antihypertensive drugs

Antihypertensive Drugs

Pharmacology for cardiovascular system

张翔南[email protected]

•八年制课程

Contents:Overview

Classification of antihypertensive drugs

Antihypertensive drugs

Clinical pharmacology of

antihypertensive drugs

1. Overview

0

10

20

30

40

50

60

<120 120-139

140-159

160-179

180+0

10

20

30

40

50

60

<75 75-84

85-94

95-104

105+

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Based on 30 year follow-up of Framingham Heart Study subjects free of coronary heart disease (CHD) at baseline

Systolic blood pressure (mmHg)

Blood Pressure and Risk for Blood Pressure and Risk for Coronary Heart Disease in MenCoronary Heart Disease in Men

Diastolic blood pressure (mmHg)

Age 65-94Age 65-94

Age 35-64Age 35-64

Age 65-94Age 65-94

Age 35-64Age 35-64

Framingham Heart Study, 30-year Follow-up. NHLBI, 1987.

High Risk Factors of Hypertension:

Stressful life-style

High dietary intake of sodium

Obesity and hyperlipidemia

Smoking

Hereditary factors

Etiology of Hypertension•Secondary hypertension(10~15%)•Essential hypertension(85~90%)

其它危险因素和病史血压

I 级 II 级 III 级

Ⅰ 无其它危险因素低危中危高危

Ⅱ1~2 个危险因素中危中危很高危

≥Ⅲ 3 个危险因素高危高危很高危

Ⅳ 靶器官损害或糖尿病并存的临床情况很高危很高危很高危

按危险分层，量化地估计预后

MI or CHF50%

Stroke33%

Kidney Failure

15%

Other2%

MI or CHFStrokeKidney FailureOther

The end organ damage of hypertension: Kidney: renal failure

Heart: coronary disease, cardiac failure

Brain: stroke

The goal of treatment: Lower the blood pressure

Protect the target organ

Reduce the morbidity and mortality rates

Best therapy and minimal risk

1. Overview

1. OverviewMajor factors influencing blood pressure

Arterial blood pressure

Cardiac output

Peripheral resistance

Venous tone

Blood volumeFilling

pressureContractilityHeart

rate

arteriolarvolume

Baroreceptors and sympathetic nervous system RAAS

2. Classifications of hypertensive Drugs

Diuretics

Calcium channel blockers

Renin-angiotensin system inhibitors

ACEIs

ARBs

Renin inhibitors

Sympathetic inhibitors

Centrally acting adrenergic drugs

Ganglion blockers

Noradrenergic nerve ending blockers

Adrenoreceptor blockers

receptor blockers

receptor blockers

and receptor blockers

Vasodilators

3. Antihypertensive Drugs

3.1 Diuretics

A Actions

Reduce plasma volume(cardiac output )

Reduce Na+-Ca2+ exchange in vascular

smooth muscle cell (peripheral resistance )

NaHCO3 NaCl

H2O

Na+ K+ Cl-

Na+ Cl-

K+

高效能中效能低效能

3.1 Diuretics

B Therapeutic uses:

Hypertension

- Single drug or combined with others

- Particularly useful in the treatment of elderly patients, pure systolic hypertension, hypertension with heart failure


DiureticsDiuretics


3.1 Diuretics

C Adverse effects:

plasma level of renin

hypokalemia ( 低钾血症 )

hyperuricemia ( 高尿酸血症 )

hyperglycemia ( 高血糖 )

hyperlipidemia ( 高脂血症 )


3.2 Calcium channel blockers (CCBs)

Nifedipine 硝苯地平A Actions

Relaxs vascular smooth muscle

B Therapeutic uses:

Mild to severe hypertension (usually combined with blockers )


nifedipine

C Adverse effects Peripheral edema

Reflex sympathetic activation

Renin activity

Other calcium channel blockers:

Verapamil

Diltiazem

Nimodipine

Amlodipine

Felodipine


Generations of calcium channel blockers

①First generation: verapamil( 维拉帕米 ), nifedipine( 硝苯地平 ), diltiazem( 地尔硫卓 ). ②Second generation: 对血管选择性高 . nimoldipine( 尼莫地平 ), felodipine( 非洛地平 ). ③Third generation: 同上 , 并且 t½ 长 . pranidipine( 普拉地平 ), amlodipine( 氨氯地平 ).

粉防己碱


3.3 Renin- angiotensin system inhibitors

ACEIs

ARBs

Renin inhibitors

AT1

Angiotensin converting enzyme, ACE

心衰心肌梗塞

GFRProteinuria

Aldosterone releaseGlomerular sclerosis

AngII 在器官损害中作用

Atherosclerosis*Vasoconstriction

Vascular hypertrophyEndothelial dysfunction

LV hypertrophyFibrosis

RemodellingApoptosis

中风

DEATH

*Preclinical dataLV = left ventricular; MI = myocardial

infarction; GFR = glomerular filtration rate

高血压

肾衰

AngII AT1 receptor

• Constricts vessels, increases peripheral resistance and returned blood volume.

• Increases sympathetic tension, promotes release of sympathetic transmitter.

• Stimulates release of aldosterone.

• Induces expression of c-fos 、 c-myc 、 c-jun rapidly.

Actions of angiotensin II

Angiotensin converting Angiotensin converting enzyme inhibitorsenzyme inhibitors((ACEIsACEIs))


3.3 Renin- angiotensin system inhibitors

ACEIs

A Actions

Inhibit the production of Ang II (dilate vessels, decrease sympathetic activity, inhibit release of aldosterone, anti-hypertrophy)

Inhibit the degradation of bradykinin

Angiotensin II

Angiotensin I

ACECirculation and

local tissues

ACEIACE

Circulation and local tissues

(—)B 2 receptor

PGI2 NO

ACEI(—)

Brandykinin

Inactive peptide

VasodilationAnti-proliferation, anti-hypertrophy

Actions of ACEIs


ACEIsB Therapeutic uses

Antihypertension

- without reflexly increasing the activity of sympathetic system

- effective in the treatment of CHF, diabetes and ischemic heart disease.


ACEIs

C Adverse effects

Hypotension ( first dose phenomenon )

Renal injury (renal artery sclerosis )

Dry cough and angioneuroedema (bradykinin

accumulation)

Hyperkalemia (aldosterone inhibition)

Rashes and altered taste

Fetotoxicity


ACEIs

D Contraindications

Renal artery stenosis

Pregnant and lactation women


ARBs

Compared with ACEIs:

• Block actions of angiotensin II directly

• No influence on bradykinin metabolism

• Protect renal function

• Used for mild to moderate hypertension

• Less adverse effects


Renin inhibitors

• Inhibit whole RAAS

• Include renin antibody, peptide and nonpeptide renin inhibitors (eg. remikiren)


3.4 Sympathetic system inhibitors

3.4.1 Adrenoreceptor blockers

receptor blockers

A ActionsDecrease cardiac output

Inhibit the release of renin from kidney (formation of angiotension and secretion of aldosterone )


receptor blockers

A ActionsDecrease sympathetic outflow from CNS and release of noradrenalin from peripheral nerve endings

Increase production of PGs

Increase sensitivity of baroreceptor


receptor blockers

B Therapeutic usesHypertension: all kinds of hypertension

- more effective in young patients than elderly

- useful in treating coexisting conditions such as supraventricular tachycardia, previous

myocardial infarction, angina pectoris, glaucoma and migraine headache




1 receptor blockers

A ActionsRelax arterial and venous smooth muscle, decrease peripheral resistance

Alterations in serum lipid patterns


1 receptor blockers

B Therapeutic usesHypertension: mild to moderate (single) and severe hypertension(combined with diuretics and blockers)

minimal changes in cardiac output, renal blood flow renin release and glomerular filtration


1 receptor blockers

C Adverse effects

First dose phenomenon (postural hypotension)

sodium retention




and 1 receptor blockers

Mild decrease of blood pressure

Minimal changes in cardiac output and heart rate

Used for all kinds of hypertension, including

hypertensive emergency

Less adverse effects



3.4.2 Centrally-acting drugs

Clonidine ( 可乐定 )

A ActionsDiminishes central adrenergic outflow

- activates 2 receptor in medulla

- activates I1 receptor in medulla


Clonidine B Therapeutic uses

Hypertension: mild to moderate

- minimal changes in renal blood flow and

glomerular filtration

- inhibits gastrointestinal secretion and

mobility


Clonidine

C Adverse effects

Atropine-like effects

Water and sodium retention (renal filtration )

Rebound phenomenon



3.4.2 Centrally-acting drugs

I1 receptor agonists

Rilmenidine

Moxonidine



3.4.3 Ganglion blockers

Trimetaphan( 米噻芬 )

Mecamylamine （美卡拉明）



3.4.4 Noradrenergic nerve ending

blockers

Reserpine ( 利舍平，利血平 )

Guanethidine ( 胍乙啶 )

3. Antihypertensive Drugs3.5 Vasodilators

Hydralazine ( 肼屈嗪 )Dilates arteries and arterioles

Decreases peripheral resistance

Reflexly elevates heart rate, cardiac output and renin release.

Administrated with blockers and diuretics.

Adverse effects due to vasodilation and lupus-like syndrome can occur.


3.5 Vasodilators

Nitroprusside sodium ( 硝普钠 )Dilates small arteries and veins

Used for treatment of emergency hypertension, hypertension with CHF, controlled hypotension and obstinate CHF

Adverse effects due to hypotension in excess and sulfocyanate poisoning.


3.5 Vasodilators

Potassium channel openersIncluding minoxidil, nicorandil, diazoxide, etc.

Dilates arteries (Ca influx )

Reflexly elevates heart rate, cardiac output and renin release.

Used for treatment of obstinate and severe hypertension

Adverse effects include sodium retention, palpitation, etc

4.1 General information

4. Clinical pharmacology of Antihypertensive Drug

• The diagnosis of hypertension should be established by

finding an elevated blood pressure on at least three

different office visits

• The physician must establish with certainty that

hypertension is persistent and requires treatment and

must exclude secondary causes of hypertension that

might be treated by definitive surgical procedures.

4.1 General information


• Consider the level of blood pressure, the age and sex of the patient, the severity of organ damage (if any) due to high blood pressure, and the presence of cardiovascular risk factors must all be considered. ------Begin the drug treatment or not.

• Selection of drugs is dictated by the level of blood pressure, the presence and severity of end-organ damage, and the presence of other diseases.

• Educate the patient about the nature of hypertension, the importance of treatment and the potential side effects of drugs.

4.2 Out-patient therapy


In general:

• Sodium restriction: A reasonable dietary goal in treating hypertension is 70–100 mEq of sodium per day

• Weight reduction;

• Regular exercise;

Lifestyle modifications to manage hypertension

Monotherapy Versus Polypharmacy


4.2.1 Prescribe according to the severity of hypertension

Mild: diuretics, blockers, ACEIs, CCBs, 1 blockers, ARBs (first line, single drug)

Moderate: combine two above drugs

Severe: add centrally acting drugs or vasodilators on the two combined drugs

4.2.2 Prescribe according to complications

Complications Options Avoidance

Severe CHF and/or

COPDDiuretics, ACEIs, prazosin

blockers

Renal failure ACEIs, CCBs

Tachycardia blockers

GI ulcer Clonidine Reserpine

Diabetes and gout ACEIs, prazosin Thiazide


4.2.3 Prescribe according to complications

hypertensive emergency: vasodilators (nitroprusside sodium, diazoxide), labetalol, loop diuretics

elderly patients:avoiding drugs that could induce postural hypotension and influence the cognizant ability (clonidine)


4.2.4 Avoid blood pressure to decrease too rapidly and excessively


ReferencesReferencesReferencesReferences

Basic & Clinical Pharmacology (10th edition), 2007.

Lipincott’s illustrated reviews - Pharmacology (2nd edition), 2002

《药理学》，杨世杰主编，人民卫生出版社， 2005

《基础医学教程各论》，陈季强主编，科学出版社， 2004

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