抗心绞痛药2016年10月

Treatmentofmyocardialischemia心肌缺血的治疗Hong

ChenDepartment

of

PharmacologyShanghaiJiaotongUniversitySchoolofMedicine陈

红 上海交通大学医学院药理学教研室冠状动脉粥样硬化性心脏病

Coronary

Heart

Disease冠心病表现与类型√心绞痛

Angina

Pectoris劳力型stable变异型variant不稳定性心绞痛unstable√心肌梗塞MyocardialInfarction冠脉综合征Coronary

Syndrome√

猝死

Sudden

Death√无症状性心肌缺血Silent

Ischemia冠脉粥样硬化斑块出血与心肌梗死coronary

atherosclerosis,

plaque

bleeding,

myocardial

infarcPathophysiology

of

ischemic

heartdiseaseAngina

pectoris,

the

primary

symptom

of

ischemic

heart

disease,is

caused

by

transient

episodes

of

myocardial

ischemia

that

aredue

to

an

imbalance

in

the

myocardial

oxygen

supply-demandrelationship.心绞痛是心肌缺血的主要症状，其发生基于氧的供需矛盾This

imbalance

may

be

caused

by

an

increase

in

myocardialoxygen

demand

(determined

by

heart

rate,

ventricularcontractility,

and

ventricular

wall

tension)

or

by

a

decrease

inmyocardial

oxygen

supply

(primarily

determined

by

coronaryblood

flow

but

occasionally

modified

by

the

oxygen-carryingcapacity

of

the

blood)or

sometimes

by

both.心率、心肌收缩力、容量负荷与压力负荷（决定室壁张力）增加均可增加氧耗，而氧供减少主要是由于冠脉流量降低Pathophysiology

of

ischemic

heartdiseaseAngina

pectoris

may

occur

in

a

stable

pattern

over

many

yearsor

may e

unstable,

increasing

in

frequency

or

severity

andeven

occurring

at

rest.

In

typical

stable

angina,

the

pathologicalsubstrate

is

usually

fixed

atherosclerotic

narrowing

of

anepicardial

coronary

artery,on

which

exertion

or

emotional

stresssuperimposes

an

increase

in

myocardial

oxygen

consumption.稳定型心绞痛与不稳定型心绞痛In

variant

angina,focal

or

diffuse

coronary

vasospasmepisodically

reduces

coronary

flow.变异型心绞痛Patients

also

may

display

a

mixed

pattern

of

angina

with

theaddition

of

altered

vessel

tone

on

a

background

of

atheroscleroticnarrowing.

In

most

patients

with

unstable

angina,

rupture

of

anatherosclerotic

plaque,

with

consequent

platelet

adhesion

andaggregation,

decreases

coronary

blood

flow.

Plaques

with

thinnerfibrous

caps

are

more

“vulnerable”

to

rupture..Pharmacological

modification

of

themajor

determinants

of

myocardialO2

supply

and

demandWhen

myocardial

O2

requirements

exceed

O2

supply,

an

ischemic

episoderesults.

This

figure

shows

the

primary

hemodynamic

sites

of

actions

ofpharmacological

agents

that

can

reduce

O2

demand

(left

side)

orenhance

O2

supply

(right

side).

Some

classes

of

agents

have

multipleeffects

(see

text).

Stents,

angioplasty,

and

coronary

bypass

surgery

aremechanical

interventions

that

increase

O2

supply.

Both

pharmacotherapyand

mechanotherapy

attempt

to

restore

a

dynamic

balance

between

O2demand

and

O2

supply.Coronary

arterioles

and

blood

supply冠脉解剖及其血液供应特点Coronary

arterioles

and

blood

supply冠脉血液供应特点Oxygen

Consumption心肌氧耗特点Heart

rate

心率(cardiac

output

and

heart

work)Myocardial

contraction

心肌收缩力

Ventricular

wall

tension

室壁张力

systole:afterload

(blood

pressure)后负荷（压力负荷，即血压）diastole:

preload

(blood

volume)前负荷（容量负荷，即血容量）Pharmacotherapy

of

angina

pectoris治疗心绞痛的药物Agents

increasing

O2

supply(vasodilators)增加氧供(扩血管药)√

Organic

nitrates硝酸酯类√

Calcium

channel

blocker钙通道阻滞剂Agents

decreasing

O2

demand降低氧耗√

β-adrenergic

antagonist

β肾上腺素能受体拮抗药√

Organic

nitrates有机硝酸酯类Anti-platelet

and

anti-thrombotic

agents抗血小板药与抗血栓药√

Aspirin

reduces

the

incidence

of

myocardial

infarction

(MI)anddeath

in

patients

with

unstable

angina.In

addition,low

doses

ofaspirin

(160

to

325

mg)appear

to

reduce

the

incidence

ofmyocardial

infarction心肌梗死in

patients

with

chronic

stableangina.√

Heparin

,

in

its

unfractionated

form

and

as

low-molecular-weightheparin,

also

reduces

symptoms

and

prevents

infarction

inunstable

angina.Organic

nitrates硝酸酯类-1Mechanism

ofReliefof

Symptoms

of

Angina

Pectoris增加氧供√

Direct

coronary

vasodilation

to

increase

blood

flow

扩张冠脉

血管增加血供√

Artery

vasodilatation

to

decrease

cardiac

work

secondaryto

the

fall

in

systemic

arterial

pressure

舒张动脉降低血压减轻

射血负荷（后负荷）√

Venous

dilatation

to

decrease

venous

return

thereforereducingpreload扩张静脉降低静脉回流减轻前负荷Organic

nitrates硝酸酯类-2Chemistry.Organic

nitrates有机硝酸盐are

polyol

estersof

nitric

acid,whereas

organic

nitrites亚硝酸盐are

estersof

nitrous

acid.Nitrate

esters(-C-O-NO2)and

nitriteesters(-C-O-NO)are

characterized

by

a

sequence

ofcarbon-oxygen-nitrogen,

whereas

nitro

compoundspossess

carbon-nitrogen

bonds

(C-NO2).

Thus

glyceryltrinitrate

is

not

a

nitro

compound,and

it

is

erroneouslycalled

nitroglycerin;however,this

nomenclature命名isboth

widespread

and

official.In

the

pure

form

(without

an

inert

carrier

such

aslactose),

nitroglycerin

is

explosive.

The

organic

nitrates

and

nitrites,

collectively

termed

nitrovasodilators,must

be

metabolized

(reduced)

to

produce

NO,

theactive

principle

of

this

class

of

compounds.Organic

nitrates硝酸酯类-3Mechanism

of

Action.Nitrites,organic

nitrates,nitroso

compounds,and

a

variety

of

other

nitrogen

oxide-containing

substances(including

nitroprusside硝普钠)lead

to

the

formation

of

the

reactive

free

radical

NO.NO

can

activate

guanylyl

cyclase,

increase

the

cellular

level

ofcyclic

GMP,

activate

PKG

(the

cyclic

GMP-dependent

proteinkinase),

and

modulate

the

activities

of

cyclic

nucleotidephosphodiesterases

(PDEs

2,

3,

and

5)

in

a

variety

of

cell

types.In

smooth

muscle,

the

net

result

is

reduced

phosphorylation

ofmyosin

light

chain,

reduced

Ca2+

concentration

in

the

cytosol,and

relaxation.The

pharmacological

and

biochemical

effects

of

thenitrovasodilators

is

identical

to

those

of

an

endothelium-derivedrelaxing

factor

NO.Organic

nitrates硝酸酯类-4Absorption,

Fate,

and

Excretion.

More

than

a

century

afterthe

first

use

of

organic

nitrates

to

treat

angina

pectoris,

theirbiotransformation

remains

the

subject

of

active

investigation.Studies

in

the

1970s

suggested

that

nitroglycerin

is

reductivelyhydrolyzed

by

hepatic

glutathione-organic

nitrate

reductase.More

recent

studies

have

implicated

a

mitochondrial

aldehydedehydrogenase

enzyme

in

the

biotransformation

of

nitroglycerin.Significant

first

pass

effect.首过消除效应大约80-90%Sublingual

nitrates

are

given

during

angina

attack

to

avoid

rapiddestruction

in

the

liver.Nitroglycerin.

Peak

plasma

concentrations

of

nitroglycerin

arefound

within

4

min

of

sublingual

administration,

with

a

half-life

of1

to

3

min.

Dinitrate

metabolites,

which

have

about

one-tenththe

vasodilator

potency,

appear

to

have

half-lives

ofapproximately

40

minutes.Organic

nitrates硝酸酯类-5Isosorbide

Dinitrate.硝酸异山梨酯

The

major

route

of

metabolism

of

isosorbide

dinitrate

is

by

enzymatic

denitrationfollowed

by

glucuronide

conjugation.Sublingual

administrationproduces

maximal

plasma

concentrations

of

the

drug

by

6

min,and

half-life

of

approximately

45

min.The

primary

initialmetabolites,isosorbide-2-mononitrate

and

isosorbide-5-mononitrate,have

longer

half-lives(3

to

6

hours)and

arepresumed

to

contribute

to

the

therapeutic

efficacy

of

the

drug.Isosorbide-5-Mononitrate.单硝酸硝酸异山梨酯

This

agent

is

available

in

tablet

form.It

does

not

undergo

significant

first-passmetabolism

and

so

has

excellent

bioavailability

after

oraladministration.The

mononitrate

has

a

significantly

longer

half-life

than

does

isosorbide

dinitrate

and

has

been

formulated

as

aplain

tablet

and

as

a

sustained-release

preparation;both

havelonger

durations

of

action

than

the

corresponding

dosage

formsof

isosorbide

dinitrate.Organic

nitrates硝酸酯类-6Toxicity

and

Untoward

Responses.

Untoward

responses

tothe

therapeutic

use

of

organic

nitrates

are

almost

all

secondaryto

actions

on

the

cardiovascular

system.√

Headache

is

common

and

can

be

severe.

It

usually

decreasesover

a

few

days

if

treatment

is

continued

and

often

can

becontrolled

by

decreasing

the

dose.√

Transient

episodes

of

tachycardia,

dizziness,

weakness,

andother

manifestations

associated

with

postural

hypotension

maydevelop,

particularly

if

the

patient

is

standing

immobile.√

Tachycardia

could

accelerate

myocardial

oxygen

demand

in

someand

combination

with

a

beta-blocker

can

counteract

thisuntoward

effect.Organic

nitrates硝酸酯类-7Rapid

tolerance快速耐受性.Sublingual

organic

nitrates

should

betaken

at

the

time

of

an

anginal

attack

or

in

anticipation

of

exercise

orstress.

Such

intermittent

treatment

provides

reproduciblecardiovascular

effects.

However,

frequently

repeated

or

continuousexposure

to

high

doses

of

organic

nitrates

leads

to

a

markedattenuation

in

the

magnitude

of

most

of

their

pharmacological

effects.Multiple

mechanisms

have

been

proposed

to

account

for

nitratetolerance,

including

volume

expansion,

neurohumoral

activation,cellular

depletion

of

sulfhydryl

groups,

and

the

generation

of

freeradicals.

Inactivation

of

mitochondrial

aldehyde

dehydrogenase,

anenzyme

implicated

in

biotransformation

of

nitroglycerin,

is

seen

inmodels

of

nitrate

tolerance,

potentially

associated

with

oxidativestress.

A

reactive

intermediate

formed

during

the

generation

of

NOfrom

organic

nitrates

may

itself

damage

and

inactivate

the

enzymesof

the

activation

pathway.A

more

effective

approach

to

restoring

responsiveness

is

to

interrupttherapy

for

8

to

12

hours

each

day.循环系统大动脉、冠脉与血流的机械应力(Circulation，coronary

artery

and

shear

stress)输送血管阻力血管缺血区非缺血区给硝酸甘油后主动脉输送血管扩张主动脉

冠脉狭窄缺血区非缺血区硝酸甘油可扩张较大的输送动脉*β受体阻断剂*β-antagonist

（*β受体阻断剂*）代表药物普萘洛尔propranolol

非选择性β受体阻断氨替洛尔atenolol比索洛尔bisoprolol美托洛尔metoprolol选择性β1阻断长效选择性β1阻断长效选择性β1阻断卡维地洛carvediolol

阻断β1、β2及α受体尚具有抗氧化作用β-Adrenergic

receptor

antagonistsβ肾上腺素能受体拮抗剂-1Therapeutic

usage.√

β

antagonists

(β

blockers),

by

reducing

heart

rate

andcontraction

therefore

myocardial

O2

consumption,

are

effectivein

reducing

the

severity

and

frequency

of

attacks

of

exertionalangina

and

in

improving

survival

in

patients

who

have

had

anmyocardial

infarction.√

β

blockers

also

prolongs

myocardial

perfusion

phase

due

to

lowerheart

rate.β-Adrenergic

receptor

antagonistsβ肾上腺素能受体拮抗剂-2Side

effects.

心功能降低 血管痉挛

支气管痉挛

变异性心绞痛者不能用√

Not

all

actions

of

β

antagonists

are

beneficial

in

all

patients.

Thedecreases

in

heart

rate

and

contractility

cause

increases

in

thesystolic

ejection

period

and

left

ventricular

end-diastolic

volume;these

alterations

tend

to

increase

O2

consumption.

However,

thenet

effect

of

β

receptor

blockade

is

usually

to

decreasemyocardial

O2

consumption,

particularly

during

exercise.Nevertheless,

in

patients

with

limited

cardiac

reserve

who

arecritically

dependent

on

adrenergic

stimulation,

β

blockade

canresult

in

profound

decreases

in

left

ventricular

function.√

β

blockers

are

not

useful

for

vasospastic

angina

(e.g.,

variantangina变异型心绞痛)due

to

its

β2

blockade

in

vessel.√

Patients

with

asthma

should

be

with

great

caution

due

to

itsblockade

of

β2

receptor.

Selective

β1

antagonists

such

asmetoprolol

and

bisoprolol

may

be

chosen

in

such

patients.Calcium

channel

blockers钙通道阻断药□

硝苯地平nifendipine迅速而强有力扩张血管短效硝苯地平缓释剂尼群地平nitrendipine、氨氯地平amlodipine长效维拉帕米verapamil抑制心率与心肌收缩力地尔硫卓diltiazem作用介于地平类与维拉帕米之间√

药理作用及特点：阻断钙内流所致的血管平滑肌收缩，血管扩张，增加心肌血供√

应用：适用于变异型心绞痛及稳定型心绞痛√

不良反应：过度扩血管导致的反射性心动过速、面红、头痛等，尽量使用缓释制剂√

因可致反射性心动过速，宜与β肾上腺素能受体拮抗剂合用，以减慢心率，防止心肌耗氧增加√

避免用于急性心肌梗死与不稳定心绞痛避免与硝酸酯类合用Combination

Therapy

forAngina-1Nitrates

and

β

Adrenoceptor

Antagonists.

The

concurrentuse

of

organicnitrates

and

β

antagonists

can

be

veryeffective

in

the

treatment

of

typical

exertional

angina.

Theadditive

efficacy

is

primarily

a

result

of

the

blockade

byone

drug

of

a

reflex

effect

elicited

by

the

other.

βantagonists

can

block

the

baroreceptor-mediated

reflextachycardia

and

positive

inotropic

effects

that

aresometimes

associated

with

nitrates,

whereas

nitrates,

byincreasing

venous

capacitance,

can

attenuate

the

increasein

left

ventricular

end-diastolic

volume

associated

withreceptor

blockade.

Concurrent

administration

of

nitratesalso

can

alleviate

the

increase

in

coronary

vascularresistance

associated

with

β

blockade.Aspirin

as

antiplatelet

therapy

is

mended

at

the

sametime.Comb