part 3 antihypertensive drugs. hypertension: the most common disease causing various complications

Part 3Part 3 Antihypertensive Antihypertensive

DrugsDrugs

Hypertension:Hypertension:

The most common disease causing various complicationsThe most common disease causing various complications

OverviewOverview Classification ofClassification of antihypertensive drugsantihypertensive drugs Antihypertensive drugsAntihypertensive drugs Rational application ofRational application of antihypertensive drugsantihypertensive drugs

Antihypertensive DrugsAntihypertensive Drugs

A.A. Overview Overview

HypertensionHypertension essential hypertension essential hypertension ~ ~ 90%90%

secondary hypertension secondary hypertension ~ ~ 10%10%

CriterionCriterion of hypertension: of hypertension: diastolic blood pressure diastolic blood pressure 90 mmHg 90 mmHg

systolic blood pressure systolic blood pressure 140 mmHg 140 mmHg

Major factors influencing blood pressureMajor factors influencing blood pressure

Arterial bloodArterial blood pressurepressure

Cardiac Cardiac outputoutput

Peripheral Peripheral resistanceresistance

Venous Venous tonetone

Blood Blood volumevolume

Filling Filling pressurepressure

ContractilityContractilityHeart Heart raterate

arteriolararteriolartonetone

Baroreceptors and sympathetic nervous systemBaroreceptors and sympathetic nervous system Renin-angiotention-aldosterol system (RAAS)Renin-angiotention-aldosterol system (RAAS)

A.A. Overview Overview

Regulation of blood pressure Regulation of blood pressure (neural & endocrine pathways)(neural & endocrine pathways)

Regulation of Regulation of blood pressure: blood pressure:

Targets of Targets of antihypertensive antihypertensive drugsdrugs

SympatheticSympathetic

Endocrine/body fluidEndocrine/body fluid

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

Arterial wall hypertrophy and Arterial wall hypertrophy and sclerosissclerosis

DiureticsDiuretics

Sympathetic nervous system inhibitorSympathetic nervous system inhibitors s mainly, adrenoceptor antagonistsmainly, adrenoceptor antagonists

Calcium channel blockersCalcium channel blockers

Regin-angiotensin system inhibitorsRegin-angiotensin system inhibitors

OthersOthers Central antihypertensive drugsCentral antihypertensive drugs VasodilatorsVasodilators

B.B. Classification of Antihypertensive Drugs Classification of Antihypertensive Drugs

Noradrenergic Noradrenergic nerve endingnerve ending blockersblockers

RAAS inhibitorsRAAS inhibitors

1. ACEIs1. ACEIs

2. AT2. AT11 blockers blockers

3. Renin inhibitors3. Renin inhibitors

Commonly used antihypertensive drugsCommonly used antihypertensive drugs(1) Diuretics:(1) Diuretics: HydrochlorothiazideHydrochlorothiazide

(2) Calcium antagonists:(2) Calcium antagonists: Nifedipine, amolodipine, verapamil, Nifedipine, amolodipine, verapamil, etcetc..(3) Angiotensin receptor antagonists:Ⅱ(3) Angiotensin receptor antagonists:Ⅱ Lasartan, Lasartan, etc.etc.

(4) Angiotensin-converting enzyme inhibitors:(4) Angiotensin-converting enzyme inhibitors: Captopril, enalapril, Captopril, enalapril, etcetc..

(5) (5) -Blockers:-Blockers: Propranolol, Propranolol, etcetc..

(6) (6) 11-Blockers:-Blockers: Prazosin, doxazosin, Prazosin, doxazosin, etcetc..

(7) Other sympatholytics:(7) Other sympatholytics: Clonidine, Clonidine, etcetc..

(8) Potassium channel agonists:(8) Potassium channel agonists: Minoxidil, diazoxide, Minoxidil, diazoxide, etcetc..

(9) Vasodilators:(9) Vasodilators: Sodium nitroprusside, Sodium nitroprusside, etc.etc.

DiureticsDiuretics

1. 1. Pharmacological effectsPharmacological effects

(1) Reducing plasma volume ((1) Reducing plasma volume (cardiac output cardiac output ))

(2) Reducing Na(2) Reducing Na++-Ca-Ca2+2+ exchange in vascular smooth exchange in vascular smooth

muscle cellsmuscle cells ((CaCa2+2+ii , peripheral resistance , peripheral resistance ) )

C. C. Antihypertensive Drugs Antihypertensive Drugs

NaNa++-Ca-Ca2+2+ exchange exchange , , CaCa2+2+

ii in vascular in vascular

smooth muscle cells smooth muscle cells

2. 2. Clinical usesClinical uses

(1) Hypertension(1) Hypertension

singlesingle or or combinedcombined with other drugs with other drugs

mild to moderate hypertensionmild to moderate hypertension

particularly useful in the treatment of elderly patients, particularly useful in the treatment of elderly patients, pure systolic hypertension, hypertension with heart pure systolic hypertension, hypertension with heart failurefailure

(2) Other uses:(2) Other uses: diuretic, diuretic, etc.etc.


3. 3. Adverse effectsAdverse effects

plasma levels of renin plasma levels of renin

hypokalemiahypokalemia

hyperuricemia hyperuricemia

hyperglycemiahyperglycemia

hyperlipidemiahyperlipidemia



1. 1. Pharmacological effectsPharmacological effects Relaxing vascular smooth musclesRelaxing vascular smooth muscles

2. 2. Clinical usesClinical uses Mild to severe hypertension (usually combined Mild to severe hypertension (usually combined

with with receptor blockers ) receptor blockers )


Nifedipine Nifedipine 硝苯地平硝苯地平

3.3. Adverse effects Adverse effects Peripheral edemaPeripheral edema Reflex sympathetic activationReflex sympathetic activation Renin activity Renin activity

Other calcium channel blockers:Other calcium channel blockers: amlamlodipine, odipine, etc.etc.


Renin-angiotensin system inhibitorsRenin-angiotensin system inhibitors

ACEIs: ACEIs: 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 enzymeAngiotensin converting enzyme

AngiotensinogenAngiotensinogen

Angiotensin IAngiotensin I (decapeptide) (decapeptide)

Angiotensin IIAngiotensin II ( octapepetide) ( octapepetide)

Angiotension III (hepAngiotension III (heptapeptide)tapeptide)

Renin-Angiotensin-Aldosterone system (RAAS)Renin-Angiotensin-Aldosterone system (RAAS)

ReninRenin

Angiotensinase AAngiotensinase A

Adrenal cortex Adrenal cortex

AldosteroneAldosterone

• Constricting vessels, increase peripheral resistConstricting vessels, increase peripheral resistance and returned blood volume.ance and returned blood volume.

• Increasing sympathetic tension, promoting relIncreasing sympathetic tension, promoting release of sympathetic transmitter.ease of sympathetic transmitter.

• Stimulating release of aldosteroneStimulating release of aldosterone..

• Inducing expression of Inducing expression of c-fosc-fos 、、 c-mycc-myc、、 c-jun c-jun rapidly.rapidly.

Actions of angiotensin ⅡActions of angiotensin Ⅱ


ACEIsACEIs

1. 1. Pharmacological effectsPharmacological effects Inhibiting the production of Ang IIInhibiting the production of Ang II

Inhibiting the degradation of bradykinin Inhibiting the degradation of bradykinin

Increasing ANP and scavenge free radicalsIncreasing ANP and scavenge free radicals


Implications of inhibition of RAAS Implications of inhibition of RAAS

ATAT11 blockers blockers

(-)(-) (+)(+)

ACEIsACEIsACEIsACEIs

Smooth muscle hypertrophySmooth muscle hypertrophy

((vascular remodelingvascular remodeling))


HypertensionHypertension

without reflex increase in the activity of without reflex increase in the activity of

sympathetic systemsympathetic system

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



hypotension hypotension ( first dose phenomenon )( first dose phenomenon )

renal injuryrenal injury dry coughdry cough hyperkalemiahyperkalemia angioneuroedemaangioneuroedema rashes and altered tastesrashes and altered tastesContraindications:Contraindications: renal artery stenosis, p renal artery stenosis, p

regnant and lactational womenregnant and lactational women


ATAT11 receptor antagonists receptor antagonists

(angiotensin II receptor antagonist)(angiotensin II receptor antagonist)


Losartan Losartan 氯沙坦氯沙坦

ATAT11 receptor antagonists receptor antagonists

Compared with ACEI:Compared with ACEI:

• Block actions of angiotensin II directlyBlock actions of angiotensin II directly

• Not influence bradykinin metabolismNot influence bradykinin metabolism

• Protect renal functionProtect renal function

• Used for mild to moderate hypertension Used for mild to moderate hypertension

• Less adverse effects Less adverse effects


Renin inhibitorsRenin inhibitors• enalkirenenalkiren 依那吉仑依那吉仑

• Inhibiting whole RAASInhibiting whole RAAS

• Including Including renin antibody, peptide and nonpeprenin antibody, peptide and nonpeptide renin inhibitorstide renin inhibitors


Sympathetic system inhibitorsSympathetic system inhibitors

CentrallyCentrally acting adrenergic drugs acting adrenergic drugs GanglionGanglion blockers blockers Noradrenergic nerve endingNoradrenergic nerve ending blockers blockers AdrenoreceptorAdrenoreceptor blockers blockers receptor blockersreceptor blockers

receptor blockersreceptor blockers

and and receptor blockers receptor blockers


Sympathetic system: Sympathetic system: Targets of antihypertensive drugsTargets of antihypertensive drugs

Adrenoreceptor blockersAdrenoreceptor blockers

Receptor blockersReceptor blockers

1. 1. Pharmacological effectsPharmacological effects(1) Decreasing cardiac output(1) Decreasing cardiac output

(2) Decreasing sympathetic outflow from CNS and releasing of (2) Decreasing sympathetic outflow from CNS and releasing of noradrenalin from peripheral nerve endingsnoradrenalin from peripheral nerve endings

(3) Inhibiting the release of renin from kidney (formation of an(3) Inhibiting the release of renin from kidney (formation of angiotension and secretion of aldosterone)giotension and secretion of aldosterone)

(4) Increasing production of PGI(4) Increasing production of PGI22

(5) Increasing sensitivity of baroreceptor(5) Increasing sensitivity of baroreceptor


Main actions of Main actions of ββ receptor blockers on blood pressure receptor blockers on blood pressure


(1) Hypertension:(1) Hypertension: all kinds of hypertension all kinds of hypertension

more effective in young patients than elderlymore effective in young patients than elderly

useful in treating coexisting conditions such as supruseful in treating coexisting conditions such as supraventricular tachycardia, previous myocardial infaraventricular tachycardia, previous myocardial infarction, angina pectoris, glaucoma and migraine headction, angina pectoris, glaucoma and migraine headacheache

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


3.3. Adverse effects Adverse effects

alterations in serum lipid patternsalterations in serum lipid patterns drug withdrawal reactionsdrug withdrawal reactions worsening asthma & COPDworsening asthma & COPD cardiac depressioncardiac depression


1 1 Receptor blockers Receptor blockers


Prazosin Prazosin 哌唑嗪哌唑嗪 Terazosin Terazosin 特拉唑嗪特拉唑嗪

Doxazosin Doxazosin 多沙唑嗪多沙唑嗪 Trimazosin Trimazosin 曲马唑嗪曲马唑嗪

1 1 Receptor blockers Receptor blockers

1. 1. Pharmacological effectsPharmacological effects RelaxingRelaxing arterial and venous smooth muscles arterial and venous smooth muscles DecreasingDecreasing peripheral resistance peripheral resistance

2.2. Clinical uses Clinical uses Hypertension:Hypertension: mild to moderate (single) and seve mild to moderate (single) and seve

re hypertension (combined with diuretics and re hypertension (combined with diuretics and blockers)blockers)

minimal changes in cardiac output, renal blood flow reminimal changes in cardiac output, renal blood flow renin release and glomerular filtration regulation of bloonin release and glomerular filtration regulation of blood lipidd lipid


3.3. Adverse effects Adverse effects

first dose phenomenonfirst dose phenomenon (postural hypotension)(postural hypotension)

water and sodium retentionwater and sodium retention


and and 1 1 Receptor blockersReceptor blockers


Labetalol Labetalol 拉贝洛尔拉贝洛尔

Carvedilol Carvedilol 卡维地洛卡维地洛

Amosulalol Amosulalol 氨磺洛尔氨磺洛尔

and and 1 1 Receptor blockersReceptor blockers

Mild decrease of blood pressureMild decrease of blood pressure Minimal changes in cardiac output and heart rateMinimal changes in cardiac output and heart rate Used for all kinds of hypertension, including Used for all kinds of hypertension, including

hypertensive emergencyhypertensive emergency Less adverse effectsLess adverse effects


Centrally acting drugsCentrally acting drugs


Clonidine Clonidine 可乐定可乐定

Methyldopa Methyldopa 甲基多巴甲基多巴

Clonidine MethyldopaClonidine Methyldopa

Action site of the centrally-acting drugsAction site of the centrally-acting drugs

1. 1. Pharmacological effectsPharmacological effects Diminishing central adrenergic outflowDiminishing central adrenergic outflow

Activating Activating 2 2 and Iand I11 receptor in medulla receptor in medulla

2.2. Clinical uses Clinical uses Hypertension:Hypertension: mild to moderate hypertension that mild to moderate hypertension that

has not has not respondedresponded adequately to treatment with di adequately to treatment with diuretics alone.uretics alone.

minimal changes in renal blood flow and glomerular filtraminimal changes in renal blood flow and glomerular filtra

tion inhibit gastrointestinal secretion and mobilitytion inhibit gastrointestinal secretion and mobility



central and atropine-like side effectscentral and atropine-like side effects

long-term uses: long-term uses:

water and sodium retention water and sodium retention

rebound phenomenonrebound phenomenon


II11 receptor agonists receptor agonists

rilmenidine rilmenidine （利美尼定）（利美尼定）

moxonidine moxonidine （莫索尼定）（莫索尼定）


Ganglionic blockersGanglionic blockers

Trimetaphan Trimetaphan (( 米噻芬米噻芬 ))

MecamylamineMecamylamine （美卡拉明）（美卡拉明）

Shor-actingShor-acting

ToleranceTolerance

For controlling hypotensionFor controlling hypotension


Noradrenergic nerve ending blockersNoradrenergic nerve ending blockers

ReserpineReserpine （利舍平，利血平（利舍平，利血平 ))

Guanethidine Guanethidine （胍乙啶）（胍乙啶）

Decreasing NE storage in noradrenergic nerve endingsDecreasing NE storage in noradrenergic nerve endings

Slow and lasting effectsSlow and lasting effects

Central depressionCentral depression



Hydralazine Hydralazine

肼曲嗪肼曲嗪

Dihydralazine Dihydralazine

双肼曲嗪双肼曲嗪

Sodium NitroprussideSodium Nitroprusside

硝普钠硝普钠

VasodilatorsVasodilators


HydralazineHydralazine （肼屈嗪）（肼屈嗪）

Dilating arteries and arteriolesDilating arteries and arterioles Decreasing peripheral resistanceDecreasing peripheral resistance Reflexly elevating heart rate, cardiac output and Reflexly elevating heart rate, cardiac output and

renin release.renin release. Combined with Combined with blockers and diuretics. blockers and diuretics. Adverse effects due to vasodilation and lupus-like Adverse effects due to vasodilation and lupus-like

syndrome can occur.syndrome can occur.


Nitroprusside sodiumNitroprusside sodium （硝普钠）（硝普钠）

Dilating small arteries and veins Dilating small arteries and veins Used for treatment of emergency hypertension, Used for treatment of emergency hypertension,

hypertension with CHF, controlled hypotension hypertension with CHF, controlled hypotension and obstinate CHF and obstinate CHF

Adverse effects due to hypotension in excess anAdverse effects due to hypotension in excess an

d sulfocyanate d sulfocyanate (( 硫氰酸盐 )) poisoning. poisoning.


Potassium channel openersPotassium channel openers

IncludingIncluding minoxidil minoxidil (( 米诺地尔米诺地尔 )), nicorandil, diazoxi, nicorandil, diazoxide de (( 二氮嗪二氮嗪 )), , etcetc..

Dilating arteries (CaDilating arteries (Ca2+2+ influx influx )) Reflexly elevating heart rate, cardiac output and Reflexly elevating heart rate, cardiac output and

renin releaserenin release Used for treatment of obstinate and severe hyperUsed for treatment of obstinate and severe hyper

tensiontension Adverse effects include sodium retention, palpitaAdverse effects include sodium retention, palpita

tion, tion, etcetc..


D. D. Rational application of Rational application of Antihypertensive DrugsAntihypertensive Drugs

DiureticsDiuretics


Regin-angiotensin system inhibitorsRegin-angiotensin system inhibitors

Sympathetic inhibitorsSympathetic inhibitors


1. 1. Prescribe according to the severity degree of Prescribe according to the severity degree of hypertensionhypertension

(1) Mild:(1) Mild: diuretics, diuretics, blockers, blockers, ACEI, calcium channel ACEI, calcium channel blockers (CCB), blockers (CCB), 11 blockers, AT blockers, AT11 blockers, blockers, single single

drug.drug.

(2) Moderate:(2) Moderate: combined with combined with two above drugstwo above drugs

(3) Severe:(3) Severe: adding centrally acting drugs or adding centrally acting drugs or vasodilators to the vasodilators to the two combined drugstwo combined drugs


2.2. Prescribe according to complications Prescribe according to complications

CHF and/or CHF and/or

COPDCOPDDiuretics, ACEI, CCDiuretics, ACEI, CCB, prazosinB, prazosin

BlockersBlockers

Renal failureRenal failureACEI, CCB ACEI, CCB methyldopamethyldopa

TachycardiaTachycardia BlockersBlockers

GI ulcerGI ulcer ClonidineClonidine ReserpineReserpine

Diabetes and Diabetes and goutgout

ACEI, prazosin, CCACEI, prazosin, CCBB

Thiazides Thiazides


indicatedindicated contraindicatedcontraindicated

hypertensive emergency:hypertensive emergency: vasodilators (nitroprussvasodilators (nitroprusside sodium, diazoxide), loop diuretics (furoseide sodium, diazoxide), loop diuretics (furosemide)mide)

elderly patients:elderly patients: avoiding drugs that could induce postural hyavoiding drugs that could induce postural hy

potension (potension (11 blocker, larger dose of diuretic blocker, larger dose of diureticss) and influence the cognizant ability () and influence the cognizant ability (clonidiclonidinene))

Cardiac ischemia:Cardiac ischemia: avoiding vasodilatorsavoiding vasodilators


3.3. Combination of drugs Combination of drugs

4.4. Avoid blood pressure to decrease too Avoid blood pressure to decrease too rapidly and excessivelyrapidly and excessively

5.5. Individual therapy Individual therapy


part 3 antihypertensive drugs. hypertension: the most common disease causing various complications

Documents

mmhg slide

overview slide

sclerosis slide

elasticity slide

drugs mild

drugs single

secondary hypertension

hypertension single