) and bisoprolol ( 比索洛尔 ).

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10 β- receptor β1β1 β2β2 Located mainly in the heart and kidneys on smooth muscle of blood vessel and bronchus The same organ has bothβ 1 和 β 2 Atrium ( 心房 ) β 1 ： β 2 ＝ 3 ： 1 Lungs ： β 1 ： β 2 ＝ 3 ： 7 3 subtypes Bronchodilation ( 支气管扩张 ) Vasodilation ( 血管舒张 ) β3β3 located in fat cells

11 Proposed binding site for epinephrine ( 肾上腺素 ) in the β 2 -receptor

12 β-Adrenergic Block Agents β-blockers (β-adrenergic blocking agents, β-adrenergic antagonists, or β-antagonists) are a class of drugs. Particularly for the management of cardiac arrhythmias, cardioprotection after myocardial infarction (heart attack), and hypertension. They work by affecting the response to some nerve impulses in certain parts of the body and decrease the heart's need for blood and oxygen by reducing its workload. They also help the heart to beat more regularly. Propranolol was the first clinically useful β- adrenergic receptor antagonist. Invented by Sir James W. Black, it revolutionized the medical management of angina pectoris and is considered to be one of the most important contributions to clinical medicine and pharmacology of the 20th century.

13 History and Development The first β-blocker reported in 1958 Pronethalol Propranolol Partial antagonist Sympathomimetic activity ( 拟交感活性 ) No Sympathomimetic activity, But cause thymic tumors 普萘洛尔 “ -lol ” James Black 1988 Nobel Prize

14 Other nonselective β 1 -receptor blocker Flestolol NadololEsmolol History and Development -----continued

15 Practolol ( 普拉洛尔 ) Metoprolol ( 美托洛尔 ) Nonselective blocker cause bronchiotetany ( 支气管痉挛 ) ( antagonistic effect on the β 2 of the bronchi ) The first cardioselective β 1 antagonist. Several toxic effects, no longer in general use. Low bioavailability because of significant first-pass metabolism Selective β 1 -receptor blocker History and Development -----continued

16 Other selective β 1 -receptor blocker Bisoprolol ( 比索洛尔 ) Betaxolol ( 倍他洛尔 ) Acebutolol ( 醋丁洛尔 ) Atenolol ( 阿替洛尔 ) all 4-substituted change

17 Classification Block the β 1 andβ 2 -receptor equally well Propranolol Metoprolol Labetalol Cardioselective β antagonists Not only block β, and α-receptor

18 Propranolol Hydrochloride ( 盐酸普萘洛尔 ) 1-Isopropylamino-3-(1-naphthyloxy)-2- propanol hydrochloride 1 2 3

19 Chemical synthesis Naphthol 3-chloro-epoxypropaneisopropylamine

20 Physicochemical property One chiral centre, levo-isomer is more active, but racemic mixture in clinic. Unstable in acid solution and light Impurity test residue Jacinth color

21 Pharmacological action Nonselective competitive β-receptor antagonists Clinical: Further investigation for the treatment of anxiety ( 焦 虑 ), schizophrenia ( 精神分裂症 ), alcohol withdrawal syndrome, and aggressive behavior. Angina pectoris ( 心绞痛 ), cardiac arrhythmias ( 心律不齐 ), hypertension, post-myocardial infarction ( 心肌梗塞 ), hypertrophic cardiomyopathy ( 心肌肥大 ), pheochromocytoma ( 嗜铬细胞瘤 ), migraine prophylaxis ( 偏头 痛预防 ), and essential tremor( 特发性震颤 ).

22 Structure Activity Relation (SAR)

23 Metoprolol Tartrate ( 酒石酸美托洛尔 ) IUPAC name: (RS)-1-(isopropylamino)-3-[4-(2- methoxyethyl)phenoxy]propan-2-ol 1 2 3

24 Metoprolol in clinic Metoprolol is a selective β1 receptor blocker used in treatment of several diseases of the cardiovascular system, especially hypertension. The active substance metoprolol is employed either as metoprolol succinate ( 琥珀酸盐 ) or metoprolol tartrate ( 酒石酸盐 ) respectively as prolonged-release or conventional-release formulation.

25 Section 2 Calcium Channel Blockers

26 Ion channel concept ： classification ：

27 Calcium Channel

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29 Voltage-dependent calcium channels (VDCC) are a group of voltage-gated ion channels found in excitable cells with a permeability to the ion Ca 2+. At physiologic or resting membrane potential, they are normally closed. Their activation allows Ca 2+ entry into the cell, results in muscular contraction, excitation of neurons, up-regulation of gene expression, or release of hormones or neurotransmitters. There are several different kinds of high-voltage-gated calcium channels, N-type, R-type, P/Q-type and L-type channels. Calcium channel blockers are a class of drugs and natural substances which disrupt the conduction of calcium channels. Calcium channel blockers (CCB)

30 Calcium channel blockers (CCB) Only act on L-type ， not T, N or P type Verapamil ( 维拉帕米 ) Nifedipine ( 硝苯地平 ) Diltiazem ( 地尔硫卓 )

31 Nifedipine ( 硝苯地平 ) IUPAC name: 3,5-dimethyl 2,6-dimethyl-4-(2- nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Other name: 1,4-Dihydro-2,6-dimethyl-4-(2- nitrophenyl)-3,5-pyridinedicarboxylic acid dimethyl ester Adalat / Procardia ( 心痛定 ) INN:International Non- proprietary Names

32 Physico-chemical property

33 Metabolism in vivo All the metabolites are not active.

34 Pharmacological action Nifedipine is a dihydropyridine calcium channel blocker. Its main uses are as an antianginal ( 抗心绞 痛药 ) and antihypertensive. It is used to treat coronary artery spasm (CAS, 冠 状动脉痉挛 ), myocardial infarction (MI 心肌梗塞 ) although a large number of other uses have recently been found for this agent. It is also commonly used for the small subset of pulmonary hypertension ( 肺性高血压 ) patients whose symptoms respond to calcium channel blockers.

35 Pharmacological action High specificity, strong vasodilator ( 血管扩张 ) action and little or no direct depressant effect on the heart. Drug combination with β-receptor blocker and cardiac glycoside (CG, 强心苷 ).

36 Other 1,4-dihydropyridine agents NifedipineNimodipine Nicardipine Nisoldipine NitrendipineAmlodipine

37 Caution S-isomer ： active; R-isomer ： block Activate calcium channel

38 SAR of Nifedipine

39 Diltiazem Hydrochloride ( 地尔硫卓 ) (2S-cis)-3-(Acetyloxy)-5-[2-(dimethyl-amino)ethyl]- 2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiazepin- 4(5H)-one hydrochloride cardizem. HCl

40 Structural feature 2 Chiral Centers 4 Stereo-isomers: trans d-/ l- isomer, and cis d-/ l-isomer Coronary arteriectasis ( 冠脉扩张 ) is sensitive to cis- d-isomer, and only cis-d in clinic.

41 Synthesis of Diltiazem Hydrochloride

42 Pharmacologic action Dilate ( 扩张 ) peripheral arteries ( 动脉 ) and arterioles ( 小动 脉 ), and bypass circuit ( 侧支循环 ). Increase myocardial oxygen ( 心肌氧 ) supply by lessening coronary artery spasm ( 冠状动脉痉挛 ). Reduces myocardial oxygen demand by decreasing heart rate and reducing overload. Various kinds of ischemic heart disease ( 缺血性心脏病 ) including variant angina ( 变异型心绞痛 ), and cardiovascular accident prophylaxis.

43 Metabolism

44 Verapamil Hydrochloride ( 盐酸维拉帕米 ) IUPAC name: (RS)-2-(3,4-dimethoxyphenyl)-5-[[2-(3,4-dimethoxyphenyl)ethyl]- (methyl)amino]-2-isopropyl pentanenitrile [(3,4-dimethoxylphenethyl)methylamino]-2- (3,4-dimethoxy phenyl)-2-isopropyl valeronitrile ( 戊腈 )

45 Physico-chemical property Asymmetic center, potency: d->>l- But racemic mixture in clinical. Chemical stability is quite good ， no matter in heat, light, acid or base condition.

46 Metabolism Metablized quickly, and low bioavailability. Metabolites-- no significant biological activity. Elimination half-life: 5hrs N-dealkylation O- and N-demethylations

47 Pharmacologic action Verapamil is an L-type calcium channel blocker of the phenylalkylamine class. It has been used in the treatment of hypertension, angina pectoris ( 心绞痛 ), cardiac arrhythmia ( 心律失常 ), and most recently, cluster headaches. Verapamil has also been used as a vasodilator ( 血管扩张剂 ) during cryopreservation of blood vessels. It is more effective than digoxin ( 地高辛 ) in controlling ventricular rate ( 心室率 ). Side effect: constipation ( 便秘 ). It was approved by the US FDA in 1981.

48 exercise （ 1 ） What can be treated byβ-receptor blockers in the following deseases A.hypertension B.Cardiac failure C.Angina pectoris D.Cardiac arrhythmia E.hyperlipidemia √ √ √

49 exercise （ 2 ） Which of the following effects taken by Ca-antagonists A.to lower blood pressure B.to anti-arrhythmia 心律失常 C.to lower blood fat D.to anti-angina 绞痛 E.to anti-anaphylaxis 过敏反应 √ √ √

50 exercise （ 3 ） Which of the following drugs match the upright chemical structure A.Nifedipine B.Nimodipine C.Anlodipine D.Verapamil E.Propranolol √

51 Case study Andy, is a 56-year-old construction worker with a 15-year history of hypertension and ischemic heart disease that was well controlled until 6 months ago Over the past 2 months, has been seen twice in the ER with chest pain unrelieved by sublingual nitroglycerin. On a third occasion, he was hospitalized with the same symptoms and was given a complete workup. He has two severe vessel disease, but refuses angioplasty or bypass surgery at this time.

52 His current medications include nifedipine, captopril, nitroglycerin, diltiazem, and aspirin. During the past week, he experienced several anginal attacks each day that were relieved by nitroglycerin; finally, Andi has decided to seek more definitive treatment. Tonight he presents to the ER with chest pain unrelieved by nitroglycerin and is sent to the critical care until with the diagnosis of unstable angina pectoris. The attending physician orders IV nitroglycerin and wants to start an IV β-adrenergic blocker to counteract any tachycardia,but is concerned about its long-term effects on overall cardiac function.

53 Question 1 Select the most appropriate β-adrenergic antagonist from the structures (90.1~90.6) provided. Justify your choice on the basis of the pharmacology and the comparative pharmacokinetics of the available structures. pindolol Metoprolol Propranololpenbutolol Esmolol Isoprenaline

54 Question 2 one of the structures is contraindicated in the patient. Which one is it, and why is it contraindicated?