Antihypertensive drugs
Lou haiyan
louhaiyan@sdu.edu.cn
Section 1
Introduction
Definition
Hypertension is defined as a sustained
diastolic blood pressure (DBP) greater than
90mmHg or systolic blood pressure (SBP)
greater than 140mmHg.
Bp≥ 140/90mmHg
Morbidity: 15%~ 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 factor
Activation of sympathetic nervous system
Activation of RAAS （renin-angiotensinaldosterone system）
Na+
Dysfunction of vascular endothelium
Normal regulation of blood pressure
Arterial
blood
pressure
Cardiac
output
≈
×
(CO)
Heart rate
Peripheral
vascular
resistance
(PVR)
Filling pressure
Arterial volume
Contractility
Response mediated by the sympathetic nervous system
Activation of β1-R
on heart
Cardiac
outrput
Activation of α 1-R
on smooth muscle
Peripheral
resistance
sympathetic activity
Increase
in BP
Renin
AngiotensinII
sodium,
water retention
Aldosterone
blood volume
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 weight
Exercise
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. Diuretics
2. Calcium channel blocks
3. RAS inhibitors:
ACEI( angiotensin converting enzyme inhibitors)
AT1 receptor antagonist (angiotensin Ⅱ
typeⅠ receptor antagonist )
Renin inhibitors
4. Sympathoplegic agents:
Centrally acting agents
Ganglion-blocking agents
Adrenergic neuron-blocking agents
Adrenoceptor antagonist
β-adrenergic antagonist
α1-adrenergic antagonist
Mixed adrenergic antagonist
5. Vasodilators
Direct vasodilators
Potassium 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
Thiazide diuretics
sodium, water
retention
Na+ in vessel wall
Na+-Ca2+ exchange
blood volume
Ca2+ in smooth muscle cell
Cardiac
outrput
Peripheral resistance
Decrease in BP
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 (2550mg/d) exert as much antihypertensive
effect as do higher doses.
Adverse Effects
1.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
diuresis
Dilate the vascular smooth muscle
Have no effect on the serum lipids
2. Loop diuretics
(high efficacy diuretics):
furosemide, etacrynic acid.
The loop diuretics act promptly and can be
used 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
avoid 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.
blocken ofβ-R in peripheral
and central nervous system
Inhibit NA release
and vasomotor center
blocken of β1-R
on heart
β-R blockers
PGI2
synthesis
Cardiac
outrput
Peripheral
resistance
AngiotensinII
Renin
Decrease
in BP
Aldosterone
sodium,
water retention
blood volume
The mechanism for reduction of BP of β-R blockers
Clinical Uses and Evaluation
All types of hypertension , especially
in high renin activity and high cardiac
output
The β-Blockers are useful in treating
conditions 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 upregulation 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 flow
Do not increase renin activity
Do 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 activity
4. 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
Angiotensinogen
Bradykinin
Renin
AngiotensinI
ACE inhibitors
ACE
AngiotensinII
inactive
ARB
vasoconstrition
Peripheral
resistance
Increased
prostaglandin
synthsis
vasodilation
Aldosterone
sodium,
water retention
Peripheral
resistance
Decrease in BP
Increase in BP
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
decrease 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 tachycardia
2. Prevent or reverse proliferation and
hypertrophy of VSMC and myocardial cells
3. Increase renal blood flow and protect renal
function.
4. Have no electrolyte disturbance and lipid
metabolism disturbance
5. Improve life quality , ↓ mortality
Clinical Use
1. 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 ACEI
2. No effect on bradykinin metabolism
Clinical Use and Evaluation
1. The action is similar to that of ACEI
2. 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 Action
1. 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
rostral ventrolateral medulla (RVLM)
3. excite α2-R and I1 receptor of peripheral
sympathetic 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
hypotensor, mainly excite I1 receptor of
RVLM. Actions 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%)
in 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 openers
Mechanism 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
disease).
6 To achieve this with no or minimal side
effects by combination administration.
20世纪90年代有关的调查显示

高血压治疗率
 法国
美国
中国
城市
农村
20%
54%
17.4%
5.4%
控制率
5.4%
27%
4.2%
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
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)
利尿剂
-blockers
 1-blockers
ARB
ACEI
ACEI
CCB
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
法国
20%
美国
54%
中国 城市 17.4%
农村 5.4%
控制率
5.4%
27%
4.2%
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