应重视胆碱脂酶抑抑剂类药物在痴呆治疗中的不良反应

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应重视胆碱脂酶抑抑剂类药物在痴呆治疗中的不良反应

王洪权  李延峰
 
 
        阿尔茨海默病(Alzheimer's disease, AD)是一种老年性中枢神经系统退行性疾病,1906年,由德国医师Alois Alzheimer首次发现并描述。AD已成为老龄人口痴呆的最常见原因(约占各型痴呆的50–60%)。60-64岁的人口发病率小于1%,65-74岁发病率大约为3%[1]。然而,AD患病率随着年龄成几何增长,因此在西方社会中大于等于85岁的人群患病率为24%~33%。其发病率随着人口的老龄化而迅速增长,已成为继心血管疾病、癌症和中风之后的又一严重危害人类健康的疾患。患痴呆病人中的60%来自发展中国家。AD现在已非常常见并成为公共卫生的主要问题。2001年痴呆患者已达2400万人,痴呆患者每20年翻一番,预计到2040年将有8100万痴呆患者。
 
        AD主要表现为记忆、认知、语言和行为障碍以及人格改变等,患者诊断AD后平均生存时间为8~10年。该病病因目前仍不明确,有许多假说来阐述AD的发病机理,这些学说包括, 胆碱能学说(The cholinergic hypothesis)、Aβ级联学说(Amyloid cascade hypothesis)、细胞因子循环学说(The cytokine cycle hypothesis)、能量代谢学说(The energy metabolism hypothesis)和自由基学说(Free radical hypothesis)等。其中胆碱能假说始于1970年代中晚期,研究发现AD患者神经递质乙酰胆碱明显减少,该递质在人脑的记忆和学习活动中起着重要作用,进一步的研究发现胆碱乙酰基转移酶(Choline acetyltransferase, ChAT)明显减少、胆碱(Choline)摄入的降低、Ach释放和Meynert基底核核周体的丢失等,基于这些发现人们提出了阿尔茨海默病胆碱能学说(Cholinergic hypothesis of Alzheimer’s disease)(Fig.1),即Mynert核胆碱能神经元的退变,以及相关连的大脑皮层和其他脑区胆碱能神经传递的丢失导致AD患者认知功能的退化[2]
 
        基于胆碱能学说人们试图通过药物增加中枢神经乙酰胆碱递质水平从而改善AD患者认知功能,其中一些乙酰胆碱酯酶抑制药(cholinesterase inhibitors,ChEIs) (e.g., tacrine, donepezil, rivastigmine, and galantamine)获得了成功,并在临床上广泛用于AD的治疗,但这些药物仅仅在某些阶段改善AD患者的症状,并不能逆转病程。同时由于此类药物在提高中枢神经系统内乙酰胆碱水平同时,不可避免地也会产生中枢神经系统以外的胆碱能副作用,既使在中枢神经系统内,也可能由于乙酰胆碱递质的增加,产生锥体外系及精神行为症状的加重,因此如何减少此类药物的不良反应,是正确治疗痴呆患者所要考虑的重要因素。
 
Fig.1Cholinergic hypothesis of AD. Schematic diagram of a neuron representing alterations in neurotransmission in Alzheimer’s disease: (1) reduced cortical cholinergic innervation; (2) reduced corticocorticalglutamatergic neurotransmission due to neuron or synapse loss; (3) reduced coupling of muscarinic M1 receptors  to second messenger system; (4) shift of tau to the hyperphosphoryalted state – precursor of neurofibrillary tangles; (5) reduced secretion of soluble APP; (6) increased production of β-amyloid protein; (7) decreased glutamate production.
 
        安理申(Aricept®),即多奈哌齐(donepezil)是强效可逆性ChEI,是胆碱脂酶抑制剂类代表药物。其主要药理学机理是升高突触间隙乙酰胆碱的浓度,进而增强参与记忆的胆碱能系统内神经元间的相互作用[3]。1996年美国FDA批准用于治疗AD。作为AD症状性治疗药物,能够对轻度、中度AD患者的认知功能具有改善作用[4]。尽管安理申作为AD主要的症状性治疗药物,并获得广泛应用,但其副作用(adverse events, AEs)也引起了学者和临床医生的关注,犹其是AD患者多数是65岁以上的老年患者,可能合并有其它老年疾病的存在,如帕金森病、冠心病、消化系统疾病等,犹其应引起注意。
 
         临床对照试验资料显示,安理申总的AEs发生率较高。研究显示AEs的发生率 (incidence)可达到43.9%(19.5~71.3%)[5, 6]。一项单中心研究显示,安理申治疗组AEs的发生率达到40.8%[6]。一项纳入5000名轻到中度AD患者的前瞻性队列研究显示,安理申治疗组AEs的发生率达到15.1%[7]。回顾性研究(retrospective studies)显示,因AEs发生导致安理申撤药的比率报道也较多,一项研究显示,因安理申AEs而撤药的比例达到14.6%[8],另一项研究显示,安理申因恶心的AEs而撤药的比例达到3.2%[6],而安理申较其他ChEI更易导致撤药的发生。前瞻性研究 (prospective studies)显示,因安理申AEs而撤药的比例在2.5%~3.0%之间[9, 10]
 
        安理申最常见的AEs为胃肠道症状,包括厌食、恶心、呕吐、腹泻、腹胀、便秘、腹部疼痛[11-15]。安理申总的胃肠道症状AEs的发病率达到13.1%[9, 16]。恶心的发生率达到11.0%[6, 9],腹泻的发生率达到6.4%[17],腹部疼痛的发生率达到4.0%[18]。文献报道,安理申也可导致严重的胃肠道出血[19, 20],因此,在大于85岁的老年患者给药时尤其注意导致胃肠道出血的AEs发生的可能性。
 
        安理申的另一常见AEs为心血管副作用。安理申可导致心律失常、晕厥发作(Syncopal episodes),其他少见的心血管AEs包括高血压、水肿和低血压等。报告显示安理申可导致心动过缓(bradycardia)[21]和窦房传导阻滞发生[21],也有文献报道安理申在加量的过程中诱发心动过速的发生[22],从而有引致猝死的风险。
 
        神经系统并发症也是安理申另一常见AEs,研究显示神经系统AEs总发病率达到14.6%。其中最常见的并发症为头痛,发病率达到2.4-14.0%不等[23],而因头痛导致撤药的发生率达到了5%[8]。报道显示,安理申可以诱发迟发性肌张力障碍综合征(Tardive dystonia syndrome)的发生,安理申相关肌张力障碍在临床实践中并不少见,许多病例报道了其可以诱发肌张力障碍的发生,文献报道单次给药后可诱发急性肌张力障碍(Acute Pisa Syndrome)发生[24],亦有文献报道单次给药后可诱发颈部肌张力障碍(cervical dystonia)[25]。有近10例报告显示,安理申可以诱发肌张力障碍发生,其发生于安理申给药后数小时至3年不等[26, 27]
 
        其他神经系统AEs包括睡眠障碍(5.9~13%)、焦虑不安(Agitation)(3~5.2%)、眩晕(2~3%)、锥体外系症状(2%)、幻觉(1.5%)、易怒(Irritability)(0.7%)、嗜睡(0.7%)、意识模糊(Confusion state)(0.7-1.6%)、昏睡(Lethargy)(1.6%)[8]。其他的神经系统并发症也应引起关注。包括肌肉痉挛(7%)、肢体无力或跌倒(4%)、噩梦(3.2%)。文献报道安理申可诱发少见AEs的发生,包括横纹肌溶解(rhabdomyolysis)[28]。另有文献报道,安理申可诱发疼痛的发生,一例85岁的女性患者安理申增量至10 mg/d后10天诱发双侧大腿持续性疼痛的发生,疼痛表现为晨轻暮重特点[29]
        同时安理申诱发精神诊症状也已引起临床医生的关注。躁狂发作(manic episode)是安理申的重要AEs之一,文献报道目前有9例患者曾发生躁狂发作。安理申在给药3天-数周不等后可诱发躁狂发作,且女性患者中更常见,男:女比例为1:2[30]
综上所述,尽管安理申为AD主要的症状治疗性药物,在商业推广上表现出了巨大的优势,但其副作用也引起广大临床医生的关注,其对消化道系统、神经系统、心血管系统的并发症尤其应引起注意。以保证用药安全。

 
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