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Chapter 4Chapter 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）

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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

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Outline

1. β-Adrenergic Blocking Agents

2. Calcium Channel Blockers

3. Sodium and Potassium Channel Blockers

4. Angiotensin Converting Enzyme Inhibitors and Angiotensin Receptor AntagonistsⅡ

Propranolol “-lol” series

Nifedipine “-dipine”

Іa 、 Іb and Іc

Captopril “-pril” Losartan “-sartan”

Angina( 绞痛 )

Arrhythmias( 心率失常 )

Hypertension

Hypertension

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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

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Section 1

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

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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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adrenergic receptors subtypes

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β-receptor

β1

β2

Located mainly in the heart and kidneyson smooth muscle of blood vessel and bronchus

The same organ has bothβ1 和 β2

Atrium ( 心房 )β1 ： β2 ＝ 3 ： 1

Lungs ： β1 ： β2 ＝ 3 ： 7

3 subtypes

Bronchodilation( 支气管扩张 )Vasodilation( 血管舒张 )

β3 located in fat cells

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Proposed binding site for epinephrine( 肾上腺素 )in the β2-receptor

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β-Adrenergic Block Agents β-blockers (β-adrenergic blocking agents, β-adrenergic antago

nists, or β-antagonists) are a class of drugs. Particularly for the management of cardiac arrhythmias, cardi

oprotection 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.

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History and Development The first β-blocker reported in 1958

Pronethalol

Propranolol

HN

OH

Cl

Cl Dichloroisoproterenol

HN

OH

HO

HOIsoproterenol

HN

OH

Pronethalol

O

OH

NH

Propranolol

Partial antagonist

Sympathomimetic activity ( 拟交感活性 )

No Sympathomimetic activity,But cause thymic tumors

普萘洛尔“ -lol” James Black 1988Nobel Prize

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Other nonselective β1-receptor blocker

O NH

HOHOH

HO

O NH

HOH

O

O

O NH

HOH

OHN

O

NH2

F

Flestolol

Nadolol Esmolol

History and Development-----continued

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Practolol( 普拉洛尔 )

Metoprolol( 美托洛尔 )

O NH

HOH

HN

O

O NH

HOH

O

Nonselective blocker cause bronchiotetany( 支气管痉挛 )

(antagonistic effect on the β2 of the bronchi)

The first cardioselective β1 antagonist.

Several toxic effects, no longer in general use.

Low bioavailability because of significant first-pass metabolism

Selective β1-receptor blocker

History and Development-----continued

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Other selective β1-receptor blocker

O NH

HOH

O

H2N

O NH

H OH

HN

O

O

O NH

HOH

O

O NH

HOH

OO

Bisoprolol( 比索洛尔 )

Betaxolol ( 倍他洛尔 )

Acebutolol ( 醋丁洛尔 )

Atenolol ( 阿替洛尔 )

all 4-substituted change

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Classification

According to affinity to the receptor

Non-selective ¦Â-Adrenergic Block Agents

selective ¦Â1-Adrenergic Block Agents

Block the β1andβ2-receptor equally well

Propranolol

Metoprolol

Labetalolatypia ¦Â-Adrenergic Block Agents

Cardioselective β antagonists

Not only block β, and α-receptor

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　Propranolol Hydrochloride( 盐酸普萘洛尔 )

1-Isopropylamino-3-(1-naphthyloxy)-2-propanol hydrochloride

O NH

H OH. HCl

1

23

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Chemical synthesis

O NH

HOH

OH

O

Cl+

O

O

HCl

H2N

O NH

HOH. HCl

Naphthol 3-chloro-epoxypropane isopropylamine

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Physicochemical property One chiral centre, levo-isomer is more

active, but racemic mixture in clinic. Unstable in acid solution and light

OH

+

N+N

SO3H

OH

NN

SO3H

Impurity test

residue

Jacinth color

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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 ).

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Structure Activity Relation (SAR)

O NH

H OH

Substituted by S,CH2 or NCH3,activity lower

S-configuration isomer¡s̄ activity is better

By tert-butyl and isopropyl ,activity highest.Or number of C more than 3.

Benzene,naphthalene,heterocycle and condensed ring.on the ring can be methyl,chloride,methoxyl and nitro-.2,4-or2,3,6-substitute simultaneously,best activity.

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　Metoprolol Tartrate ( 酒石酸美托洛尔 )

IUPAC name: (RS)-1-(isopropylamino)-3-[4-(2-meth

oxyethyl)phenoxy]propan-2-ol

. HOOH

O

OH

OH

OO

O NH

H OH

12

3

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Metoprolol in clinic Metoprolol is a selective β1 receptor blocker us

ed 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.

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Section 2

Calcium Channel Blockers

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Ion channel concept ：

classification ：

a kind of transmembrane biomacromolecule

take the action of ion pump like activating enzyme

and adjust many kinds of physiologic function

produce and transmit electrical signal

sodium channel potassium channel

calcium channel chlorine channel

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Calcium Channel

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Voltage-dependent calcium channels (VDCC) are a group of voltage-gated ion channels found in excitable cells with a permeability to the ion Ca2+.At physiologic or resting membrane potential, they are normally closed. Their activation allows Ca2+ 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)

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Calcium channel blockers (CCB) Only act on L-type ， not T, N or P type

structure and classification

nonselective CCB

selective CCB

phenylalkylamine

1,4-dihydropyridine

benzothiazepine

flunarizine

prenylamine

Verapamil( 维拉帕米 )

Nifedipine( 硝苯地平 )

Diltiazem ( 地尔硫卓 )

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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

HN

O

O

O

O

NO2

1 2

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5

6

Adalat / Procardia( 心痛定 )

INN:International Non-proprietary Names

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Physico-chemical property

HN

O

O

O

O

NO2

N

O

O

O

O

NO

N

O

O

O

O

NO2

¹â[ O ]

Dihydropyridine is aromatized

Nitro- converted nitroso-

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Metabolism in vivoHN

O

O

O

O

NO2

N

O

OH

O

O

NO2

N

O

O

O

O

NO2

N

O

O

NO2

O

O

N

O

OH

O

O

NO2

OH

[ O ]

- CH3OH- 2H

All the metabolites are not active.

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Pharmacological action Nifedipine is a dihydropyridine calcium channel b

locker. 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.

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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 ).

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Other 1,4-dihydropyridine agentsHN

O

O

O

O

NO2

HN

O

O

O

O O

NO2

N

HN

O

O

NO2

O

O

HN

O

O

O

O

NO2

HN

O

O

O

O

NO2

HN

O

O

O

O

Cl

ONH2

Nifedipine Nimodipine Nicardipine

Nisoldipine Nitrendipine Amlodipine

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Caution

HN

NO2

O

OF

FF

HN

O

OO

OO F

F F

HN

NO2

O

O

NO

N

BayK8644 PN202791 CGP28392

S-isomer ： active; R-isomer ： block

Structure¡s̄ minute difference make the channel in either open(O),resting(R) or inactivated(I) state,and action chang

Some belong to dihydropyridine in chemical structure, but its action opposite to Nifedipine

Activate calcium channel

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SAR of Nifedipine

HN

OO

OONO2

position 4 requires an aromatic substitution ortho- and/or meta-position requir

an electron-withdrawing group

position 3 and 5 must be carboxylic ester

nitro group is essential

position 2 and 6 substituted with an alkyl group

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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

N

S

O

O

O

ON

12

3

45

cardizem

.HCl

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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.

potency: cis d-£¾cis dl-£¾cis l-£¾trans dl-

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Synthesis of Diltiazem Hydrochloride

SH

NH2

OO

O NH

S

O

OH

O

N

S

O

OH

O

N

N

S

O

O

O

NO

HCl

+

Ac2O

HCl

ClN

NaH, DMSO

O

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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.

clinic

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.

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Metabolism

N

S

O

O

OH

ON

ÍÑÒÒõ£»ù ÍÑN-¼×»ù

ÍÑO-¼×»ù

N

S

OH

O

ON

N

S

O

O

O

ONH

N

S

O

O

O

ON

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　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

O

O

N

N

O

O

. HCl

1

23

4

5

5-[(3,4-dimethoxylphenethyl)methylamino]-2- (3,4-dimethoxy phenyl)-2-isopropyl valeronitrile ( 戊腈 )

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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 co

ndition.

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Metabolism

Metablized quickly, and low bioavailability. Metabolites-- no significant biological activity. Elimination half-life: 5hrs

metabolic pathway

N-dealkylation

O- and N-demethylations

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Pharmacologic action Verapamil is an L-type calcium channel blocker of the ph

enylalkylamine 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.

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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

√

√√

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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

√√

√

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exercise （ 3 ） Which of the following drugs match the upright

chemical structure

HN

O

O

O

O O

NO2

A. Nifedipine

B. Nimodipine

C. Anlodipine

D. Verapamil

E. Propranolol

√

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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.

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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.

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Question 1 Select the most appropriat

e 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.

N

O

OH

N

H

H

90.1 90.2

N

OH

HO

OH

H

H

90.3

O N

OH

H

90.4

O N

OH

O

H

90.5

O N

OH

O

O

HO N

OH

90.6

pindolol

Metoprolol

Propranolol penbutolol

Esmolol

Isoprenaline

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Question 2 one of the structures is contraindicated in th

e patient. Which one is it, and why is it contraindicated?