Download 3. Antihypertensive Drugs

Antihypertension Drugs
Shi-Hong Zhang (张世红)
Pharmacology, Dept. of
[email protected]
1
Outline
Overview
Classification of antihypertensive drugs
Antihypertensive drugs
Clinical pharmacology of antihypertensive
drugs
2
1. Overview
Criteria of hypertension diagnosis
3
Etiology:
Secondary hypertension(10~15%)
Essential hypertension(85~90%)
High Risk Factors:
Stressful life-style
High dietary intake of sodium
Obesity and hyperlipidemia
Smoking
Hereditary factors (30%)
4
The end organ damage of hypertension:
Kidney: renal failure
Heart: coronary disease, cardiac failure
Brain: stroke
Kidney
Failure
15%
Other
2%
MI or CHF
50%
Stroke
33%
5
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
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。
6
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
7
(CHD) at baseline
Framingham Heart Study, 30-year Follow-up. NHLBI, 1987.
8
Goals of antihypertensive treatment:
 Lower the blood pressure
 Protect the end organ
 Reduce the morbidity and mortality rates
 Best therapy and minimal risk
9
Normal regulation of blood pressure:
Arterial blood pressure
Cardiac output
Heart rate Contractility
Peripheral resistance
Filling pressure
Baroreceptors and sympathetic nervous system
RAAS
arteriolar
volume
Blood
volume
Venous
tone
10
Normal regulation of blood pressure:
11
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)
12
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)
13
14
3. Antihypertensive Drugs
3.1 Diuretics
Thiazide, loop, potassium-sparing diuretics
A Actions
Reduce plasma volume (cardiac output )
Reduce Na+-Ca2+ exchange in vascular
smooth muscle cell (peripheral resistance  )
15
3. Antihypertensive Drugs
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
16
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)
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3. Antihypertensive Drugs
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 
18
3. Antihypertensive Drugs
3.3 Renin-angiotensin system inhibitors
ACEIs: Captopril
AR1Bs: Losartan
Renin inhibitors: renin antibody, peptide
and nonpeptide renin inhibitors (eg.
aliskiren)
19
血管紧张素原
激肽原
激肽释放酶
Chymase
20
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
21
3. Antihypertensive Drugs
ACEIs
B Therapeutic uses
Hypertension
- first line drug
- without reflex increase in sympathetic activity
- effective in the treatment of CHF, diabetes and
ischemic heart disease.
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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 (-SH-related)
Fetotoxicity (esp. the second trimester)
23
3. Antihypertensive Drugs
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
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3. Antihypertensive Drugs
3.4 Sympathetic system inhibitors
3.4.1 Adrenoreceptor blockers
 receptor blockers
A Actions
Decrease cardiac output
Inhibit renin release from kidney
(formation of angiotensin and secretion
of aldosterone )
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3. Antihypertensive Drugs
 receptor blockers
A Actions
Decrease sympathetic outflow from the CNS
Decrease the release of noradrenalin from
peripheral nerve endings
Increase production of PGs
Increase sensitivity of baroreceptor
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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.
27
3. Antihypertensive Drugs
 receptor blockers
C Adverse effects
- Hyperglycemia
- Hyperlipidemia
- Asthma
- AV block
- Bradycardia
- Cardiac inhibition
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3. Antihypertensive Drugs
3.4 Sympathetic system inhibitors
3.4.1 Adrenoreceptor blockers
1 receptor blockers
Prazosin哌唑嗪，terazosin特拉唑嗪
A Actions
Relax arterial and venous smooth muscle,
decrease peripheral resistance
Modulate serum lipid patterns (↓ TG, TC,
LDL; ↑HDL)
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3. Antihypertensive Drugs
1 receptor blockers
B 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)
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3. Antihypertensive Drugs
3.4 Sympathetic system inhibitors
3.4.1 Adrenoreceptor blockers
 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
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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 2A receptor in the medulla
- activates I1 receptor in the medulla
32
3. Antihypertensive Drugs
33
3. Antihypertensive Drugs
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
34
3. Antihypertensive Drugs
3.4 Sympathetic system inhibitors
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
35
3. Antihypertensive Drugs
3.4 Sympathetic system inhibitors
3.4.3 Ganglion blockers
Trimetaphan(樟磺咪芬)
Mecamylamine (美卡拉明)
36
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)
37
3. Antihypertensive Drugs
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.
38
3. Antihypertensive Drugs
3.5 Vasodilators
Diuretics
β blockers
39
3. Antihypertensive Drugs
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).
40
3. Antihypertensive Drugs
3.5 Vasodilators
Potassium channel openers
Including 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.
41
4. Clinical pharmacology of antihypertensive drugs
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.
42
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. ------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.
43
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 (< 6 g
NaCl)
•
Weight reduction;
•
Regular exercise;
44
Lifestyle modifications to manage
hypertension
45
DASH diet
46
47
48
4. Clinical pharmacology of antihypertensive drug
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
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4. Clinical pharmacology of antihypertensive drug
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 cognitive
ability (clonidine)
4.2.3 Combination therapy
4.2.4 Avoid blood pressure to decrease too rapidly and
excessively
4.2.5 Individual therapy
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4. Clinical pharmacology of antihypertensive drug
4.2.2 Prescribe according to complications
51
Antianginal drugs
52
Outline
1 OVERVIEW
2 ANTIANGINAL DRUGS
- Organic nitrates
- β-blockers
- Calcium channel blockers
3 CLINICAL USE OF ANTIGANGINAL DRUGS
53
1.1 What is angina pectoris?
Frequency: in America, about 6.3 million
people are estimated to experience angina.
An estimated 350,000 new cases of angina
occur every year. One million died of angina
each year in China
A comprehensive approach to diagnosis and
to medical management of angina is an
integral part of the daily responsibilities of
physicians.
54
Leading Sources of Disease Burden*
•
•
•
•
•
•
•
Ischemic Heart Disease
Unipolar Major Depression
Cardiovascular Disease
Alcohol Use
Traffic Accidents
Lung and other cancers
Dementia and Neurodegenerative
Disorders
*based on DALY’s (Disability Adjusted Life Years, WHO) which measure
55
lost years of healthy life due to premature death or disability
1.1 What is angina pectoris?
Symptoms: Sudden,
uncomfortable pressure,
fullness, squeezing or severe
substernal pain, radiating to
the left arm, shoulders, neck,
etc.
56
1.2 How does angina pectoris happen?
Demand of the myocardium for oxygen
Normal
Ischemia
Oxygen delivery to the myocardium
by the coronary circulation
57
1.2 How does angina pectoris happen?
Demand
 Preload (venous return )
 Afterload (arteriolar resistance)
 Heart rate
Delivery
 Atherosclerosis plaque
 Thrombus
 Spasm of coronary arteries
58
1.3 Classification of angina pectoris:
Stable angina pectoris
Unstable angina pectoris
initial onset type
Caused by
atherosclerosis
plaque and
thrombus formation
accelerated type
spontaneous type
+
Variant/Prinzmetal’s angina pectoris
Caused by spontaneous
spasm of coronary arteries
59
Occurrence of stable and unstable angina pectoris
Extreme weather
Strong emotion
Excessive food intake
Exercise
Excessive smoking
Variant/Prinzmetal’s angina: usually occur when a person is at
rest between midnight and 8am
60
1.4 Strategy for angina treatment
Decrease the oxygen demand
and/or increase the delivery
BY
- Dilating arteries, especially coronary arteries,
including relieving spasm and opening collateral
circulation
- Dilating veins
- Cardiac inhibition: decrease HR, contractility,
tensility of myocardium
- Anti-platelet coagulation and thrombus formation
61
1.5 Antianginal drugs
 Nitrates 硝酸酯类
 -receptor blockers
 Calcium channel blockers
62
2. Antianginal drugs
2.1 Nitrates （硝酸酯类）
Nitroglycerin硝酸甘油
A Actions
Dilate vessels --- pre- and after-load↓
Redistribution of coronary blood flow --subendocardial area心内膜下区域↑
preload, epicardial vessels, collateral circulation,
LVFP↓
Cardiac protection against ischemia
Inhibit coagulation of platelets
63
B Mechanisms of action
Nitrates (prodrug)
NO
GC activated
[Ca2+]i
cGMP
Dephosphorylation of
myosin light chain
Vascular smooth muscle relaxation
Anticoagulation of platelets
64
C Pharmacokinetics
Time to peak effect
Duration of action
2 min
Nitroglycerin
Sublingual
25 min
15 min
Isosorbide dinitrate
Sublingual
1 hour
硝酸异山梨酯
65
D Adverse effects

Symptoms due to vasodilation: headache,
increase of intraocular pressure, postural
hypotension, facial flushing and tachycardia

Allergy

Methaemoglobinaemia高铁血红蛋白 (at very
high dose)
66
2.1 Nitrates
E Tolerance
Provision of daily “nitrate-free interval”
 To supplement -SH

E Interactions with other drugs
Antihypertensive drugs
 Alcohol and Viagra

67
2. Antianginal drugs
2.2 β-blockers
Catecholamine
 receptors
Na+ influx ↑ during Ca2+ influx ↑ during
phase 0
phase 4
K+ efflux ↑ during
repolarization
Physiological effects of  receptors in the heart
68
2. Antianginal drugs
2.2 β-blockers
Propranolol, metoprolol, atenolol
A Actions
- Decrease myocardial oxygen consumption
- Increase blood supply to ischemic area
- Improve myocardial metabolism (FFA ) and
increase oxygen supply to tissues
- Inhibit coagulation of platelets
69
2. Antianginal drugs
2.2  receptor blockers
B Therapeutic uses:
- stable and unstable type, especially
associated with hypertension or arrhythmias,
even with myocardial infarction.
- not suitable for variant type.
70
2. Antianginal drugs
2.2  receptor blockers
C Notices:
• Begin with small doses
• Withdraw gradually (rebound phenomenon)
• Better to be combined with nitroglycerin
71
2. Antianginal drugs
2.3 L-type calcium channel blockers:
2.3.1 Classificaiton
a：phenylalkylamines(苯烷胺类): verapamil(维拉帕米)
b：benzothiazepines(苯硫卓类): diltiazem(地尔硫卓)
c：dihydropyridines(二氢吡啶类):
nifedipine(硝苯地平) ，nimoldipine(尼莫地平)，
amlodipine(氨氯地平)
d：tetrandrine (粉防己碱)
72
2. Antianginal drugs
2.3.2 Antianginal effect:
- Decrease myocardial oxygen consumption
- Increase myocardial blood supply
- Protect ischemic myocardial cells
- Inhibit coagulation of platelets
73
2. Antianginal drugs
2.3.3 Therapeutic uses of CCBs:

Angina pectoris
- Stable angina: ver, dil
- Variant angina: nif
- Unstable angina: ver, dil, nif +  blockers
74
2. Antianginal drugs

Arrhythmias(ver, dil) :
- Supraventricular tachycardia
- Arrhythmias induced by triggered activity
following after-depolarization



Hypertension
- Severe: nif; - Mild to moderate: ver, dil
Cerebrovascular diseases (nif): transient ischemia
attack, cerebral thrombosis, and cerebral
embolism
Other diseases: peripheral vascular spasmodic
disease, arteriosclerosis, migraine
75
2. Antianginal drugs
Adverse effects:
Contraindications
A Peripheral edema
A Hypotension
B Sympathetic
excitation (nif)
B Severe heart failure
C Bradycardia (ver, dil)
D Atrioventricular
block
D Hypotension (nif)
C Sinus bradycardia
76
3. Combination of antianginal drugs
受体阻断药 硝酸酯类+ 受体阻断药
作用
硝酸酯类
动脉压



心率
（反射性）


心肌收缩力
（反射性）

抑制或不变
射血时间


不变
舒张期灌流时间


延长
左室舒张末压


不变或降低
心室容积


不变或缩小
Notice：
• Hypotension
• Cardiac low perfusion
77