β-blocker 在女性中的应用 大连医科大学附属一院 姜一农

女性与男性心血管疾病发病率区别 CVD发病率： 欧美男性下降，女性无变化；中国男性上升 Lancent 1999；353：1547-57

女性与男性心血管疾病相关死亡率

中国人群冠心病死亡粗率 占心血管病死亡42.9% 男性城镇高于女性 农村无区别 中国心血管病报告2006

女性与男性心衰住院率区别

女性与男性房颤相关死亡与卒中区别 Arch Intern Med 1998;158:229-34.

肾上腺能受体分布和生理作用 器 官 优势受体 生理作用 心 肌 1> 2 心肌收缩力加强，心率加快 支气管平滑肌 2 支气管扩张 器 官 优势受体 生理作用 心 肌 1> 2 心肌收缩力加强，心率加快 支气管平滑肌 2 支气管扩张 血管平滑肌 1 血管收缩 2 血管收缩 2 血管舒张 1 血管舒张 泌尿生殖器官平滑肌 1 肌肉收缩 2 肌肉舒张 脂肪组织 2 抑制脂解 2> 1 刺激脂解 器 官 优势受体 生理作用 血小板 2 聚 集 肝 脏 2 糖原分解 2 糖原分解 胰 腺 2 抑制胰岛素分泌 2 刺激胰岛素分泌 骨骼肌 2 糖原分解 肾 脏 1 肾素分泌 CNS 1 2 升高血压  降低血压 眼 2 升高眼内压 淋巴细胞 2 调节免疫功能

1与2受体阻断的作用 心脏保护作用 临床副作用 组织、器官 优势受体 (1 / 2 ) 阻断受体的作用 心肌 1 优势受体 (1 / 2 ) 阻断受体的作用 心肌 1 心脏保护作用 减慢心率，降低心肌收缩力 肾脏 减少肾素分泌，舒张血管，降低血压 交感神经系统 降低交感活性，降心肌耗氧量，改善左室和血管的重构及功能 冠状血管， 小血管 2 临床副作用 血管收缩，血压升高 小动脉、静脉 间歇性跛行、雷诺氏综合征 肝脏，胰腺，骨骼肌 糖代谢紊乱 脂肪组织 脂代谢紊乱 支气管 气道阻力增加，加重支气管哮喘症状 泌尿生殖器官 ED风险 《实用心血管受体学》,科学出版社

受体阻滞剂心血管保护机制 降低交感神经活性，减慢心率 抑制过度、持续的神经激素活性增高 减少心律失常，提高心室颤动阈值 减少心肌耗氧，缓解心肌缺血，缩小梗死面积 长期应用可以改善患者的远期预后，提高生存率，益于冠心病的二级预防

受体阻滞剂 在心血管疾病的治疗中地位 European Heart Journal. 2004;25:1341–1362

女性药物代谢特点（1） 吸收和生物利用度的不同 月经周期变化对胃肠吸收和胃排空率的影响 脂肪组织的比例较大,药物分布会存在分布容积差异 生物转化,Ⅰ期(细胞色素P450)和Ⅱ期代谢(尤其是葡萄糖醛酸化)有性别差异 男性的CYP1A2，CYP2D6或是CYP3A4亚型有较高的活性;女性CYP3A4mRAN表达高于男性2倍,参与一半以上的心血管药物代谢

女性药物代谢特点（2） 肾小球滤过率以及肌酐清除率低于男性,药物排泄减少,体内发生蓄积中毒的风险高于男性50%~70%" 外源性雌激素的影响。如,口服避孕药(OC)和绝经期后的雌激素替代疗法。 受体密度和敏感性存在着性别差异。

The Effectiveness of β-blockers in Women With Congestive Heart Failure There were 14,693 women (52% were prescribed β-blockers) and 13,144 men (49% were prescribed β-blockers). Women were older and had more hypertension, whereas men had more myocardial infarction. There was a significant survival benefit with β- blockers use in both sexes (hazard ratio [HR] 0.79, 95% confidence interval [CI] 0.75–0.83 in women, and 0.76, 95% CI 0.72–0.80 in men). Sensitivity analyses adjusting for selection bias showed similar survival benefits in both sexes. Overall, men had a worse survival than women (HR 1.2, 95% CI 1.2–1.3 in men). CONCLUSIONS: β-blockers appear to improve survival from CHF as much in women as in men. Clinical trials involving large numbers of women are necessary to demonstrate potential treatment benefits. Society of General Internal Medicine 2007;22:955–961

Sex Differences in the Prognosis of Congestive Heart Failure : Results From theCardiac Insufficiency Bisoprolol Study (CIBIS II) CIBIS II的再分析 随机、双盲、安慰剂对照 男：2132 女：515 心功能Ⅲ-Ⅳ，已用利尿剂+ACEI 全因死亡下降34% In multivariable analysis adjusted for co-morbidities, but also possible physician’s confounders such as time since medical board examination, female gender of physicians was an independent predictor of use of beta-blockers. Circulation. 2001;103:375-380

Sex Differences in the Prognosis of Congestive Heart Failure : Results From theCardiac Insufficiency Bisoprolol Study (CIBIS II) 女性心衰患者是否有更好的预后 性别与β-blocker 应用是否存在相关 In multivariable analysis adjusted for co-morbidities, but also possible physician’s confounders such as time since medical board examination, female gender of physicians was an independent predictor of use of beta-blockers. Circulation. 2001;103:375-380

Sex Differences in the Prognosis of Congestive Heart Failure : Results From the Cardiac Insufficiency Bisoprolol Study (CIBIS II) Kaplan-Meier analysis revealed a lower percentage of death among women treated with bisoprolol compared with men (6% versus 12% at mean follow-up, respectively, P<0.01), whereas in the placebo group, the reduced rate of mortality in women was not significant (13% versus 18%, respectively, P<0.10). P<0.01 P<0.1

Sex Differences in the Prognosis of Congestive Heart Failure : Results From theCardiac Insufficiency Bisoprolol Study (CIBIS II)

Sex Differences in the Prognosis of Congestive Heart Failure : Results From theCardiac Insufficiency Bisoprolol Study (CIBIS II) In multivariable analysis adjusted for co-morbidities, but also possible physician’s confounders such as time since medical board examination, female gender of physicians was an independent predictor of use of beta-blockers.

Sex Differences in the Prognosis of Congestive Heart Failure : Results From theCardiac Insufficiency Bisoprolol Study (CIBIS II) WHY? sex-related differences in adrenergic receptor sensitivity or postreceptor effector activity. sex-related differences exist in the pharmacokinetics and pharmacodynamics of b-blockers, resulting in greater drug exposure in women. Maqbool et al recently reported 2 common variants of the b1-adrenoreceptor. In multivariable analysis adjusted for co-morbidities, but also possible physician’s confounders such as time since medical board examination, female gender of physicians was an independent predictor of use of beta-blockers.

Influence of gender of physicians and patients on guideline-recommended treatment of chronic heart failure in a cross-sectional study Use of beta-blockers was more frequent in male than in female patients, but dosage was not different. In contrast, male physicians favoured male patients for both prescription and dosage. A female patient was likely to receive the worst medical treatment from a male physician, whereas male patients were best treated by a female physician. In multivariable analysis adjusted for co-morbidities, but also possible physician’s confounders such as time since medical board examination, female gender of physicians was an independent predictor of use of beta-blockers. European Journal of Heart Failure (2009) 11, 299–303

Infiuence of gender of physicians and patients on guideline-recommended treatment of chronic heart failure in a cross-sectional study Consecutive patients with CHF (n ¼ 1857) were evaluated regarding co-morbidities, New York Heart Association classification, current medical treatment, and dosage of angiotensin-converting enzyme-inhibitors (ACE-Is) and betablockers. Gender of patients and treating physicians was recorded. Baseline characteristics of patients and physicians were comparable for males and females. Female patients were less frequently treated with ACE-Is, angiotensinreceptor blockers, or beta-blockers. Achieved doses were lower in female compared with male patients. Guideline- recommended drug use and achieved target doses tended to be higher in patients treated by female physicians. There was no different treatment for male or female patients by female physicians, whereas male physicians used significantly less medication and lower doses in female patients. In multivariable analysis, female gender of physicians was an independent predictor of use of beta-blockers.

Infiuence of gender of physicians and patients on guideline-recommended treatment of chronic heart failure in a cross-sectional study In multivariable analysis adjusted for co-morbidities, but also possible physician’s confounders such as time since medical board examination, female gender of physicians was an independent predictor of use of beta-blockers.

Trends and inequities in beta-blocker prescribing for heart failure British Journal of General Practice, 862 December 2008

2006年中国基层医院慢性心衰用药情况调查 17个地区2066所2级以下基层医院 中国心血管病报告2006

Β-blocker在心衰患者中应用不足 age/sex inequit Not class effect

MERIT- HF: 不同严重程度心衰的死亡原因 NYHA II NYHA III NYHA IV other 11% other 15% other 24% SCD 33% SCD 64% CHF 26% SCD 59% CHF 12% CHF 56% MERIT-HF, Lancet 1999; 353: 2001-07

b-阻滞剂降低MI后的危险性 24个RCT’s的荟萃分析 (n=23,000) 安慰剂 b阻滞剂 RR 死亡 10.0 % 7.9 % 0.77 (0.10-0.85) 猝死 5.2 % 3.6 % 0.70 (0.60-0.80) 再次MI 7.5 % 5.7 % 0.74 (0.68-0.83)

不同性别冠心病患者用药情况 Anesth Analg 2008;107:185–92

不同性别AMI患者用药情况 Circulation. 2008;118:2803-2810 Conclusions—Overall, no sex differences in in-hospital mortality rates after AMI were observed after multivariable adjustment. However, women with STEMI had higher adjusted mortality rates than men. The underuse of evidence-based treatments and delayed reperfusion among women represent potential opportunities for reducing sex disparities in care and outcome after AMI Circulation. 2008;118:2803-2810

Relation of Beta-Blocker–Induced Heart Rate Lowering and Cardioprotection in Hypertension J Am Coll of Cardiol 2008,52:1482-9

Relation of Beta-Blocker–Induced Heart Rate Lowering and Cardioprotection in Hypertension J Am Coll of Cardiol 2008,52:1482-9

Relation of Beta-Blocker–Induced Heart Rate Lowering and Cardioprotection in Hypertension J Am Coll of Cardiol 2008,52:1482-9

Relation of Beta-Blocker–Induced Heart Rate Lowering and Cardioprotection in Hypertension J Am Coll of Cardiol 2008,52:1482-9

CAD，post MI预后在流行病调查证实与心率增加呈正相关，BB减低心率与减少事件有关 Relation of Beta-Blocker–Induced Heart Rate Lowering and Cardioprotection in Hypertension CAD，post MI预后在流行病调查证实与心率增加呈正相关，BB减低心率与减少事件有关 高血压无CAD患者，Framingham证实心率与心血管疾病死亡呈正相关，但是降低BB降低心率增加了心血管事件风险。 J Am Coll of Cardiol 2008,52:1482-9

β阻滞剂用于高血压治疗的中国专家共识 （2007年版） 阻滞剂仍然是临床上治疗高血压的有效、安全的药物，是临床上常用的降血压药物之一。但鉴于阿替洛尔在临床试验中所暴露的问题，不推荐将其作为降血压治疗的首选用药。 目前正在使用β阻滞剂进行治疗的患者，如血压稳定控制，应当继续使用，不宜换药。 β阻滞剂对合并以下情况的患者具有不可替代的地位，应当首选：快速性的心律失常（如心房颤动）、冠心病（稳定/不稳定性心绞痛、心肌梗死后）、心力衰竭合并高血压患者；交感神经活性增高患者(高血压发病早期伴心率增快者、社会心理应激者、焦虑等精神压力增加者、围手术期高血压、高循环动力状态如甲亢、高原生活者等)和妊娠高血压；禁忌使用或不能耐受ACEI或ARB的年轻高血压患者。

β阻滞剂用于妊娠高血压治疗 2007ESC/ESH:口服甲基多巴、拉贝洛尔、CCB、阻滞剂。 紧急：硝酸甘油、硝普钠、利尿剂、硝苯地平 2005中国高血压指南 常用缓慢降压的药物： 氧希洛尔 （Oxprenolol）:20-40mg, 每日3次 （可引起心动过缓） 阿替洛尔：100mg，1次/日 长期使用-受体阻断剂，有引起胎儿生长迟缓的可能。 甲基多巴：0.25-0.5g ，3次/日 肼苯达嗪（Hydralazine）：口服25-50mg，3次/日 依拉地平（Isradipine）：2.5mg，2次/日

β-blockers and fracture ‚-agonists stimulate osteoclastogenesis both by direct actions on osteoblasts and via stimulation of local cytokine production6. Consistent with these cell culture findings, norepinephrine has been shown to increase bone resorption in bone organ culture, and propranolol to have the opposite effect3,8.

β-blockers and fracture Observational studies of the use of ‚-blockers are confounded by the indications for which these drugs are prescribed, and by other medications that are commonly co-prescribed with them. These data are inconsistent, although a recent meta-analysis did conclude that ‚-blocker use was associated with a significant decrease in fracture risk. However, the more recent studies cast doubt on this finding, and the limited data regarding fractures in randomized controlled trials certainly do not support this conclusion. Therefore, there is not an adequate evidence base to support using ‚- blockers as a treatment for osteoporosis, nor can they be regarded as a discriminating risk factor for fracture assessment. Until there are definitive randomized, controlled trials of ‚-blockers, which include fracture as an endpoint, it is unlikely that the current confusing situation will be resolved. Keywords: Sympathetic Nervous System, Adrenergic Receptors, Osteoporosis, Osteoblast Case-control and prospective cohort studies of β-blockers and fracture

Β-blocker在女性药物代谢特点与机制 美托洛尔有证据显示,男性酶的活性高,清除快,耐受剂量大于女性; 标准体重下,女性对美托洛尔的容积分布明显小,血浆浓度显著升高,最大者可达男性的2倍；普萘洛尔,女性血药浓度高出男性80% OC影响BB代谢 正在使用OC的23例年轻妇女接受美托洛尔100mg后,其血药浓度明显高于未服用OC者, 同等剂量的B受体阻滞剂,女性的心率与血压下降幅度较男性明显

Β-blocker在女性药物代谢特点与机制 健康人群中抗心律失常药物的试验，女性QT间期延长比男性明显,在排卵期与月经期尤其显著 雌激素对离子通道的修饰作用，心肌上是否存在钾离子通道的性别差异？是否与延长QT间期药物副作用有关？

Β-blocker在女性应用小结 药代动力学有特点,血药浓度高，可能增加副作用 心血管保护作用至少与男性患者一样有效，可能更有效 存在问题：用药比例小，用药量不足 适应征：缺血性心脏病 高血压：交感兴奋型高、年轻、焦虑 更年期 妊娠高血压 慢性心衰 快速心律失常

谢 谢