第18章治疗高血压病药物

1、第第1818章章 抗高血压药物抗高血压药物Antihypertensive AgentsAntihypertensive AgentsHypertensionHypertensionBackground: Hypertension is one of the most common diseases afflicting humans throughout the world. Because of the associated morbidity and mortality and the cost to society, hyperten-sion is an important publ

2、ic health challenge. Definition :Defining abnormally high blood pressure is extremely difficult and arbitrary. Furthermore, the relationship between systemic arterial pressure and morbidity appears to be quantitative rather than qualitative. 血压水平的定义和分类（血压水平的定义和分类（WHO/ISH） Difinition Systolic Diastol

3、ic 正常血压 140 and 90 Optimal* 120 and 80 Normal 130 and =140 or =90 Grade 1 - 140-159 or 90-99 Grade 2 - 160-179 or 100-109 Grade 3 - 180-209 or 110-1191高血压可分为原发性和继发性两大类 原发性高血压原发性高血压也称高血压病是一种病因尚未明确,以动脉血压长期升高为主要表现的疾病。约占90以上。高血压病的发病率在我国已超过10%。 继发性高血压继发性高血压也称症状性高血压是某些疾病的一部分表现,如肾炎、肾动脉狭窄、嗜铬细胞瘤、皮质醇增多症、原发性醛固

4、酮增多症、主动脉缩窄性病变(上肢血压增高而下肢血压降低)等。2原发性高血压可分为两型，缓进型和急进型。 缓进型高血压缓进型高血压或称良性高血压 (95%)起病隐匿,病程进展缓慢，达二三十年以上。对心、脑、肾等靶器官的损害缓慢进行，不易觉察。 急进型高血压急进型高血压或称恶性高血压 病情严重，发展迅速，舒张压持续在130140 mmHg以上，常于数月至12年内发生肾、脑、心并发症而死亡。Target Organ Damage Cardiovascular Disease 心心 Heart diseases Left ventricular hypertrophy Angina pectoris

5、/prior myocardial infarction Heart failure Stroke or transient ischemic attack 脑脑 Nephropathy 肾肾 Retinopathy 视网膜视网膜 Peripheral arterial disease 外周动脉外周动脉Pathogenesis of hypertension The pathogenesis of essential hypertension is multifactorial and highly complex. Multiple factors modulate the blood pr

6、essure for adequate tissue perfusion and include humoral mediators, vascular reactivity, circulating blood volume, vascular caliber, blood viscosity, cardiac output, elasticity of the blood vessels, and neural stimulation. A possible pathogenesis of essential hypertension is proposed whereby multipl

7、e factors, including genetic predisposition, excess dietary salt intake, and adrenergic tone, may interact to produce hypertension. Although genetics appears to contribute to essential hypertension, the exact mechanism has not been established 高血压病的发病机理虽未十分清楚,但目前已知机体内有许多系统与血压的维持有密切的关系,其中重要的有: 中枢神经系统

8、, 交感-肾上腺素系统, 肾素-血管紧张素-醛固酮系统, 血管舒缓肽-激肽-前列腺素系统, 血管内皮松弛因子-收缩因子系统,这些系统的功能受内外环境的影响而变化,从而参与机体血压的调控,上述各种致病因素都有可能影响以上各系统而使血压升高。上述各个系统中以哪个系统、哪些受体或递质与高血压病发病机制关系最为密切?目前还不能肯定,一般认为可能为多种机制的综合结果。 抗高血压治疗目的:1平缓降低血压 2阻止或延缓心, 脑, 肾等靶器官的损害3使病变的血管树和肥厚心肌重构(remodelling)和回归(regression) 抗高血压药的临床评价：1持久平稳降压：波动小, 峰谷比50%2不良反应：对血

9、糖、血脂、水盐代谢、性功能无影响；不影响神经系统功能（影响开车，智力等），即不影响生活质量3对心、脑的第一次保护和第二次保护作用，防止和减轻心肌肥厚，血管硬化等。 抗高血压药物 血压的调节和影响因素很多，血压调节系统中任何一个部位都可以被药物影响而致血压降低,抗高血压药就是作用于这些部位中一个或多个部位而发挥作用的。根据抗高血压药主要作用部位,可以分为以下几类：1利尿药2交感神经抑制药（1）中枢性降压药：可乐定、莫索尼定。（2）神经节阻滞药：美加明。（3）交感神经末梢抑制药：利血平、胍乙啶。（4）1受体阻滞剂：哌唑嗪、多沙唑嗪（5）受体阻滞剂：普萘洛尔、阿替洛尔、美托洛尔。（6）受体与受体阻滞

10、剂：拉贝洛尔、卡维地洛。3影响血管紧张素系统药： （1）血管紧张素转化酶抑制剂：卡托普利、依那普利、雷米普利；（2）血管紧张素受体阻滞剂：洛沙坦。4钙拮抗剂：硝苯地平、尼群地平、氨氯地平、非洛地平。5血管舒张药 （1）直接舒张血管药：肼屈嗪、硝普钠。（2）钾通道开放剂：米诺地尔、吡那地尔。（3）其它血管舒张药：吲达帕胺、乌拉地尔。 尽管抗高血压药物种类很多，但要让每个病人能找到降压效果好，不良反应小，不易出现耐受失效，且经济适用的药物却不很容易。目前6类药物为抗高血压的一线药物类药物为抗高血压的一线药物：利尿药、利尿药、受体阻滞剂、钙拮抗剂、血管受体阻滞剂、钙拮抗剂、血管紧张素转化酶抑制剂、血

11、管紧张素紧张素转化酶抑制剂、血管紧张素AT1受体阻滞剂及受体阻滞剂及1受体阻滞剂等受体阻滞剂等。DiureticsDiuretics各类利尿药均可降压，但以氢氯氢氯 噻嗪噻嗪（hydrochlorothiazide）等噻嗪类最常用。 袢利尿药：如速尿、利尿酸以及留钾利尿药等亦均可降低血压。长期使用会使肾血流量下降,会使肾素活性提高抵消部分降压药效,故而宜与阻断剂合用,而使增强降压药效。食盐量大的地区可作为首选降压药。 Thiazides and Related AgentsThiazides and Related Agents - used in patients with mild to

12、moderate hypertension and normal cardiac/renal function; most frequently used antihypertensive agents in the U.S Side Effects: hypokalemia, impaired diabetes control, hyperuricemia, muscle cramps, increased LDL/HDL Loop Diuretics - shorter duration of actionLoop Diuretics - shorter duration of actio

13、n than thiazide-type diuretics; reserved for use in than thiazide-type diuretics; reserved for use in subjects refractory to thiazides subjects refractory to thiazides furosemidefurosemide (Lasix) (Lasix) Side Effects: dehydration, most metabolic effects as Side Effects: dehydration, most metabolic

14、effects as thiazides (i.e., hypokalemia, impaired diabetes control, thiazides (i.e., hypokalemia, impaired diabetes control, increased LDL/HDL)increased LDL/HDL)Potassium-Sparing Diuretics - often used: 1) in Potassium-Sparing Diuretics - often used: 1) in combination with other diuretics (i.e., thi

15、azides) to combination with other diuretics (i.e., thiazides) to prevent or correct hypokalemia; 2) to avoid prevent or correct hypokalemia; 2) to avoid potassium depletion in patients taking digitalis potassium depletion in patients taking digitalis spironolactonespironolactone - antagonizes effect

16、 of aldosterone - antagonizes effect of aldosterone Side Effects: Side Effects: hyperkalemiahyperkalemia, gynecomastia , gynecomastia Therapeutic Notes:Therapeutic Notes: Thiazide diuretics are available as fixed-dose combinations with potassium-sparing or other antihypertensive drugs. Often used in

17、 combination with antihypertensive agents that impair vascular responsiveness (i.e., vasodilators) since blood pressure can become very sensitive to blood volume in the presence of these agents. Potassium supplements can be prescribed to compensate for hypokalemia. The thiazides are not useful in pa

18、tients with renal insufficiency (glomerular filtration rate 40 ml/min). Beta-Adrenergic AntagonistsBeta-Adrenergic Antagonists More effect for the white and the youngMore effect for the white and the young Mechanisms of action include: 1) decrease myocardial contractility and CO; 2) decrease renin s

19、ecretion and hence decrease levels of angiotensin II 3)block presynaptic receptors and inhibit the release of NE from the terminal of nervespropranolol, metoprolol, atenolol Side Effects of Most Beta-Blockers:Side Effects of Most Beta-Blockers: mild chronic fatigue, low exercise tolerance, sedation,

20、 nightmares, increased airway resistance, bradycardia Therapeutic Notes:Therapeutic Notes: beta-blockers must be withdrawn gradually to avoid withdrawal beta-blockers are roughly equivalent in efficacy as antihypertensive agents beta-blockers may mask insulin-induced hypoglycemiaL-Type Calcium Chann

21、el BlockersL-Type Calcium Channel Blockers More effect for the black and the olderMore effect for the black and the older Primary Mechanisms of ActionPrimary Mechanisms of Action: inhibit Ca+ influx into vascular smooth muscle; relax peripheral arteriole smooth muscle and thereby decrease total peri

22、pheral resistance; interfere with both angiotensin II and alpha2-mediated vasocontriction, and perhaps alpha1-mediated vasoconstriction. Nifedipine, nitridipine, amlodipine, felodipine etc - dihydropyridines; relatively selective vasodilator and less cardiac depression than verapamil or diltiazem Si

23、de Effects: tachycardia, headache, peripheral edema, flushing Diltiazem (Cardizem) - intermediate action on heart and blood vessels Side Effects: dizziness, headache, edema, bradycardia Verapamil (Calan) - greatest effect on heart Side Effects: dizziness, headache, edema, constipation, bradycardia T

24、herapeutic Notes:Therapeutic Notes: Ca+ channel blockers are only rarely associated with abnormalities in electrolyte, carbohydrate, or lipid metabolism. The drugs do not alter plasma concentrations of uric acid. Ca+ channel blockers are useful in hypertensive patients with a wide variety of concomi

25、tant illnesses including ischemic heart disease, chronic pulmonary disease, diabetes mellitus and variant angina. Angiotensin Converting Enzyme (ACE) Angiotensin Converting Enzyme (ACE) InhibitorsInhibitors Primary Mechanisms of ActionPrimary Mechanisms of Action: inhibit production of angiotensin II (vaso