Download - Antihypertensive Drugs
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
3. Antihypertensive Drugs
DiureticsDiuretics
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
Other calcium channel blockers:
Verapamil
Diltiazem
Nimodipine
Amlodipine
Felodipine
3. Antihypertensive Drugs
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
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. 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
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
3. Antihypertensive Drugs
ACEIsB 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 ActionsDecrease cardiac output
Inhibit the release of renin from kidney (formation of angiotension and secretion of aldosterone )
3. Antihypertensive Drugs
receptor blockers
A ActionsDecrease 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 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
3. Antihypertensive Drugs
3.4 Sympathetic system inhibitors
3.4.1 Adrenoreceptor blockers
1 receptor blockers
A ActionsRelax arterial and venous smooth muscle, decrease peripheral resistance
Alterations in serum lipid patterns
3. Antihypertensive Drugs
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
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 ActionsDiminishes 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 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. 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 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
4. Clinical pharmacology of Antihypertensive Drug
• 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
4. Clinical pharmacology of Antihypertensive Drug
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
4.2.2 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. 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
4. Clinical pharmacology of Antihypertensive Drug
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