Chapter 6

Chapter Chapter 6.6.Drugs acting on Drugs acting on

cardiovascular cardiovascular system(CVS)system(CVS)

Part 1. Part 1. Drugs Acting Ion Drugs Acting Ion Channels in CVSChannels in CVS(( 作用心血管离作用心血管离子通道的药物子通道的药物 ))

Part 2. Part 2. Antiarrhythmic DrugsAntiarrhythmic Drugs(( 抗心抗心律失常药律失常药 ))Part 3.Part 3. Drugs for Treatment of Drugs for Treatment of Chro-nic Cardiac Chro-nic Cardiac DysfunctionDysfunctionPart 4. Antianginal DrugsPart 4. Antianginal Drugs(( 抗心绞痛抗心绞痛

药药 ))Part 5. Antiatheroscleotic drugsPart 5. Antiatheroscleotic drugs

(( 抗动脉粥样硬化药抗动脉粥样硬化药 ))Part 6. Part 6. Antihypertensive DrugsAntihypertensive Drugs

(( 抗高血压药抗高血压药 ))Part 6. Part 6. Antihypertensive DrugsAntihypertensive Drugs

(( 抗高血压药抗高血压药 ))

Part 6.Part 6. Antihypertensive Antihypertensive Drugs (Drugs ( 抗高血压药抗高血压药 ))

ⅠⅠ. . OverviewOverviewⅡⅡ.. Antihypertensive drugsAntihypertensive drugs

most in usemost in useⅢⅢ. . Other Other antihypertensive antihypertensive

drugsdrugsⅣⅣ. . Rational application of Rational application of

anti-hypertensive drugsanti-hypertensive drugs

ContentsContents

ⅠⅠ.. OverviewOverview

高血压是冠心病、卒中、外周血管病、高血压是冠心病、卒中、外周血管病、慢性心力衰竭和慢性肾功能衰竭的主要危慢性心力衰竭和慢性肾功能衰竭的主要危险因素险因素 ..

我国饮食结构从我国饮食结构从 2020 世纪世纪 50~7050~70 年代的以年代的以粮食和蔬菜为主粮食和蔬菜为主 , , 油、鸡蛋、鱼、肉等的定量油、鸡蛋、鱼、肉等的定量供给供给 , , 转变成现在的高脂肪、高蛋白、高热量转变成现在的高脂肪、高蛋白、高热量的三高饮食的三高饮食 , , 人们的运动减少人们的运动减少 , , 超重和肥胖的超重和肥胖的比例显著增加比例显著增加 . . 存在与生活方式有关的心血管存在与生活方式有关的心血管危险因素的人群急剧增加危险因素的人群急剧增加 , , 这些危险因素直接这些危险因素直接导致了上述我国心脑血管疾病的严峻形势导致了上述我国心脑血管疾病的严峻形势 . . 高血压的患病率高血压的患病率 :: 2020 世纪世纪 7070 年代年代 , 7.73%;, 7.73%; 19911991 年调查为年调查为 , 11.88%;, 11.88%; 目前比目前比 19911991 年又上升年又上升 31%, 31%, 达达 15.56%.15.56%.


HypertensionHypertension can be divided can be divided into:into:

Essential hypertension: Essential hypertension: 90~95%90~95%

Secondary hypertension: Secondary hypertension: 5~10%5~10%

Normal blood pressure(BP), Normal blood pressure(BP), 2004:2004:

Diastolic BP ≤ 80 mmHgDiastolic BP ≤ 80 mmHg Systolic BP ≤ 120 mmHgSystolic BP ≤ 120 mmHg

CriterionCriterion of hypertension:of hypertension: Diastolic BP ≥ 90 mmHgDiastolic BP ≥ 90 mmHg Systolic BP ≥ 140 mmHgSystolic BP ≥ 140 mmHg


20042004 《中国高血压防治指南》《中国高血压防治指南》与与 19991999 年的指南相比年的指南相比 , , 一个重要的区别是一个重要的区别是将正常血压确定为＜将正常血压确定为＜ 120/80120/80mmHg(mmHg(19991999 年年指南为指南为 130/85130/85mmHgmmHg). ). 这种改变的依据来这种改变的依据来自国内外心血管流行病学调查资料自国内外心血管流行病学调查资料 .. 国内的资料显示国内的资料显示 , , 当血压＞当血压＞115/75115/75mmHgmmHg 时时 , , 随着血压增加随着血压增加 , , 心血管危心血管危险显著增加险显著增加 . . 每升高每升高 20/1020/10mmHg, mmHg, 因心血因心血管疾病死亡的危险都将增加管疾病死亡的危险都将增加 11 倍倍 . . 而降低血压而降低血压可以降低与高血压相关的心血管疾病的危险可以降低与高血压相关的心血管疾病的危险 . .


将正常血压定在将正常血压定在 120/80120/80mmHgmmHg 这个水平这个水平 ,, 并不是要求降压治疗一定要达到这个水平并不是要求降压治疗一定要达到这个水平 , , 指南确定的正常血压水平与降压治疗的目标目指南确定的正常血压水平与降压治疗的目标目前还有一定距离前还有一定距离 .. 美国高血压预防监测、评估和治疗委员会美国高血压预防监测、评估和治疗委员会第第 77 次报告次报告 ((JNC7)JNC7) 提出提出 , , 年龄＞年龄＞ 1818 岁普通岁普通人群的血压控制目标是＜人群的血压控制目标是＜ 140/90140/90mmHg, mmHg, 但但糖尿病和高危病人应＜糖尿病和高危病人应＜ 130/80130/80mmHg, mmHg, 肾功肾功能衰竭和蛋白尿病人更应＜能衰竭和蛋白尿病人更应＜ 125/75 125/75 mmHg. mmHg.


Major factors influencing blood Major factors influencing blood pressure:pressure:

Arterial Arterial bloodblood

pressurepressure

CardiaCardiac c

outputoutput

PeripherPeripheral al

resistancresistancee

Venous Venous tonetone

Blood Blood volumevolume

Filling Filling pressurpressur

ee

ContractilitContractilit

yy

Heart Heart raterate

arteriolararteriolartonetone

Baroreceptors and sympathetic nervous Baroreceptors and sympathetic nervous system system

Renin-angiotention-aldosterol system Renin-angiotention-aldosterol system (RAAS)(RAAS)


Peripheral resistance Peripheral resistance and vascular tone and and vascular tone and

elasticityelasticity

Arterial wall Arterial wall hypertrophy and hypertrophy and sclerosissclerosis

Classification of Antihypertensive Classification of Antihypertensive DrugsDrugs

(1)Diuretics(1)Diuretics(2)Adrenoceptor blockers(2)Adrenoceptor blockers(3)Calcium channel blockers(3)Calcium channel blockers(4)Regin-angiotensin (4)Regin-angiotensin

system inhibitorssystem inhibitors

Classification of Classification of DrugsDrugs

1. 1. Drugs most in use:Drugs most in use:

2. 2. Other drugs:Other drugs:(1)Centrally-acting drugs (1)Centrally-acting drugs (2)Ganglion blockers;(2)Ganglion blockers;(3)Noradrenergic nerve ending (3)Noradrenergic nerve ending

blockers;blockers;(4)Vasodilators(4)Vasodilators

ⅡⅡ. . AntihypertensiAntihypertensive drugsve drugs most most

in usein use

DiureticsDiuretics

1. Pharmacological effects:1. Pharmacological effects: (1)Reducing plasma volume (1)Reducing plasma volume

cardiac output cardiac output ;; (2)Owing to excretion of Na(2)Owing to excretion of Na+ + , ,

Na Na++-Ca-Ca2+2+ exchange exchange in in vascular smooth muscle cells, vascular smooth muscle cells, CaCa2+2+

ii , , peripheral peripheral resistance resistance ..

ⅡⅡ. . Drugs most in Drugs most in use(1)use(1)

Mechanism Mechanism

of of diuretics:diuretics:

①①blood blood vol-ume vol-ume ;;

②②NaNa++-Ca-Ca2+2+ exchangeexchange, , CaCa2+2+

ii in va-in va-scular scular smo-oth smo-oth muscle muscle cells cells

2. 2. Clinical uses:Clinical uses:(1)Hypertension:(1)Hypertension: singlesingle or or combinedcombined with other with other drugs;drugs; mild to moderate hypertensionmild to moderate hypertension particularly useful in the particularly useful in the treatment of elderly patients, pure treatment of elderly patients, pure systolic hyperten-sion, hypertension systolic hyperten-sion, hypertension with heart failure.with heart failure.

(2)Other uses:(2)Other uses:

diuresis, anti-CHF, diuresis, anti-CHF, etc.etc.

DiureticDiureticss

3. 3. Adverse effects:Adverse effects: plasma levels of renin plasma levels of renin hypokalemiahypokalemia

hyperuricemia hyperuricemia

hyperglycemiahyperglycemia

hyperlipidemiahyperlipidemia

DiureticDiureticss

DiureticDiureticss

Adrenoreceptor blockersAdrenoreceptor blockers Receptor blockers:Receptor blockers: propranolol propranolol1. Pharmacological effects:1. Pharmacological effects:(1)Decreasing cardiac output;(1)Decreasing cardiac output;(2)Inhibiting the release of renin (2)Inhibiting the release of renin

from kidney(to inhibit formation from kidney(to inhibit formation of angio-tension and secretion of of angio-tension and secretion of aldosterone); aldosterone);

(3)Decreasing sympathetic outflow (3)Decreasing sympathetic outflow from CNS;from CNS;

(4)Decreasing releasing of (4)Decreasing releasing of noradrenalin (NA) from peripheral noradrenalin (NA) from peripheral nerve endings;nerve endings;

(5)Increasing production of PGs.(5)Increasing production of PGs.


Main actions of Main actions of ββ receptor receptor antagonists on blood antagonists on blood

pressurepressure

3. 3. Clinical uses:Clinical uses: (1)Hypertension:(1)Hypertension: All kinds of hypertension,All kinds of hypertension, more effective in young patients more effective in young patients than eld-erly.than eld-erly. Useful in treating coexisting Useful in treating coexisting con-ditions, such as con-ditions, such as supraventricular tachycardia, supraventricular tachycardia, previous myocardial infarction, previous myocardial infarction, angina pectoris, glauco-ma and angina pectoris, glauco-ma and migraine headache.migraine headache.

Receptor Receptor blockersblockers

(2)Other uses:(2)Other uses: angina pectoris; angina pectoris;

arrhythmias.arrhythmias.

3. 3. Adverse effects:Adverse effects: cardiac depressioncardiac depression drug withdrawal;drug withdrawal; inducing attack of asthma, inducing attack of asthma,

etc.etc.



1 1 Receptor Receptor blockersblockers

Prazosin(Prazosin( 哌唑哌唑嗪嗪 ))

TerazosinTerazosin(( 特拉唑特拉唑嗪嗪 ))

Doxazosin(Doxazosin( 多沙唑多沙唑嗪嗪 ))

Trimazosin(Trimazosin( 曲马唑曲马唑嗪嗪 ))


Prazosin(Prazosin( 哌唑嗪哌唑嗪 ))

1. Pharmacological effects:1. Pharmacological effects:(1)Blocking (1)Blocking 11--receptor of bloodreceptor of blood

smooth musclessmooth muscles and relaxing and relaxing small artery and vein;small artery and vein;

(2)Decreasing peripheral (2)Decreasing peripheral resistance.resistance.


2.2. Clinical uses:Clinical uses: Hypertension:Hypertension: mild to moderate(single);mild to moderate(single); severe hypertension(combined severe hypertension(combined with diuretics and with diuretics and blockers). blockers). minimal changes in renal blood minimal changes in renal blood flow, glomerular filtration, and flow, glomerular filtration, and renin release.renin release.

3.3. Adverse effects:Adverse effects: first dose phenomenonfirst dose phenomenon(postural (postural hypo-tension);hypo-tension); water and sodium retention.water and sodium retention.

1 1 Receptor Receptor blockersblockersPrazosiPrazosi

nn


and and 1 1 Receptor blockersReceptor blockers

Labetalol(Labetalol( 拉贝洛拉贝洛尔尔 ))

Carvedilol(Carvedilol( 卡维地卡维地洛洛 ))

Amosulalol(Amosulalol( 氨磺洛氨磺洛尔尔 ))


Characteristics of Characteristics of and and 1 1

Receptor blockers:Receptor blockers:

(1)(1) blood pressure moderately; blood pressure moderately;(2)Minimal changes in cardiac (2)Minimal changes in cardiac

output and heart rate;output and heart rate;(3)Used for all kinds of (3)Used for all kinds of

hypertension, including hypertension, including hypertensive emergency;hypertensive emergency;

(4)Less adverse effects.(4)Less adverse effects.

and and 1 1 Receptor Receptor blockersblockers

Let’s take a rest !Let’s take a rest !

Calcium channel blockersCalcium channel blockers

Nifedipine(Nifedipine( 硝苯地平硝苯地平 ))


1. Pharmacological effects:1. Pharmacological effects: Relaxing vascular smooth Relaxing vascular smooth muscles.muscles.

2. Clinical uses:2. Clinical uses: Mild to severe hypertension.Mild to severe hypertension.

3. 3. Adverse effects:Adverse effects: Peripheral edema;Peripheral edema; Reflex sympathetic Reflex sympathetic

activation;activation; Renin activity Renin activity . .

Other calcium channel Other calcium channel blockers:blockers:

Amlodipine(Amlodipine( 氨氯地平氨氯地平 ), ), etc.etc.

Calcium channel Calcium channel blockersblockers

Calcium channel Calcium channel blockersblockers

Renin-angiotensin system Renin-angiotensin system inhibitorsinhibitors

ACEI: ACEI: captopril (captopril ( 卡托普利卡托普利 )), , enalapril (enalapril ( 依那普利依那普利 )) ATAT11 receptor antagonists: receptor antagonists: losartan (losartan ( 氯沙坦氯沙坦 )) Renin inhibitors: Renin inhibitors: enalkiren (enalkiren ( 依那吉仑依那吉仑 ))


Renin inhibitors

angiotensin converting angiotensin converting enzyme inhibitorsenzyme inhibitors(ACEI)(ACEI)


1. Pharmacological effects:1. Pharmacological effects: (1)Inhibiting(1)Inhibiting thethe productionproduction ofof

AngⅡ;AngⅡ; (2)Inhibiting the degradation of (2)Inhibiting the degradation of

bradykinin, to vasodilatation; bradykinin, to vasodilatation; (3)Decreasing the activity of (3)Decreasing the activity of

sympa-thetic system;sympa-thetic system; (4)Inhibiting ventricular (4)Inhibiting ventricular

remodeling;remodeling; (5)decreasing aldosterone.(5)decreasing aldosterone.

ACEIACEI

2. 2. Clinical uses:Clinical uses: HypertensionHypertension

not reflexly increasing the not reflexly increasing the activity of sympathetic system;activity of sympathetic system;

effective in the patients with effective in the patients with CHF, diabetes and ischemic CHF, diabetes and ischemic heart disease also.heart disease also.

ACEIACEI

3. 3. Adverse effects:Adverse effects: hypotensionhypotension(first dose (first dose phenomenon)phenomenon)

renal injuryrenal injury dry coughdry cough hyperkalemiahyperkalemia angioneuroedemaangioneuroedema rashes and altered tastesrashes and altered tastesContraindications:Contraindications: renal artery stenosis, renal artery stenosis, pregnant and lactational pregnant and lactational women.women.

ACEIACEI

ATAT11 antagonists antagonists

Losartan(Losartan( 氯沙坦氯沙坦 ))


Compared with ACEI:Compared with ACEI:(1)Block actions of angiotensin Ⅱ (1)Block actions of angiotensin Ⅱ

di-rectly;di-rectly;(2)Not influence bradykinin (2)Not influence bradykinin

metabo-lism;metabo-lism;(3)Protect renal funtion;(3)Protect renal funtion;(4)Used for mild to moderate (4)Used for mild to moderate

hyper-tension; hyper-tension; (5)Less adverse effects. (5)Less adverse effects.

ATAT11 antagonistsantagonists

Renin inhibitorsRenin inhibitors

Enakiren(Enakiren( 依那吉仑依那吉仑 ))Remikiren(Remikiren( 瑞米吉仑瑞米吉仑 ))

peptide or nonpeptide peptide or nonpeptide renin inhibitors.renin inhibitors.

They inhibit whole RAASThey inhibit whole RAAS

Other drugs:Other drugs: renin antibody. renin antibody.


ACEI & ACEI & ATAT11antagonistsantagonists

ⅢⅢ.. Other Other anti-anti-hypertensive hypertensive

drugsdrugs

Centrally-acting drugs:Centrally-acting drugs:

Clonidine(Clonidine( 可乐定可乐定 ))

ⅢⅢ. . Other Other Drugs(1)Drugs(1)

1. 1. Pharmacological effects:Pharmacological effects: Diminishing central adrenergic Diminishing central adrenergic outflow;outflow; Activating Activating 2 2 and Iand I11 receptor in receptor in medulla.medulla.

2.2. Clinical uses:Clinical uses: Hypertension:Hypertension: mild to moderate mild to moderate hyper-tension that has not hyper-tension that has not responded adequa-tely to treatment responded adequa-tely to treatment with diuretics alone.with diuretics alone. minimal changes in renal blood minimal changes in renal blood flow and glomerular filtration inhibit flow and glomerular filtration inhibit gastro-intestinal secretion and gastro-intestinal secretion and mobility.mobility.

Centrally-acting Centrally-acting drugsdrugsClonidinClonidin

ee

3. 3. Adverse effects:Adverse effects:(1)Central and atropine-like side (1)Central and atropine-like side

effects;effects;(2)long-term uses: (2)long-term uses: water and sodium retention; water and sodium retention; rebound phenomenon.rebound phenomenon.

Centrally-acting Centrally-acting drugsdrugsClonidinClonidin

ee

Ganglionic blockers:Ganglionic blockers:

Trimetaphan(Trimetaphan( 米噻芬米噻芬 )) Mecamylamine(Mecamylamine( 美卡拉明美卡拉明 )) Short-acting;Short-acting; Tolerance;Tolerance; For controlling hypotension.For controlling hypotension.


Noradrenergic nerveNoradrenergic nerve ending blockersending blockers

Reserpine(Reserpine( 利舍平利舍平 , , 利血平利血平 )) Guanethidine(Guanethidine( 胍乙啶胍乙啶 ))(1)Decresing NA storage in (1)Decresing NA storage in

noradre-nergic nerve endings;noradre-nergic nerve endings;(2)Slow and lasting effects;(2)Slow and lasting effects;(3)Central depression.(3)Central depression.


Hydralazine Hydralazine ((肼屈嗪肼屈嗪 ))

Dihydralazine Dihydralazine ((双肼屈嗪双肼屈嗪 ))

Sodium Sodium Nitroprusside Nitroprusside

(( 硝普钠硝普钠 ))

VasodilatorsVasodilators(Peripheral vasodilators)(Peripheral vasodilators)


Adverse effects:Adverse effects: due to vasodilation;due to vasodilation; and lupus-like syndrome.and lupus-like syndrome.

Hydralazine(Hydralazine( 肼屈嗪肼屈嗪 ))(1)Dilating arteries and arterioles;(1)Dilating arteries and arterioles;(2)Decreasing peripheral resistance;(2)Decreasing peripheral resistance;(3)Reflexly elevating heart rate, (3)Reflexly elevating heart rate,

cardiac output and renin release.cardiac output and renin release. Combined with Combined with blockers blockers and and

diuretics.diuretics.


VasodilatoVasodilatorsrs

Nitroprusside sodium(Nitroprusside sodium( 硝普钠硝普钠 )) Dilating small arteries and veins. Dilating small arteries and veins. Clinical Uses:Clinical Uses: (1)emergency hypertension; (1)emergency hypertension; (2)hypertension with CHF and (2)hypertension with CHF and

obstinate CHF;obstinate CHF; (3)controlled blood pressure in (3)controlled blood pressure in

surgical operation. surgical operation. Adverse effects:Adverse effects: due to hypotension in excess;due to hypotension in excess; and sulfocyanate(and sulfocyanate( 硫氰化物硫氰化物 ) ) poisoning. poisoning.


VasodilatoVasodilatorsrs

Potassium channel openersPotassium channel openers Including: Including: minoxidil(minoxidil( 米诺地尔米诺地尔 ),),

nicorandil(nicorandil( 尼可地尔尼可地尔 )), , diazoxide (diazoxide ( 二氮嗪二氮嗪 ), ), etcetc..

(1)Dilating arteries (Ca(1)Dilating arteries (Ca2+2+ influx influx );); (2)Reflexly elevating heart rate, (2)Reflexly elevating heart rate,

cardiac output and renin release.cardiac output and renin release. Used for treatment of obstinateUsed for treatment of obstinate(( 顽固性顽固性 ) ) and severe hypertensionand severe hypertension

Adverse effects:Adverse effects: include sodium retention, include sodium retention, palpitation, palpitation, etcetc..


ⅣⅣ. . Rational application Rational application of antihypertensive of antihypertensive

drugsdrugs

1. 1. Prescription according to the Prescription according to the degree of hypertension:degree of hypertension:

ⅣⅣ. . Rational Rational application of application of

antihypertensive antihypertensive drugsdrugs

(1)Mild:(1)Mild: single drug:single drug: diuretics, diuretics, blockers, blockers, ACEI, calcium channel blockers, ACEI, calcium channel blockers, 11

blockers,blockers, or or AT AT11 blockers.blockers. (2)Moderate:(2)Moderate: combined withcombined with two above drugs.two above drugs. (3)Severe:(3)Severe: adding adding centrally acting drugscentrally acting drugs or or vaso-dilatorsvaso-dilators to the to the two combined two combined drugs.drugs.

2. 2. Prescription according to Prescription according to compli-cations:compli-cations:

CHF and/or CHF and/or COPD, COPD, AsthmaAsthma

Diuretics, Diuretics, ACEI,ACEI, PrazosinPrazosin

BlockersBlockers

Renal failureRenal failure ACEI,ACEI, MethyldopaMethyldopa

TachycardiaTachycardia BlockersBlockers

GI ulcerGI ulcer ClonidineClonidine ReserpineReserpineDiabetes Diabetes and gout(and gout( 痛痛风风 ))

ACEI,ACEI, prazosinprazosin ThiazidesThiazides

indicateindicatedd

contraindicatecontraindicatedd



(1)Hypertensive emergency:(1)Hypertensive emergency: vasodilatorsvasodilators(nitroprusside (nitroprusside sodium, diazoxide), labetalol, sodium, diazoxide), labetalol, loop diuretics.loop diuretics.(2)Elderly patients:(2)Elderly patients: avoiding drugs that could avoiding drugs that could induce postural hypotension(induce postural hypotension(eg.eg. 11blockers)blockers) and influence the and influence the cognizant ability.cognizant ability. (clonidine, (clonidine, methyldopa). methyldopa). (3)Cardiac ischemia:(3)Cardiac ischemia: avoiding (peripheral) avoiding (peripheral) vasodilators.vasodilators.



3. 3. Combination of drugs; Combination of drugs;

4. Avoid blood pressure to 4. Avoid blood pressure to decrease too rapidly and decrease too rapidly and excessively;excessively;

5. Individual therapy.5. Individual therapy.



The class is over The class is over !!

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Chapter 6