1. Antihypertension Drugs Shi-Hong Zhang ( 张世红 ) Pharmacology, Dept. of shzhang713@zju.edu.cn

2. Outline Overview Classification of antihypertensive drugs Antihypertensive drugs Clinical pharmacology of antihypertensive drugs

3. 1. Overview Criteria of hypertension diagnosis

4. 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%)

5. The end organ damage of hypertension: Kidney: renal failure Heart: coronary disease, cardiac failure Brain: stroke MI or CHF 50% Stroke 33% Kidney Failure 15% Other 2%

6. 其它危险因素和病史 血压 I级I级 II 级 III 级 Ⅰ 无其它危险因素低危中危高危 Ⅱ 1~2 个危险因素中危 很高危 Ⅲ ≥3 个危险因素高危 很高危 Ⅳ靶器官损害或糖尿 病并存的临床情况 很高危 按危险分层，量化地估计预后 低危患者 30% 的风险在未来十年发生心血管事件。

7. Age-adjusted annual incidence of CHD 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 Coronary Heart Disease in Men Diastolic blood pressure (mmHg) Age 65-94 Age 35-64 Age 65-94 Age 35-64 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. Arterial blood pressure Cardiac outputPeripheral resistance Venous tone Blood volume Filling pressureContractility Heart rate arteriolar volume Baroreceptors and sympathetic nervous system RAAS 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 ) - AR 1 Bs ( 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 )

14. 3. Antihypertensive Drugs 3.1 Diuretics Thiazide, loop, potassium-sparing diuretics A Actions Reduce plasma volume (cardiac output  ) Reduce Na + -Ca 2+ exchange in vascular smooth muscle cell (peripheral resistance  )

15. 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. Antihypertensive Drugs

16. 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. Antihypertensive Drugs

17. 3.2 Calcium channel blockers (CCBs) Nifedipine 硝苯地平 A Actions: Relaxes vascular smooth muscle B Therapeutic uses: m ild to severe hypertension (usually combined with  blockers ) C Adverse effects: peripheral edema, reflex sympathetic activation, and renin activity  3. Antihypertensive Drugs

18. 3.3 Renin-angiotensin system inhibitors ACEIs: Captopril AR 1 Bs: Losartan Renin inhibitors: renin antibody, peptide and nonpeptide renin inhibitors (eg. aliskiren)

19. Chymase 激肽释放酶 激肽原 血管紧张素原

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.

22. 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 AR 1 Bs 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

24. 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  )

25. 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

26. 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

28. 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)

29. 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)

30. 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

31. 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 I 1 receptor in the medulla

32. 3. Antihypertensive Drugs

33. 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 I 1 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. Diuretics β blockers 3. Antihypertensive Drugs 3.5 Vasodilators

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 (Ca 2+ 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. 4.1 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.

42. 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

43. 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;

44. Lifestyle modifications to manage hypertension

45. DASH diet

48. 4.2.1 Prescribe according to the severity of hypertension Mild: monotherapy from ACEIs, CCBs, AR 1 Bs, 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. Clinical pharmacology of antihypertensive drug

49. 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. Clinical pharmacology of antihypertensive drug 4.2.3 Combination therapy 4.2.4 Avoid blood pressure to decrease too rapidly and excessively 4.2.5 Individual therapy

50. 4.2.2 Prescribe according to complications 4. Clinical pharmacology of antihypertensive drug

51. 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 ” 。

52. 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

53. 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