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1、.药物与肠内营养相互作用的研究进展综 述肠内营养是经口或管饲由胃肠道提供代谢需要的营养基质及其他各种营养素的支持方式1。20世纪80年代,肠内营养开始提供全营养素支持,小肠营养配方及胃食管技术得到长足的发展。随着接受各种方式肠内营养的患者增加,药物营养物质的相互作用Drug-nutrition interrelations,DNIs也越来越受到重视。药物与营养物质发生的药剂学、药动学及药理学、生理学、病理生理相互作用都有可能使治疗结果反转1。如何全面正确地掌握药物与其它常用药物之间的相互作用知识, 并在临床实践中加以合理的应用,是摆在医药工作者们面前的一个艰巨而重要的任务。本文针对DNIs的最
2、重要三方面因素综述如下：1 药剂学影响药剂学方面药物营养物质相互作用主要指药物的剂型不适当地改变以致药物穿过胃食管造成不正确的用药途径,药物毒性或胃肠道刺激。液体制剂通常能够通过喂食管给药,为某些特殊用途设计的片剂或胶囊剂也同样可以通过喂食管给药,而固体剂型必须转变为粉末或小颗粒后与水混匀方能穿过喂食管。但是在治疗过程中,当药物的剂型遭到不同程度的破坏时,药物制剂的稳定性、安全性和有效性就发生一定程度的改变。因此,在临床治疗过程中,应选择最合适的剂型给药。由于液体制剂易被吸收,而且不大可能造成胃食管阻塞,而通常作为首选,酊剂或混悬剂相对糖浆剂不易与肠内营养发生结块而更受青睐3。而只有当液体制剂
3、不适用时才会考虑某些固体制剂,但大多要粉碎后,导致最低限度的药动学改变。固体制剂中肠衣片与长效片剂最容易发生药剂学相互作用。肠溶衣片剂或微囊剂被压碎通过口服或插管给药进入机体后,由于去掉了保护膜就会暴露在胃酸中或对机体产生刺激、毒性反应。如果将药物直接运送到空肠,就不需要肠溶衣。但是,粉碎肠溶衣剂型也可能带来相互作用等问题。粉碎肠溶衣是件很麻烦的事,其碎片加水后容易成团,堵塞胃食管4。无论何种情况,改变给药途径都要比试图通过胃食管给药更好。通过研究发现一些微囊剂可以将制剂中的药物取出后再通过胃食管。尽管这样会有部分残留,除非用酸性液体强烈的冲刷,或者可以将这些残留浸泡在酸性果汁中,这样的方法同
4、样有胃食管阻塞的风险2。无论哪种方法都需要很小的管子,特别是手术用的管子,它可以用碳酸氢盐10倍地溶解肠溶衣,之后可以压碎或溶解药物形成膏状物。如果药物设计的剂型是控释制剂,那么不能为了经胃食管给药而将其粉碎或在其他方面有所改变,这种剂型在片剂或胶囊里通常包含了几种剂量的药物。压碎或溶解缓释药物使其立即释放,则会出现在开始阶段过量而几小时后药物失去活性的现象。此时,毒性作用会增加。药物对病情控制也会不稳定。例如地尔硫卓Tiazac, Biovail Pharmaceutical, Morrisville, NC和维拉帕米Verelan, UCB Pharma, Smyrna,GA68。Ferr
5、one等9描述了如何将含有肠溶微球的缓释胰腺酶胶囊Pancrecarb MS-4, Digestive Care,Inc., Bethlehem, PA打开与苹果酱或苹果汁混合在一起后由胃食管送下。某些肠溶衣的缓释剂可以通过大口径的胃食管给药。其他包被片如薄膜衣即使碾碎也很难从管壁上洗下,同样很麻烦。然而有文献报道有些药物经过一些改变后仍然可以使用10。粘稠性液体制剂如混悬剂可能会粘附在胃食管上导致药物在冲洗后还停留在导管表面,这会直接影响药物的运送、吸收,产生药动学相互作用11,12。辅料作为药物的辅助性添加剂,尽管不与机体发生反应但有时也产生生理学的影响。有研究表明小麦和玉蜀黍淀粉通常作为
6、片剂的粘合剂可能会引起患者的肠病如口炎性腹泻。Hyams也发现通常作为增溶剂以防止蔗糖结晶的山梨醇,在20g50g剂量下可作为泻药,因此可能引发患者严重痉挛及腹泻13。1. 药动学影响药动学的影响主要指由于营养物质和药物的相互作用,导致药物在人体的吸收、分布、代谢、消除等过程的改变。2.1吸收 其与生物利用度直接相关。药物或营养的吸收的紊乱常会导致它们的吸收的减少14,15。一般情况下,理化不兼容性和胃肠道pH的干扰都与无活性产物的形成有关。另一方面,胃肠运动,分泌物,菌群及粘膜形态与功能更易诱发吸收速率的改变。在个别情况下直接将药物加入到营养配方中引起理化不相容性,从而降低了药物的吸收,增加
7、胃食管阻塞的风险和潜在的微生物污染1618。根据统计数据可以看出,吸收似乎与纤维的含量有关。食用纤维能够增加阿莫西林的吸收速率,但是明显的降低吸收的总量,因此Chandler等人19 得出这可能是阿莫西林对纤维基质的吸收作用导致的结论。高果胶的膳食中果胶是作为对乙酰氨基酚的吸收剂20。果胶和燕麦麸纤维都能减少洛伐他汀的吸收21。因此,在服用类似药物时,服药与进食最好间隔2个小时。在药物和营养物质相互影响中,络合是一个不同的机制。例如膳食中的矿物质锌,铁,钙,镁的可溶性盐都会与四环素,喹诺酮和抗酸剂络合14,20。而包含铝镁类的抗酸剂通常会由于不可溶性铝或镁的磷酸盐的产生引起临床上明显的磷酸盐耗
8、竭症状14,22。左旋多巴与铁的螯合会减弱对帕金森病情的控制23。硫酸铝与膳食中的蛋白质结合易引起不溶性物质胃肠结石的产生及药物疗效的降低24。所以,上述药物都应饭前1小时空腹服用。胃肠道中pH值的改变能影响药物或营养物质的离子和非离子的形式,从而影响吸收过程20。引起胃肠道PH的降低的药物抗酸剂,组胺H2受体拮抗剂和蛋白泵抑制剂与硫胺、氯钴胺、和铁同时服用会引起后者吸收的降低23,25。另一方面,胃内持续的营养会增加胃肠道的PH,从而阻止异烟肼的溶解与吸收20。硫糖铝为达到治疗效应需要一个酸性的环境来成为有活性的物质24。酮康唑需要酸性环境来溶解吸收24-30。相反,环丙沙星和奥美拉唑在碱性
9、环境中更易吸收。去羟肌苷嘌呤核苷类抗艾滋病药需要防止酸的催化分解。胃内营养能提高去羟肌苷的吸收总量但是不能提高吸收速率21。总之,胃肠道PH值的影响是有争议的,无论是本能的还是诱导的变化都应对已知的相互作用进行研究,从而避免这种相互作用。2.2分布 药物与营养物质的分布是与转运蛋白竞争结合引起的DNI的另一种形式。理论上,高脂肪的膳食能迅速增加血浆中的游离脂肪酸量,瞬间的取代药物结合与白蛋白上,可能会增加药物的药理作用19虽然还没有相关的临床案例报道。长期的摄入蛋白不足可能会减少白蛋白的数量,当药物的分布与蛋白结合基有关时就会影响药物的分布。2.3代谢 其与营养配方和药物的代谢形式有关14。由
10、于营养物质影响代谢酶的合成与活性,同样,同时服用药物与营养物质会影响肝微粒体复合功能氧化酶活性的激活或抑制14,28。高蛋白摄入能刺激微粒体复合功能氧化酶系统活性,对某些药物的清除作用会升高。烟酸、维生素B2大剂量的维生素C也能增加微粒体复合功能氧化酶系统活性。而且,这些影响通常与肝血流量的改变有关28。很多文献都报道了当病人将高蛋白或是低碳水化合物的饮食与茶碱同服后茶碱的半衰期能明显的降低19,28,29,30；而同时服用高脂的饮食会产生茶碱的毒性症状14。然而,膳食中蛋白质和脂肪能刺激内脏的肝血流量,这与药物的肝提取率有关,如普萘洛尔和拉贝洛尔14,20,28。但是,在对这些观察结果的临床
11、影响做出任何结论性的论断之前,还需要更多的研究。大多数关于饮食对微粒体复合功能氧化酶系统活性的影响都进行了动物实验研究。2.4排泄 饮食与药物都可引起尿酸或是尿碱14。低蛋白饮食会导致尿液PH值增加。碱化尿液可以增加呋喃妥因的排泄及其效应。此外,当呋喃妥因与食物同食时,会引起其耐受性及吸收的增加31。低蛋白饮食可能会增加肾脏对喹诺酮的重吸收,增加药物的毒性。相似的饮食也能促进肾小管对别嘌呤醇的主要代谢物奥昔嘌醇的重吸收,导致对于老年人具有重要实际意义的毒性作用14。相反,高蛋白饮食引起的尿酸会增加阳离子表面活性剂类药物的排泄,例如：阿密曲替林高蛋白饮食也会增加肾脏的血流量和由胰高血糖素介导的肾
12、小球滤过率14,19。2. 药理学影响当一个药物的作用机制会干扰营养物质的吸收,或者引起肠道喂食不耐受时,即发生了药理学相互作用。服用能刺激胃肠道活动能力的药物,像阿托品、红霉素、东莨菪碱等配方特性,通过延迟或加速胃排空的时间而影响肠内营养的吸收。对于早期的危重病人胃排空的改善更倾向于给予肠内营养。Ritz和他的同事32随机挑选了35名机械通气患者平均健康状况评分19,进行了给予红霉素70克或200克或安慰剂的随机化双盲实验。他们发现给予70克或200克的实验组的胃排空比安慰剂组的更快。接着他们又比较了70克和200克的实验组在提高胃排空上无明显差异,因此在实际治疗中选择70克的低剂量来代替2
13、00毫克来改善胃排空,以降低毒副作用。病人自身的疾病状况与条件亦影响胃肠道的活力。型和型糖尿病易致胃轻瘫的并发症,Nguyen等人33将12名危重的2型糖尿病患者和15名非糖尿病患者在年龄和性别上相匹配进行试验,发现糖尿病病人的胃排空比非糖尿病病人的胃排空更快,几乎和健康受试者排空相似。但是由于样本的数目的相对比较小,所得结果可能存在偏差,还有待于对其进行大样本更细致的研究。而对于肠内营养中的配方组分也能通过影响机体的某些生理机制而干扰药物的作用机制药物的。最典型的例子就是较高维生素K含量的肠内营养配方拮抗华法林抗凝作用。华法林通过以致维生素K依赖性凝血因子、和在肝脏发挥作用,对于接受华法林治
14、疗的患者只要谨慎的选择小肠配方就可以很好的避免这一相互作用。因此在临床选择药物时,必须考虑药物药理作用对胃肠道的影响,以最大限度的减少不良影响。3. 结论以上几方面都受到医学界的广泛关注,接受肠内营养治疗患者发生DNI的影响因素,即药剂学、药动学、药理学三方面的因素,虽是重点内容,但仍然是研究不是很充分的。比如苯妥英是发现与小肠配方有明显相互作用的第一个药物,虽然距其发现已将近30年,但是对于相互作用的产生原因及临床表征依然存在争议,那些数据只能证明它们之间存在着相互作用34,35。并且由于鉴定药物和小肠营养配方成分之间相互作用的资料太少,并且常常是矛盾的,给药技术也太少。同样用于控制DNI的
15、技术也是有限的。国内对肠内营养的研究更少,国外相对多但是资料也是太陈旧或是不适用于现在使用的产品。但药物与营养物质的DNI确实存在,且严重的影响人类的健康,因此需要医学界的广泛关注,在今后的临床实践当中能够尽量的降低患者发生DNI的风险,并减少不良反应的发生。参考文献：1中华医学会.临床诊疗指南:肠外肠内营养学分册 .北京:人民卫生出版社,2009:352Williams NT. Medication administration through enteral feeding tubes.Am J Health Syst Pharm. 2008 Dec 15;65:2347-57.3Phil
16、lips NM, Nay R. A systematic review of nursing administration of medication via enteral tubes in adults.J Clin Nurs. 2008 Sep;17:2257-654Matsuba CS, De Gutirrez MG, Whitaker IY. Development and evaluation of standardized protocol to prevent nasoenteral tube obstruction in cardiac patients requiring
17、enteral nutrition with restricted fluid volumes.J Clin Nurs. 2007 Oct;16:1872-71 杜冠华译.药物与营养物质的相互作用.北京：人民卫生出版社. 2008：378-404.2 Magnuson BL, Clifford TM, Hoskins LA,et al.Enteral nutrition and drug administration, interactions, and complications. Nutr. Clin. Pract. 2005; 20:618-24.3 Thomson FC, Naysmi
18、th MR, Lindsay A. Managing drug therapy in patients receiving enteral and parenteral nutrition.Hosp Pharmacist. 2000; 7:155-64.4 Lourenco R. Enteral feeding: drug/nutrient interaction. Clin Nutr. 2001; 20:187-93.Magnuson BL, Clifford TM, Hoskins LA, Bernard AC.Enteral nutrition and drug administrati
19、on, interactions, and complications.Nutr Clin Pract. 2005 Dec;20:618-245 Beckwith MC, Feddema SS, Barton RG et al. A guide to drug therapy in patients with enteral feeding tubes: dosage form selection and administration methods.Hosp Pharm. 2004; 39:225-37.6 Gilbar PJ. A guide to enteral drug adminis
20、tration in palliative care. J Pain Symptom Manage. 1999; 17:197-207.7 Mitchell JF. Institute for Safe Medication Practices Oral dosage forms that should not be crushed.Farm Clin. 1998; 5: 324-3388 Ferrone M, Raimondo M, Scolapio JS. Pancreatic enzyme parmacotherapy. harmacotherapy. 2007; 27:910-2010
21、.9 Mitchell JF, Oral dosage forms that should not be crushed. Hosp Pharm 2002;35:553-567.10 Clark-Schmidt AL, Garnett WR, Lowe DR, etal. Loss of carbamazepine susupengsion through nasogastic feeding tubes. J. Hosp. Pharm. 1990;47:2034-2037.11 McGoodwinPE,Seifert CF, Bradberry JC, Recovery of phenyti
22、on form a percutaneous endoscopic gastrostomy pezzar catheter following in vitro delivery of multiple doses of phenytoin suspension and phenytoin capsules. Pharmacotherapy 1990;10:233.12 Hyams JS. Sorbitol intolerance. An unappreciated cause of functional gastrointestinal complaints. Gastroenterolog
23、y 1983;84:30-33.13 Utermohlen V. Shills ME, Olson JA, Diet, nutrition and drug interactions. Modern nutrition in health and disease. 1999:1619-1641.14 Palleja A M, Pera D, Falga S J, A.Managing drug therapy in patients receiving enteral and parenteral nutrition. Farm Clin. 1988; 5: 324-338.15 Kumpf
24、VJ, Chessman KH.etal. Pharmacotherapy: a pathophysiologic approach. Enteral nutrition; 2005:2615-34.16 Gora ML, Tschampel MM, Visconti JA. Considerations of drug therapy in patients receiving enteral nutrition. Nutr. Clin. Pract. 1989; 4:105-10.17 Thomson FC, Naysmith MR, Lindsay A. Managing drug th
25、erapy in patients receiving enteral and parenteral nutrition. Hosp Pharmacist. 2000; 7:155-64.18 Chandler M H, Blouin R A,. Applied pharmacokinetics. Principlesof therapeutic drug monitoring. Vancouver: Applied Therapeutics, 1992;12-1: 12-16.19 Thomas J A. Drug-nutrient interactions. Nutr. Rev. 1995
26、; 53:271-282.20 Gibaldi. Drug interactions: part II. Ann Pharmacoth 1992; 26: 829-83421 Knapp H. In: Zigler E E, Filer L J Present knowledge in nutrition. Nutrient-drug interactions, 1996; 540-546.22 Mason P. Nutrition and dietary advice in the pharmacy. Drug-nutrient interaction, 1994; 223-237.23 J
27、ohnson D R, Nyffeler M S. Drug-nutrient considerations for enteral nutrition. In: American Society for Parenteral and Enteral Nutrition The ASPEN nutrition support practice manual. 1st ed. Silver Spring: American Society for Parenteral and Enteral Nutrition 1998; 61: 6-20.24 Marcuard S P, Albernaz L
28、, Khazanie P G. Omeprazole therapy causes malabsorption of cyanocobalamin. Ann Intern Med 1994; 120: 211-215.25 Thomson C A, Rollins C J, Rolandelli R H, Enteral and tube feeding, Nutrient-drug interactions.1997: 523-539.26 Yuk J H, Nightingale C H. Relative bioavailability in healthy volunteers of
29、ciprooxacin administered through a nasogastric tube with and without enteral feedings. Antimicrob Agents Chemother 1989; 33: 1118-1120.27 Walter-Sack I, Klotz U. Influence of diet and nutritional status on drug metabolism. Clin. Pharmacokinet 1996; 31: 47-64.28 Strom J G, Miller S W. Stability of dr
30、ug with enteral nutrient formulas. Ann Pharmacother 1990; 24: 130-134.29 Varella L, Jones E, Meguid M M. Drug-nutrient interactions in enteral feeding: a primary care focus. Nurse Practitioner 1997; 22:98-104.30 Rosenberg I, Berry E. Basic principles in therapeutics. Nutrition 1992:248-269.31 Ritz M
31、A, Chapman MJ, Fraser RJ, Erythromycin dose of 70 mg accelerates gastric emptying as effectively as 200mg in the critically ill. Intensive Care Med.2000; 31:949954.32 Nguyen NQ, Chapman M, Fraser RJ, Long-standing type II diabetes mellitus is not a risk factor for slow gastric emptying in critically
32、 ill patients. Intensive Care Med. 32:13651370.33 Aueung SC EnsomM.H., Phenytoin and enteral feedings: does evidence support an interaction. Ann. Pharmaceutics. 2000; 34:896.34 Gilbert, S., How to minimize interaction between phenytoin and enteral feedings: two approaches-a strategic approach, Nutr.
33、Clin. Prac. 1996; 11:28.Gago Snchez AI, Garzas Martn de Almagro C, Crdenas Aranzana M, Calaas Continente A, Calleja Hernndez MA.Pharmaceutical care for patients with enteral nutrition.Farm Hosp. 2006 Jan-Feb;30:44-8.OBJECTIVE: To detect potential complications and interactions between drugs and ente
34、ral nutrition as to describe the interventions carried out by the pharmacist in those circumstances and to propose strategies of improvement. METHOD: Prospective assessment of patients admitted to hospital candidates to receive EN. The pharmacist worked as part of the team of Endocrinology and Nutri
35、tion for one month. A data collection form was designed for the study in which the following information had to be recorded: NE indications, nutrition characteristics , pharmacological therapy, drug/EN interaction and complications. RESULTS: The study included 14 patients in which digestive and neur
36、ological complications were the most frequent indications for EN. Eleven patients reported complications associated to EN, mostly digestive . The main cause for consultation was related to the administration of drugs via NGT . A total of 77 drugs were prescribed, 23 of which were administered in thi
37、s way, so a guidelines for the administration of drugs via nasogastric tube was prepared. CONCLUSIONS: The hospital pharmacist can actively cooperate with nutritional support units, given the need to assess the nutritional support administered and to manage potential complications and interactions b
38、etween nutritional status, drugs and artificial nutrition. The pharmacist also plays a significant role in the prevention and identification of problems related to the administration of drugs via NGT.临床药师作用:Cerulli J, Malone M.Assessment of drug-related problems in clinical nutrition patients.JPEN J
39、 Parenter Enteral Nutr. 1999 Jul-Aug;23:218-21Anoz Jimnez L, Borrs Almenar C, Cavera Rodrigo E.Pharmaceutical procedures in patients under treatment with total parenteral nutritionFarm Hosp. 2004 Sep-Oct;28:349-55OBJECTIVE: To describe and analyse pharmaceutical care activities, medication errors an
40、d/or drug-related problems in patients with total parenteral nutrition. METHODS: A prospective study was carried out over a six-month period. All pharmaceutical care activities for patients in treatment with total parenteral nutrition were registered and classified. Daily patient medical and pharmac
41、otherapy chart review plus patient interviews allowed the identification of medication errors and/or drug-related problems associated with both total parenteral nutrition and other pharmacological treatments. RESULTS: During the study period, 49 patients received total parenteral nutrition. 415 phar
42、maceutical care activities were carried out, representing a median of 8 pharmaceutical care activities per patient . In 33 patients, at least one medication error was detected , therefore representing 1 medication error per patient with total parenteral nutrition every 5 days. Most frequent errors w
43、ere: wrong dose , incorrect treatment duration and wrong drug . All these errors originated a potential drug-related problem which affected indication in 50.8% of the cases; safety in 41.3% and effectiveness in 7.9%. CONCLUSION: Results obtained during this study show a high demand for pharmaceutical attention in patients with total parenteral nutrition treatment. Identification and classification of medication errors and drug-related problems help to identify system points that can be improved, thus increasing assistential quality.
