Antihypertension Drugs Shi-Hong Zhang ( 张世红 ) Pharmacology, Dept. of [email protected]

Antihypertension Drugs

Antihypertension Drugs

Shi-Hong Zhang ( 张世红 )

Pharmacology, Dept. of

[email protected]

OutlineOverview

Classification of antihypertensive drugs

Antihypertensive drugs

Clinical pharmacology of antihypertensive drugs

1. OverviewCriteria of hypertension diagnosis

High Risk Factors:

Stressful life-style

High dietary intake of sodium

Obesity and hyperlipidemia

Smoking

Hereditary factors (30%)

Etiology:Secondary hypertension(10~15%)

Essential hypertension(85~90%)

The end organ damage of hypertension: Kidney: renal failure

Heart: coronary disease, cardiac failure

Brain: stroke

MI or CHF50%

Stroke33%

Kidney Failure

15%

Other2%

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

低危患者 <15% , 中危患者 15%~20%, 高危患者 20%~30% , 很高危患者 >30% 的风险在未来十年发生心血管事件。

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+

Ag

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dju

ste

d a

nn

ual

incid

en

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per

1000

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.

Goals of antihypertensive treatment:

Lower the blood pressure Protect the end organ Reduce the morbidity and mortality

rates Best therapy and minimal risk

Arterial blood pressure

Cardiac output Peripheral resistance

Venous tone

Blood volumeFilling pressureContractilityHeart rate

arteriolarvolume

Baroreceptors and sympathetic nervous system RAAS

Normal regulation of blood pressure:

Normal regulation of blood pressure:

2. Classification of antihypertensive drugs

Diuretics (氢氯噻嗪 )

Calcium channel blockers (硝苯地平 )

Renin-angiotensin system inhibitors

- ACEIs (卡托普利 )

- AR1Bs (缬沙坦 )

- Renin inhibitors (阿利吉仑 )

Vasodilators

- Direct acting vasodilators (硝普钠 )

- Potassium channel openers (米诺地尔 )

Sympathetic inhibitors

- Centrally acting adrenergic drugs (可乐定 )

- Ganglion blockers ( 樟磺咪芬 )

- Noradrenergic nerve ending blockers ( 利舍

平 )

- Adrenoreceptor blockers

- receptor blockers (普萘洛尔 )

- receptor blockers (哌唑嗪 )

- and receptor blockers (拉贝洛尔 )

3. Antihypertensive Drugs

3.1 DiureticsThiazide, loop, potassium-sparing diuretics

A Actions

Reduce plasma volume (cardiac output )

Reduce Na+-Ca2+ exchange in vascular

smooth muscle cell (peripheral resistance )

3.1 Diuretics

B Therapeutic uses:

Hypertension

- first-line agent

- Single drug or combined with others

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


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: Relaxes vascular smooth muscle

B Therapeutic uses: mild to severe hypertension (usually combined with blockers )

C Adverse effects: peripheral edema, reflex

sympathetic activation, and renin activity



3.3 Renin-angiotensin system inhibitors

ACEIs: Captopril

AR1Bs: Losartan

Renin inhibitors: renin antibody, peptide

and nonpeptide renin inhibitors (eg.

aliskiren)

Chymase

激肽释放酶

激肽原血管紧张素原


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


ACEIsB Therapeutic uses

Hypertension

- first line drug

- without reflex increase in sympathetic activity

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

3. Antihypertensive DrugsACEIs

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 (-SH-related)

Fetotoxicity (esp. the second trimester)


AR1Bs

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


3.4 Sympathetic system inhibitors

3.4.1 Adrenoreceptor blockers

receptor blockers

A ActionsDecrease cardiac output

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


receptor blockers

A ActionsDecrease sympathetic outflow from the CNS

Decrease the release of noradrenalin from peripheral nerve endings

Increase production of PGs

Increase sensitivity of baroreceptor


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.


receptor blockers

C Adverse effects

- Hyperglycemia

- Hyperlipidemia

- Asthma

- AV block

- Bradycardia

- Cardiac inhibition




1 receptor blockers

Prazosin哌唑嗪， terazosin特拉唑嗪

A ActionsRelax arterial and venous smooth muscle, decrease peripheral resistance

Modulate serum lipid patterns (↓ TG, TC, LDL; ↑HDL)


1 receptor blockersB Therapeutic uses

Hypertension: mild to moderate (single) and severe

hypertension (combined with diuretics and β blockers)

minimal changes in cardiac output, renal blood flow,

renin release and glomerular filtration

C Adverse effects

First dose phenomenon (postural hypotension)

Sodium retention (+diuretics)




and 1 receptor blockers

Mild decrease in blood pressure

Minimal changes in cardiac output and heart rate

Used for all kinds of hypertension, including

hypertensive emergency (iv)

Less adverse effects

Include labetalol, carvedilol



3.4.2 Centrally-acting drugs

Clonidine (可乐定 )

A ActionsDiminishes central adrenergic outflow

- activates 2A receptor in the medulla

- activates I1 receptor in the medulla



Clonidine B Therapeutic uses

Hypertension: mild to moderate

- inhibits gastrointestinal secretion and mobility (M

antagonism)

C Adverse effects

Atropine-like effects (dry month, sedation, etc), sedation, water and sodium retention (renal filtration ), rebound effect



3.4.2 Centrally-acting drugs

I1 receptor agonists

Rilmenidine利美尼定 Moxonidine莫索尼定 Similar efficacy to CCBs, ACEIs, beta-blockers.

Similar adverse effect to clonidine without

rebound effect



3.4.3 Ganglion blockers

Trimetaphan(樟磺咪芬 )

Mecamylamine (美卡拉明 )



3.4.4 Noradrenergic nerve ending

blockers

Reserpine (利舍平，利血平 )

Guanethidine (胍乙啶 )


3.5 Vasodilators

Hydralazine (肼屈嗪 )Increase the release of nitric oxide from endothelium

Dilates arteries and arterioles

Decreases peripheral resistance

Reflexly elevates heart rate, cardiac output and renin release.

Combined with blockers and diuretics for moderate and severe hypertension.

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

Diuretics

β blockers

3. Antihypertensive Drugs3.5 Vasodilators


3.5 Vasodilators

Nitroprusside sodium (硝普钠 )Serves as a prodrug of nitric oxide

Dilates small arteries and veins

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

Adverse effects due to excessive hypotension and sulfocyanate poisoning (硫氰酸盐中毒 ).


3.5 Vasodilators

Potassium channel openersIncluding minoxidil, nicorandil, diazoxide, etc.

Dilates arteries (Ca2+ influx )

Reflexly elevates heart rate, cardiac output and renin release.

Used for the treatment of obstinate and severe hypertension

Adverse effects include sodium retention, palpitation, etc.

4.1 General information

4. Clinical pharmacology of antihypertensive drugs

• 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. ------Initiate 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

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 (< 6 g NaCl)

• Weight reduction;

• Regular exercise;

Lifestyle modifications to manage hypertension

DASH diet

4.2.1 Prescribe according to the severity of hypertension

Mild: monotherapy from ACEIs, CCBs, AR1Bs, diuretics, blockers (first line), 1 blockers

Moderate: combine two of the above drugs

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


4.2.2 Prescribe according to complications

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

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


4.2.3 Combination therapy

4.2.4 Avoid blood pressure to decrease too rapidly and excessively

4.2.5 Individual therapy

4.2.2 Prescribe according to complications


病例回顾病例回顾患者 ×××，女， 74岁，发现血压升高十余年，胸闷心悸 7 年，晕厥 3 次。

现病史：患者于十余年前体检发现血压升高，当时无头晕头痛，无视物模糊，无胸闷气促，无胸痛心悸等不适。规律服用“复方降压片”，血压控制不理想。近 10年来反复有头晕。 8 年前曾爬二楼后出现胸闷、心悸后晕厥，无四肢抽搐，无口角歪斜，约 10秒钟后自醒，醒后伴冷汗。之后反复出现活动后胸闷、心悸，无明显气促，曾在多家医院住院治疗，诊断为“高血压，高心病”。患者有夜尿增多 2 － 3 年，夜间睡眠需两个枕头，无睡眠中憋醒。近 2 － 3 年出现胸骨后隐痛，无恶心呕吐，无大汗淋漓，无后背及手臂放射痛，胸痛与活动无明显关系，休息几分钟可缓解。平时一直服用“麝香保心丸”、“阿司匹林”。

病例回顾病例回顾昨天下午爬 2 楼后出现胸闷、胸口不适，后又晕厥一次，伴小便失禁，约 10秒钟自醒。醒后有冷汗，四肢乏力，无肢体活动障碍。即至我院，头颅 CT 示“两侧基底节多发腔隙性脑梗塞”。心电图示“窦性心律， I° 房室传导阻滞，完全性右束支传导阻滞”。今为进一步诊疗入院。

入院体检： T 37.2 度， P 72 次 / 分， R 18 次 /分， BP 145/80mmHg ，呼吸音粗，右肺可及少许湿罗音。心界左下扩大。心电图提示右心室扩大可能。

入院诊断：高血压病 2 级（极高危）高血压性心脏病，心功能 III级冠状动脉粥样硬化性心脏病，心绞痛腔隙性脑梗塞

病例回顾病例回顾住院治疗：非洛地平速尿单硝酸异山梨酯 ( 欣

康 )阿司匹林肠溶片左氧氟沙星安体舒通 ( 螺内酯 )培哚普利美托洛尔

出院带药：非洛地平培哚普利美托洛尔阿司匹林肠溶片

Documents

Antihypertension Drugs Shi-Hong Zhang ( 张世红 ) Pharmacology, Dept. of [email protected]