Antihypertensive drugs

Lou haiyan

louhaiyan@sdu.edu.cn

Definition

Hypertension is defined as a sustained diastolic blood pressure (DBP) greater than 90mmHg or systolic blood pressure (SBP) greater than 140mmHg.

Section 1 Introduction

Bp≥ 140/90mmHgBp≥ 140/90mmHg

Morbidity: Morbidity: 15%~ 20% 20%

Complication:

The Types of Hypertension

Essential hypertension 90% Secondary hypertension 10%

Primary (essential) hypertension

Nearly 90% of patients have no specific cause. Elevated blood pressure is usually caused by

several abnormalities such as genetic inheritance, psychological stress, dietary factors.

Treatment: Such hypertension can be controlled by some combination of antihypertensive drugs and changes in

daily habits.

Secondary hypertension

10% -15% of patients has a specific cause, such as renal artery constriction, primary aldosteronism or tumors of the adrenal glands (pheochronocytoma).

Treatment:

Pathophysiology of hypertension

Genetic factorActivation of sympathetic nervous systemActivation of RAAS （ renin-angiotensin-al

dosterone system ）Na+

Dysfunction of vascular endothelium

Normal regulation of blood pressure

Arterial blood

pressure

Cardiac output

(CO)

Peripheral vascular

resistance

(PVR)≈ ×

Heart rate

Contractility

Filling pressureArterial volume

Response mediated by the sympathetic nervous system

sympathetic activity

Activation of β1-R on heart

Activation of α 1-R on smooth muscle

Cardiacoutrput

Peripheralresistance

Renin AngiotensinII Aldosterone

sodium, water retention blood volume

Increase in BP

Response mediated by the renin-angiotensin-aldosterone system

全国高血压日历年主题

10 月 8 日1998 年：“了解您的血压”。1999 年：“控制高血压，保护心脑肾”。2000 年：“普及高血压知识，减少高血压危害”。2001 年：“控制高血压，享受健康生活”。2002 年：“战胜高血压从社区做起！”2003 年：“保持健康生活方式，控制高血压”2004 年：“高血压与代谢综合征”。2005 年 : “ 血压与卒中”。 2006 年 : “降压达标”

Treatment of hypertension

Diet Loss weightExercise Antihypertensive

drugs

高血压的治疗目标

确切降压稳定降压阻断 RAS, 减轻或逆转靶器官损伤，降低

并发症的发生率和病死率。

抗高血压治疗的目标血压： 一般 < 140/90mmHg 糖尿病、肾病患者 < 130/80mmHg

The classification of antihypertensive agents

1. Diuretics2. Calcium channel blocks3. RAS inhibitors:

ACEI( angiotensin converting enzyme inhibitors) AT1 receptor antagonist (angiotensin tyⅡ

peⅠ receptor antagonist ) Renin inhibitors

4. Sympathoplegic agents:Centrally acting agentsGanglion-blocking agentsAdrenergic neuron-blocking agentsAdrenoceptor antagonist

β-adrenergic antagonistα1-adrenergic antagonistMixed adrenergic antagonist

5. VasodilatorsDirect vasodilatorsPotassium channel openers

Section 2

Basic Antihypertensive Drugs

Ⅰ. Diuretics

1. Thiazide Diuretics

(moderate efficacy diuretics): Hydrochlorothiazide Chlorothiazide

Characteristics: Mildness, Lasting, No tolerance. Decrease

morbidity and mortality of hypertension

complications after long-term use.

The Mechanism for Reduction of BP

1. Early:↑ Na+ and H2O excretion,

↓extracellular volume and blood

volume , ↓ cardiac output 2. Long:↓ Na+ of vessel wall, ↓ Na+-Ca2+

exchange, ↓ intracellular Ca2+, ↓

sensitivity of VSM to vasoconstrictors (NE). 3. Dilate VSM directly

sodium, waterretention

blood volume

CardiacoutrputPeripheral resistance

Decrease in BP

Thiazide diuretics

Na+ in vessel wall

Na+-Ca2+ exchange

Ca2+ in smooth muscle cell

initial

Long-

term

The mechanism for reduction of BP of thiazide Diuretics

Clinical Uses and evaluation

Low-dose of thiazide diuretic therapy is safe, effective and cheap for hypertension.

Thiazide diuretics are appropriate for most patients with mild or moderate hypertension, particularly elderly patients.

Low doses of hydrochlorothiazide (25-50mg/d) exert as much antihypertensive effect as do higher doses.

Adverse Effects1.Thiazide diuretics induce electrolyte disturbance:

hypokalemia, hypomagnesaemia, hyposodium et al

2. Thiazide diuretics can increase TC, TG, LDL level and renin activity, impair glucose tolerance.

Therefore diuretics should be avoided in treatment of

hypertensive diabetics or patients with hyperlipidemia.

Indapamide( 吲哒帕胺）Increase in renal Na+ excretion

diuresisDilate the vascular smooth muscleHave no effect on the serum lipids

2. Loop diuretics

(high efficacy diuretics):

furosemide, etacrynic acid. The loop diuretics act promptly and can be u

sed in hypertensive emergencies or hypertension combined with renal function failure.

3. Potassium-sparing diuretics

(low efficacy diuretics):

spironolactone, amiloride. Potassium-sparing diuretics are useful both to a

void excessive potassium depletion and to enhance the natriuretic effect of other diuretics.

II. Adrenergic Receptor Blockers

1. β-receptor blockers

Propranolol

Metoprolol

Atenolol

The Mechanism of Action

(1) Blocking β1-R of heart , ↓ cardiac output .

(2) Blocking β1-R of kidney, inhibit renin release,

↓ RAS activity. (3) Blocking peripheral sympathetic presynaptic

β2- R ,↓ NA release .

(4) Blocking β-R of CNS , ↓ peripheral

sympathetic activity.

(5) Increase synthesis of PGI2.

The mechanism for reduction of BP of β-R blockers

β-R blockers

blocken of β1-R on heart

Cardiacoutrput

Peripheralresistance

Renin AngiotensinII

Aldosterone

sodium, water retention blood volume

Decrease in BP

blocken ofβ-R in peripheraland central nervous system

Inhibit NA release and vasomotor center

PGI2

synthesis

Clinical Uses and Evaluation

All types of hypertension , especially in high renin activity and high cardiac outp

utThe β-Blockers are useful in treating conditi

ons that may coexist with hypertension, such as superventricular tachyarrhythmia, previous myocardial infarction, angina pectoris, migraine headache.

Adverse effects

(1) Common effects: CNS side effects: fatigue, lethargy, insomnia;

Sexual dysfunction (impotence) can severely reduce patient compliance.

(2) Alteration in serum lipid patterns: decrease HDL and increase plasma triacylglycerol (TG).

(3)Drug withdrawal: Abrupt withdrawal may cause rebound hypertension, probably as a result of up-regulation of β receptor.

Application Attention

(1) Be avoided in treating patients with

(Contraindication)

serious AV conduction block, bradycardia, bronchial asthma, peripheral vascular disease, et al.

(2) Beginning with small dose: (individual variation is larger)

(3) Combining with diuretics

2.α1-adrenoreceptor antagonist

Prazosin ( 哌唑嗪 ) Terazosin ( 特拉唑嗪 )

Pharmacological Action : Blocking α1-R selectively

Dilate A and V vessel BP↓

Merit :

Do not reduce the renal blood flowDo not increase renin activityDo not reflex increase in heart rate↓TG, TC, LDL-c, ↑ HDL-c

Clinical uses

All types hypertension , be united with β-R blockers and diuretics.

Prostate hypertrophy

Untoward Reactions 1. First dose phenomenon 2. Retention of salt and fluid

3. αandβ-Receptor Antagonist

Labetalol ( 拉贝洛尔） Carvedilol ( 卡维地洛） Blocking β1= β2 > α1

Blocking α1 and β-R ,↓ BP

Light effect on heart rate and

cardiac output Used for all types of hypertension

III. Calcium Channel Blockers

Nifedipine ( 硝苯地平） Amlodipine （氨氯地平） Verapamil （维拉帕米） Diltiazem （地尔硫卓）

Mechanism of Antihypertension:

Calcium antagonists block the entry of calcium into the smooth muscle of the blood vessels, causing it to dilate.

Certain types such as verapamil and diltiazem can also slow the heart rate and inhibit cardiac contractility.

Therapeutic uses

Calcium channel blockers are useful in the treatment of hypertensive patients who also have asthma, diabetes, angina, and/or peripheral vascular disease.

Nifedipine

1. Action of dilating vessel is stronger than other calcium antagonist.2. Treatment of all types hypertension.3. Reflex increase in sympathetic activity: tachycardia, ↑CO ,↑renin activity4. Short action , can increase mortality if used for long time.

Amlodipine

Amlodipine belongs to long-acting calcium channel blockers which are better than nifedipine.

(1) It takes effect slowly (1--2w), lower BP steadily and continuously

(2) It does not affect heart obviously.(3) It can reverse myocardial hypertrophy.

Ⅳ . Inhibitors of RAS

Peripheralresistance

Renin

Aldosterone

sodium, water retention

Decrease in BP

AngiotensinI

AngiotensinII

Angiotensinogen Bradykinin

inactive

Increased prostaglandin

synthsis

vasodilation

Peripheralresistance

vasoconstrition

Increase in BP

ACE inhibitors

ARB

ACE

RAAS and its inhibitors

1. Angiotensin Converting Enzyme Inhibitors(ACEI) Catopril ( 卡托普利 ) Enalapril ( 依那普利 ) Cilazapril ( 西拉普利 ) Benazapril ( 贝那普利 ) Ramipril ( 雷米普利 )

The Mechanism of Action

1. Inhibit ACE that cleaves Ang I to form the potent vasoconstrictor Ang II both in circulating system and local tissue.

2. diminish the degradation of bradykinin---increase

bradykinin levels----increase the release of NO, PGI2 3.inhibit NA release, inhibit RAS in CNS, and decrea

se central and peripheral sympathetic

nerve activity

The Mechanism of Action

4. Inhibit generation of AngII in local tissue, inhibit or reverse myocardial and vascular remodeling

5. Decrease the secretion of aldosterone, result in decreased sodium and water retention.

6. Protect vascular endothelial cell

The Merits of Treatment of Hypertension

1. Have no tachycardia2. Prevent or reverse proliferation and hypertrophy of VSMC and myocardial cells3. Increase renal blood flow and protect renal function.4. Have no electrolyte disturbance and lipid metabolism disturbance5. Improve life quality , ↓ mortality

Clinical Use1. The ACE inhibitors are appropriate for

most patients with mild or moderate hypertension, particularly hypertension with high renin activity.

2. The ACE inhibitors are useful in treating conditions that may coexist with hypertension, such as CHF, myocardial ischemia, diabetes.

Adverse Reactions

hypotension (2%), dry cough (5-20%), angioedema, hyperkalemia, influence on development of fetus.

2. Angiotensin II Receptor Antagonist (AT1- Receptor Blocking Agents)

Losartan ( 氯沙坦） Valsartan （缬沙坦） Irbesartan （厄贝沙坦）

Pharmacological Actions Arrest Ang II combine with AT1R

1. More selective blockers of AⅡ effects than ACEI2. No effect on bradykinin metabolism

Clinical Use and Evaluation1. The action is similar to that of ACEI2. Does not cause cough and angioedema .

Section 3 Other Hypotensors

1.Centrally-acting sympathoplegic drugs

2. Vasodilators

1.Centrally-acting sympathoplegic drugs

Clonidine （可乐定）

Pharmacological Action1. Antihypertensive effect ( iv or oral)2. Sedative effect 3. Inhibit gastrointestinal secretion

and motion

The Mechanism of Action

1. excite α2-R of medulla oblongata

2. activate type 1 imidazoline receptor (I1) of ro

stral ventrolateral medulla (RVLM)

3. excite α2-R and I1 receptor of peripheral sym

pathetic presynaptic membrane---- decrease release of NA

Clinical Use

1. Moderate hypertension: appropriate for patients with peptic ulcer

2. Morphine addiction: increase the release of endogenous opioid peptides, such as enkephalin

Adverse Effects

1. Dry mouth, sedation, headache,

sexual dysfunction, constipation.2. Withdrawal reaction: tachycardia,

sweating, acute rising in BP.

Rilmenidine （利美尼定 ) Moxonidine( 莫索尼定 )

They belong to secondary central hypotens

or, mainly excite I1 receptor of RVLM. Acti

ons on central and peripheral α2-R are very

weak, so the adverse reaction is rare. They

also have no

withdrawal reaction.

2. Vasodilators

Hydralazine( 肼屈嗪 ) 1. Mainly dilate small arteriols 2. reflex ↑ sympathetic and ↑ renin

activity, can induce angina 3. Used in moderate hypertension,

combined with other hypotensors 4. Can cause resembles erythematosus(10-20%) i

n large dose

Nitroprusside Sodium ( 硝普钠 )

1. Nitroprusside Sodium lowers BP rapidly by releasing NO.

2. It take effects rapidly (30S after iv), the effects disappear quickly too (3min after stopping iv).

3.Sodium nitroprusside is always used to treat hypertensive emergency and severe cardiac failure.

Minoxidil ( 米诺地尔 ) Diazoxide( 二氮嗪 )

Potassium channel openersMechanism of hypotension:

↑KATP →↑K+ efflux → ↓ Ca2+ influx

→ artery dilation → BP↓ Clinical Uses

obstinate serious hypertension (hypertension

emergency and hypertensive encephalopathy)

Minoxidil

1. It can promote the growth of hair besides antihypertensive effect.

2.Treating obstinate hypertension must combine with diuretics and β-R blockers; It also try to treat male alopecia.

The antihypertensive treatment strategies

1. To normalize blood pressure effectively.

2. Controlling hypertension is usually a

lifelong treatment (patient compliance)

3. To prevent target-organ damage to the

heart, brain, kidneys and blood vessels.

4 To decrease the blood pressure steadily.

5 Individualized care (age, concomitant diseas

e).

6 To achieve this with no or minimal side effect

s by combination administration.

20 世纪 90 年代有关的调查显示

高血压治疗率 控制率

法国 20% 5.4%美国 54% 27%中国 城市 17.4% 4.2% 农村 5.4% 0.9%

高血压的治疗原则

1. 根据高血压程度选药

First – line hypotensive drugs

Diuretics

β-R antagonist

ACEI (ARB) Calcium channel blockers

α1-R blockers

2. 根据病情特点选药合并支气管哮喘不宜用 β-R阻断剂合并肾功能不良者，宜用 ACEI， CCB

合并窦速， 50岁以下者，宜用 β-R阻断剂合并消化性溃疡者、用可乐定，禁用利血平伴精神抑郁者，不宜用利血平。合并糖尿病或痛风者，不宜用噻嗪类

合并 CHF，宜用氢氯噻嗪， ACEI合并高血脂者，不宜用噻嗪类和 β-R阻断药老年高血压避免使用能引起体位性低血压的药物和影响认知功能的药物

高血压危象和脑病，可 iv硝普钠、二氮嗪

3. 联合用药4. 避免降压过快 , 过剧5. 个体化治疗

ACEI

利尿剂

-blockers

1-blockers CCB

ARB

ACEI

不同种类降压药物的可能组合 ( 最合理的组合用粗线条表示 )

高血压药物治疗的新概念

1. 有效治疗与终生治疗 有关研究显示：高血压者收缩压每降低

10~14mmHg ，舒张压每降 5~6mmHg ，脑卒中↓ 40% ，心肌梗死↓ 15 ％，总死亡率↓ 13 ％，心血管病死亡率↓ 18％，总的心血管并发症↓ 26 ％。

20 世纪 90 年代有关的调查显示

高血压治疗率 控制率法国 20% 5.4%美国 54% 27%中国 城市 17.4% 4.2% 农村 5.4% 0.9%

2. 保护靶器官 具有靶器官保护作用的药物：

ACEI AT1 受体拮抗剂 长效钙拮抗剂

3. 平稳降压 Blood pressure variability( BPV, 血压波动

性） BPV 高，靶器官损伤严重 抗高血压药的“谷峰比值”：第一天用安

慰剂，第二天用治疗药，药物效应最大时两天的差值称为“峰”，下次给药前的差值称为“谷”。

谷峰比值应在 50 ％以上