1、.,1,高血壓的擇時給藥,.,2,內(nèi)容提綱:,簡 介,文獻(xiàn)分析與評論,結(jié) 論,1,2,3,.,3,一、簡 介,血壓晝夜節(jié)律 血壓是血管內(nèi)流動的血液對于單位面積血管壁的側(cè)壓力，在生理狀態(tài)下，機(jī)體血壓呈晝夜節(jié)律性波動。 健康機(jī)體血壓全天呈現(xiàn)雙峰一谷、晝高夜低的杓型曲線：,張振服,劉啟德,楊蕾. 血壓晝夜節(jié)律特征及其分子調(diào)控機(jī)制J. 現(xiàn)代生物醫(yī)學(xué)進(jìn)展,2011,11(6):1181-1183.,.,4,一、簡 介,但高血壓患者、老年人、甚至部分健康人群中，其血壓的晝夜節(jié)律特征可能有所變化。習(xí)慣上，根據(jù)夜間血壓的下降情況分可將其分為4型： （1）杓型(dippers)：夜間血壓較日間下降1020%；

2、（2）非杓型(non-dippers)：夜間血壓下降010%； （3）超杓型或深杓型(over-dippers或extreme-dippers)：夜間下降20%； （4）反杓型(reverse-dippers)：夜間血壓水平高于日間者。 大量臨床資料研究表明，血壓晝夜節(jié)律異常與高血壓靶器官損害和心血管事件發(fā)生呈明顯相關(guān)關(guān)系，是獨(dú)立于血壓水平的重要致病因素。,.,5,目前高血壓治療重心：,保護(hù)靶器官和降低心、腦血管疾病的發(fā)生率和死亡率。,充分控制血壓，包括增加藥物劑量、改進(jìn)降壓藥物以及聯(lián)合運(yùn)用具有協(xié)同作用的藥物等措施。,無論是單一藥物治療,還是聯(lián)合藥物治療,都存在一個共同點,即把降壓藥在早上一次

3、性服用(白天活動的開始或是在早飯時)。,.,6,高血壓患者中存在較高的非杓形血壓發(fā)病率,大多數(shù)降壓藥不能持續(xù)平穩(wěn)作用24h,針對所有高血壓患者都使用早上一次性給藥的治療策略是否恰當(dāng)？,問 題,一、簡 介,.,7,近年來，國內(nèi)外許多學(xué)者提出，全面的高血壓治療策略是在控制血壓的同時恢復(fù)高血壓患者血壓正常的近日節(jié)律，這就需要調(diào)整降壓藥的給藥時間。,蒲小波,杜一平. 血壓的近日節(jié)律與高血壓的時間治療學(xué)J.重慶醫(yī)學(xué),2009,38(21):2748-50.,一、簡 介,.,8,二、文獻(xiàn)分析與評論,Two earlier conducted morbidity trialsthe Syst-Eur and

4、 the Heart Outcomes Prevention Evaluation (HOPE) studies. In the Syst-Eur trial, participants were randomized to an evening schedule of either placebo or the dihydropyridine calcium channel blocker nitrendipine. In the HOPE study, participants in the active-treatment group ingested the angiotensin-c

5、onverting enzyme inhibitor ramipril at bedtime, a critical piece of information withheld from the original publication.,1、Staessen JA, Thijs L, Fagard R, and et al. The Systolic Hypertension in Europe Trial Investigators. Predicting cardiovascular risk using conventional vs ambulatory blood pressure

6、 in older patients with systolic hypertensionJ. JAMA, 1999,282:539546. 2、Yusuf S, Sleight P, Pogue J, and et al. The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patientsJ. N. Engl. J.

7、 Med,2000,342:145153.,.,9,二、文獻(xiàn)分析與評論,Both studies found that the evening drug administration schedule reduced the incidence of the non-dipping BP pattern among treated hypertensive patients. Furthermore, the HOPE trial demonstrated that the treatment-conferred normalization of the 24-h BP dipping pat

8、tern was associated with a lower incidence of stroke and myocardial infarction relative to those displaying the abnormal non-dipper pattern. However, the major shortcoming of both the Syst-Eur and HOPE trials is that each was devoid of a comparison treatment group randomized to morning therapy.,.,10

9、,Smolensky MH, Hermida RC, Ayala DE, and et al. Administration-time-dependent effects of blood pressure-lowering medications: basis for the chronotherapy of hypertensionJ. Blood Press Monit.,2010,15:173180.,.,11,THE MAPEC STUDY: HYPERTENSION CHRONOTHERAPY AND CVD RISK,A total of 2156 hypertensive su

10、bjects were evaluated by 48-h ABPM at base-line and with identical assessment conducted annually, or more frequently (quarterly) if adjustment of treatment was required. At baseline, the two treatment-time groups were mostly comparable in terms of their clinic and mean ambulatory SBP and DBP and pre

11、valence of non-dipping BP pattern.,Francesco Portaluppi, Michael H. Smolensky. PERSPECTIVES ON THE CHRONOTHERAPY OF HYPERTENSION BASED ON THE RESULTS OF THE MAPEC STUDYJ. Chronobiology International, 2010,27(8): 16521667.,Monitorizacin Ambulatoria para Prediccin de Eventos Cardiovasculares, i.e., Am

12、bulatory Blood Pressure Monitoring for Prediction of Cardiovascular Event (MAPEC).,.,12,Results:,Subjects who ingested 1 of their medications at bedtime showed at their last available evaluation significantly lower mean sleeptime BP, higher sleep-time relative BP decline (an index of BP dipping calc

13、ulated as (awake BP mean asleep BP mean)/awake BP mean 100), reduced prevalence of non-dipping (34% versus 62%; p .001), and higher prevalence of controlled ambulatory BP (62% versus 53%, p .001).,.,13,Results:,After a median follow-up of 5.6 yrs, the group of subjects ingesting 1 BP-lowering medica

14、tions at bedtime showed a significantly lower relative risk of total cardiovascular events than the group of subjects ingesting all medications upon awakening (0.39 0.290.51;.p .001).,.,14,Conclusion:,Results from the prospective MAPEC study thus indicate that bedtime chronotherapy with 1 hypertensi

15、on medications, compared to conventional upon-waking treatment with all medications, more effectively improves BP control, better decreases the prevalence of non-dipping and, most importantly, significantly reduces CVD morbidity and mortality.,.,15,MECHANISMS UNDERLYING THE ADVANTAGE OF BEDTIME CHRO

16、NOTHERAPY,Under usual circumstances, BP is normally lowest at night as is sodium excretion. However, in acute and chronic situations when sodium intake is excessive or its excretion hampered during the daytime, BP is adjusted by means of the pressure/natriuresis mechanism to the higher level needed

17、to compensate overnight, thereby resulting in non-dipping 24h patterning(Bankir et al., 2008; Fujii et al., 1999;Uzu et al., 2001). The pressure-natriuresis mechanism and relationship is modulated during the daytime by the effects of upright posture and activity, such that it is mainly during the ni

18、ghttime when sodium sensitivity (which is present in each person, but to a different extent) most strongly exerts its corrective effects, thus inducing the non-dipping BP patterning.,.,16,Administration-time differences in the PK of BP medications.,Hence, one might expect hypertensive medications to

19、 be cleared more slowly overnight, thereby potentially prolonging their duration of action when ingested at bedtime as compared to in the morning upon awakening (Hermida et al., 2007a). Administration-time differences in the PD of BP medications, in the absence of differences in PK, are also known (see Smolensky et al., 2010); they result from circadian rhythms in circulating drug-free fraction, rate-limiting steps of key biochemical and metabolic processes, receptor number and conformation, and/or second messenger and signaling pathways (Witte (ii) the conceptual approach to