Pharmacology for cardiovascular system
•八年制课程
Antihypertensive Drugs
张翔南
xiangnan_zhang@zju.edu.cn
Contents:
Overview
Classification of antihypertensive drugs
Antihypertensive drugs
Clinical pharmacology of
antihypertensive drugs
1. Overview
Age-adjusted annual
incidence of CHD per 1000
Blood Pressure and Risk for
Coronary Heart Disease in Men
60
60
50
50
40
40
Age 65-94
30
20
Age 65-94
30
Age 35-64
20
10
10
0
0
<120 120- 140- 160- 180+
139 159 179
Age 35-64
<75
7584
8594
95- 105+
104
Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg)
Based on 30 year follow-up of Framingham Heart Study subjects free of coronary heart disease
(CHD) at baseline
Framingham Heart Study, 30-year Follow-up. NHLBI, 1987.
Etiology of Hypertension
•Secondary hypertension(10~15%)
•Essential hypertension(85~90%)
High Risk Factors of Hypertension:
Stressful life-style
High dietary intake of sodium
Obesity and hyperlipidemia
Smoking
Hereditary factors
按危险分层，量化地估计预后
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
The end organ damage of hypertension:
Kidney: renal failure
Heart: coronary disease, cardiac failure
Brain: stroke
Kidney
Failure
15%
Other
2%
MI or CHF
Stroke
Kidney Failure
Other
MI or CHF
50%
Stroke
33%
1. Overview
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
Major factors influencing blood pressure
Arterial blood
pressure
Heart
rate

Cardiac
output
Contractility

Peripheral
resistance
Filling
pressure
Baroreceptors and sympathetic nervous system
RAAS
arteriolar
volume
Blood
volume
Venous
tone
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
Na+ Cl-
K+
Na+ K+ Cl-
高效能
中效能
低效能
H2 O
3. Antihypertensive Drugs
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
Diuretics
3. Antihypertensive Drugs
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. Antihypertensive Drugs
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 )
3. Antihypertensive Drugs
nifedipine
C Adverse effects
Peripheral edema
Reflex sympathetic activation
Renin activity 
3. Antihypertensive Drugs
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. Antihypertensive Drugs
3.3 Renin- angiotensin system inhibitors
ACEIs
ARBs
Renin inhibitors
Angiotensin converting
enzyme, ACE
AT1
AngII 在器官损害中作用
Atherosclerosis*
Vasoconstriction
Vascular hypertrophy
Endothelial dysfunction
AngII AT1
receptor
LV hypertrophy
Fibrosis
Remodelling
Apoptosis
GFR
Proteinuria
Aldosterone release
Glomerular sclerosis
中风
高血压
心衰
心肌梗塞
DEATH
肾衰
*Preclinical data
LV = left ventricular; MI = myocardial infarction;
GFR = glomerular filtration rate
Actions of angiotensin II
• 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.
Angiotensin converting enzyme
inhibitors(ACEIs)
3. Antihypertensive Drugs
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
Actions of ACEIs
Angiotensin II
Angiotensin I
Inactive peptide
Brandykinin
ACEI
(—)
B 2 receptor
ACEI
(—)
ACE
Circulation and
local tissues
PGI2
NO
ACE
Circulation and
local tissues
Vasodilation
Anti-proliferation, anti-hypertrophy
3. Antihypertensive Drugs
ACEIs
B Therapeutic uses
Antihypertension
- without reflexly increasing the activity of
sympathetic system
- effective in the treatment of CHF,
diabetes and ischemic heart disease.
3. Antihypertensive Drugs
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
3. Antihypertensive Drugs
ACEIs
D Contraindications
Renal artery stenosis
Pregnant and lactation women
3. Antihypertensive Drugs
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
3. Antihypertensive Drugs
Renin inhibitors
•
Inhibit whole RAAS
•
Include renin antibody, peptide and
nonpeptide renin inhibitors (eg. remikiren)
3. Antihypertensive Drugs
3.4 Sympathetic system inhibitors
3.4.1 Adrenoreceptor blockers
 receptor blockers
A Actions
Decrease cardiac output
Inhibit the release of renin from kidney
(formation of angiotension and secretion
of aldosterone )
3. Antihypertensive Drugs
 receptor blockers
A Actions
Decrease sympathetic outflow from CNS
and release of noradrenalin from
peripheral nerve endings
Increase production of PGs
Increase sensitivity of baroreceptor
3. Antihypertensive Drugs
 receptor blockers
B Therapeutic uses
Hypertension: 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
3. Antihypertensive Drugs
3.4 Sympathetic system inhibitors
3.4.1 Adrenoreceptor blockers
1 receptor blockers
A Actions
Relax arterial and venous smooth muscle,
decrease peripheral resistance
Alterations in serum lipid patterns
3. Antihypertensive Drugs
1 receptor blockers
B Therapeutic uses
Hypertension: 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
3. Antihypertensive Drugs
1 receptor blockers
C Adverse effects
First dose phenomenon (postural
hypotension)
sodium retention
3. Antihypertensive Drugs
3.4 Sympathetic system inhibitors
3.4.1 Adrenoreceptor blockers
 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. Antihypertensive Drugs
3.4 Sympathetic system inhibitors
3.4.2 Centrally-acting drugs
Clonidine (可乐定)
A Actions
Diminishes central adrenergic outflow
- activates 2 receptor in medulla
- activates I1 receptor in medulla
3. Antihypertensive Drugs
Clonidine
B Therapeutic uses
Hypertension: mild to moderate
- minimal changes in renal blood flow and
glomerular filtration
- inhibits gastrointestinal secretion and
mobility
3. Antihypertensive Drugs
Clonidine
C Adverse effects
Atropine-like effects
Water and sodium retention (renal
filtration )
Rebound phenomenon
3. Antihypertensive Drugs
3.4 Sympathetic system inhibitors
3.4.2 Centrally-acting drugs
I1 receptor agonists
Rilmenidine
Moxonidine
3. Antihypertensive Drugs
3.4 Sympathetic system inhibitors
3.4.3 Ganglion blockers
Trimetaphan(米噻芬)
Mecamylamine（美卡拉明）
3. Antihypertensive Drugs
3.4 Sympathetic system inhibitors
3.4.4 Noradrenergic nerve ending blockers
Reserpine (利舍平，利血平)
Guanethidine (胍乙啶)
3. Antihypertensive Drugs
3.5 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 lupuslike syndrome can occur.
3. Antihypertensive Drugs
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. Antihypertensive Drugs
3.5 Vasodilators
Potassium channel openers
Including 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. Clinical pharmacology of
Antihypertensive Drug
4.1 General information
•
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. Clinical pharmacology of
Antihypertensive Drug
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. Clinical pharmacology of
Antihypertensive Drug
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. Clinical pharmacology of
Antihypertensive Drug
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. Clinical pharmacology of
Antihypertensive Drug
4.2.2 Prescribe according to complications
Complications
Severe CHF and/or
COPD
Options
Avoidance
Renal failure
ACEIs, CCBs
Tachycardia
 blockers
GI ulcer
Clonidine
Reserpine
Diabetes and gout
ACEIs, prazosin
Thiazide
Diuretics, ACEIs,
 blockers
prazosin
4. Clinical pharmacology of
Antihypertensive Drug
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. Clinical pharmacology of
Antihypertensive Drug
4.2.4 Avoid blood pressure to decrease too
rapidly and excessively
References
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