药物相互作用致华法林抗凝作用增强引起出血的病例分析

1例82岁女性房颤患者,服用华法林治疗2年余,INR控制在1.5～2.5,因肺部感染,合用氟康唑及头孢哌酮/舒巴坦钠等药物,用药后第4天,INR升至12.28,咯血.分析出血原因,建议立即停用华法林、输注冰冻血浆并给予维生素K1注射液等,2d后INR降至1.3,出血停止.     

艾拉莫德与华法林联用致血浆凝血酶原时间延长

1例59岁女性患者因风湿性心脏病、慢性心功能不全急性加重、类风湿关节炎、肺部感染等给予改善心功能、抗风湿(白芍总苷胶囊0.6 g口服、2次/d, 艾拉莫德25 mg口服、2次/d)和抗感染等治疗。用药前凝血酶原时间(PT)15.5 s, 国际标准化比值(INR)1.2。因考虑患者有心脏瓣膜病、左心房内附壁血栓等, 次日加用华法林2.5 mg口服、1次/d。患者PT延长和INR升高, 至应用华法林第10天, PT 45.0 s、INR 4.8。停用华法林, 将艾拉莫德剂量降至25 mg口服、1次/d。停用华法林第2天, PT 53.2 s、INR 5.9;第3天, PT 80.8 s、INR 10.1, 遂停用艾拉莫德, 给予维生素K1治疗。3 d后, PT 22.4 s、INR 2.0。后因病情需要加用华法林2 mg口服、1次/d, 患者PT为19.8～27.4 s、INR为2.1～2.9。考虑患者PT延长可能与艾拉莫德与华法林联用有关。     

华法林与苯溴马隆联用致国际标准化比值升高

1例45岁男性患者,因扩张型心肌病、心房颤动、肺动脉高压、心力衰竭给予托拉塞米、呋塞米、螺内酯、培哚普利、美托洛尔、头孢地嗪、多烯磷脂酰胆碱治疗,同时口服华法林2.5 mg,1次/d.第3天实验室检查：国际标准化比值（INR） 1.16,尿素8.9 mmol/L,尿酸625 μmol/L.加服苯溴马隆50 mg,3次/d.次日患者INR升至3.43,第9天升至4.56.当日停用华法林.停用华法林第7天INR降至1.28,第14天恢复华法林2.5 mg口服,1次/d.6d后,INR升至3.52.当日停用苯溴马隆,次日停用华法林.3d后,INR降至1.98.     

华法林与氟康唑联合应用致国际标准化比值升高

1例72岁女性患者因可疑肺栓塞给予华法林及那屈肝素钙联合治疗,国际标准化比值(INR)稳定在1.23～2.81。联合用药8 d后,停用那屈肝素钙,单用华法林3 mg/d口服2 d后,检查INR为3.31。因行痰培养检查示白色念珠菌阳性,遂加用氟康唑0.4 g,1次/d静脉滴注,且华法林剂量调整为1.5 mg/d。氟康唑与华法林联用后第1、6天INR分别为3.91,7.31。立即停用华法林,氟康唑继续按原剂量应用,并给予维生素K1 40 mg肌内注射。停药后第1、2、3天INR分别为4.91,2.01,1.30。停药后第5天再次应用华法林1.5 mg/d,同时氟康唑调整至0.2 g/d。两药联用后第4天INR为1.68。     

华法林合并喜炎平致INR值异常1例

【】 1例51岁女性二、三尖瓣瓣膜置换术后,长期服用华法林,INR控制在2.5-3,因上呼吸道感染,合并使用喜炎平等药物,用药后第4天,INR升至5.66。第5日停用喜炎平后,INR值逐渐降至2.06,分析原因可能与合并使用喜炎平有关。     

1例房颤患者服用华法林期间INR值异常波动的药学监护

1例78岁房颤患者长期服用华法林,1NR值控制在1．6～2．5。入院当日测PT41．6S,INR3．53,遂停用华法林。4d后测INR1．25,低于正常水平,患者重新口服华法林。因关节疼痛加用塞来昔布,监测凝血四项显示PT、INR值分别由14．4S、1．25上升至36．7S、3．12。临床药师分析患者所用药物中,氯雷他定、塞来昔布均可加强华法林的抗凝作用,建议停用华法林、静脉注射维生素K1,医师采纳。此后,继续监测患者的凝血指标,至INR值回落后恢复使用华法林。患者住院期间未发生出血及栓塞事件。     

2例服用华法林合用苯溴马隆致INR值升高的分析

2例女性患者,因心脏病症而需长期服用华法林作抗凝治疗,其INR值控制尚可。后因尿酸升高,合并服用苯溴马隆,发现INR异常升高,分别为6与4.5左右,停用苯溴马隆后INR则恢复到正常,故推断INR异常高值为两药相互作用的结果。通过5例循证医学得到确证。此案例启示：长期服用华法林患者,需要联用苯溴马隆降低尿酸时,建议降低30%~50%的华法林剂量,以预防INR值异常升高。     

非诺贝特与华法林相互作用致血尿1例及文献复习

目的 探讨非诺贝特对华法林抗凝作用的影响、作用机制和处理方法。方法 1位78岁老年男性患者长期稳定服用华法林抗凝治疗,在服用非诺贝特2周后出现咳血、血尿和左下肢疼痛,急诊查INR值为5.9,予停用华法林、肌注维生素K1 10 mg处理后出院,随后根据INR值调整华法林周剂量下降40%后INR值达到稳定,半个月后患者因肌痛停用非诺贝特,INR值连续2周持续下降,调整华法林剂量至接近服用非诺贝特前。结果 患者在稳定的华法林治疗剂量基础上加用非诺贝特后,增加了华法林的抗凝效果。非诺贝特蛋白结合率高,可能把与白蛋白结合的华法林置换下来,导致抗凝效果增强;非诺贝特也是轻到中度的CYP2C9抑制剂,CYP2C9为S型华法林的代谢酶。这2种作用合起来可增强华法林的药效。结论 在长期华法林稳定抗凝治疗的情况下加用非诺贝特后,建议连续监测INR值并考虑经验性降低华法林剂量20%,之后根据INR值继续调整剂量至稳定。     

机械瓣膜置换术后再手术的抗凝治疗

目的探讨机械瓣膜置换术后再手术的抗凝治疗。方法回顾并随访1997年3月-2010年1月在我科行心脏机械瓣膜置换术后并再次行其他外科手术患者96例,术前2～3d停用华法林,检测凝血酶原国际标准化比值（INR）,术后2-3d恢复服用华法林,并依据INR调整用量。结果全组再手术患者均安全渡过围手术期,未出现血栓、颅内出血及胃肠道等异常出血。结论机械瓣膜置换术后再手术必须合理调整华法林的使用;依据INR值维持一个有效的抗凝强度,可以安全地进行手术,也可以安全地妊娠、分娩。     

华法林治疗房颤中的护理体会

目的探讨华法林治疗房颤中的护理要点。方法回顾分析120例患者的临床资料及护理经验。结果华法林起始剂量为2.5mg,根据INR调整华法林用量,维持剂量为1.25～3.25mg,INR达到1.6～2.5水平需时间为5～12d,INR稳定于1.6～2.5水平需10～28d。在华法林剂量调整过程中INR最高达6.93,患者无出血并发症;随访2～4年,其中4例有并发出血;所有患者随访期间无缺血脑卒中及其他部位的血栓。结论华法林的应用是安全可靠的,但其出血的不良反应也不能忽视,应严密观察,定期复查凝血酶原,随时调整剂量,精心护理,以充分发挥其治疗作用,减少其不良反应。     

Warfarin and acetaminophen interaction

A 74-year-old man who was receiving warfarin for atrial fibrillation experienced an abrupt increase in his international normalized ratio (INR) after taking acetaminophen. To investigate this effect, the patient's anticoagulation therapy was stabilized, and he was given acetaminophen 1 g 4 times/day for 3 days. His INR rose from 2.3 before receiving acetaminophen to 6.4 on the day after acetaminophen was discontinued. Warfarin was stopped for 2 days, and the patient's INR returned to 2.0. Warfarin was restarted at the same dosage, and his INR remained within 2.0-3.0 for 6 months. Factor VII activity decreased from 29.4% before acetaminophen therapy to 15.5% when his INR was 6.4, and factor X activity fell from 27.0% to 20.2%. His warfarin plasma concentration was 1.54 microg/ml before acetaminophen compared with 1.34 microg/ml when his INR was 6.4. No significant changes in drug intake, clinical status, diet, or lifestyle were noted. Changes in INR of this magnitude with the addition of another drug during stable anticoagulation therapy suggest a drug interaction. The lack of an increase in warfarin plasma concentration associated with the increased INR suggests a possible pharmacodynamic mechanism for this interaction. Acetaminophen or a metabolite may enhance the effect of oral coumarin anticoagulants by augmenting vitamin K antagonism. Thus, the anticoagulant effect of warfarin may be significantly elevated after only a few days of acetaminophen therapy. Patients receiving warfarin should be counseled to have their INR monitored more frequently when starting acetaminophen at dosages exceeding 2 g/day.     

亚洲人群心房颤动华法林抗凝治疗预防脑栓塞的最佳INR值

国内外大量的流行病学调查均显示心房颤动（房颤）的发病率呈明显升高趋势,华法林目前仍是治疗非瓣膜性心房颤动及预防脑栓塞的主要药物。欧美指南建议75岁以下房颤患者对血栓栓塞事件的一级预防及二级预防国际标准化比值（INR）应控制在2．0～3．0,75岁以上房颤患者的出血风险增加,INR应控制在1．6—2．6。亚洲人群华法林肝脏代谢酶活性与西方人群存在明显差异,且相关临床研究显示中等抗凝强度仍能取得与高抗凝强度相同的临床结局,因此华法林剂量应调低。国内初步研究显示,华法林抗凝治疗将INR控制在1．7-2．5范围内是安全有效的,其预防非瓣膜性房颤患者发生血栓栓塞事件的疗效明显优于阿司匹林,但仍需进一步大量临床试验及循证医学提供证据。     

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

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.     

长期口服华法林后肌内注射安乃近致臀部血肿

1例心脏瓣膜置换术后一直口服华法林（2．5mg,17欠／d,已5年）的51岁男性患者因感冒肌内注射安乃近（剂量不详）,第3天出现左臀部肿痛、皮下瘀斑。超声检查示左臀部皮下低回声区。实验室检查：国际标准化比值（INR）6．2。停用华法林,静脉滴注维生素K,40mg,1次/d。3d后,INR降至1．0,行左臀切开引流术。术后第2天INI／1．2,恢复原剂量华法林口服。2周后,瘀斑面积减小,INR2．0。术后6周瘀斑完全消退,INR2．1。     

Drug interaction between capecitabine and warfarin: a case report and review of the literature

OBJECTIVE: To report on possible adverse interaction between capecitabine and warfarin in a patient with cancer, who developed subconjunctival and nose bleeding during treatment with these drugs and review of the previously reported five cases in the literature. CASE SUMMARY: In the second week of capecitabine treatment the patient was hospitalized owing to subconjunctival hemorrhage and nose bleeding. Her international normalized ratio (INR) level was found to have increased, and both drugs were discontinued. Fresh frozen plasma replacement was administered. Warfarin and capecitabine treatment were restarted again but the warfarin dose was decreased. The patients INR was kept between 2.5-3 with the reduced dose of warfarin. DISCUSSION: Capecitabine is an orally active prodrug of fluorouracil (FU) and is extensively used as an antineoplastic agent. It is converted to 5-FU in the liver and tumor tissues. Warfarin is an antithrombolytic agent and is metabolized by liver cytochorom P450 (CYP) isoenzymes in liver. Preclinical in vitro studies using human liver microsomes report no inhibitory effects between capecitabine and substrates of CYP. However, the concomitant administration of capecitabine and warfarin resulted in gastrointestinal, retroperitoneal bleeding and hemorrhagic blisters in the five cases previously reported. The exact mechanism of this interaction is unknown; however, a significant pharmacokinetic interaction between capecitabine and S-warfarin resulting in exaggerated anticoagulant activity has recently been demonstrated. Here, we describe another case and use of the Naranjo adverse drug reaction (ADR) probability scale, which indicated a probable relationship between subconjunctival bleeding and epistaxis in this patient after concomitant warfarin and capecitabine use. CONCLUSION: Capecitabine is extensively used in outpatient clinics, and physicians should be aware of ADRs arising from combined used of capecitabine and warfarin. In the light of the current data, INR levels should be closely monitored in patients using this medication regimen.     

观察华法林及阿司匹林分别对非瓣膜性心房颤动患者血栓栓塞的影响

目的观察华法林及阿司匹林对非瓣膜性心房颤动患者血栓栓塞事件的影响。方法80例非瓣膜性心房颤动患者分为华法林组及阿司匹林组,阿司匹林组每天服用阿司匹林100 mg,华法林组根据国际标准化比值(INR)调整华法林用量,随访时间为2 a。结果阿司匹林组死亡2例,1例为缺血性卒中,另1例为心力衰竭;华法林组1例为猝死。阿司匹林组发生栓塞事件共8例,出血并发症3例;华法林组发生栓塞事件共3例,出血并发症7例。结论华法林可明显降低非瓣膜性房颤患者血栓栓塞事件,但出血并发症稍增多,关键是要严密随访INR。     

临床药师对1例慢性肾功能不全合并心房血栓患者抗凝治疗的药学监护

目的:了解华法林在特殊患者中的药学监护关注点。方法:总结分析1例慢性肾功能不全合并心房血栓患者的诊治经过、用药情况。结果:发现该患者使用华法林进行抗凝,华法林与较多药物如广谱抗菌药物、茶碱、奥美拉唑等存在相互作用,同时患者的疾病状态也影响着华法林的代谢。临床医师结合药师意见,对药物治疗方案进行了调整,使患者的国际标准化比值(INR)恢复正常。结论:临床上使用华法林时应格外重视,并加强监测。     

Comparison of Two Methods for INR Determination in a Pharmacist-Based Oral Anticoagulation Clinic

Warfarin is a commonly used oral anticoagulant that is usually initiated after the definitive diagnosis of a certain thromboembolic disorder or disease. Warfarin therapy will usually be prescribed for 6–12 weeks or more, and some patients may continue therapy throughout life, depending on the type of thromboembolic disorder. Major problems associated with warfarin therapy include adverse effects such as bleeding complications and drug-drug or drug-food interactions. In addition, thromboembolic complications may occur due to subtherapeutic dosages of warfarin. The laboratory reference standards for monitoring warfarin therapy are the prothrombin time (PT) and the International Normalized Ratio (INR). While both the PT or INR will reflect the clinical response in the patient, results reported as INR values have been shown to be more accurate than those reported as PT values. Thirty-two patients were enrolled in this study. Our objectives were to compare INR values measured by both the Coumatrak and conventional laboratory method, and to demonstrate the effects of pharmacist intervention on managing patients receiving warfarin therapy. Results from our study reveal that INR monitoring by Coumatrak is similar to the conventional laboratory method. In addition, our study indicates that patients receiving warfarin therapy can be monitored and managed effectively by pharmacists.