1. Antihypertensive Drugs (抗高血压药)
Pharmacology

2. Contents Ⅰ. Overview Ⅱ. Antihypertensive drugs most in use
Ⅲ. Other antihypertensive drugs
Ⅳ. Rational application of anti-hypertensive drugs

3. Ⅰ. Overview 指以血压升高为特征的疾病或病理状态，同时伴有动脉血管功能及组织结构形态重建。 诊断标准 在静息状态下，
收缩压（Systolic BP ）≥18.7kPa（140mmHg）
和/或舒张压（Diastolic BP ）≥12.0kPa （90mmHg）

4. Hypertension can be divided into: Essential hypertension: 90~95%
Ⅰ. Overview
Hypertension can be divided into:
Essential hypertension: 90~95%
Secondary hypertension: 5~10%
Normal blood pressure(BP), 2004:
Diastolic BP ≤ 80 mmHg
Systolic BP ≤ 120 mmHg
Criterion of hypertension:
Diastolic BP ≥ 90 mmHg
Systolic BP ≥ 140 mmHg

5. Ⅰ. Overview 2004《中国高血压防治指南》
与1999年的指南相比, 一个重要的区别是将正常血压确定为＜120/80mmHg(1999年指南为130/85mmHg). 这种改变的依据来自国内外心血管流行病学调查资料.
国内的资料显示, 当血压＞115/75mmHg时, 随着血压增加, 心血管危险显著增加. 每升高20/10mmHg, 因心血管疾病死亡的危险都将增加1倍. 而降低血压可以降低与高血压相关的心血管疾病的危险.

6. Ⅰ. Overview
将正常血压定在120/80mmHg这个水平, 并不是要求降压治疗一定要达到这个水平, 指南确定的正常血压水平与降压治疗的目标目前还有一定距离.
美国高血压预防监测、评估和治疗委员会第7次报告(JNC7)提出, 年龄＞18岁普通人群的血压控制目标是＜140/90mmHg, 但糖尿病和高危病人应＜130/80mmHg, 肾功能衰竭和蛋白尿病人更应＜125/75 mmHg.

7. The end organ damage of hypertension: Kidney: renal failure Heart: coronary disease, cardiac failure Brain: stroke

8.   Major factors influencing blood pressure: Arterial blood pressure
Ⅰ. Overview
Major factors influencing blood pressure:
Arterial blood
pressure
Cardiac
output
Peripheral
resistance  
arteriolar
tone
Blood
volume
Heart
rate
Contractility
Filling
pressure
Venous
tone
Baroreceptors and sympathetic nervous system
Renin-angiotention-aldosterol system (RAAS)

9. Peripheral resistance and vascular tone and elasticity

10. Arterial wall hypertrophy and sclerosis

11. Classification of Antihypertensive Drugs

12. Classification of Drugs
1. Drugs most in use:
(1)Diuretics
(2)Adrenoceptor blockers
(3)Calcium channel blockers
(4)Regin-angiotensin system inhibitors
2. Other drugs:
(1)Centrally-acting drugs
(2)Ganglion blockers;
(3)Noradrenergic nerve ending blockers;
(4)Vasodilators

13. Antihypertensive drugs
2003年，主要抗高血压商标名药在全球的销量中的市场份额

14. Ⅱ. Antihypertensive drugs most in use

15. Diuretics 1. Pharmacological effects:
Ⅱ. Drugs most in use(1)
Diuretics
1. Pharmacological effects:
(1)Reducing plasma volume  cardiac output ;
(2)Owing to excretion of Na+ ,  Na+-Ca2+ exchange  in vascular smooth muscle cells, Ca2+i ,  peripheral resistance .

16. Mechanism of diuretics:
①blood vol-ume ;
②Na+-Ca2+ exchange, Ca2+i in va-scular smo-oth muscle cells

17. 2. Clinical uses: (1)Hypertension:
Diuretics
2. Clinical uses:
(1)Hypertension:
single or combined with other drugs;
mild to moderate hypertension
particularly useful in the treatment of elderly patients, pure systolic hypertension, hypertension with heart failure.
(2)Other uses:
diuresis, anti-CHF, etc.

18. plasma levels of renin  hypokalemia hyperuricemia hyperglycemia
Diuretics
3. Adverse effects:
plasma levels of renin 
hypokalemia
hyperuricemia
hyperglycemia
hyperlipidemia

19. Diuretics

20. Adrenoreceptor blockers
Ⅱ. Drugs most in use(2)
Adrenoreceptor blockers
 Receptor blockers: propranolol
1. Pharmacological effects:
(1)Decreasing cardiac output;
(2)Inhibiting the release of renin from kidney(to inhibit formation of angiotension and secretion of aldosterone);
(3)Decreasing sympathetic outflow from CNS;
(4)Decreasing releasing of noradrenalin (NA) from peripheral nerve endings;
(5)Increasing production of PGs.

21. Main actions of β receptor antagonists on blood pressure

22. 3. Clinical uses: (1)Hypertension:
 Receptor blockers
3. Clinical uses:
(1)Hypertension:
All kinds of hypertension, more effective in young patients than eld-erly.
Useful in treating coexisting con-ditions, such as supraventricular tachycardia, previous myocardial infarction, angina pectoris, glauco-ma and migraine headache.

23. (2)Other uses: angina pectoris; arrhythmias. (3) Adverse effects:
 Receptor blockers
(2)Other uses:
angina pectoris; arrhythmias.
(3) Adverse effects:
cardiac depression
drug withdrawal;
inducing attack of asthma, etc.

24.  Receptor blockers

25. 1 Receptor blockers Prazosin(哌唑嗪) Terazosin(特拉唑嗪) Doxazosin(多沙唑嗪)
Ⅱ. Drugs most in use(2)
1 Receptor blockers
Prazosin(哌唑嗪)
Terazosin(特拉唑嗪)
Doxazosin(多沙唑嗪)
Trimazosin(曲马唑嗪)

26. Prazosin(哌唑嗪) 1. Pharmacological effects:
1 Receptor blockers
Prazosin(哌唑嗪)
1. Pharmacological effects:
(1)Blocking 1-receptor of blood smooth muscles and relaxing small artery and vein;
(2)Decreasing peripheral resistance.

27. 2. Clinical uses: Prazosin Hypertension: mild to moderate(single);
1 Receptor blockers
Prazosin
2. Clinical uses:
Hypertension:
mild to moderate(single);
severe hypertension(combined with diuretics and  blockers).
minimal changes in renal blood flow, glomerular filtration, and renin release.
3. Adverse effects:
first dose phenomenon(postural hypo-tension);
water and sodium retention.

28. 1 Receptor blockers

29.  and 1 Receptor blockers
Ⅱ. Drugs most in use(2)
 and 1 Receptor blockers
Labetalol(拉贝洛尔)
Carvedilol(卡维地洛)
Amosulalol(氨磺洛尔)

30.  and 1 Receptor blockers
Characteristics of  and 1 Receptor blockers:
(1) blood pressure moderately;
(2)Minimal changes in cardiac output and heart rate;
(3)Used for all kinds of hypertension, including hypertensive emergency;
(4)Less adverse effects.

31. Generations of calcium channel blockers
Ⅱ. Drugs most in use(3)
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).

32. 2. Pharmacological effects:
(1)Cardiac effects:
①Negative inotropic effect:
 excitation-contraction discoupling.
②Negative chronotropic and slowing conduction action:
 spontaneous depolarization of phase 4 and phase 0 of slow response auto-nomic cells.
③Protective effect on cardiac ischemia

33. (2)Effects on smooth muscles:
①Vascular smooth muscle:
relaxing the arterial smooth muscles,   blood pressure(BP),
especially relaxing the coronary artery, increasing blood supply to cardiac muscle.
②Other smooth muscle:
relaxing smooth muscle of bronchus (支气管), gastro-intestinal tract(胃肠道), ureter(输尿管), and uterus(子宫).

34. (3)Anti-atherosclerosis:
①Alleviating Ca2+ overload;
②Inhibiting proliferation of smooth muscle cells and protein synthesis of arterial matrix;
③Inhibiting lipid peroxidation;
④Decrease cholesterol level.

35. (4)Hemodynamic effects:
①Improving membrane stability of erythrocytes;
②Inhibiting platelet aggregation.
(5)Others:
①Kidney:
Increase the blood flow of kidney.
②Endocrine:
inhibiting the release of ACTH, TSH, insulin, etc.

36. 4. Clinical uses: (1)Angina pectoris: ①Variant angina: nifedipine
②Stable angina:
verapamil, diltiazem
③Unstable angina:
verapamil, diltiazem,
nifedipine +  receptor blockers

37. (2)Arrhythmias: ①Supraventricular tachycardia;
②Arrhythmias induced by triggered activity following afterdepolarization.
—— verapamil, diltiazem

38. (3)Hypertension: ①Severe: nifedipine ②Mild to moderate:
verapamil, diltiazem
③Complicated with:
coronary heart disease;
myocardial ischemia;
peripheral vascular diseases;
bronchial asthma;
COPD(chronic obstructive pulmonary diseases), etc.

39. (4)Cerebrovascular diseases:
transient ischemic attack;
cerebral thrombosis;
subarachnoid hemorrhage.
(5)Others:
peripheral vascular spasmodic diseases;
arteriosclerosis;
etc.

40. 5. Adverse effects: (1)peripheral edema:
nifedipine >verapamil >diltiazem
(2)symptoms of sympathetic excitation(  heart rate ):
nifedipine;
(3)heart rate reduced:
verapamil, diltiazem;
(4)hypotension: nifedipine.

41. 6. Contraindications: nifedipine: hypotension;
verapamil and diltiazem:
severe heart failure;
sinus bradycardia;
atrioventricular(AV) conduction block.

42. Selectively acting on cerebral vasculature
Nimodipine(尼莫地平)
Selectively acting on cerebral vasculature

43. Potent efficacy on the heart, and weaker on the vessels
Verapamil(维拉帕米)
Potent efficacy on the heart, and weaker on the vessels

44. Potent efficacy on the heart and the vessels
Diltiazem(地尔硫卓) 艹
Potent efficacy on the heart and the vessels

46. 1. Pharmacological effects: 2. Clinical uses:
Ⅱ. Drugs most in use(3)
Nifedipine(硝苯地平)
1. Pharmacological effects:
Relaxing vascular smooth muscles.
2. Clinical uses:
Mild to severe hypertension.

47. Reflex sympathetic activation; Renin activity .
Ⅱ. Drugs most in use(3)
3. Adverse effects:
Peripheral edema;
Reflex sympathetic activation;
Renin activity .
Other calcium channel blockers:
Amlodipine(氨氯地平), etc.

48. Ⅱ. Drugs most in use(3)

49. Renin-angiotensin system inhibitors
Ⅱ. Drugs most in use(4)
Renin-angiotensin system inhibitors
ACEI:
captopril (卡托普利),
enalapril (依那普利)
AT1 receptor antagonists:
losartan (氯沙坦)
Renin inhibitors:
enalkiren (依那吉仑)

50. Ⅱ. Drugs most in use(4)
Renin inhibitors

51. AngII 在器官损害中作用 Ⅱ. Drugs most in use(4) AngII AT1 receptor
Atherosclerosis*
Vasoconstriction
Vascular hypertrophy
Endothelial dysfunction 中风
高血压
AngII AT receptor
LV hypertrophy
Fibrosis
Remodelling
Apoptosis 心衰
心肌梗塞
DEATH
GFR
Proteinuria
Aldosterone release
Glomerular sclerosis 肾衰
*Preclinical data
LV = left ventricular; MI = myocardial infarction; GFR = glomerular filtration rate

52. Ⅱ. Drugs most in use(4)

54. Angiotensin converting enzyme inhibitors(ACEI)
Ⅱ. Drugs most in use(4)
Angiotensin converting enzyme inhibitors(ACEI)

55. 1. Pharmacological effects:
ACEI
1. Pharmacological effects:
(1)Inhibiting the production of AngⅡ;
(2)Inhibiting the degradation of bradykinin, to vasodilatation;
(3)Decreasing the activity of sympathetic system;
(4)Inhibiting ventricular remodeling;
(5)decreasing aldosterone.

56. 2. Clinical uses: Hypertension
ACEI
2. Clinical uses:
Hypertension
not reflexly increasing the activity of sympathetic system;
effective in the patients with CHF, diabetes and ischemic heart disease also.

57. hypotension(first dose phenomenon) renal injury dry cough hyperkalemia
ACEI
3. Adverse effects:
hypotension(first dose phenomenon)
renal injury
dry cough
hyperkalemia
angioneuroedema
rashes and altered tastes
Contraindications:
renal artery stenosis, pregnant and lactational women.

58. Ⅱ. Drugs most in use(4)
AT1 antagonists
Losartan(氯沙坦)

59. (1)Block actions of angiotensin Ⅱ directly;
AT1 antagonists
Compared with ACEI:
(1)Block actions of angiotensin Ⅱ directly;
(2)Not influence bradykinin metabolism;
(3)Protect renal funtion;
(4)Used for mild to moderate hypertension;
(5)Less adverse effects.

60. Renin inhibitors Enakiren(依那吉仑) Remikiren(瑞米吉仑)
Ⅱ. Drugs most in use(4)
Renin inhibitors Enakiren(依那吉仑) Remikiren(瑞米吉仑)
peptide or nonpeptide renin inhibitors.
They inhibit whole RAAS
Other drugs: renin antibody.

61. ACEI & AT1antagonists

62. Ⅲ. Other anti-hypertensive drugs

63. Centrally-acting drugs:
Ⅲ. Other Drugs(1)
Centrally-acting drugs:
Clonidine(可乐定)

65. Centrally-acting drugs
Clonidine
1. Pharmacological effects:
Diminishing central adrenergic outflow;
Activating 2 and I1 receptor in medulla.
2. Clinical uses:
Hypertension: mild to moderate hyper-tension that has not responded adequately to treatment with diuretics alone.
minimal changes in renal blood flow and glomerular filtration inhibit gastro-intestinal secretion and mobility.

66. Centrally-acting drugs
Clonidine
3. Adverse effects:
(1)Central and atropine-like side effects;
(2)long-term uses:
water and sodium retention;
rebound phenomenon.

67. Ganglionic blockers Trimetaphan(米噻芬) Mecamylamine(美卡拉明) Short-acting;
Ⅲ. Other Drugs(2)
Ganglionic blockers
Trimetaphan(米噻芬)
Mecamylamine(美卡拉明)
Short-acting;
Tolerance;
For controlling hypotension.

68. Noradrenergic nerve ending blockers
Ⅲ. Other Drugs(3)
Noradrenergic nerve ending blockers
Reserpine(利舍平, 利血平)
Guanethidine(胍乙啶)
(1)Decresing NA storage in noradre-nergic nerve endings;
(2)Slow and lasting effects;
(3)Central depression.

69. Vasodilators (Peripheral vasodilators)
Ⅲ. Other Drugs(4)
Vasodilators (Peripheral vasodilators)
Hydralazine
(肼屈嗪)
Dihydralazine
(双肼屈嗪)
Sodium Nitroprusside
(硝普钠)

70. Hydralazine(肼屈嗪) Vasodilators (1)Dilating arteries and arterioles;
Ⅲ. Other Drugs(4)
Hydralazine(肼屈嗪)
(1)Dilating arteries and arterioles;
(2)Decreasing peripheral resistance;
(3)Reflexly elevating heart rate, cardiac output and renin release.
Combined with  blockers and diuretics.
Adverse effects:
due to vasodilation;
and lupus-like syndrome.

71. Nitroprusside sodium(硝普钠)
Vasodilators
Ⅲ. Other Drugs(4)
Nitroprusside sodium(硝普钠)
Dilating small arteries and veins.
Clinical Uses:
(1)emergency hypertension;
(2)hypertension with CHF and obstinate CHF;
(3)controlled blood pressure in surgical operation.
Adverse effects:
due to hypotension in excess;
and sulfocyanate(硫氰化物) poisoning.

72. Potassium channel openers
Ⅲ. Other Drugs(4)
Potassium channel openers
Including: minoxidil(米诺地尔), nicorandil(尼可地尔), diazoxide (二氮嗪), etc.
(1)Dilating arteries (Ca2+ influx );
(2)Reflexly elevating heart rate, cardiac output and renin release.
Used for treatment of obstinate(顽固性) and severe hypertension
Adverse effects:
include sodium retention, palpitation, etc.

73. Ⅳ. Rational application of antihypertensive drugs

74. Ⅳ. Rational application of antihypertensive drugs
Prescription according to the degree of hypertension:
(1)Mild:
single drug: diuretics,  blockers, ACEI, calcium channel blockers, 1 blockers, or AT1 blockers.
(2)Moderate:
combined with two above drugs.
(3)Severe:
adding centrally acting drugs or vasodilators to the two combined drugs.

75. 2. Prescription according to complications:
Ⅳ. Rational application of antihypertensive drugs
2. Prescription according to complications:
Complications
Options
Avoidance
Severe CHF and/or
COPD
Diuretics, ACEIs, prazosin
 blockers
Renal failure
ACEIs, CCBs
Tachycardia
GI ulcer
Clonidine
Reserpine
Diabetes and gout
ACEIs, prazosin
Thiazide

76. Ⅳ. Rational application of antihypertensive drugs
(1)Hypertensive emergency:
vasodilators(nitroprusside sodium, diazoxide), labetalol, loop diuretics.
(2)Elderly patients:
avoiding drugs that could induce postural hypotension(eg. 1blockers) and influence the cognizant ability. (clonidine, methyldopa).
(3)Cardiac ischemia:
avoiding (peripheral) vasodilators.

77. Ⅳ. Rational application of antihypertensive drugs
3. Combination of drugs;
4. Avoid blood pressure to decrease too rapidly and excessively;
5. Individual therapy.

78. The drugs for treatment of CHF
Ⅰ. Cardiac glycosides(强心苷类)
Ⅱ. Diuretics and vasodilators(利尿药和血管扩张药)
Ⅲ. ACE inhibitors and relative recep-tor antagonists(血管紧张素Ⅰ转换酶抑制药和相关受体拮抗药)
Ⅳ. Other anti-CHF drugs(其他抗心衰药)

79. Diuretics
CHF
CHF: grand Ⅰ-Ⅳ(mainly used in Ⅱ-Ⅲ), alone or combined with other drugs
Edema, hypertension, etc.
Commonly used drugs:
Thiazide(噻嗪类):
hydrochlorothiazide(氢氯噻嗪)
Semide(塞米类):
furosemide(呋塞米)
Renone(螺内酯类):
spironolactone(螺内酯)
Adverse effects:
Thiazide(噻嗪类), Furoemide(呋塞米)
inducing hypokalemia
 digitalis cardiotoxicity 
should replenish KCl.

80. Vasodilators  Cardiac preload and afterload,   cardiac output.
CHF
Vasodilators
 Cardiac preload and afterload,   cardiac output.
Nitroglycerin(硝酸甘油);
Nitroprusside sodium(硝普钠),
Hydralazine(肼屈嗪),
Prazosin(哌唑嗪), etc.

81. Angiotensin Ⅰconverting enzyme inhibitor: ACEI
CHF
Angiotensin Ⅰconverting enzyme inhibitor: ACEI
Commonly used drugs:
Captopril(卡托普利)
Enalapril(依那普利)

82.  receptor blockers Carvedilol(卡维地洛) and Labetalol(拉贝洛尔), etc.
CHF
 receptor blockers
Main drugs:
Carvedilol(卡维地洛) and
Labetalol(拉贝洛尔), etc.
 receptor blockers can inhibit cardiac function, but Carvedilol is a nonselective  receptor blockers and an 1-selective  receptor blockers.
In patients randomized to carvedilol there was a 65% reduction in all-cause mortality, which was indenpent of age, gender, and etiology of heart failure, etc.

83. Antianginal Drugs A. Organic nitrates(硝酸酯类) B.  receptor blockers
Nitroglycerin(硝酸甘油)
Other organic nitrates(其他硝酸酯类):
Isosorbide dinitrate(硝酸异山梨酯)
Isosorbide mononirate(单硝酸异山梨酯)
B.  receptor blockers
stable and unstable type, especially associated with hypertension or arrhythmias, even with myocardial infarction.
C. Calcium channel blockers
(1)stable and variant type (nifedipine, verapamil, diltiazem)
(2)unstable type (verapamil, diltiazem)

84. Combination of antianginal drugs
心肌氧供需决定因素
硝酸酯类
受体阻断药
钙拮抗药
室壁张力 
心室容积 
心室压力
心脏体积 心率
收缩性
心内外膜
血流比率
侧枝血流量

85. Combination of antianginal drugs作用
硝酸酯类
受体阻断药
硝酸酯类+
动脉压 
  心率
(反射性)
心肌收缩力
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