1. Antihypertensive drugs
Lou haiyan

2. Section 1 Introduction Definition
Hypertension is defined as a sustained diastolic blood pressure (DBP) greater than 90mmHg or systolic blood pressure (SBP) greater than 140mmHg.
Bp≥ 140/90mmHg
Morbidity: 15%~ 20%

3. Complication:

4. The Types of Hypertension
Essential hypertension 90%
Secondary hypertension 10%

5. Primary (essential) hypertension
Nearly 90% of patients have no specific cause.
Elevated blood pressure is usually caused by several abnormalities such as genetic inheritance, psychological stress, dietary factors.
Treatment: Such hypertension can be controlled by some combination of antihypertensive drugs and changes in
daily habits.

6. Secondary hypertension
10% -15% of patients has a specific cause, such as renal artery constriction, primary aldosteronism or tumors of the adrenal glands (pheochronocytoma).
Treatment:

7. Pathophysiology of hypertension
Genetic factor
Activation of sympathetic nervous system
Activation of RAAS （renin-angiotensin-aldosterone system）
Na+
Dysfunction of vascular endothelium

8. Normal regulation of blood pressure
Peripheral vascular resistance
(PVR)
Cardiac output
(CO)
Arterial blood pressure ≈ ×
Heart rate
Filling pressure
Arterial volume
Contractility

9. Response mediated by the sympathetic nervous system
sympathetic activity
Activation of β1-R
on heart
Activation of α 1-R
on smooth muscle
Cardiac
outrput
Peripheral
resistance
Renin
AngiotensinII
Aldosterone
sodium,
water retention
blood volume
Increase
in BP
Response mediated by the renin-angiotensin-aldosterone system

10. 全国高血压日历年主题 10月8日 1998年：“了解您的血压”。 1999年：“控制高血压，保护心脑肾”。
2000年：“普及高血压知识，减少高血压危害”。
2001年：“控制高血压，享受健康生活”。
2002年：“战胜高血压从社区做起！”
2003年：“保持健康生活方式，控制高血压”
2004年：“高血压与代谢综合征”。
2005年: “血压与卒中”。
2006年: “降压达标”

11. Treatment of hypertension
Diet
Loss weight
Exercise
Antihypertensive
drugs

12. 高血压的治疗目标 确切降压 稳定降压 阻断RAS,减轻或逆转靶器官损伤，降低并发症的发生率和病死率。
抗高血压治疗的目标血压： 一般 < 140/90mmHg 糖尿病、肾病患者< 130/80mmHg

13. The classification of antihypertensive agents
1. Diuretics
2. Calcium channel blocks
3. RAS inhibitors:
ACEI( angiotensin converting enzyme inhibitors)
AT1 receptor antagonist (angiotensin Ⅱ typeⅠ receptor antagonist )
Renin inhibitors

14. 4. Sympathoplegic agents:
Centrally acting agents
Ganglion-blocking agents
Adrenergic neuron-blocking agents
Adrenoceptor antagonist
β-adrenergic antagonist
α1-adrenergic antagonist
Mixed adrenergic antagonist
5. Vasodilators
Direct vasodilators
Potassium channel openers

15. Basic Antihypertensive Drugs
Section 2
Basic Antihypertensive Drugs

16. Ⅰ. Diuretics Mildness, Lasting, No tolerance. Decrease
1. Thiazide Diuretics
(moderate efficacy diuretics):
Hydrochlorothiazide
Chlorothiazide
Characteristics:
Mildness, Lasting, No tolerance. Decrease
morbidity and mortality of hypertension
complications after long-term use.

17. The Mechanism for Reduction of BP
1. Early:↑ Na+ and H2O excretion,
↓extracellular volume and blood
volume , ↓ cardiac output
2. Long:↓ Na+ of vessel wall, ↓ Na+-Ca2+
exchange, ↓ intracellular Ca2+, ↓
sensitivity of VSM to vasoconstrictors (NE).
3. Dilate VSM directly

18. Peripheral resistance Ca2+ in smooth muscle cell
sodium, water
retention
blood volume
Cardiac
outrput
Peripheral resistance
Decrease in BP
Thiazide diuretics
Na+ in vessel wall
Na+-Ca2+ exchange
Ca2+ in smooth muscle cell
initial
Long-term
The mechanism for reduction of BP of thiazide Diuretics

19. Clinical Uses and evaluation
Low-dose of thiazide diuretic therapy is safe, effective and cheap for hypertension.
Thiazide diuretics are appropriate for most patients with mild or moderate hypertension, particularly elderly patients.
Low doses of hydrochlorothiazide (25-50mg/d) exert as much antihypertensive effect as do higher doses.

20. Adverse Effects 1.Thiazide diuretics induce electrolyte disturbance:
hypokalemia, hypomagnesaemia, hyposodium et al
2. Thiazide diuretics can increase TC, TG, LDL level and renin activity, impair glucose tolerance.
Therefore diuretics should be avoided in treatment of
hypertensive diabetics or patients with hyperlipidemia.

21. Indapamide(吲哒帕胺） Increase in renal Na+ excretion diuresis
Dilate the vascular smooth muscle
Have no effect on the serum lipids

22. 2. Loop diuretics (high efficacy diuretics):
furosemide, etacrynic acid.
The loop diuretics act promptly and can be used in hypertensive emergencies or hypertension combined with renal function failure.

23. 3. Potassium-sparing diuretics (low efficacy diuretics):
spironolactone, amiloride.
Potassium-sparing diuretics are useful both to avoid excessive potassium depletion and to enhance the natriuretic effect of other diuretics.

24. II. Adrenergic Receptor Blockers
Propranolol
Metoprolol
Atenolol

25. The Mechanism of Action
(1) Blocking β1-R of heart , ↓ cardiac output .
(2) Blocking β1-R of kidney, inhibit renin release,
↓ RAS activity.
(3) Blocking peripheral sympathetic presynaptic
β2- R ,↓ NA release .
(4) Blocking β-R of CNS , ↓ peripheral
sympathetic activity.
(5) Increase synthesis of PGI2.

26. blocken ofβ-R in peripheral and central nervous system
Inhibit NA release
and vasomotor center
blocken of β1-R
on heart
Cardiac
outrput
β-R blockers
Peripheral
resistance
Decrease
in BP
PGI2
synthesis
Renin
AngiotensinII
Aldosterone
sodium,
water retention
blood volume
The mechanism for reduction of BP of β-R blockers

27. Clinical Uses and Evaluation
All types of hypertension , especially
in high renin activity and high cardiac output
The β-Blockers are useful in treating conditions that may coexist with hypertension, such as superventricular tachyarrhythmia, previous myocardial infarction, angina pectoris, migraine headache.

28. Adverse effects
(1) Common effects: CNS side effects: fatigue, lethargy, insomnia;
Sexual dysfunction (impotence) can severely reduce patient compliance.
(2) Alteration in serum lipid patterns: decrease HDL and increase plasma triacylglycerol (TG).
(3)Drug withdrawal: Abrupt withdrawal may cause rebound hypertension, probably as a result of up-regulation of β receptor.

29. Application Attention
(1) Be avoided in treating patients with
(Contraindication)
serious AV conduction block, bradycardia, bronchial asthma, peripheral vascular disease, et al.
(2) Beginning with small dose: (individual variation is larger)
(3) Combining with diuretics

30. 2.α1-adrenoreceptor antagonist
Prazosin (哌唑嗪)
Terazosin (特拉唑嗪)
Pharmacological Action :
Blocking α1-R selectively
Dilate A and V vessel BP↓

31. Do not reduce the renal blood flow Do not increase renin activity
Merit :
Do not reduce the renal blood flow
Do not increase renin activity
Do not reflex increase in heart rate
↓TG, TC, LDL-c, ↑ HDL-c

32. Clinical uses Untoward Reactions Prostate hypertrophy
All types hypertension , be united with β-R blockers and diuretics.
Prostate hypertrophy
Untoward Reactions
1. First dose phenomenon
2. Retention of salt and fluid

33. 3. αandβ-Receptor Antagonist
Labetalol (拉贝洛尔）
Carvedilol (卡维地洛）
Blocking β1= β2 > α1
Blocking α1 and β-R ,↓ BP
Light effect on heart rate and
cardiac output
Used for all types of hypertension

34. III. Calcium Channel Blockers
Nifedipine (硝苯地平）
Amlodipine（氨氯地平）
Verapamil （维拉帕米）
Diltiazem （地尔硫卓）

35. Mechanism of Antihypertension:
Calcium antagonists block the entry of calcium into the smooth muscle of the blood vessels, causing it to dilate.
Certain types such as verapamil and diltiazem can also slow the heart rate and inhibit cardiac contractility.

36. Therapeutic uses
Calcium channel blockers are useful in the treatment of hypertensive patients who also have asthma, diabetes, angina, and/or peripheral vascular disease.

37. Nifedipine 1. Action of dilating vessel is stronger
than other calcium antagonist.
2. Treatment of all types hypertension.
3. Reflex increase in sympathetic activity:
tachycardia, ↑CO ,↑renin activity
4. Short action , can increase mortality
if used for long time.

38. Amlodipine
Amlodipine belongs to long-acting calcium channel blockers which are better than nifedipine.
(1) It takes effect slowly (1--2w), lower BP steadily and continuously
(2) It does not affect heart obviously.
(3) It can reverse myocardial hypertrophy.

39. Ⅳ . Inhibitors of RAS

40. RAAS and its inhibitors
Peripheral
resistance
Renin
Aldosterone
sodium,
water retention
Decrease in BP
AngiotensinI
AngiotensinII
Angiotensinogen
Bradykinin
inactive
Increased
prostaglandin
synthsis
vasodilation
vasoconstrition
Increase in BP
ACE inhibitors
ARB
ACE
RAAS and its inhibitors

41. 1. Angiotensin Converting Enzyme Inhibitors(ACEI)
Catopril (卡托普利)
Enalapril (依那普利)
Cilazapril (西拉普利)
Benazapril (贝那普利)
Ramipril (雷米普利)

42. The Mechanism of Action
1. Inhibit ACE that cleaves Ang I to form the potent vasoconstrictor Ang II both in circulating system and local tissue.
2. diminish the degradation of bradykinin---increase bradykinin levels----increase the release of NO, PGI2
3.inhibit NA release, inhibit RAS in CNS, and decrease central and peripheral sympathetic
nerve activity

43. The Mechanism of Action
4. Inhibit generation of AngII in local tissue, inhibit or reverse myocardial and vascular remodeling
5. Decrease the secretion of aldosterone, result in decreased sodium and water retention.
6. Protect vascular endothelial cell

44. The Merits of Treatment of Hypertension
1. Have no tachycardia
2. Prevent or reverse proliferation and
hypertrophy of VSMC and myocardial cells
3. Increase renal blood flow and protect renal
function.
4. Have no electrolyte disturbance and lipid
metabolism disturbance
5. Improve life quality , ↓ mortality

45. Clinical Use
1. The ACE inhibitors are appropriate for most patients with mild or moderate hypertension, particularly hypertension with high renin activity.
2. The ACE inhibitors are useful in treating conditions that may coexist with hypertension, such as CHF, myocardial ischemia, diabetes.

46. Adverse Reactions dry cough (5-20%), angioedema, hyperkalemia,
hypotension (2%),
dry cough (5-20%),
angioedema,
hyperkalemia,
influence on development of fetus.

47. 2. Angiotensin II Receptor Antagonist (AT1- Receptor Blocking Agents)
Losartan (氯沙坦）
Valsartan（缬沙坦）
Irbesartan（厄贝沙坦）

48. Arrest Ang II combine with AT1R 1. More selective blockers of AⅡ
Pharmacological Actions
Arrest Ang II combine with AT1R
1. More selective blockers of AⅡ
effects than ACEI
2. No effect on bradykinin metabolism
Clinical Use and Evaluation
1. The action is similar to that of ACEI
2. Does not cause cough and angioedema .

49. Section 3 Other Hypotensors
1.Centrally-acting sympathoplegic drugs
2. Vasodilators

50. 1.Centrally-acting sympathoplegic drugs

51. Clonidine（可乐定） Pharmacological Action
1. Antihypertensive effect ( iv or oral)
2. Sedative effect
3. Inhibit gastrointestinal secretion
and motion

52. The Mechanism of Action
1. excite α2-R of medulla oblongata
2. activate type 1 imidazoline receptor (I1) of rostral ventrolateral medulla (RVLM)
3. excite α2-R and I1 receptor of peripheral sympathetic presynaptic membrane---- decrease release of NA

53. Clinical Use
1. Moderate hypertension: appropriate for patients with peptic ulcer
2. Morphine addiction: increase the release of endogenous opioid peptides, such as enkephalin

54. Adverse Effects 1. Dry mouth, sedation, headache,
sexual dysfunction, constipation.
2. Withdrawal reaction: tachycardia,
sweating, acute rising in BP.

55. Rilmenidine（利美尼定) Moxonidine(莫索尼定)
They belong to secondary central hypotensor, mainly excite I1 receptor of RVLM. Actions on central and peripheral α2-R are very weak, so the adverse reaction is rare. They also have no
withdrawal reaction.

56. 2. Vasodilators Hydralazine(肼屈嗪) 1. Mainly dilate small arteriols
2. reflex ↑ sympathetic and ↑ renin
activity, can induce angina
3. Used in moderate hypertension,
combined with other hypotensors
4. Can cause resembles erythematosus(10-20%) in large dose

57. Nitroprusside Sodium (硝普钠)
1. Nitroprusside Sodium lowers BP rapidly by releasing NO.
2. It take effects rapidly (30S after iv), the effects disappear quickly too (3min after stopping iv).
3.Sodium nitroprusside is always used to treat hypertensive emergency and severe cardiac failure.

58. Minoxidil (米诺地尔) Diazoxide(二氮嗪)
Potassium channel openers
Mechanism of hypotension:
↑KATP →↑K+ efflux → ↓ Ca2+ influx
→ artery dilation → BP↓
Clinical Uses
obstinate serious hypertension (hypertension
emergency and hypertensive encephalopathy)

59. Minoxidil
1. It can promote the growth of hair besides antihypertensive effect.
2.Treating obstinate hypertension must combine with diuretics and β-R blockers; It also try to treat male alopecia.

60. The antihypertensive treatment strategies
1. To normalize blood pressure effectively.
2. Controlling hypertension is usually a lifelong treatment (patient compliance)
3. To prevent target-organ damage to the heart, brain, kidneys and blood vessels.

61. 4 To decrease the blood pressure steadily.
5 Individualized care (age, concomitant disease).
6 To achieve this with no or minimal side effects by combination administration.

62. 20世纪90年代有关的调查显示 法国 20% 5.4% 美国 54% 27% 中国 城市 17.4% 4.2% 农村 5.4% 0.9%
高血压治疗率 控制率
法国 % % 美国 % % 中国 城市 % % 农村 % %

63. 高血压的治疗原则 Diuretics β-R antagonist ACEI (ARB) Calcium channel blockers
1. 根据高血压程度选药
First – line hypotensive drugs
Diuretics
β-R antagonist
ACEI (ARB) Calcium channel blockers
α1-R blockers

64. 2. 根据病情特点选药 合并支气管哮喘不宜用β-R阻断剂 合并肾功能不良者，宜用ACEI，CCB
合并CHF，宜用氢氯噻嗪，ACEI 合并高血脂者，不宜用噻嗪类和β-R阻断药 老年高血压避免使用能引起体位性低血压的药物和影响认知功能的药物
高血压危象和脑病，可iv硝普钠、二氮嗪

65. 3. 联合用药
4. 避免降压过快,过剧
5. 个体化治疗

66. 不同种类降压药物的可能组合 (最合理的组合用粗线条表示)
不同种类降压药物的可能组合 (最合理的组合用粗线条表示)
利尿剂
-blockers
ARB
ACEI
 1-blockers
CCB
ACEI

67. 1. 有效治疗与终生治疗 高血压药物治疗的新概念
1. 有效治疗与终生治疗
有关研究显示：高血压者收缩压每降低10~14mmHg，舒张压每降5~6mmHg，脑卒中↓40%，心肌梗死↓15％，总死亡率↓ 13％，心血管病死亡率↓18％，总的心血管并发症↓26％。

68. 20世纪90年代有关的调查显示
高血压治疗率 控制率 法国 % % 美国 % % 中国 城市 17.4% % 农村 5.4% %

71. 2. 保护靶器官
具有靶器官保护作用的药物：
ACEI
AT1受体拮抗剂
长效钙拮抗剂

72. Blood pressure variability( BPV,血压波动性）
3. 平稳降压
Blood pressure variability( BPV,血压波动性）
BPV高，靶器官损伤严重
抗高血压药的“谷峰比值”：第一天用安慰剂，第二天用治疗药，药物效应最大时两天的差值称为“峰”，下次给药前的差值称为“谷”。
谷峰比值应在50％以上