Cardiovascular drugs Drugs used to treat cardiovascular disorders Drugs for congestive heart failure Antiarrhythmics Antianginals Antihypertensives Di

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1 Cardiovascular drugs Drugs used to treat cardiovascular disorders Drugs for congestive heart failure Antiarrhythmics Antianginals Antihypertensives Diuretics Anti lipemics Diabetes High Blood Pressure Smoking Tobacco Cholesterol Malnutrition Sexually transmitted diseases 1 Preventable Causes of Death Worldwide Poor diet Overweight and obesity Physical inactivity Alcohol Air pollution and poor sanitation World Health Organization Number of Deaths (000s) Worldwide Incidence of hypertension 2002: 18.8% in China 2002~ 35~74 year old: 27% in China Hypertension Patients: > 100million Stroke patients: 5 million 1 in 5 adults have systolic and/or diastolic blood pressure above normal pressure. 51.5% 46.1% 16.9% Antihypertensive drugs 四川大学药理教研室朱玲 (zhuling529@163.com) Basic information of hypertension 70 million Americans 1 billion people 1 in 2 controlled 40% of heart attacks, 50% of strokes Cost to US healthcare $43 billion/yr Definition Major Risk Factors Complication: High blood pressure increases the risk of: What Determines Arterial Pressure? Therapeutic lifestyle changes antihypertensive drugs Pharmacological Management of Hypertension 1

2 Basic information of hypertension Blood pressure The resting (>5min), Bp SBP: 90 ~140mmHg H DBP:60 ~ 90mmHg Category Optimal Normal High- normal Stage 1 Stage 2 Stage 3 Systolic (mm Hg) <120 < Hypertension >180 and and or or or or China 2018 新指南 90 Diastolic (mm Hg) <80 < >110 Severity of end-organ damage Sustained hypertension Damages blood vessels brain stroke in heart CHF, coronary disease kidney renal failure morbidity and mortality. Blindness 美 2017 年高血压指南的新定义 Classified on the basis of the cause of hypertension : 1. Essential hypertension (also know as primary or idiopathic hypertension) Accounting for more than 90%. 2. Secondary hypertension Renal artery constriction Endocrine disorders : Cushing s disease (hyperadrenocorticism), thyroid disorders, Pheochromocytoma of adrenal medulla Aortic coarctation Autoimmune disorders such as periarteritis nodosa Alcohol abuse Atherosclerosis Cocaine use Diabetes.. Stroke Nephrosclerosis Thickened left ventricle Dyspnea, Orthopnea, pulmonary edema, Peripheral edema, Retinopathy High blood pressure increases the risk of: 2

3 Multifactorial causes Genetic inheritance 20-40% Psychologic stress Dyslipidemia,Diabetes mellitus, Age Life style: intake: salt potassium calcium fat obesity smoking drunk Body mass index (BMI) : BMI= Mass(kg) (height(m)) 2 Based on WHO: below 18.5 are considered underweight. between 18.5 and 24.9 are considered normal weight. between 25.0 and 29.9 are considered overweight BMI of 30.0 and above are considered obese. 有关腹型肥胖的标准 : 中国人 waistline 男性 85cm 女性 80cm Therapeutic lifestyle changes (TLC)? Salt and high blood pressure Daily salt consumption: 1,000 mg Na =2.5 g NaCl Prehistoric level: 0.5 g Current U.S. level: 10 g 80% from processed food 3.5 g NaCl 7.4 g NaCl DASH eating plan---decrease SBP 8-14mmHg DASH: Dietary Approaches to Stop Hypertension an eating plan low in total fat, saturated fat, and cholesterol; and rich in fruits, vegetables, and low fat dairy products. Lifestyle Modifications Approximate SBP Reduction mmhg Weight reduction 5 20 eating plan 8 14 Reduced Sodium Intake 2 8 Physical activity 4 9 Moderation of alcohol consumption 2 4 3

4 Most patients Diabetes Goal Blood Pressure Chronic Renal Disease SBP mm Hg < 138 < 83 < 130 < 80 < 130 < 80 DBP mmhg 保持心脏健康的方法 Treatment of hypertension Diet Loss weight Exercise Antihypertensive drugs Antihypertensives drugs The antihypertensives drugs are a class of drugs that are used to treat hypertension Evidence suggests that reduction of the blood pressure by 5 mmhg can decrease the risk of stroke by 34%, of ischaemic heart disease by 21%, and reduce the likelihood of dementia, heart failure, and mortality from cardiovascular disease 根本目标减少心, 脑, 肾及血管并发症并发症, 延长寿命, 降低死亡的危险 What Determines Arterial Pressure? Arterial Pressure Mechanism Blood volume Heart Rate Filling Pressure Cardiac Output ~ X Contractility Venous tone Peripheral Resistance Arteriolar volume Hormonal and nervous regulation Baroreceptors and chemoreceptors Renal response 4

5 Regulation : Sympathetic nervous system Renin - angiotensin - aldosterone system αr blocker What would you do? Differential diagnosis Pharmacological options What should you be ready for? How would you treat this patient? Drugs Drugs used to treat hypertension must lower blood pressure Some act through the autonomic nervous system Others by regulating fluid balance or endocrine mechanisms <140/90 mmhg <130/80 mmhg Case Study A 35-year-old man presents with a blood pressure of 150/95 mm Hg. He has been generally healthy, is sedentary, drinks several cocktails per day, and does not smoke cigarettes. He has a family history of hypertension, and his father died of a myocardial infarction at age 55. Physical examination is remarkable only for moderate obesity. Total cholesterol is 220 and high-density lipoprotein (HDL) cholesterol level is 40 mg/dl. Fasting glucose is 105 mg/dl. Chest x-ray is normal. Electrocardiogram shows left ventricular enlargement. How would you treat this patient? Generously used antihypertensive drugs 1. Drugs reducing blood volume: Diuretics: thiazide, furosemide, spironolactone, triamterene. 5

6 利尿剂 Diuretics : 临床试验 SHEP 试验 (Systolic Hypertension in the Elderly Program)5 年观察, 氯噻酮治疗组卒中相对危险减少 36%, 各种原因的死亡减少 36%, 主要心血管事件下降 32% 近期 NetworkMetaanalysis42 项临床研究, 发现多种终点事件, 包括冠心病 心力衰竭心血管总死亡率等, 噻嗪类利尿剂显著优于安慰剂 Antihypertensive effects Lowing blood pressure of 10% Initially lowers blood pressure by reducing plasma volume Maintaining effect after few weeks by reducing the peripheral resistance. [Na + ] [Na + ] [Ca 2+ ] Potassium sparing diuretics: Hypertension with potassium deletion or primary aldosteronism Usually togetherth with thiazide. id Adverse reaction? Diuretics ++++ Thiazides and thiazides-like diuretics ++ Aldosterone antagonists + Potassium sparing diuretics + Loop diuretics Therapeutic uses Thiazide: Used in all kinds of hypertension, alone or together with other antihypertensive, such as vasodilator drugs or beta-blocking drugs. HCT mg/d. 25mg/d Furosemide: Hypertension with pulmonary edema or renal failure 吲达帕胺 (indapamide) Structure: not-thiazidesthiazides Mechanism diuresis natriuresis arteriolar vasodilator Ca 2+ EDRF Clinical uses mild,moderate hypertension (hyperlipidemia) Adverse reaction slight 6

7 Indapamide Dosage and administration The adult dosage is 1.25 to 5 mg by orally once daily usually in the morning. Contraindications Indapamide is contraindicated in known hypersensitivity to sulfonamides, severe renal failure, hepatic encephalopathy or severe hepatic failure and hypokalemia There is insufficient safety data to recommend indapamide use in pregnancy or breastfeeding. Blood pressure 2. 1 肾上腺素受体阻断药 Predominant Sympathetic Tone Cardiac output Peripheral vascular resistance alpha 1,2 beta 2 constriction dilatation Sympathetic nervous inhibitors 2 交感抑制药 Sympatholytics Centrally Active Clonidine Methyldopae y Guanabenz Guanfacine Adrenergic Neuron Blocker Guanadrel Guanethidine e Reserpine α- 受体阻断药 Adrenoceptor Antagonists Propranolol (beta) Labetalol (alpha & beta) Prazosin, Terazosin (alpha) alpha-arenoceptor Antagonist? alpha1-arenoceptor Antagonist 哌唑嗪 (Prazosin) 特拉唑嗪 (Terazosin) 多沙唑嗪 (Doxazosin) 7

8 Adrenoreceptor blockers (1). Prazosin pharmacological effects (a) Selective blockade the α 1 -receptor of the peripheral blood vessels(arteriole and vein), the efficacy is like to clothidine, (b) Not change the cardiac output, renal blood flow, glomerulus filtration and heart rate(not like phentolamine) (c) Reduce the preload and afterload (d) Increase the level of the HDL in blood prazosin Adverse reaction The venous dilation is probably the cause of the first dose phenomenon ( First dose hypotension) orthostatic hypotension how to avoid? (2)β-receptor blockers Propranolol Actions The effect is mild, the haemodynamic picture changes and blood pressure begins to fall progressively in several weeks after oral administration. It is not liable to cause orthostatic hypotension. 宜从小剂量开始 (40~60mg), 每周增加 20mg, 以不超过 300mg 为宜 Therapeutic uses Used in moderate or severe hypertension with kidney dysfunction or with prostatic hypertrophy; better maintained by giving prazosin together with diuretics. Congestive heart failure. Prostate hyperplasia. β 受体阻断剂 特拉唑嗪 (Terazosin) 多沙唑嗪 (Doxazosin) prazosin 临床试验 HAPPHY (Heart Attack Prevention in Hypertension) 与 MAPHY (Metoprolol Atherosclerosis Prevention in Hypertension) 试证明 β 受体阻滞剂降压作用明显, 在降低总死亡率 CVD 与卒中的死亡率良好, 与利尿剂比较, 不同试验的结果不尽相同??? Mechanism of action Blockade central β-receptor Blockade the peripheral presynaptic β-receptor, inhibiting positive feedback, finally blockade the noradrenaline release, PG Prostacyclin. 8

9 Uses of propranolol It is used in mild, moderate and severe hypertension Especially hypertension with coronary atherosclerotic heart disease, cerebrovascular pathologic change,young patients. The effects is well when combination with vasodilators, diuretics. Angina pectoris, Myocardial infarction Cardiac arrhythmia, tachycardia,atrial fibrillation Contraindication? α,β -receptor blockers 拉贝洛尔 (labetolol) 卡维洛尔 (carvedilol) β 1 -receptor blockers 美托洛尔 (metoprolol) l) 阿替洛尔 (atenolol) 比索洛尔 (bisoprolol ) β-receptor blockers 2.2 Sympathetic nervous inhibitor (1)Antihypertensive drugs of acting on CNS Clonidine Effects 1) Fall in blood pressure companying effects of a reduced cardiac output and heart rate. 2) It inhibits secretion of renin and alimentary canal, it also inhibits the motion of alimentary canal. 3) Clonidine has sedative action. Contraindications Acute heart failure Sick sina syndrom, AV-Blockage of second and third degree, bradycardia (pulse less than 50 bpm) asthmatics(may cause bronchoconstriction) Peripheral vascular disease, Raynaud's syndrome 中枢性抗高血压药 中枢神经系统 Withdrawal syndrome! 其他抗高血压药交感神经抑制药 抑制性神经元 :α 2 受体, 兴奋 外周交感神经活性 兴奋性神经元 :β 受体, 兴奋 外周交感神经活性 代表药 : 可乐定 甲基多巴 利美尼定 莫索尼定等 Methyldopa guanfacine Guanabenz clonidine Moxonidine Rilmenidine imidazole receptors 9

10 Clonidine Mechanism of action ⑶ In peripheral, stimulation of presynaptic α 2 -receptor diminishes release of transmitter, feedback system for control of intrasynaptic norepinephrine concentration. It then has peripheral action by adding to inhibition of norepinephrine release. Clonidine Clinical Uses Used in moderate and severe hypertension, especially hypertension with gastric ulcer, conjunction to diuretics or vasodilators when other drugs are ineffective. Used to treat other withdrowal syndromes such as that from opium. Clonidine Mechanism of action ⑴It achieve its effect by stimulation of imidazole receptors (I 1 R). ⑵ Also It reduces sympathetic tone, within the brain stem, by stimulating α 2A - receptor on neurons of vasomotor centers which inhibit outflow of impulses to spinal preganglionic neurons. Clonidine mechanism of action However, α 2b -receptors at post- or nonsynaptic sites on cardiac or smooth-muscle cells may be stimulated by α 2 agonists, causing an increase in pressure. Thus a transient rise in pressure may occur within the first hour after giving a single dose of clonidine Clonidine Adverse effects Dry mouth, drowsiness, constipation, dizziness, nausea or gastric upset, fatigue, weight gain, gynecomastia( 男性乳房发育 ), pruritis, allergic rash, sexual impotence, urinary retention, sleep disturbance (insomnia, nightmare), parotid pain, rebound. 10

11 神经节阻断药 选择性与神经节细胞 N 1 胆碱受体结合, 妨碍 Ach 与受体结合, 阻断神经冲动在神经节中的传递 阻断交感神经节 A V 舒张 外周阻力 BP 阻断副交感神经节 心率 视力模糊 口干 便秘 尿潴留等 仅用于高血压危象 主 A 夹层动脉瘤 外科手术控制血压 樟磺咪芬 (Trimetaphan, 米噻芬 ) 美卡拉明( Mecamylamine) 潘必定(Pempidine) 潘托安( Pentolonium) 等 3 Calcium Channel Blockers 钙拮抗药 Dihydropyridines Amlodipine 氨氯地平 Lacidipine 拉西地平 Felodipine 非洛地平 nitrendipine 尼群地平 Nimodipine 尼莫地平 Isradipine 伊拉地平 Nicardipine 尼卡地平 Nifedipine 硝苯地平 Non-Dihydropyridines Bepridil (Vascor) Diltiazem (Cardiazem) 地尔硫卓 Verapamil 维拉帕米 (Isoptin, Calan) tetrandrine 粉防己碱 Reserpine acts by depleting norepinephrine and dopamine from vesicles. 2.3 Reserpine acts by depleting norepinephrine and dopamine from vesicles. Reserpine Calcium Channel Blockers Pharmacological effect Cardiac function: inhibition Vascular smooth muscle: artery dilation Other smooth muscle: relaxation (generally higher dose) Anti-atherosclerosis Other: inhibition of platelet activation, increased renal blood flow, etc. 11

12 3 Calcium channel blockers Dihydropyridines Nifedipine Inhibits extracellular calcium inflow vascular smooth muscle relaxation. It also inhibits renal vessel contraction induced by endothelin. Had no significant effect on glucose and lipid metabolism Nifedipine ( 硝苯地平, 心痛定 ) Adverse reaction A case control study has found that hypertensive patients taking short-acting nifedipine, diltiazem or verapamil were 1.6 times more likely to have a myocardial infarction compared to patients taking other antihypertensive drugs. Always combination with β-receptor blocker or diuretics. Recommended release tablets 钙拮抗剂的降压作用 增加心血管事件 癌症及出血危险? 支持 :Furberg Pstay Pahor 反对 :APSIS PRAISE MIDAS 试验 上海治疗老年高血压临床试验 (STONE) 中国老年收缩期高血压临床试验 (Syst-China) Nifedipine ( 硝苯地平, 心痛定 ) Therapeutic uses All kinds of hypertension, especially hypertension combined with angina (variant), or elderly patients. It is used alone or combination with β- receptor blocker or diuretics, ACEI. Recommended release tablets Calcium Channel Blockers Adverse Effects Dizziness, headache, fatigue, ankle edema. SA nodal inhibition may lead to bradycardia or SA nodal arrest. GI reflux constipation Negative inotropic are augmented if beta- adrenergic receptor antagonists are concurrently administered. Calcium channel blockers should not be administered if the patient has SA or AV nodal abnormalities or in patients with significant congestive heart failure. 钙拮抗剂增加不良反应的机制 Pstay: 激活交感神经 心血管事件 Pahor: 抑制细胞凋亡 癌症危险 Pahor: 抑制血小板聚集, 正常血管 收缩反应减弱 出血危险 12

13 Amlodipine 氨氯地平 Long-acting drug ( 24 24h) Amlodipine decreases in blood pressure are not accompanied by a significant change in heart rate or plasma catecholamine levels with chronic dosing. Remolding cardiac hypertrophy Clinical Use: hypertension Stable angina pectoris Prinzmetal s variant angina petoris 补钙为什么能降低血压呢? 国外对 580 例高血压病人和 330 例正常人进行观察, 让他们每日服用超过正常规定量 800 毫克的钙,8 周后发现高血压患者收缩压和舒张压都有下降, 而正常人不变 目前认为, 可能由如下机制所致 : 补钙是为了纠正负钙平衡, 防止体内的钙代谢紊乱和骨钙丢失, 同时避免钙盐异常沉积在血管 软组织内, 减少动脉粥样硬化的发生 1 钙的膜稳定作用 钙结合在细胞膜上可降低细胞膜通透性, 提高兴奋阈, 使血管平滑肌松弛? 2 钙自身可阻断钙通道, 使细胞外的钙离子不能进入细胞内? 3 高钙可对抗高钠所致的尿钾排泄增加, 而钾离子对稳定细胞膜起重要作用 维持足够的高钙摄入, 可抵抗高钠的有害作用 4 有学者认为,40% 的血压升高与甲状旁腺有关 甲状旁腺可产生一种耐高热的多肽物质, 这是引起高血压的罪魁祸首, 称为 致高血压因子 致高血压因子 的产生受低钙饮食刺激, 而高钙饮食可抑制其产生 4.1 血管紧张素转化酶抑制剂 Angiotensin converting enzyme inhibitors ACEI 荟萃分析认为 ACEI 比 Diuretics 和 β receptor blocker 能更好地预防心血管事件的发生, 特别可以明显降低心力衰竭与冠心病的危险 尼莫地平 nimodipine: 氟桂嗪 (flunarizine) Strong cerebral vascular relaxation Indications: hypertension associated with cerebrovascular disease, cerebral ischemia, i cerebral vasospasm and subarachnoid hemorrhage 维拉帕米 verapamil: Hypertension associated with tachyarrhythmias 4 Drugs of inhibiting renin- angiotensin system (RAS) (1) Angiotensin-converting enzyme inhibitors (ACEI) (2) Angiotensin Ⅱreceptor antagonists (ARB) (3) Renin inhibitors (4) Antagonist of aldosterone Indications ACE Inhibitors 80 s - Hypertension 90 s - Heart Failure 95 - Left Ventricular Dysfunction 95 - Diabetic Nephropathy 96 - Acute Myocardial Infarction 13

14 Case study A hypertensive patient, male, 42y, accompa nied by diabetic nephropathy, gout, left vent ricular hypertrophy, which antihypertensive drugs the patient t is preferred? Diuretics? β-receptor blockers? Calcium Channel Blockers? ACE inhibitors kidney renin Na + Fluid Sodium retention Renin ACE AT 1 receptor Renin Angiotensin Aldosterone System Angiotensinogen Angiotensin-I Angiotensin-II gote NA Angiotensinogen Angiotensin I (AI) Angiotensin II (AII) Aldosterone Vasoconstriction PR liver VASOPRESSIN BP Bp AT (1-7) 受体 ACEI ACE LV/vascular hypertrophy AT 2 receptor Reverse limits remodelling/ myocardial hypertrophy activity No tachycardia Increase renal blood flow Prevent or reverse Have proliferation no obviously and electrolyte hypertrophy disturbance of and VSMC lipid metabolism and myocardial cells disturbance ACEI Mechanism 药物与 ACE 结合方式 : ACE Zn ++ H + S O CH 2 CH C O N CH C Captopril 卡托普利 Angiotensin-II plays a central role in organ damage A-II AT 1 receptor ACEI Atherosclerosis* Vasoconstriction Vascular hypertrophy Endothelial dysfunction LV hypertrophy Fibrosis Remodelling Apoptosis GFR Proteinuria Aldosterone release Glomerular sclerosis Stroke Hypertension *Preclinical data LV = left ventricular; MI = myocardial infarction; GFR = glomerular filtration rate Heart failure MI Renal failure DEATH 14

15 kidney renin vasodilation PG, NO ACEI Kininogens Angiotensinogen Bradykinin ACEIs Inactive Peptides Angiotensin-I Angiotensin-II BK receptors Kallikrein liver ACEI ACE Renin Kininogens Brady kinin Inactive Peptides PG NO 扩血管抗肥大增生重构抗血小板聚集 BP Angiotensin Converting Enzyme A C E vasoconstriction aldosterone norepinephrine hypertrophy Therapeutic uses Angiotensinogen Angiotensin I ACEIs Angiotensin II AT-1 AT-2 receptors receptors Mainly used in essential hypertension. effective in renin-dependent hypertension, and the effect can be amplified by combination with diuretic. Particularly effective in renovascular and malignant hypertension. It is also used in CHF, Myocardial infarction, LV hypertrophy Diabetic nephropathy and other kidney diseases (proteinuria) Vasodilation Release of NO, PGI2, t PA Natriuresis Inhibition of the formation of Ang II and its actions Diminution of the degradation of bradykinin Actions of Bradykinin (BK) Vascular permeability BK Stimulation of sensory nerves Contraction of visceral smooth muscle Pharmacological effects Antihypertensive effects Release of inflammatory mediators Prevention of LVH and cardiovascular remodeling 心肌保护 Protection of endothelial dysfunction and the development of atherosclerosis Protection of myocardial ischemia(mi) Nephroprotective effect 保护血管内皮细胞增敏胰岛素受体 血管紧张素转化酶抑制药 Angiotensin converting enzyme inhibitors ACEI 卡托普利 (captopril) 依那普利 (enalapril) 赖诺普利 (lysinopril) 贝那普利 (benazepril) 福辛普利 (fosinopril) 等 15

16 福辛普利 (Fosinopril) 1 口服吸收 30%, 不受食物影响 2 含-COOH, 可直接起效, 作用及维持时间比依那 1 口服吸收 36%, 属前药, 需转化起效 普利稍强 3 应用及不良反应同依那普利 2 亲脂性高, 对心脑作用强而持久, 对肾作用弱而短 3 经肝肾双通道排泄, 在肝 / 肾功能减退者, 不需减量, 较少引起蓄积中毒 4 应用及不良反应同依那普利 ACEI ACEI 对靶器官的保护研究 Adverse Effects ACEI have a favorable side effect profile. 巯基与 ACE 的 Zn 2+ Initial dose of an ACE inhibitor 结合, 终使酶失 may precipitate an excessive hypotensive response (postural hypotension). 去活性 Dry cough(5% 5%-20% ), rhinorrhea, allergic, Zn 2+ 在降压治疗 Angioedema(in 0.1%-0.2%) 0.2%), although rare, may be potentially fatal K + Hyperkalemia Neutropenia or proteinuria, particularly when given in high doses Captopril to patients with renal insufficiency ACE inhibitiors should not be used during pregnancy or bilateral renal artery stenosis (2) Angiotensin Ⅱreceptor (AT1) antagonists Ang II losartan (COZZAR) ARB AT 1 AT Ib Irbesatan 2 Valsatan Candesartan Telmisata 赖诺普利 (Lisinopril) ACEI 的心脏保护作用主要集中在对心肌梗死 心力衰竭与 LVH 的防治方面 临床试验发现即使患者血压正常, ACEI 也能明显降低心血管危险 ACEI 对肾功能损害的预防保护及逆转的作用 : ESPIRAL 试验福辛普利 ACEI 在应用于糖尿病合并高血压患者时, 在降压治疗的同时, 对糖尿病人的靶器官损害的保护作用优于其他一线降压药物 ACEI 对脑卒中的防治研究 :PROGRESS 试验 6015 例患者, 培哚普利加吲哒帕胺与安慰剂对照, 结果治疗组比安慰剂组血压平均下降 9.0/4.0mmHg, 卒中危险性下降 28%, 认知功能异常和痴呆的进程也有改善 16

17 血管紧张素 Ⅱ 受体拮抗剂 Angiotensin Ⅱreceptor antagonists (ARB) 临床试验降压治疗试验 :LIFE 试验, 该试验以氯沙坦为基础治疗与阿替洛尔为基础治疗相比, 对合并 LVH 的高血压患者, 获得同样降压效果时, 氯沙坦进一步减少心血管患病与死亡 13%, 卒中减少 25% 这与氯沙坦使 LVH 消退有关 此外该药尚使新发糖尿病减少 25% ARB Pharamcological effects Inhibitor of AT1 receptor 1) Lowing the blood pressure 2)Decreasing the Ang-Ⅱconcentration of local RAS in left ventricular to inversion or prevention the development of cardiac hypertrophy. 3) Modulating balance of water and salts Angiotensin II receptor (AT) antagonists Adverse reaction rare Headache, contraindicated during pregnancy etc The tendency is for potassium retention, which may be serious in patients with renal disease or if the patient is also taking potassium sparing diuretics. ARB angiotensin II receptor antagonist drug Similar indication and contraindication with ACEI ARB Therapeutic uses It is mainly used to treat mild or moderate essential hypertension 血管紧张素 Ⅱ 受体拮抗药 (ARB) 血管紧张素 Ⅱ 受体 (AT1 受体 ) 拮抗药, 作用更为专一 代表药物 :losartan Valsartan Irbesartan 等 直接阻断 AngII 与受体的结合, 阻断作用更完全 ; 拮抗 AngII 的促生长作用 不产生缓激肽增多, 不产生咳嗽 losartan( 氯沙坦 )PO 吸收,F 为 33%, 高度选择性阻断 AT1 受体, 对高血压 糖尿病合并肾功不全者有保护作用 ; 促进尿酸排泄, 对合用利尿药者有利 ; 长期用能逆转左室肥厚和血管增生 可用于高血压 CHF 不产生咳嗽, 血管神经性水肿 Irbesartan 与 AT1 受体结合力强, 生物利用度高 (60-80%), 半衰期长 (11-15 小时 ), 吸收不受食物影响等优势, 具有长效平稳的降压作用 Ang II ARB AT 1 AT 2 Vascular smooth muscle cells 17

18 抗 RAAS 药物作用机理 抑制肾素 - 血管紧张素系统的药物 ACE 抑制剂 (ramipril,perindopril) ANGII 受体 (AT1R) 阻断剂 (losartan,irbesartan) Reinin 抑制剂 (Aliskiren) 阻止 reinin 释放 :beta 受体阻断剂, 普萘洛尔 Antagonist of aldosterone Spironolactone 螺内酯 Eplerenone 依普利酮 high selectivity Reduce extra fluid in the body Inhibit reconstruction of heart Inhibit increasing of intra-cellular Ca++ Anti-thrombosis thrombosis action Anti-inflammatory inflammatory action VASODIALATORS Pharmacokinetics: Absorbed rapidly; distributed well; metabolized in the liver; excreted by the kidneys. Pharmacodynamics: Direct vasodilators relax peripheral vascular smooth muscles, causing vasodilation, lowering the BP. Renin 抑制剂 Renin 位于 RAAS 系统的顶端, 并有着高度的底物专一性, 因此阻断该酶的活性能有效降低该系统的活性 抑制 ACE 会引起体内 ANGI 含量升高, 体内存在的不依赖 ACE 酶的催化体系同样可以催化 ANGI 向 ANGII 的转变, 因此阻断 ACE 的活性并不能影响这些反应体系的运行 ARBs 也会引起体内 ANGII 水平的升高 而 Renin 抑制剂并不会引起该现象的发生 Renin 抑制剂不会影响体内缓激肽的代谢, 因此个体不会产生干咳或者血管神经性水肿等症状 阿利吉仑 (aliskiren) 是新一代 非肽类肾素阻滞药, 起到降血压和治疗心血管疾病的作用, 并具有肾脏保护作用 other antihypertensive drugs Vasodilators 肼苯哒嗪 (hydralazine 肼屈嗪 ) 硝普钠 (sodium nitroprusside) 米诺地尔 (minoxidil 长压定 loniten ) 二氮嗪 (diazoxide diazoxide) 吲达帕胺 (indapamide) 酮色林 (ketanserin ketanserin) Vein and arteriolar vasodilator Nitropruss 硝普钠 (sodium nitroprusside) cgmp EDRF(NO) vasocular Bp resistance sympathetic reflexes heart rate cardiac output plasma rennin activity salt and water retention ide 18

19 硝普钠 (sodium nitroprusside) Direct-acting, nonselective peripheral vasodilator Immediate onset of action High-potency Short duration (requires continuous IV administration to maintain effect) Effect diminishes rapidly upon drug discontinuation sodium nitroprusside Side effects are mainly due to excessive vasodilation. Much less commonly, toxicity may result from conversion of nitroprusside to cyanide and thiocyanate. Risk of toxicity due to thiocyanate increases after 24 to 48 hours. Nitroprusside sodium (Nipride) can worsen arterial hypoxemia in patients with obstructive pulmonary airway disease since nitroprusside will interfere with hypoxic pulmonary vasoconstriction. A result is increasing ventilation-perfusion mismatching. Other antihypertensive drugs Vasodilators - hydralazine Direct arteriolar vasodilator Independent of any receptor antagonism. Its mechanism of action may be relate to formation of nitric oxide and /or hyperpolarezation of vascular smoothmuscle cells and interruption of intracellular calcium action. Clinical uses Sodium nitroprusside 1.Treatment of hypertensive emergencies Used for acute management of hypertensive crisis or malignant hypertension 2.Acute & chronic heart failure (CHF) 3.Control hypotension during anesthesia and surgery arteriolar vasodilator hydralazine 肼苯哒嗪 ( 肼屈嗪 )hydralazine cgmp EDRF(NO) vasocular resistance sympathetic reflexes heart rate Bp cardiac output plasma rennin activity salt and water retention Properties of Hydralazine Reduction of systemic vasocular resistance with activation of sympathetic reflexes, increased heart rate, and cardiac output Chronic administration of hydralazine stimulates renin release, raising plasma rennin activity; salt and water retention with gain in weight are also observed. 19

20 Clinical uses of Hydralazine 1) Essential hypertension usually limited to those patients with very high pretreatment pressure, typically >110mmHg diastolic pressure, who do not respond adequately to other agents or combination. 2) Pregnancy induced hypertension 3) Congestive heart failure potassium channel openers ATP Na+-Ca++change Ca 2+ 外流 K + Ca 2+ channel 失活 Ca 2+ Vein and arteriolar vasodilator vasocular resistance hyperpola rization sympathetic reflexes Bp heart rate cardiac output plasma rennin activity salt and water retention(edema) minoxidil Adverse effects include those induced by vasodilation such as: hypotension palpitation tachycardia fluid retention headache angina A drug-induced hypertrichosis is associated with minoxidil (Loniten). Adverse effects of Hydralazine headaches, flushing, tachycardia, angina-like chest discomfort or true angina of myocardial ischemia. dizziness, arthostatic hypotension, sympathetic reflex activation, Lupus erythematosus-like syndrome 米诺地尔 (minoxidil;; 长压定,loniten) Orally active,high potency, long duration Similar to hydralazine :arteriolar vasodilator o o o o o When combined with diuretic sympatholytic (e.g. beta-blocker) blocker): and Minoxidil can very effective for management of severe hypertension--associated with: renovascular disease transplant rejection renal failure Hirsutism 二氮嗪 (diazoxide ( diazoxide,, 氯甲苯噻嗪 ) Structure:similar to thiazide, Effect: arteriolar vasodilator Adverse effects include salt and water retention and hyperglycemia. Diazoxide inhibits insulin release. Clinical Uses: hypertension emergency 20

21 BP = 210/150 Hypertensive Crisis Drugs that may be used: Sodium Nitroprusside Dilates arterial and venous smooth muscle Diazoxide vasodilator Labetolol - and β-blocker Drug of choice Other antihypertensive drugs Cicletanine( 西氯他宁 ):PG Bosentan( 波生坦 R ) 0203) Endothelin-1 R antagonist Pharmacological Management of Hypertension Non-pharmacological interventions: Diet, Stress reduction, regular aerobic exercise, weight reduction as needed, control of other risk factors (blood lipids, smoking) o Diet involves several aspects that may include: reduction of sodium intake caloric restriction for obese patients restriction of cholesterol and saturated fat intake. 酮色林 (ketanserin( ketanserin) 5-HT receptor blocker selective 5-HT 2 R vasodilator blocking α 1 R platelet congregating H 1 R lipid Tch TG LDL, HDL HDL, always used in agedness patient nearly no tolerance ANTILIPEMICS Used to lower abnormally high blood levels of lipids such as cholesterol, triglycerides, and phospholipids. Include: bile-sequestering drugs (bile acid sequestrants), fibric acid derivatives (fibrates), and cholesterol synthesis inhibitors (HMG-CoA reductase inhibitors hydroxymethylglutaryl-coenzyme A reductase) or STATINS. Pharmacological Management of Hypertension Pharmacological Management 1 characteristic and degree of disease 2 drug in combination 3 individualized care 21

22 用药选择 脂质代谢异常 :α 1 受体阻滞, 不用 β 阻滞剂 利尿剂 妊娠 : 不用 ACEI ATII 受体阻滞剂, 可用甲基多巴 支气管哮喘 抑郁症 糖尿病 : 不用 β 受体阻滞剂 传导障碍 : 不用 β 受体阻滞剂. 非二氢吡啶类 痛风 : 不用利尿剂 22 Bottles of Filled Blood Pressure Medication.Most Unopened Think Efficacy Think Quality of Life 用药选择 CHF: 目标为 <130/80 mmhg, 首选 ACEI, 不能耐 受 ARB β 受体阻滞剂和醛固酮拮抗剂 利尿剂 糖尿病 蛋白尿或轻 中度肾功能不全 : 首选 ACEI 或 ARB 合并冠心病 : 稳定性心绞痛首选 β 受体阻滞剂或 钙拮抗剂 老年人收缩期高血压 : 长效二氢吡啶 利尿剂 Deaths Preventable in the U.S. by Improved Use of Clinical Services TA Farley et al., Am J Prev Med, 2010 思考题 抗高血压药物的分类可分为哪几类? 各举一代表药 简述氢氯噻嗪 普萘洛尔 硝苯地平 ACEI 哌唑嗪 可乐定的抗高血压作用机制及临床应用 为什么肼屈嗪等血管扩张药很少单用于抗高血压病而需与利尿药及 - 受体阻断药合用? 22

23 1. 八年制 : 药理学 参考资料 2. Kartzung BG. Basic and Clinical Pharmacology. 8th ed.new York: McGraw-Hill, Fisher ND, Hollenberg NK Is there a future for rennin inhibitors? Expert Opin Investig Drugs, 10: 陈宇, 祝善俊. 心血管病学进展 2006,02: 高血压药物的药物基因组研究进展