临床药理HTN40517.pptx
高血压药物高血压药物的临床用药的临床用药 高血压高血压高血压是以体循环动脉血压升高为特征的疾病或症状，是一种常见的病理综合征。由于正常人的血压可受各种因素的影响，在较大的范围内进行波动，而且随着年龄的增长而增高，因此正常血压与高血压之间的界限划分比较困难，二者之间并无绝对的界限。根据世界卫生组织的建议，正常成人的血压定在1218.7/812kPa（90140/6090mmHg）之间。凡收缩压在140mmHg或以上，和(或)舒张压在90mmHg或以上者,定为高血压。HypertensionHypertensionBackground: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,hypertension is an important public 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 Diastolic 正常血压140 and 90Optimal*120 and 80 Normal 130 and =140 or =90Grade 1-140-159 or 90-99Grade 2-160-179 or 100-109Grade 3-180-209 or 110-119血压水平的定义和分类（血压水平的定义和分类（WHO/ISH）分分类类收缩压（收缩压（mmHg）舒张压（舒张压（mmHg）理想血压理想血压12080正常血压正常血压130=180=110单纯收缩期高血压单纯收缩期高血压=14090-亚组：临界收缩期高血压亚组：临界收缩期高血压140-14995%)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130140mmHg以上，常于数月至12年内发生肾、脑、心并发症而死亡。高血压病的病因及发病机制与高血压病相关的致病因素很多，与体重指数、膳食因素和遗传因素都有密切关系,我国近年由于营养改善,因此人群中体重指数(BMI)上升,高脂肪摄入增加,有不少地区是高钠、低钙、低钾、低动物蛋白膳食结构,这些地区人群血压较高。此外,大量饮酒、吸烟等因素也与高血压的发病有一定关系。高血压病具有明显的家族聚集倾向,家系分析和双生子研究报告亦提示遗传因素与高血压病密切相关。研究表明，部分高血压患者的交感兴奋性增高，其血浆中去甲肾上腺素含量明显高于正常人。另一些高血压病人的血浆肾素活性和血管紧张素的含量高于正常人。但亦有部分病人表现为交感功能低下，或血浆肾素活性及血管紧张素并不高于甚至低于正常人者。所以高血压的发病机制不能简单地归于某一因素或某一系统的功能失调，不同的患者其发病机制可能不同。近年在遗传因素方面的研究有很大的进展,最近相继报道了肾素、血管紧张素原、血管紧张素转化酶等基因在高血压病因中的作用。还有报告曾观察到自发性高血压大鼠的一氧化氮(NO)合成酶基因表达水平明显低于对照组大鼠,并认为内皮细胞功能不良可能是高血压发病的一个重要原因。Pathogenesis of hypertensionThe pathogenesis of essential hypertension is multifactorial and highly complex.Multiple factors modulate the blood pressure 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 multiple 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:中枢神经系统肾上腺素能系统肾素-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。按危险分层、量化估计预后按危险分层、量化估计预后由于高血压病的预后，心脑血管事件的发生率不仅与血压高低有密切关系，而且还与心血管疾病的危险因素有密切关系。所以考虑治疗和预后时就要综述考虑这些问题，通常将血压高低与有关的心血管疾病危险因素结合起来进行危险分层估计考虑。与心血管疾病有关的危险因素有：1用于危险性分层的危险因素用于危险性分层的危险因素血压：收缩压和舒张压的水平(13级)年龄：男性55岁，女性65岁吸烟总胆固醇5.72mmol/L(220mg/dl)糖尿病早发心血管疾病家族史(发病年龄男55岁，女性65岁)2加重预后的其他危险因素加重预后的其他危险因素高密度脂蛋白胆固醇降低低密度脂蛋白胆固醇升高糖尿病伴微白蛋白尿葡萄糖耐量减低肥胖以静息为主的生活方式血浆纤维蛋白原增高高危经济阶层、高危种族、高危地区人群症状性血管疾病视网膜出血或渗出视神经乳头水肿Target Organ DamageCardiovascular Disease 心心Heart diseasesLeft ventricular hypertrophyAngina pectoris/prior myocardial infarctionHeart failureStroke or transient ischemic attack 脑脑Nephropathy 肾肾Retinopathy 视网膜视网膜Peripheral arterial disease 外周动脉外周动脉靶器官损害：左心室肥厚(心电图、超声心动图或X线)蛋白尿和(或)血浆肌酐浓度轻度升高106177mmol/L(1.22.0mg/dl)超声或X线证实有动脉粥样硬化斑块(颈、髂、股或主动脉)视网膜普遍或灶性动脉狭窄我国高血压情况我国高血压情况据2002年全国居民营养和健康状况调查，我国成年人群高血压患病率为18.8，比1991年增长了31，增加高血压患者7000万，估计全国有高血压患者1.6亿。每5个成人就有1人是高血压。北方高于南方；老年人常发生收缩期高血压。高血压的并发症脑卒中、心脏病及肾脏病严重危害我国人民健康，成为重大公共卫生问题。然而，人群高血压的知晓率，治疗率和控制率却很低，分别为30，25和6。抗高血压治疗目的抗高血压治疗目的:随着对高血压病研究的深入，对其造成的危害有了进一步的认识。现在认为，高血压是导致心脑血管疾病的重要因素，特别是冠心病，脑血管意外，心力衰竭等。也是早死的最重要的独立危险因素。因此，抗高血压治疗的长期目的是防止和减少心肌梗死和脑卒中的发生。考虑到高血压对靶器官的长期损害及其心脑血管并发症的关系，抗高血压的治疗目的应以下三个方面考虑：1平缓降低血压,目标：控制血压140/90,糖尿病130/80老年人SBP50%2不良反应：对血糖、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：噻嗪类、吲哚帕胺、醛固酮拮抗剂。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：吲哚帕胺、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5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：利利尿尿药药duretics、受受体体阻阻滞滞剂剂-blockers、钙钙拮拮抗抗剂剂CCBs、血血管管紧紧张张素素转转化化酶酶抑抑制制剂剂ACEIs及及血血管管紧紧张张素素AT1受受体体阻阻滞滞剂剂ARBs。DiureticsDiuretics各 类 利 尿 药 均 可 降 压，但 以 氢氢 氯氯 噻噻 嗪嗪（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 moderate hypertension and normal cardiac/renal function;most frequently used antihypertensive agents in the U.SSide Effects:hypokalemia,impaired diabetes control,hyperuricemia,muscle cramps,increased LDL/HDLLoop DiureticsLoop Diuretics-shorter duration of action than thiazide-type diuretics;reserved for use in subjects refractory to thiazides furosemidefurosemide(Lasix)Side Effects:dehydration,most metabolic effects as thiazides(i.e.,hypokalemia,impaired diabetes control,increased LDL/HDL)Potassium-Sparing DiureticsPotassium-Sparing Diuretics-often used:1)in combination with other diuretics(i.e.,thiazides)to prevent or correct hypokalemia;2)to avoid potassium depletion in patients taking digitalis spironolactonespironolactone-antagonizes effect of aldosteroneSide Effects:hyperkalemia,gynecomastia Therapeutic Notes:Therapeutic Notes:Thiazide diuretics are available as fixed-dose combinations with potassium-sparing or other antihypertensive drugs.Often used in 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.Thethiazidesarenotusefulinpatientswithrenalinsufficiency(glomerularfiltrationrate40ml/min).Beta-Adrenergic AntagonistsBeta-Adrenergic AntagonistsMore effect for the white and the youngMore effect for the white and the young （年轻（年轻人和白人）人和白人）Mechanisms of action include:1)decrease myocardial contractility and CO;2)decrease renin secretion and hence decrease levels of angiotensin II 3)block presynaptic receptors and inhibit the release of NE from the terminal of nervespropranolol,metoprolol,atenolol脂溶性强药物效果比水溶性强药物好（metoprolol,atenolol）Side Effects of Most Beta-Blockers:Side Effects of Most Beta-Blockers:mild chronic fatigue,low exercise tolerance,sedation,nightmares,increased airway resistance,bradycardiaTherapeutic 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 Channel BlockersL-Type Calcium Channel BlockersMore effect for the black and the olderMore effect for the black and the older （老年人和黑人）（老年人和黑人）Primary Mechanisms of ActionPrimary Mechanisms of Action:inhibit Ca+influx into vascular smooth muscle;relax peripheral arteriole smooth muscle and thereby decrease total peripheral resistance;interfere with both angiotensin II and alpha2-mediated vasocontriction,and perhaps alpha1-mediated vasoconstriction.Nifedipine,nitridipine,amlodipine,felodipineetc-dihydropyridines;relativelyselectivevasodilatorandlesscardiacdepressionthanverapamilordiltiazemSideEffects:tachycardia,headache,peripheraledema,flushingDiltiazem(Cardizem)-intermediateactiononheartandbloodvesselsSideEffects:dizziness,headache,edema,bradycardiaVerapamil(Calan)-greatesteffectonheartSideEffects:dizziness,headache,edema,constipation,bradycardiaTherapeutic 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 concomitant illnesses including ischemic heart disease,chronic pulmonary disease,diabetes mellitus and variant angina.不适用于心衰病人。Angiotensin Converting Angiotensin Converting Enzyme(ACE)InhibitorsEnzyme(ACE)InhibitorsPrimary Mechanisms of ActionPrimary Mechanisms of Action:inhibit production of angiotensin II(vasoconstriction and sodium-retaining activity);decrease total peripheral resistance血管紧张素原血管紧张素原Angiotensin收缩血管肾素激肽原激肽原缓激肽缓激肽降解失活AngACE糜酶ACEIsAng分泌醛固酮NOPGI(-)ACE和ACEIs作用示意图舒张血管Side Effects of ACE Inhibitors:Side Effects of ACE Inhibitors:hyperkalemia,rash,dry cough,angioneurotic edema(0.2%cases)Therapeutic Note:Therapeutic Note:contraindicated in second and third trimesters of pregnancy 损伤胚胎Angiotensin II antagonists(ARBs)AngiotensinIIreceptorantagonistsareeffectiveinloweringthebloodpressureofhypertensivesandareusefulincombinationwithdiuretics.ThedrugsmaybeusefulinthosepatientswhohaveunacceptableACEinhibitor-inducedcough.However,towhatextenttheymaysharethebenefitsofACEinhibitorsinhypertensivepatientswithcongestiveheartfailureortypeIdiabetesisnotyetknown.药物治疗原则药物治疗原则从小剂量开始，逐渐加量至合适剂量。可减少不良反应。长效制剂，给药一天一次，早上服用。增加病人用药依从性。联合用药（合并用药）。联合用药联合用药高血压病发病因素复杂，单种药物治疗常常不能很好控制血压，因而常合并使用2至3种药物用于抗高血压。不同作用机制的药物合用后产生协同或相加的抗高血压作用。减少单药用量，降低不良反应的发生。D+B，D+ACEI，D+ARBB+CACEI+ARB治疗冠心病药物治疗冠心病药物Agents to treat CHDAgents to treat CHDcoronary heart diseaseBackground:IHD is the leading single cause of death in the US and is responsible for 1 of every 4.8 deaths.About half of the patients with IHD initially present with chronic stable angina.IHD manifests as an imbalance in myocardial oxygen supply and demand that results in myocardial hypoxemia.IHD is usually due to atherosclerotic disease of the coronary arteries(coronary heart disease CHD and coronary artery disease CAD)。病因学病因学EtiologyTheexactpathogenesisofCADisnotclear,andnosingletheoryadequatelyexplainstheatheroscleroticprocess.Twomainexplanationshavebeenproposed:thelipidhypothesisandthechronicendothelialinjuryhypothesis.Theseexplanationsareprobablyinterrelatedandarecertainlynotmutuallyexclusive.RiskFactorsPositivefamilyhistory,particularlywithonsetbeforeage50insame-sexparentMalegenderAgeAbnormalitiesinbloodlipids/lipidmetabolism,HighWaist/HipRatio(Rexrodeetal,1998)ElevatedbloodhomocysteineElevatedfibrinogen(Bielaketal,2000)Highultra-sensitiveC-reactiveproteinHighlevelsofironstores(Salonenetal,1992)Lowlevelsofselenium(Suadicanietal,1992)Sedentarylifestyle/poorphysicalfitnessCigarettesmokingAlcoholabuseDietshighinanimalfatandcaloriesandlowinfruits,vegetables,andfiberDietslowinpolyunsaturatedfattyacidsDietshighintransfats(Willettetal,1993)PoorstressmanagementHighbloodlevelsofinsulinDecreasedoxidativeradicalantioxidantcapacity(ORAC)(Fazendasetal,2000)DiabetesmellitusHypertensionHypothyroidismMaritalstress(Orth-Gomer,2002)1动脉粥样硬化与冠心病动脉粥样硬化是冠心病的病理基础。胆固醇等脂质沉着在大中动脉血管壁，形成粥样斑块，尤其在动脉分叉处。在心外膜下中等动脉分支的内膜下胆固醇沉着，管腔内新月形隆起，表面为纤维帽，含增殖平滑肌、胶原、脂质及泡沫细胞，内膜下形成坏死区，含胆固醇结晶、胆固醇酯，钙盐等。冠冠脉脉狭狭窄窄为偏狭窄，开始为新月形，狭窄50%为轻度，对供血影响不大，无明显症状；狭窄50%-70%为重度，供血大减，可出现心绞痛。若管腔被血栓迅速阻塞，可产生急性心肌梗死。冠冠脉脉痉痉挛挛亦导致缺血性心脏病，可造成心绞痛（如变异型心绞痛），甚至心肌梗死。2冠心病的临床分型及表现冠心病共分为五型，分述如下：隐匿型：病人无症状，仅心电图有缺血改变（包括运动试验），如T波低平，下降，S-T段压低等。心绞痛（anginapectoris）：心绞痛的发生是由于心肌耗氧增加或供血不足，导致心肌氧供需失衡所致。急性心肌梗死（acutemyocardialinfarction，AMI）：心肌严重缺血缺氧持续时间过长，导致心肌代谢和功能障碍，心肌细胞坏死。心力衰竭及心律失常型：为长期心肌缺血导致心肌纤维化所致。表现为心脏扩大，心力衰竭及心律失常。猝死型冠心病：因缺血心肌电生理紊乱引起严重心律失常所致的原发性心脏猝死。通常将心绞痛分为稳定型心绞痛、不稳定型心绞痛和变异型心绞痛三型，现根据WHO意见将心绞痛分为劳累性和自发性两类：劳累性心绞痛：由体力活动、情绪激动、寒冷或其他增加心肌需氧量的活动诱发。又分为三种：稳稳定定型型心心绞绞痛痛（stableangina）：为最常见的一种类型。病情稳定一个月以上，静息时无症状，在劳累或情绪激动时发病，病情稳定，有规律性。心电图改变主要有S-T段压低，T波低平倒置等。初发劳累性心绞痛：劳累性心绞痛病程在一个月以内。恶化型劳累性心绞痛：同等程度劳累所诱发的心绞痛发作次数、严重程度及持续时间突然加重。自发性心绞痛：包括变变异异型型心心绞绞痛痛（variantangina），较少见。主要由冠脉痉挛所致，在休息静止时发作。其特点为发作与心肌需氧量增加无明显关系，时间较长，程度较重，且不易为硝酸甘油缓解。心电图主要表现为S-T段抬高。不不稳稳定定型型心心绞绞痛痛：包括初发劳累性，恶化型，及自发性心绞痛，易发生心肌梗死。PathophysiologyMyocardialischemiareflectsanimbalancebetweenmyocardialoxygensupplyanddemand.Myocardialoxygendemandismainlydeterminedbyheartrate,theforceofventricularcontraction,andventricularwalltension,whichisproportionaltotheventricularvolumeandpressure.Themyocardiumsextractionofoxygenisnearlymaximalintherestingstate.Therefore,intheabsenceofanemiaorsystemichypoxia,anincreaseincoronarybloodflowisessentiallytheonlymechanismavailabletocompensateforincreasesinmyocardialoxygendemand.影响心肌耗氧量的影响影响心肌耗氧量的影响心肌收缩力心肌收缩力心室壁张力（与心室内压和心室半径乘积成正比）心室壁张力（与心室内压和心室半径乘积成正比）心率和射血时间心率和射血时间通常用简便的方法来估算心肌耗氧量通常用简便的方法来估算心肌耗氧量二重乘积（心率二重乘积（心率收缩压，收缩压，HRSBP）三重乘积（心率三重乘积（心率收缩压收缩压射血时间射血时间(Q-T)，HRSBPET）。）。凡使心率加快，血压升高，心肌收缩加强及心室凡使心率加快，血压升高，心肌收缩加强及心室扩大的因素都可增加心肌氧耗。扩大的因素都可增加心肌氧耗。Factors that Affect Myocardial Factors that Affect Myocardial Oxygen DemandOxygen DemandThemajordeterminantsofmyocardialoxygenconsumptioninclude:ventricularwallstressheartrateinotropicstate(contractility)Bothpreloadandafterloadaffectthestressontheventricularwalldoubleproduct(HeartRatexSystolicBloodPressure)TreatmentLifestyle Measures counsel patients about smoking cessation,diet,regular exercise,and weight reduction Pharmacological treatmentPharmacological treatment of CAD can be divided into agents that prolong survival(eg,aspirin,statin drugs,ACE inhibitors,beta-blockers)and those that treat symptoms(eg,calcium channel blockers,nitrates).抗血栓形成抗血栓形成Aspirin has been shown to decrease mortality and reinfarction after an MI.Administer aspirin immediately,which the patient should chew if possible upon presentation.Continue aspirin indefinitely unless an obvious contraindication,such as a bleeding tendency or an allergy,is present.Clopidogrel may be used as an alternative to aspirin in cases of aspirin resistance or allergyStartallpatientswithsuspectedcoronaryarterydisease(CAD)orischemicheartdisease(IHD)onaspirin(75to150milligramsmgonetimeaday),unlesscontraindicatedAspirinreducestheriskofadversecardiovasculareventsby25%to33%inpatientswithstableangina.Clopidogrel(75mgaday)appearstobeaseffectiveasaspirin,butitismuchmoreexpensive;itisrecommendedforpatientswithcontraindication(s)toaspirin缓解心绞痛Three categories of agents are used in the Three categories of agents are used in the treatment of anginatreatment of angina1.Organic nitrates(reduce preload,reduce afterload,vasodilate coronary arteries,inhibit platelet aggregation)2.Calcium channel blockers(reduce afterload,vasodilate coronary arteries,may inhibit platelet aggregation;some also decrease heart rate,decrease contractility)3.Beta-adrenergic antagonists(decrease heart rate,decrease contractility,decrease afterload due to decrease in cardiac output,may inhibit platelet aggregation)硝酸酯及亚硝酸酯是缓解心绞痛的主要药物增加氧供，改善侧支循环降低心室内压，改善心内膜下心肌供血（此处常是缺血最严重的部位），舒张冠脉痉挛减少氧耗舒张外周静脉和动脉血管，降低心脏前后负荷，缩小心室容积一般短效，可产生反射性心动过速Beta-阻断剂阻断交感对心脏的兴奋作用，减慢心率，抑制心肌收缩，降低氧耗量对劳作型心绞痛效好，对变异性无效？可用于先兆心肌梗死和急性心肌梗死钙拮抗剂舒张动静脉血管，减轻后负荷和前负荷冠脉解痉效果好，最适用于变异性心绞痛要用长效药物，短效者可使血压波动过大，兴奋交感Usebeta-blockersasfirst-lineanti-anginaltherapy,unlesscontraindicated.Beta-blockersdecreasemyocardialoxygendemandbydecreasingmyocardialcontractility,arterial(blood)pressure,andheartrate.Leftventricularperfusionisenhancedbytheincreaseddurationofdiastole.Ofallofthemedicationsusedintreatinganginapectoris,onlybeta-bloc
