抗凝门诊华法林联合抗癫药物2例分析及文献回顾

丁征¹^,, 陈星伟¹, 张宜梅¹, 曾丽华², 郑英丽¹^,

中国医学科学院阜外医院1.药剂科

2.心外科,北京 100037

DING Zheng¹^,, CHEN Xingwei¹, ZHANG Yimei¹, ZENG Lihua², ZHENG Yingli¹^,

1.Department of Pharmacy

2.Cardial Surgery Department,Fuwai Hospital,Chinese Academy of Medical Sciences,Beijing100037,China

通信作者郑英丽(1971-),女,内蒙古人,主任药师,硕士,研究方向:药事管理。电话:010-88398665,E-mail:zhengyl1625@sina.com。

作者简介丁征(1987-),女,河南人,药师,硕士,研究方向:抗栓治疗。电话:010-88398289,E-mail:409883075@qq.com。

中图分类号: R973.2 文献标识码: B 文章编号: 1004-0781(2017)08-0923-03

摘要:

目的探讨抗癫药物卡马西平、奥卡西平对华法林抗凝作用的影响和作用机制及处理方法。方法 1例78岁老年女性患者开始服用华法林后出现抵抗,根据患者用药情况判断为卡马西平导致的华法林抵抗,逐渐增加剂量后国际标准化比值(INR)稳定在治疗范围内;另1例女性患者长期服用稳定维持剂量的华法林抗凝治疗,因需联合使用奥卡西平向抗凝门诊咨询,根据药师建议按照原剂量服用并加强INR值监测,INR值未有波动。结果卡马西平通过诱导华法林的代谢导致华法林代谢增加,所需剂量增加;奥卡西平的代谢不通过诱导型的的肝细胞酶,因此不会影响INR值的波动。结论卡马西平可能会降低华法林的药效,奥卡西平作为抗癫药物在某些方面优于卡马西平,特别是与华法林联合用药时。

关键词: 华法林 ; 卡马西平 ; 奥卡西平 ; 相互作用

Abstract:

Objective To explore the interaction between warfarin and antiepileptic drugs such as carbamazepine and oxcarbazepine. Methods A 78-year-old woman suffered from warfarin resistance after initial warfarin dosing for several days.Based on her medication review,clinical pharmacist found that the warfarin resistance resulted from co-administered carbamazepine.Her warfarin dosage was increased,and the international normalized ratio(INR) increased to the target range.Another woman had been taking warfarin therapy for long time with a stable maintenance dose.She consulted clinical pharmacist for the influence of co-administered oxcarbazepine on warfarin.The patient was advised to maintain the dose and monitor her INR more closely.Her INR did not fluctuate. Results Carbamazepine induced warfarin metabolism.As a result,the patient needed increased dosage of warfarin to maintain the INR in the therapeutic target range.Oxcarbazepine does not induce liver enzymes,and therefore the INR did not fluctuate. Conclusion Carbamazepine may reduce the efficacy of warfarin.Oxcarbazepine offers a clinical advantage over carbamazepine,especially when co-administration of warfarin is required.

Key words: Warfarin ; Carbamazepine ; Oxcarbazepine ; Interaction

华法林为目前使用最广泛的口服抗凝药,其治疗窗窄,个体化差异大,与药物和食物相互作用多,需要频繁监测凝血酶原时间(prothrombin time,PT)和国际标准化比值(international normalized ratio,INR)来调整剂量。长期服用华法林的患者在一些特定的临床情况下需要联用其他药物,新开始使用或停止使用某种联合用药后,有可能引起INR值波动,甚至导致严重的不良事件。为了规避这些药物可能对华法林产生的影响,需要及早了解两种相互作用药物的作用机制、影响程度、解决方案。抗凝门诊药师需根据患者的具体情况,评估可能发生的药物相互作用并采取适当措施,最大程度地降低可能发生的不良事件。

1 病例概况

例1,女,78岁,身高151 cm,体质量43.5 kg,体质量指数19.0 kg·(m²)^-1。因阵发性房颤服用华法林抗凝治疗,于普通心内科门诊调整华法林剂量,25 d后剂量调整至5 mg时,INR仍为1.01;接诊医师怀疑该患者华法林遗传性抵抗,建议患者进行华法林相关药物基因检测,检测结果示VKORC1-1639AA型,CYP2C9*1/*1型,即为非抵抗基因型,医师推荐患者至抗凝门诊就诊。患者诉服药依从性好,饮食均衡规律,未服用膳食补充剂,经临床药师问诊得知患者自50岁起因癫服用卡马西平片100 mg,每晚1次;为预防卡马西平可能导致的白细胞减少和(或)血小板计数降低同时服用利可君片10 mg,每晚1次;维生素C片100 mg,每天1次;维生素B₂片5 mg,每天1次。考虑到卡马西平为华法林代谢酶CYP2C9的诱导剂,临床药师判断该患者为卡马西平导致的华法林抵抗,因患者年龄较大,出血风险高,建议谨慎增加华法林剂量,经过49 d,其INR值接近目标范围,剂量调整至8.75 mg并维持治疗。见表1。

日期	INR值	剂量/ mg	服用时间/ d
2015年10月30日	1.02	2.5	4
2015年11月3日	1.00	2.5	3
2015年11月6日	1.02	3.125	5
2015年11月11日	1.05	3.75	6
2015年11月17日	1.01	5.0	7
2015年11月24日	1.12	6.25	7
2015年12月1日	1.24	6.875	7
2015年12月8日	1.26	7.5	7
2015年12月15日	1.01	8.125	15
2015年12月30日	1.65	8.75	13
2016年1月12日	1.94	8.75	30
2016年2月13日	1.72	8.75	-

表1 患者服用华法林期间的INR值和剂量调整方案

Tab.1 INR value and dosage adjustment regiments of the patients taking warfarin

例2,女,44岁,身高159 cm,体质量55 kg,体质量指数21.7 kg·(m²)^-1。5年前因风湿性心脏瓣膜病行二尖瓣机械瓣置换术,术后长期服用华法林抗凝治疗,INR维持在1.8~2.5之间,稳定维持剂量为2.25 mg,无出血或血栓栓塞病史。近1个月因有癫发作就诊神经内科,医师建议开始服用奥卡西平片,患者就诊抗凝门诊咨询药物相互作用。因奥卡西平说明书及相关文献中未显示其有诱导CYP2C9酶的作用,因此予暂不调整华法林剂量,加强监测INR值的处理。患者服用1周后INR值仍维持在目标范围,因此建议按原剂量服用。

2 讨论

第1例患者开始服用华法林后,随着剂量的增加INR值仍然徘徊在低值,曾怀疑为遗传性华法林抵抗,但基因检测显示非遗传性抵抗。排除患者漏服药物、摄入过多含有维生素K的食物、服用膳食补充剂、检验错误等因素,根据问诊情况临床药师判断其为卡马西平导致的抵抗。根据国际华法林药物基因组学联盟(international warfarin pharmacogenetics consortium,IWPC)发布的华法林剂量公式纳入患者的年龄78岁、身高151 cm、体质量43.5 kg、VKORC1和CYP2C9基因型(VKORC1-1639AA型,CYP2C9*1/*1)、种族(Asian)、是否服用酶诱导剂(Yes)、是否服用胺碘酮(No)信息,得出患者的华法林周剂量应为25 mg(平均每日3.57 mg),但患者的INR值远未达标,遂谨慎增加剂量直至INR值达标^[1]。由此可见,对于联合服用酶诱导剂的患者,根据IWPC公式计算的剂量可能并不准确。

第2例患者因需服用奥卡西平特来咨询,根据奥卡西平的药动学特点和相关的文献检索未见有相互作用的报道,剂量保持并增加监测频率后也未发现INR值的波动。

3 文献回顾

卡马西平在临床广泛应用于预防和控制癫发作以及治疗三叉神经疼痛,其主要通过氧化代谢消除,重复给药可诱导细胞色素P₄₅₀酶家族CYP1A2、CYP2C9和CYP3A4。这种作用不仅加速卡马西平和其他抗癫药物的代谢,也加速了经过同一肝药酶家族代谢的药物代谢,例如华法林。华法林为消旋异构体R型和S型的混合物,其中S型华法林抗凝强度是R型华法林的5倍,因此药物相互作用中干扰S型华法林的代谢影响更明显,S型华法林是通过CYP2C9代谢消除,R型华法林主要通过CYP1A1/CYP1A2/CYP3A4代谢消除。因此卡马西平同时诱导了R型和S型华法林的代谢,造成华法林浓度大大降低,需要更高的剂量和更频繁的INR监测以维持在治疗水平。相反,当卡马西平剂量减小或停药时,华法林抗凝效果的突然增加可能会带来潜在的出血风险。曾报道1例患者在停用卡马西平后,出现抗凝效果增强的现象(之前稳定服用卡马西平和华法林),使得华法林剂量显著降低^[2]。PARRISH等^[3]报道了1例老年女性因房颤规律服用稳定剂量的华法林,因三叉神经疼痛开始服用卡马西平片200 mg·d^-1,之后患者INR值降低了60%,华法林周剂量增加80%后INR又维持在目标范围,当患者停用卡马西平后,INR增至3.6,遂逐渐降低剂量至服用卡马西平前的稳定剂量。该个案报道使用Naranjo不良反应可能性评分评估,由卡马西平引起的相互作用为很可能。使用Lexicomp online医药信息数据库查询卡马西平与华法林的相互作用,已证实卡马西平可降低华法林血浆浓度(约50%),对凝血酶原时间的降低幅度也接近50%^[4-8]。

尽管奥卡西平和卡马西平化学结构相似,两者代谢途径是不同的。奥卡西平是一种前体药物,几乎完全降解为有药理活性的代谢产物10,11-二氢-10-羟基卡马西平(monohydroxycarbazepine,MHD)而发挥作用,随后大部分的MHD在UDP-葡萄糖醛酸转移酶的作用下与葡萄糖醛酸发生结合反应形成葡萄糖醛酸苷,小部分则被氧化成无药理活性的反式二醇卡马西平。根据奥卡西平的药动学特点,预计比卡马西平引起的药物相互作用更少,因为奥卡西平的还原代谢需要非诱导型的肝细胞还原酶,在与华法林联合用药时,这可能是一个优点。KRAMER等^[9]研究了奥卡西平对华法林抗凝效果的影响,10个健康男性志愿者重复给药并获得稳态华法林剂量后,予单次(600 mg)和多次服用奥卡西平(450 mg,bid,持续1周),通过测定PT值评估其影响,结果显示奥卡西平对华法林的抗凝效果没有任何影响。使用Lexicomp online医药信息数据库查询奥卡西平与华法林也未显示二者有相互作用。

4 结束语

很多情况下,基于细胞色素P₄₅₀诱导作用的药物相互作用鲜有临床意义,但对于治疗窗狭窄的药物,诱导作用有可能严重降低药效,甚至导致致命的后果。诱导华法林代谢酶的药物包括巴比妥类、利福平、卡马西平等。目前已明确卡马西平会加速华法林的代谢,最终降低抗凝效果;另一方面,卡马西平停药或降低剂量会导致凝血酶原时间延长的风险增加,因此在一些临床情况下需要及早干预可能发生的不良事件。例如长期服用稳定剂量华法林的患者,若有需要开始服用卡马西平,需要及时增加华法林剂量并加强监测INR值;对于长期服用卡马西平的患者,若有需要开始服用华法林,应考虑到所需的华法林剂量可能增大。奥卡西平作为抗癫治疗当需要与华法林联合用药时优于卡马西平。

The authors have declared that no competing interests exist.

参考文献

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[1]	International Warfarin Pharmacogenetics Consortium,KLEIN T E,et al.Estimation of the warfarin dose with clinical and pharmacogenetic data[J].N Engl J Med,2009,360(8):753-764. BACKGROUND: Genetic variability among patients plays an important role in determining the dose of warfarin that should be used when oral anticoagulation is initiated, but practical methods of using genetic information have not been evaluated in a diverse and large population. We developed and used an algorithm for estimating the appropriate warfarin dose that is based on both clinical and genetic data from a broad population base. METHODS: Clinical and genetic data from 4043 patients were used to create a dose algorithm that was based on clinical variables only and an algorithm in which genetic information was added to the clinical variables. In a validation cohort of 1009 subjects, we evaluated the potential clinical value of each algorithm by calculating the percentage of patients whose predicted dose of warfarin was within 20% of the actual stable therapeutic dose; we also evaluated other clinically relevant indicators. RESULTS: In the validation cohort, the pharmacogenetic algorithm accurately identified larger proportions of patients who required 21 mg of warfarin or less per week and of those who required 49 mg or more per week to achieve the target international normalized ratio than did the clinical algorithm (49.4% vs. 33.3%, P or = 49 mg per week). CONCLUSIONS: The use of a pharmacogenetic algorithm for estimating the appropriate initial dose of warfarin produces recommendations that are significantly closer to the required stable therapeutic dose than those derived from a clinical algorithm or a fixed-dose approach. The greatest benefits were observed in the 46.2% of the population that required 21 mg or less of warfarin per week or 49 mg or more per week for therapeutic anticoagulation. DOI:10.1056/NEJMoa0809329 PMID:19228618 URL [本文引用:1]
[2]	DENBOW C E,FRASER H S.Clinically significant hemorr-hage due to warfarin-carbamazepine interaction[J].South Med J,1990,83(8):981. [本文引用:1]
[3]	PARRISH R H,PAZDUR D E,O'DONNELL P J.Effect of carbamazepine initiation and discontinuation on antithrom-botic control in a patient receiving warfarin:case report and review of the literature[J].Pharmacotherapy,2006,26(11):1650-1653. A 72-year-old Caucasian woman with paroxysmal atrial fibrillation had been taking warfarin therapy for 5 years with a stable international normalized ratio (INR). Her dentist then prescribed carbamazepine 200 mg/day to control facial nerve pain. At her next physician visit about 2 weeks after the start of the carbamazepine, the patient's INR had dropped from 3.3 to 1.3; she reported no contributing changes in her diet or warfarin dosage, nor had she taken other interacting drugs. Her warfarin dosage was increased, and the INR returned to the target range of 2.0-3.0 approximately 2 months later. The patient's INR remained stable for approximately 6 more months, until she had facial surgery. During that time, her warfarin was discontinued for 5 days, and the patient had stopped taking the carbamazepine because she had no pain. One month later, her INR increased from 2.2 to 3.6. She did not experience any thrombotic or hemorrhagic episodes. Warfarin undergoes hepatic metabolism through cytochrome P450 2C9, and carbamazepine induces this isoenzyme. Inducing warfarin metabolism necessitates an increase in the warfarin dosage to maintain the INR in the therapeutic target range. To our knowledge, this is the first report documenting the effect of the carbamazepine initiation and discontinuation in a patient receiving anticoagulation therapy with warfarin. In patients taking warfarin, clinicians should monitor the INR closely when carbamazepine is started or discontinued, or when either dosage is changed. DOI:10.1592/phco.26.11.1650 PMID:17064211 URL [本文引用:1]
[4]	ROSS J R,BEELEY L.Interaction between carbamazepine and warfarin[J].Br Med J,1980,280(6229):1415-1416. Describes the interaction between carbamazepine and warfarin. Reduction of hypoprothrombinemic effect; Increase of metabolism rate of warfarin; Management of patients on anticoagulants. DOI:10.1136/bmj.280.6229.1415-a URL [本文引用:1]
[5]	KENDALL A G,BOIVIN M.Warfarin-carbamazepine inter-action[J].Ann Intern Med,1981,94(2):280. [本文引用:0]
[6]	MASSEY E W.Effect of carbamazepine on coumadin metabolism[J].Ann Neurol,1983,13(6):691-692. ABSTRACT No abstract is available for this article. DOI:10.1002/ana.410160520 URL [本文引用:0]
[7]	PENRY J K,NEWMARK M E.The use of antiepileptic drugs[J].Ann Intern Med,1979,90(2):207-218. The use of antiepileptic drugs has become increasingly effective through several factors: new techniques that allow better diagnosis of the seizure disorder and its underlying cause; the development of new medications and increased knowledge of old ones; and the widespread use of antiepileptic drug-level determinations. The choice of a drug depends heavily on an accurate diagnosis of seizure type, which may determine the response to the medication. Because of better diagnostic criteria and intensive monitoring procedures, the correct seizure disorder can be more easily diagnosed and, therefore, the proper medication selected. Minimal efficacious and toxic blood concentrations have now been identified for most antiepileptic drugs. Several, including primidone, carbamazepine, methsuximide, and mephenytoin, have pharmacologically active metabolites that affect both the toxicity and efficacy of the prescribed drug and can now be measured in the plasma. The most effective use of the antiepileptic drugs depends on a combination of reliable blood level measurements, clinical observation, and knowledge of their pharmacokinetics and biotransformation. DOI:10.7326/0003-4819-90-2-207 PMID:375789 URL [本文引用:0]
[8]	HANSEN J M,SIERSBOEK-NIELSEN K,SKOVSTED L.Carbamazepine-induced acceleration of diphenylhydantoin and warfarin metabolism in man[J].Clin Pharmacol Ther,1971,12(3):539-543. ABSTRACT Diphenylhydantoin half-life was determined in 5 patients before and during treatment with carbamazepine. It caused a significant decrease in the diphenylhydantoin half-life from 10.6 hours to 6.4 hours. Seven patients who for a period had been given diphenylhydantoin were also started on carbamazepine. This resulted in a fall in serum diphenylhydantoin levels in 3 of the patients. Alterations in war f arin half-life, serum war f arin, and plasma prothrombin proconvertin concentration during carbamazepine treatment were compatible with a stimulation of warfarin metabolism. The effect of carbamazepine on diphenylhydantoin and warfarin metabolism is probably explained by an induction of the drug-metabolizing enzyme system in the liver. DOI:10.1002/cpt1971123539 PMID:5567804 URL [本文引用:1]
[9]	KRAMER G,TETTENBORN B,KLOSTERSKOV JENSEN P,et al.Oxcarbazepine does not affect the anticoagulant activity of warfarin[J].Epilepsia,1992,33(6):1145-1148. Summary: The possible interaction of the antiepileptic drug oxcarbazepine (OCBZ) on the anticoagulant effect of warfarin was investigated in 10 healthy male volunteers. After reaching steady-state conditions by repeated administration of warfarin, the prothrombin time (Quick value) was assessed before and after single (600 mg) and multiple dosing (450 mg twice daily in 1 week) of OCBZ. In 7 of the 10 volunteers with evaluable data, the prothrombin time was not significantly different (paired t test) from baseline either after single (p = 0.299) or repeated dosing (p = 0.333), indicating that OCBZ does not interact to any relevant extent with the hypothrombinemic effect of warfarin. DOI:10.1111/j.1528-1157.1992.tb01772.x PMID:1464277 URL [本文引用:1]

Estimation of the warfarin dose with clinical and pharmacogenetic data

2009

... 第1例患者开始服用华法林后,随着剂量的增加INR值仍然徘徊在低值,曾怀疑为遗传性华法林抵抗,但基因检测显示非遗传性抵抗.排除患者漏服药物、摄入过多含有维生素K的食物、服用膳食补充剂、检验错误等因素,根据问诊情况临床药师判断其为卡马西平导致的抵抗.根据国际华法林药物基因组学联盟(international warfarin pharmacogenetics consortium,IWPC)发布的华法林剂量公式纳入患者的年龄78岁、身高151 cm、体质量43.5 kg、VKORC1和CYP2C9基因型(VKORC1-1639AA型,CYP2C9*1/*1)、种族(Asian)、是否服用酶诱导剂(Yes)、是否服用胺碘酮(No)信息,得出患者的华法林周剂量应为25 mg(平均每日3.57 mg),但患者的INR值远未达标,遂谨慎增加剂量直至INR值达标^[1].由此可见,对于联合服用酶诱导剂的患者,根据IWPC公式计算的剂量可能并不准确. ...

Clinically significant hemorr-hage due to warfarin-carbamazepine interaction

1990

... 卡马西平在临床广泛应用于预防和控制癫发作以及治疗三叉神经疼痛,其主要通过氧化代谢消除,重复给药可诱导细胞色素P₄₅₀酶家族CYP1A2、CYP2C9和CYP3A4.这种作用不仅加速卡马西平和其他抗癫药物的代谢,也加速了经过同一肝药酶家族代谢的药物代谢,例如华法林.华法林为消旋异构体R型和S型的混合物,其中S型华法林抗凝强度是R型华法林的5倍,因此药物相互作用中干扰S型华法林的代谢影响更明显,S型华法林是通过CYP2C9代谢消除,R型华法林主要通过CYP1A1/CYP1A2/CYP3A4代谢消除.因此卡马西平同时诱导了R型和S型华法林的代谢,造成华法林浓度大大降低,需要更高的剂量和更频繁的INR监测以维持在治疗水平.相反,当卡马西平剂量减小或停药时,华法林抗凝效果的突然增加可能会带来潜在的出血风险.曾报道1例患者在停用卡马西平后,出现抗凝效果增强的现象(之前稳定服用卡马西平和华法林),使得华法林剂量显著降低^[2].PARRISH等^[3]报道了1例老年女性因房颤规律服用稳定剂量的华法林,因三叉神经疼痛开始服用卡马西平片200 mg·d^-1,之后患者INR值降低了60%,华法林周剂量增加80%后INR又维持在目标范围,当患者停用卡马西平后,INR增至3.6,遂逐渐降低剂量至服用卡马西平前的稳定剂量.该个案报道使用Naranjo不良反应可能性评分评估,由卡马西平引起的相互作用为很可能.使用Lexicomp online医药信息数据库查询卡马西平与华法林的相互作用,已证实卡马西平可降低华法林血浆浓度(约50%),对凝血酶原时间的降低幅度也接近50%^[4-8]. ...

Effect of carbamazepine initiation and discontinuation on antithrom-botic control in a patient receiving warfarin:case report and review of the literature

2006

Interaction between carbamazepine and warfarin

1980

Warfarin-carbamazepine inter-action

1981

Effect of carbamazepine on coumadin metabolism

1983

The use of antiepileptic drugs

1979

Carbamazepine-induced acceleration of diphenylhydantoin and warfarin metabolism in man

1971

Oxcarbazepine does not affect the anticoagulant activity of warfarin

1992

... 尽管奥卡西平和卡马西平化学结构相似,两者代谢途径是不同的.奥卡西平是一种前体药物,几乎完全降解为有药理活性的代谢产物10,11-二氢-10-羟基卡马西平(monohydroxycarbazepine,MHD)而发挥作用,随后大部分的MHD在UDP-葡萄糖醛酸转移酶的作用下与葡萄糖醛酸发生结合反应形成葡萄糖醛酸苷,小部分则被氧化成无药理活性的反式二醇卡马西平.根据奥卡西平的药动学特点,预计比卡马西平引起的药物相互作用更少,因为奥卡西平的还原代谢需要非诱导型的肝细胞还原酶,在与华法林联合用药时,这可能是一个优点.KRAMER等^[9]研究了奥卡西平对华法林抗凝效果的影响,10个健康男性志愿者重复给药并获得稳态华法林剂量后,予单次(600 mg)和多次服用奥卡西平(450 mg,bid,持续1周),通过测定PT值评估其影响,结果显示奥卡西平对华法林的抗凝效果没有任何影响.使用Lexicomp online医药信息数据库查询奥卡西平与华法林也未显示二者有相互作用. ...