Antihypertensive Drugs ( 抗高血压药)

1. Antihypertensive Drugs (抗高血压药) Pharmacology tanghuifang@zju.edu.cn 2012-2-21

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

17. Diuretics 2. Clinical uses: (1)Hypertension: single orcombinedwith 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. Diuretics 3. Adverse effects: plasma levels of renin  hypokalemia hyperuricemia hyperglycemia hyperlipidemia

19. Diuretics

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

24.  Receptor blockers

25. 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. 1 Receptor blockers Prazosin(哌唑嗪) 1. Pharmacological effects: (1)Blocking 1-receptor of bloodsmooth musclesand relaxing small artery and vein; (2)Decreasing peripheral resistance.

27. 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. 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. 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; ②Arrhythmiasinduced 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 sympatheticexcitation(  heart rate ): nifedipine; (3)heart rate reduced: verapamil, diltiazem; (4)hypotension:nifedipine.

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

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

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

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

46. 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. 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. 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