老年人质子泵抑制剂合理应用专家共识
中华老年医学杂志, 2015,34(10) : 1045-1052. DOI: 10.3760/cma.j.issn.0254-9026.2015.10.001

质子泵抑制剂(proton pump inhibitors,PPIs)自上世纪80年代问世至今20多年来,显著地改善了酸相关性疾病的临床结局,对酸相关性疾病的治疗具有里程碑式的意义。由于其突出的疗效和良好的安全性,在临床上的应用范围不断扩大,处方量与日俱增。但是近几年来,PPIs过度使用(超适应证、超剂量、超疗程)的问题日益突出,潜在的不良反应也备受重视[1,2,3]。PPIs是老年人的常用药物之一,老年人共病多,常多重用药,药物间相互作用机会多,药物不良反应发生率高[4]。因此,老年患者如何科学、合理应用PPIs也尤为重要。为此,中华医学会老年医学分会老年消化学组和《中华老年医学杂志》编辑委员会,组织国内部分老年病、消化病和临床药理学专家,制定了本共识,供广大老年病科和全科医生应用PPIs时参考。

一、老年人PPIs的药代动力学特点及作用机制

老年肝脏对药物的代谢转化能力降低,肾脏对药物的清除能力降低,药物半衰期延长、肾毒性增加[5]。因此,了解老年人PPIs的药代动力学特点及作用机制,对合理应用PPIs具有重要意义。

PPIs在体内代谢迅速,血浆半衰期在2 h以内,蛋白结合率均在90%以上。PPIs主要通过细胞色素P450系统中的CYP2C19和CYP3A4在肝内代谢,并经肾脏清除。CYP2C19是大部分PPIs在肝内代谢的主要途径,80%以上的奥美拉唑、50%以上的埃索美拉唑和兰索拉唑经CYP2C19代谢,其次是经CYP3A4、CYP1A2代谢;泮托拉唑虽主要经CYP2C19代谢,但对其亲和力较低,且其特有的二相代谢,也降低了其对CYP2C19的依赖性;雷贝拉唑主要经烟酰胺嘌呤二核苷酸磷酸(NADP)代谢,其次经CYP3A4、CYP2C19代谢;由此可见,常用的5种PPIs对CYP2C19的依赖性存在差异,泮托拉唑和雷贝拉唑对CYP2C19的依赖性较低[6,7]。老年人、肾功能不全和轻中度肝功能不全患者的PPIs药代动力学与青年人相似,所以无需调整剂量[7];但严重肝功能不全患者,其最大曲线下面积(AUCmax)值为肝功能正常者的2~3倍,血浆半衰期明显延长,应用PPIs应相应减量[8,9,10,11,12]

PPIs是苯并咪唑的衍生物,主要在小肠吸收,特异性地作用于胃底腺壁细胞内管泡膜上的胃酸分泌的最后环节H-K-ATP酶(即质子泵),与质子泵不可逆结合使其失去活性,从而高效抑制胃酸分泌,直到新的质子泵产生,壁细胞才能恢复泌酸功能,从而使胃内pH值24 h维持在较高水平,是目前作用最强的胃酸分泌抑制剂。

二、老年人应用PPIs的适应证

1.消化性溃疡;

2.胃食管反流病;

3.急性胃黏膜病变(包括应激性溃疡、急性糜烂出血性胃炎等);

4.Zollinger-Ellison综合征;

5.非静脉曲张性上消化道出血;

6.与抗菌药物等联用根除幽门螺杆菌(Hp);

7.非甾体类抗炎药(NSAIDs)或糖皮质激素(GCs)相关胃十二指肠黏膜损伤;

8.医源性或理化因素所致的上消化道黏膜损伤;

9.慢性非萎缩性或慢性萎缩性胃炎伴糜烂(简称慢性糜烂性胃炎);

10.功能性消化不良;

三、老年人应用PPIs的安全性

PPIs是目前公认的治疗酸相关性疾病最为有效的药物,该类药物总体安全性良好。一般不良反应包括头痛、腹泻、恶心、胃肠道胀气、腹痛、便秘、头晕等,发生率在1%~5%之间,老年人发生率略高。这些不良反应通常较为轻微,为自限性。偶有文献报道PPIs导致过敏性休克、全血细胞减少症、血管炎、红斑狼疮、间质性肾炎、支气管哮喘、骨骼肌肉疼痛甚至横纹肌溶解等严重不良反应[13,14,15],在临床上应予重视。胃酸具有一系列重要的生理功能,长期强力抑酸很可能产生一些潜在的不良反应,近几年PPIs长期应用的安全性备受关注,且仍存在争议。PPIs长期应用存在下列潜在的不良反应,其在老年患者中发生的可能性较中青年患者大;坚持个体化原则,认真权衡PPIs治疗利弊,正确掌握PPIs的适应证、剂量和疗程,不仅可将其风险最小化,而且可降低医疗费用[3]

1.骨质疏松与骨折:

长期应用PPIs并不增加骨质疏松及骨折的风险,不应影响长期应用PPIs的临床决策[16,17]。但老年人本身是骨质疏松症的高危高发人群,PPIs强力抑酸后影响钙吸收,长期钙吸收不足将引起血钙浓度降低,刺激甲状旁腺素释放,继而促进破骨细胞介导的骨质吸收,诱发或加重老年患者的骨质疏松,从而增加骨折的风险[18,19]。有研究提示:每天口服2倍标准剂量的PPIs、连续1年以上会导致髋骨、腕骨、椎骨骨折风险增加[20,21,22,23]。为此,我国食品药品监督管理总局2013年5月发布通报警告:长期使用较高剂量PPIs可使骨折风险升高,尤其是老年患者,要求医生处方PPIs时应考虑低剂量、短疗程的治疗方式[24]

2.肺炎:

PPIs的长期应用,使胃内长期处于低酸状态,对细菌的灭活作用下降,从而使胃内处于有菌状态。当发生生理性或病理性胃食管反流时,或实施治疗性干预时(如鼻饲管、气管内插管等),含菌胃内容物会反流至咽喉部,随之误吸入肺,从而导致肺部感染[25]。大型病例对照研究结果显示,应用PPIs会增加肺炎的风险,且该风险值与PPIs剂量呈正相关[26,27,28,29,30,31]。短期应用PPIs会增加社区获得性肺炎的风险[28,32]。尽管也有一些不同意见的报道[3,33],但老年人是肺炎的易感人群、胃食管反流病的高发人群,也是实施治疗性干预最多的人群,且老年人吞咽协调功能减退,较易发生吸入性肺炎,因此更应尽量避免大剂量、长期应用PPIs,以免影响胃酸对胃内细菌的廓清作用。

3.肠道感染:

长期应用PPIs,胃内pH的升高,胃酸屏障功能降低,胃内细菌定植和肠道菌群过度生长[34],使患者腹泻的发生率增加。多项研究结果提示,长期应用PPIs与难辨梭状芽孢杆菌(clostridium difficile,CD)感染的发生及复发有关,PPIs的应用可能是CD感染的一个独立危险因素[1034,35,36,37,38,39,40]。但也有学者认为,尚无明确证据表明PPIs使用和CD感染之间存在因果关系[41]。对存在免疫功能缺陷或有慢性基础病的老年患者,应权衡长期PPIs治疗的获益和风险,当患者有致命性的肠道感染,而没有紧急抑酸治疗的适应证时,应中断PPIs治疗[42]

4.缺铁性贫血:

食物中的铁为三价铁,需在酸性胃液(pH<3)中还原为二价铁,才能在十二指肠和空肠中被吸收。长期服用PPIs抑制胃酸分泌,影响铁的吸收,导致铁缺乏,进而可引起缺铁性贫血[43,44]。对长期服用PPIs的患者出现不能解释的缺铁性贫血时,应考虑到PPIs所致的可能性,如不能停用PPIs,建议补充铁剂,纠正贫血。

5.维生素B12缺乏:

胃酸及胃蛋白酶将维生素B12从饮食中的维生素B12-蛋白结合状态释放出来,使之与壁细胞生产的内因子结合,最终被回肠末端吸收入血,故胃内酸性环境是维生素B12吸收的重要条件[44,45]。长期应用PPIs抑制胃酸,可能影响维生素B12的吸收,而老年患者维生素B12缺乏或储备不足较为多见[3,46,47]。故对长期使用PPIs的老年患者,特别是全身营养情况较差者,可以检测血清维生素B12水平,如缺乏应及时补充。

6.低镁血症:

PPIs引起低镁血症的机制尚不清楚。临床观察发现,在服用PPI s 3个月及以上(多数在12个月以上)的患者可出现低镁血症,主要表现为疲劳、手足搐搦、谵妄、惊厥、头晕及室性心律失常等[24]。对于需要长期PPIs治疗的患者,特别是同时服用地高辛或其他可能导致低镁血症的药物(如利尿剂)的患者,可考虑在开始PPIs治疗前对患者进行血镁浓度测定,并在治疗期间定期检查。当低镁血症患者在增加镁摄入仍不能纠正时,建议停用PPIs。尽管该不良反应较为罕见,但考虑到PPIs的广泛应用和低镁血症的严重后果,临床上仍应引起高度重视[8,48,49,50]

7.胃底腺息肉:

胃底腺息肉是胃内最常见的息肉,应用PPIs 1年以上,其发生风险是不用PPI患者的4倍[51]。胃底腺息肉均为良性,停用PPIs后可以退化、消失。

四、PPIs与其他药物的相互作用

应用PPIs后胃内pH值升高,影响某些口服药物生物利用度,一些不耐酸的口服药(如阿莫西林、克拉霉素等),在胃内pH值升高后其生物利用度升高,MIC90(抑制90%的细菌所需的最低药物浓度)降低;而另外一些药物(如酮康唑、伊曲康唑、阿扎那韦等),胃内pH升高后,在胃内的崩解延缓,其生物利用度和血药浓度降低。

PPIs主要通过CYP2C19和CYP3A4等代谢,与其他通过这些药酶代谢的药物发生竞争抑制,影响彼此的疗效。由于5种PPIs对CYP2C19的依赖性不同,因此,与其他药物发生相互作用的情况也各异。从现有的资料看,老年人常用药物与5种PPIs之间的相互作用,以奥美拉唑的发生率较高,泮托拉唑的发生率最低[12,52]。奥美拉唑或埃索美拉唑与华法林同时使用时,华法林清除率降低[52]。未发现泮托拉唑、雷贝拉唑与华法林、茶碱、克拉霉素及他克莫司等相互作用[53,54,55]

血小板聚集抑制剂氯吡格雷与PPIs一样为前体药,且都主要通过CYP2C19代谢,二者同时应用将产生竞争抑制,影响氯吡格雷的疗效。曾有研究报道,PPIs与氯吡格雷联用会增加心血管事件的发生率[56,57]。为此,美国食品药品管理局(FDA)曾在2009年多次就氯吡格雷与PPIs的联合应用提出了"黑框警告",建议避免在应用氯吡格雷的同时联用奥美拉唑和埃索美拉唑[58]。如果正在使用氯吡格雷的患者必须使用PPIs,应考虑使用不会产生明显相互作用的PPIs,如泮托拉唑等[24];或者正在使用PPIs的患者,需要使用抗血小板药物时,避免选用氯吡格雷。但国内外也有研究结果提示,PPIs与氯吡格雷联用并未增加心血管事件的发生率,这些研究结果得到有关指南的认可[18,59,60,61,62,63,64]

五、老年人PPIs的合理选用

传统观念认为,老年人胃泌酸功能是减退的,或老年人缺乏胃酸。因此,临床上曾用稀盐酸治疗老年人消化不良。近20年的研究结果证明,老年人分泌胃液的能力及胃内酸度并未随增龄而减退,老年人基础酸排量和最大酸排量与青年人相仿,甚至发现健康老年人基础、餐后及胃泌素刺激后的胃酸分泌量比中青人还要高[65,66]。老年人胃内基础pH、中位pH和平均pH与中青年人无区别,各年龄段的老年人胃内酸度与青年人相似[67,68]。随着年龄增长,老年人胃壁细胞内与泌酸功能直接相关的细胞器无退化表现,H-K-ATP酶表达有增加趋势,健康老年人存在维持良好泌酸功能的超微结构和分子生物学物质基础[69]。少数老年人存在低胃酸症(pH>3.5),是由于患有慢性萎缩性胃体胃炎或严重的Hp感染所致[70,71]。因此,老年人酸相关性疾病与中青年人一样,可以用PPIs治疗。

1.严格掌握适应证:

应做到不超适应证用药;当用作诊断性治疗时,由于PPIs亦可缓解某些上消化道恶性肿瘤的症状,要警惕服用PPIs掩盖症状、延误其诊断,应及时行胃镜等检查,早日明确诊断。

2.掌握合适的剂量和疗程:

不同适应证,对胃内pH值有不同的要求,据此选择对应剂量的PPIs[72];除严重肝功能障碍者需酌情减量外,其他老年人应用PPIs与中青年人一样,无需调整剂量;根据适应证,严格控制PPIs应用的疗程;尽量避免大剂量(加倍标准剂量或以上)、长时间(6个月或以上)应用PPI;维持治疗时,一般采用标准剂量或标准剂量的半量。

3.选择合适种类的PPIs:

目前常用的5种PPIs对老年人都是安全有效的,近期(2周)疗效稍有差异,但4周以上的疗效基本相同,常见不良反应轻微,严重不良反应少见。由于代谢途径和药代动力学的差异以及受CYP2C19多态性的影响,5种PPIs仍有一些差异,同时考虑到老年人因多种疾病并存而同时服用多种药物,因此,老年人宜优先选用与其他常用药物相互作用较少的PPIs,如泮托拉唑、雷贝拉唑[24,52]

4.选择合适剂型的PPIs:

对吞咽困难的老年人宜选用含肠溶颗粒或含多微粒胶丸的胶囊、片剂或颗粒剂,可将胶囊内容物、药片(置于温水中溶解,但不能咀嚼、研磨)或颗粒剂放在温开水中、酸奶中或糊状食物中服用,也可以放在流汁中鼻饲。口崩片(Oro-Dispersible tablet,目前兰索拉唑有该剂型)置于舌上即可崩解,不需饮水就能咽下,而且药代动力学和疗效不变[73],这种剂型特别适用于身体虚弱和吞咽困难的老年人,提高老年人服药的依从性[74]

5.正确的服药时间:

由于PPIs是前体药,经代谢生成的活性产物作用于活化的质子泵才能取得最佳抑酸效果,晨起时壁细胞上新生质子泵最多,进餐使其活化,因此,PPI应在早餐前0.5~1 h服用,若每天服用2次,另1次应在晚餐前0.5~1 h服用。

6.重视PPIs安全性监测:

PPIs的严重不良反应及长期应用的潜在不良反应虽然少见或罕见,但对老年患者仍应保持警惕。一是重视临床监测,及时识别和处理各种并发症;二是实验室监测,如定期监测骨密度、血骨代谢指标、血清铁、血红蛋白、血维生素B12及血镁水平等,发现异常及时处理,必要时停用PPIs。

六、简要PPIs治疗方案

常用PPIs的标准剂量(常规剂量)分别为:奥美拉唑20 mg/d,兰索拉唑30 mg/d,泮托拉唑40 mg/d,雷贝拉唑10 mg/d,埃索美拉唑20 mg/d;艾普拉唑10 mg/d,临床应用较少。

1.消化性溃疡:

抑酸要求:胃内pH>3的时间超过18 h/d。应用标准剂量PPIs,十二指肠球部溃疡连续使用4~6周,胃溃疡连续使用6~8周。对于Hp阳性的消化性溃疡病,在抗Hp治疗结束后,仍应继续应用PPIs至疗程结束[75]

2.胃食管反流病[64,74]

抑酸要求:胃内pH>4的时间超过18 h/d。应用标准剂量PPIs,疗程至少8周;症状控制不满意时,可用加倍标准剂量或更换PPI品种。合并食管裂孔疝或重度食管炎(洛杉矶分类为C级、D级)患者,则需服用加倍剂量的PPI。老年人胃食管反流病常需维持治疗,依病情可用标准剂量、标准剂量的半量,每天1次或隔天1次,或按需治疗予以维持。

3.急性胃黏膜病变:

包括应激性溃疡、急性糜烂出血性胃炎等。一般应激源,采用标准剂量PPIs预防;急性胃黏膜病变,视病情可采用标准剂量或加倍标准剂量,疗程4~6周;严重应激(如严重创伤、严重疾病等)患者应激性溃疡的预防及合并出血者的治疗[76],需静脉应用PPI(见后述)。

4.Zollinger-Ellison综合征:

应用加倍标准剂量的PPI,常需原剂量长期维持治疗[76]

5.非静脉曲张性上消化道出血[77,78]: 抑酸要求:

胃内pH>6的时间超过20 h/d。应在内镜下先了解病灶出血情况,如为活动性出血,应积极采取内镜、介入或手术治疗止血,同时强力抑酸,促进止血或预防再出血。需要静脉应用PPIs,奥美拉唑或埃索美拉唑或泮托拉唑40 mg或兰索拉唑30 mg,静脉推注(3 min以上)或静脉滴注(30 min以内)后,1次/12 h,连续5~7 d;出血停止后改为口服,剂量和疗程依原发病确定。严重肝功能障碍者需酌情减量。

6.与抗菌药物联用根除Hp:

抑酸要求:胃内pH>5的时间超过18 h/d。需要口服加倍标准剂量的PPIs,即标准剂量2次/d。根除Hp方案参照《第四次全国幽门螺杆菌感染处理共识报告》,如根除治疗前正在服用PPIs,建议停服PPIs2周以上,再行根除[79]。老年人(尤其是高龄老年人),根除Hp须仔细权衡其利弊。

7.NSAIDs或GCs相关的胃十二指肠黏膜损伤:

老年患者应用NSAIDs可发生胃肠道不耐受和消化性溃疡,且NSAIDs是老年患者药物性消化道出血的首要原因[80,81]。老年患者应用NSAIDs时,若存在以下情况之一,建议应用PPIs预防消化道黏膜损伤[82,83,84,85,86,87,88]。有消化性溃疡史者;有消化不良或胃食管反流症状者;接受双联抗血小板治疗的患者;服用华法林等抗凝药物的患者;合用另一种NSAIDs(包括低剂量和高剂量阿司匹林)的患者;合用GCs的患者;Hp感染者。老年患者长期应用GCs,消化性溃疡和上消化道出血的发生率会显著增加[89,90],老年患者使用GCs时,若存在以下因素之一,建议应用PPIs预防上消化道黏膜损伤:高剂量、长疗程应用GCs;同时使用NSAIDs;有消化道溃疡或伴出血病史。预防性应用PPIs的剂量为标准剂量,疗程决定于所用NSAIDs或GCs的疗程。

8.医源性或理化因素所致的上消化道黏膜损伤:

无活动性出血的较小创面(直径<2 cm),应用标准剂量PPIs,疗程6~8周;较大创面(直径≥2 cm,如黏膜剥离术后等)或伴活动性出血者,则需禁食,静脉应用PPIs,5~7 d后改为口服加倍标准剂量PPIs,疗程至少8周[91,92]

9.慢性非萎缩性或慢性萎缩性胃炎伴糜烂(简称慢性糜烂性胃炎)[93]

应用标准剂量PPIs,疗程4~6周;应检测并根除Hp。

10.功能性消化不良[94,95,96]

抑酸要求:胃内pH>3的时间超过12 h/d。PPI常用于非进餐相关的消化不良,即上腹痛综合征,也可用于餐后不适综合征。应用标准剂量或半量PPIs,疗程4~6周,此后可停药或按需服用。

各适应证的详细治疗方案可参阅国内外有关共识、规范或指南。

执笔:郑松柏 姚健风

专家组成员

专家组成员(按汉语拼音排序):陈新宇(浙江医院),戴宁(浙江大学医学院附属邵逸夫医院),甘华田(四川大学华西医院),郭永红(中南大学湘雅二医院),江华(同济大学附属东方医院),刘世雄(兰州大学第一医院),阮继刚(宁夏医科大学总医院),史丽萍(陕西省人民医院),孙忠实(解放军海军总医院),万军(中国人民解放军总医院),王瑞玲(解放军第二炮兵总医院),王小众(福建医科大学附属协和医院),吴本俨(中国人民解放军总医院),吴静(首都医科大学附属北京世纪坛医院),谢建洪(浙江省人民医院),许乐(卫生部北京医院),严祥(兰州大学第一医院),杨云梅(浙江省第一医院),姚健风(复旦大学附属华东医院),姚萍(新疆医科大学第一附属医院),于普林(北京医院),袁耀宗(上海交通大学医学院附属瑞金医院),张玉(复旦大学附属华山医院),张志广(天津医科大学第二医院),郑松柏(复旦大学附属华东医院),钟碧慧(中山大学附属第一医院),周永宁(兰州大学第一医院)

学术秘书:李小雯(复旦大学附属华东医院消化科 老年医学科)

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