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華法林 (Warfarin) - 可邁丁 (Coumadin)
       華法林 (Warfarin，華法令、可邁丁或滅鼠靈)是一種只可口服的抗凝血素，學名為苄丙酮香豆素，一般都以苄丙酮香豆素鈉來儲存及處方，較著名的品牌有Coumadin®。由於其化學結構與維生素K非常相似，所以能夠干擾血液素的運作，降低患者血液凝結的風險。不過也由於它的強效，一般只會處方與血凝結風險比較高的患者使用，比如心律不整或者有人工心臟瓣膜的患者。
運作機制
      一般來說，維生素K會在肝臟裡轉化成為氧代維生素K (vitamin K epoxide)，之後再由「環氧化物還原酵素」還原。華法林能夠抑制這種在肝臟裡的酵素作用，使凝血酶原(prothrombin)失去功能，從而防止血液凝固。
功用
醫療用途
       華法林適用於預防或治療靜脈血栓及其延伸和肺栓塞，預防或治療心房顫動或與心臟瓣膜置換關聯的血栓併發症，降低死亡、再發性心肌梗死和血栓事件(如中風或心肌梗死後的系統性栓塞)的風險。
防治蟲鼠
      其毒性必須在第二次食用才易顯現出來，家鼠或幼鼠可能對它產生抗藥性，因此苯甲香豆醇已被其他藥效更強的殺蟲劑取代。
副作用
       可口服的華法林俗稱「薄血丸」，但服用後必須注意飲食，有兩種維生素會影響藥物效能，如下：
維生素E：會加強華法林之效用，易引起內出血。
維生素K：會減弱華法林之功效。

可邁丁(Coumadin)交互作用 (圖解) 
虞希禹 醫師 
抗凝血劑warfarin的交互作用，『圖解可邁丁交互作用』
(1). 維他命K是製造凝血因子的主要原料，來自消化道，所以吃太多深綠蔬菜或腸道環境改變(拉肚子，清腸，吃抗生素)都有可能改變『原料』的進貨量。
(2). 可邁丁 (Coumadin)就像是卡在生產線上的阻擋物，使維生素K原料供應變少，因而凝血因子產量減少。從胃腸吸收(建議儘量避免與食物混吃而改變吸收量)，肝臟酵素(細胞色素cytochrome P450)就像推土機一樣會分解掉Coumadin，所以很多藥物（或食物）就是因為改變這個酵素的功能，使得Coumadin的濃度改變 (生產線上卡位的東西變多或變少)。
(3). 肝工廠：當然乾機能衰退(肝硬化，心衰竭肝鬱血)會使工廠產能下降。相反的，很多情形會使肝功能暫時提升，所以抗凝血因子產量增加。
(4). 在血管壁產生血塊凝集，如果有其他抑制血小板凝結的藥物存在(阿斯匹靈等)或一些『活血』的食物(當歸等)，就容易讓一些小出血變成大出血。

可邁丁(Coumadin)交互作用

您在服用可邁丁嗎?
文 / 周敏慧藥師 (藥劑科)   和信醫院   (最後編寫：2013/09/30)
何謂可邁丁？
 　　可邁丁的化學成分名為warfarin Sodium，商品名為 Coumadin®，是一個被使用超過六十年的口服抗凝血劑。可邁丁在體內可以減弱維他命K的作用，維他命K為肝臟合成凝血因子的必要元素，透過拮抗維他命K的作用，可邁丁可以減少凝血因子，達到防止血塊形成的目的。
 在醫療上，可邁丁被用來預防或降低血管栓塞、中風及在其他身體部位引發深部靜脈栓塞或肺栓塞的情況；也用於預防心房纖維顫動或更換人工瓣膜後血塊的形成。
可邁丁的發明史-- 由毒鼠藥變成被廣泛使用的重要藥品
 　　在1920年，美國中西部及加拿大西部地區發現牛隻因攝食腐敗的甜宿苜 (sweet clover) 發生出血致死的情形。1931年Roderick 進一步發現出血情形與牛隻血液中凝血因II (Prothrombin)下降有關，直到1939年，Cambell及Link兩人確認引起出血的物質為一種coumarin的衍生物dicoumarol，接著在1948年合成出 warfarin。1940年中期，warfarin曾被用來作為毒鼠藥，鼠類誤食後數日因內出血而死亡。1950年後，warfarin正式被用於中風及心肌梗塞的病人，也就是今日的可邁丁(商品名Coumadin®)。幾十年來的廣泛使用，可邁丁已成為不可或缺的重要藥品。
如何調整可邁丁錠的劑量？
　　可邁丁的劑量必須嚴格監控，它能有效的降低凝血因子，減少血栓的形成，但劑量太強會增加出血機率，太弱又達不到預防血栓的目的；藥品本身還有許多的藥物食品交互作用；使用期間，必須定期抽血監測藥效強度。實在是個令人又愛又恨的藥品。
 　　可邁丁的劑量因人而異，也與病人平日飲食有關。病人必須抽血，測得凝血時間 (PT) 或INR (國際標準化凝血酶元時間比值)；根據凝血時間的數值，醫師可以調整病人最適合的劑量。一般我們希望控制 INR於2-3之間 (正常人約為 1，INR愈高表示凝血時間愈慢，藥效愈強)，這個程序通常需要數次的門診後才能調整到最穩定的狀態。
食物及藥物的影響
　　飲食習慣 (含有高維他命K的食物) 及併用藥物 (如西藥、成藥、中藥、草藥及健康食品) 都可能影響此藥的抗凝血效果。
 　　服用可邁丁期間最重要的就是維持飲食穩定。由於可邁丁是靠拮抗維他命K的作用而達到減少凝血因子的目的，飲食中的維他命K會影響可邁丁的效果。突然的大量攝取維他命K會降低藥效 (INR降低)，突然減少維他命K攝取會使藥效過強 (INR上升)，所以劑量一旦調整好了，維持正常而穩定的飲食是非常重要的。
 　　食物中含有豐富維他命K的食物主要來自深綠色蔬菜，如菠菜，花椰菜，甘藍菜等，綠茶也含有豐富的維他命K。但病人不必因此而完全不敢食用這些食物，只要飲食穩定不要變化太大，靠著監測INR值，我們仍能調整最適當的劑量。
 　　許多藥物也會影響可邁丁的藥效，中草藥中有許多成分也已被證明會影響INR值，如當歸、丹參、銀杏可能使INR上升增加出血的機率，而人蔘曾被報告會降低可邁丁的作用。由於中藥種類繁多，目前確實的報告不多，所以建議不要隨意服用中草藥或其他不明藥品。
病人自我照顧
　　服用可邁丁的病人必須學會自我照顧，注意是否有劑量過高的跡象，如皮膚容易瘀青、小便變紅、齒齦易出血，咳血、流鼻血等現象。若有前述出血跡象，必須停藥回醫院就診。在做任何侵入性檢查治療或牙醫拔牙前，必須讓醫師知道您在服用可邁丁，一般會先停藥5日，使凝血功能回復正常，避免大量出血。
 　　可邁丁看似是一個危險的藥品，過量會有出血危險，但因為臨床上大量使用，我們對它有豐富的經驗與了解，反而是相對可靠安全的藥品。若一旦過量或出血，除了停藥外，醫師可以給予維他命K作為解藥，危急時也可直接給予凝血因子。
忘記服用可邁丁錠時應如何處理？
　　可邁丁一日服用一次，如果忘記服藥，十二個小時內想起時，可盡快補服。如過超過十二個小時，則建議跳過一次劑量，並按正常服用時間表服用，不要一次服兩倍的份量，而使抗凝血作用過強。
結語
　　可邁丁 (warfarin, Coumadin®) 是一個歷史悠久的抗凝血藥品，在預防或治療血管栓塞至今仍是不可或缺的藥品。雖然它有許多藥品食品交互作用，也必須經常抽血監測藥效，但只要病人依照醫師指示按時服藥及追蹤，學會自我照顧，可邁丁便可發揮最大的功效。

Warfarin
       Warfarin (also known by the brand names Coumadin, Jantoven, Marevan, Uniwarfin, Warf) is an anticoagulant normally used in the prevention of thrombosis and thromboembolism, the formation of blood clots in the blood vessels and their migration elsewhere in the body respectively. It was initially introduced in 1948 as a pesticide against rats and mice and is still used for this purpose, although more potent poisons such as brodifacoum have since been developed. In the early 1950s, warfarin was found to be effective and relatively safe for preventing thrombosis and thromboembolism in many disorders. It was approved for use as a medication in 1954 and has remained popular ever since; warfarin is the most widely prescribed oral anticoagulant drug in North America.
       Despite its effectiveness, treatment with warfarin has several shortcomings. Many commonly used medications interact with warfarin, as do some foods (particularly leaf vegetable foods or "greens," since these typically contain large amounts of vitamin K1) and its activity has to be monitored by blood testing for the international normalized ratio (INR) to ensure an adequate yet safe dose is taken. A high INR predisposes to a high risk of bleeding, while an INR below the therapeutic target indicates that the dose of warfarin is insufficient to protect against thromboembolic events.
       Warfarin and related 4-hydroxycoumarin-containing molecules decrease blood coagulation by inhibiting vitamin K epoxide reductase, an enzyme that recycles oxidized vitamin K1 to its reduced form after it has participated in the carboxylation of several blood coagulation proteins, mainly prothrombin and factor VII. Despite being labeled a vitamin K antagonist, warfarin does not antagonize the action of vitamin K1, but rather antagonizes vitamin K1 recycling, depleting active vitamin K1. Thus, the pharmacologic action may always be reversed by fresh vitamin K1. When administered, these drugs do not anticoagulate blood immediately. Instead, onset of their effect requires about a day before remaining active clotting factors have had time to naturally disappear in metabolism, and the duration of action of a single dose of warfarin is 2 to 5 days. Reversal of warfarin's effect when it is discontinued or vitamin K1 is administered, requires a similar time.
       Warfarin is a synthetic derivative of dicoumarol, a 4-hydroxycoumarin-derived mycotoxin anticoagulant originally discovered in spoiled sweet clover-based animal feeds. Dicoumarol, in turn, is derived from coumarin, a sweet-smelling but coagulation-inactive chemical found naturally in "sweet" clover (to which it gives its odor and name), tonka beans (also known as "cumaru" from which coumarin's name derives) and many other plants. The name warfarin stems from its discovery at the University of Wisconsin, incorporating the acronym for the organization that funded the key research (WARF, for Wisconsin Alumni Research Foundation) and the ending -arin, indicating its link with coumarin.

Medical Uses
Warfarin is used to decrease the tendency for thrombosis or as secondary prophylaxis (prevention of further episodes) in those individuals that have already formed a blood clot (thrombus). Warfarin treatment can help prevent formation of future blood clots and help reduce the risk of embolism (migration of a thrombus to a spot where it blocks blood supply to a vital organ).
       Warfarin is best suited for anticoagulation (clot formation inhibition) in areas of slowly running blood (such as in veins and the pooled blood behind artificial and natural valves) and in blood pooled in dysfunctional cardiac atria. Thus, common clinical indications for warfarin use are atrial fibrillation, the presence of artificial heart valves, deep venous thrombosis, and pulmonary embolism (where the embolized clots first form in veins). Warfarin is also used in antiphospholipid syndrome. It has been used occasionally after heart attacks (myocardial infarctions), but is far less effective at preventing new thromboses in coronary arteries. Prevention of clotting in arteries is usually undertaken with antiplatelet drugs, which act by a different mechanism from warfarin (which normally has no effect on platelet function).
Alternative anticoagulants
       In some countries, other coumarins are used instead of warfarin, such as acenocoumarol and phenprocoumon. These have a shorter (acenocoumarol) or longer (phenprocoumon) half-life, and are not completely interchangeable with warfarin. Several types of anticoagulant drugs offering the efficacy of warfarin without a need for monitoring, such as dabigatran and rivaroxaban, have recently been approved in a number of countries for classical warfarin uses like the more common types of atrial fibrillation, and others in the same drug classes are under development.
Dosing
       Dosing of warfarin is complicated by the fact that it is known to interact with many commonly used medications and even with chemicals that may be present in certain foods. These interactions may enhance or reduce warfarin's anticoagulation effect. In order to optimize the therapeutic effect without risking dangerous side effects such as bleeding, close monitoring of the degree of anticoagulation is required by blood testing (INR). During the initial stage of treatment, checking may be required daily; intervals between tests can be lengthened if the patient manages stable therapeutic INR levels on an unchanged warfarin dose.
       When initiating warfarin therapy ("warfarinization"), the doctor will decide how strong the anticoagulant therapy needs to be. The target INR level will vary from case to case depending on the clinical indicators, but tends to be 2–3 in most conditions. In particular, target INR may be 2.5–3.5 (or even 3.0–4.5) in patients with one or more mechanical heart valves.
       In addition, for the first three days of "warfarinization", the levels of protein C and protein S (proteins of anticoagulation) drop faster than pro-coagulation proteins such as factor II, VII, IX and X. Therefore bridging anticoagulant therapies (usually heparin) are often used to reverse this temporary hypercoagulable state.
Maintenance Dose
       Vitamine K1-warfarin interaction effects. When warfarin act above its therapeutic window, patient will suffer from bleeding, while high consumption of vitamin k1 rich diet lead warfarin to act below its therapeutic range, resulting in high blood clots.
Recommendations by many national bodies including the American College of Chest Physicians have been distilled to help manage dose adjustments.
       The maintenance dose of warfarin can fluctuate significantly depending on the amount of vitamin K1 in the diet. Keeping vitamin K1 intake at a stable level can prevent these fluctuations. Leafy green vegetables tend to contain higher amounts of vitamin K1. Green parts of members of the family Apiaceae such as parsley, cilantro and dill are extremely rich sources of vitamin K; Cruciferous vegetables such as cabbage and broccoli as well as the darker varieties of lettuces and other leafy greens are also relatively high in vitamin K1. Green vegetables such a peas and green beans do not have such high amounts of vitamin K1 as leafy greens. Certain vegetable oils have high amounts of vitamin K1. Foods that are low in vitamin K1 include roots, bulbs, tubers, and most fruits and fruit juices. Cereals, grains and other milled products are also low in vitamin K1.
Self-testing
 INR self-monitoring
       Patients are making increasing use of self-testing and home monitoring of oral anticoagulation. International guidelines on home testing were published in 2005. The guidelines stated: "The consensus agrees that patient self-testing and patient self-management are effective methods of monitoring oral anticoagulation therapy, providing outcomes at least as good as, and possibly better than, those achieved with an anticoagulation clinic. All patients must be appropriately selected and trained. Currently available self-testing/self-management devices give INR results that are comparable with those obtained in laboratory testing." A 2006 systematic review and meta-analysis of 14 randomized trials showed that home testing led to a reduced incidence of complications (thrombosis and major bleeding) and improved the time in the therapeutic range.FDA approved INR meters and the required training can be obtained through an Independent Diagnostic Testing Facility(IDTF).

Adverse Effects
Haemorrhage
        The only common side effect of warfarin is haemorrhage (bleeding). The risk of severe bleeding is small but definite (a median annual rate of 0.9 to 2.7% has been reported) and any benefit needs to outweigh this risk when warfarin is considered as a therapeutic measure. Risk of bleeding is augmented if the INR is out of range (due to accidental or deliberate overdose or due to interactions), and may cause haemoptysis (coughing up blood), excessive bruising, bleeding from nose or gums, or blood in urine or stool.
       The most accurate clinical prediction rule for estimating the risk of bleeding is the HAS-BLED score.
       The risks of bleeding is increased when warfarin is combined with antiplatelet drugs such as clopidogrel, aspirin, or other nonsteroidal anti-inflammatory drugs. The risk may also be increased in elderly patients and in patients on haemodialysis.
Warfarin Necrosis
      A rare but serious complication resulting from treatment with warfarin is warfarin necrosis, which occurs more frequently shortly after commencing treatment in patients with a deficiency of protein C. Protein C is an innate anticoagulant that, like the procoagulant factors that warfarin inhibits, requires vitamin K-dependent carboxylation for its activity. Since warfarin initially decreases protein C levels faster than the coagulation factors, it can paradoxically increase the blood's tendency to coagulate when treatment is first begun (many patients when starting on warfarin are given heparin in parallel to combat this), leading to massive thrombosis with skin necrosis and gangrene of limbs. Its natural counterpart, purpura fulminans, occurs in children who are homozygous for certain protein C mutations.
Osteoporosis
       After initial reports that warfarin could reduce bone mineral density, several studies have demonstrated a link between warfarin use and osteoporosis-related fracture. A 1999 study in 572 women taking warfarin for deep venous thrombosis, risk of vertebral fracture and rib fracture was increased; other fracture types did not occur more commonly. A 2002 study looking at a randomly selected selection of 1523 patients with osteoporotic fracture found no increased exposure to anticoagulants compared to controls, and neither did stratification of the duration of anticoagulation reveal a trend towards fracture.
       A 2006 retrospective study of 14,564 Medicare recipients showed that warfarin use for more than one year was linked with a 60% increased risk of osteoporosis-related fracture in men; there was no association in women. The mechanism was thought to be a combination of reduced intake of vitamin K, which is necessary for bone health, and inhibition by warfarin of vitamin K-mediated carboxylation of certain bone proteins, rendering them nonfunctional.
Purple Toe Syndrome
       Another rare complication that may occur early during warfarin treatment (usually within 3 to 8 weeks of commencement) is purple toe syndrome. This condition is thought to result from small deposits of cholesterol breaking loose and causing embolisms in blood vessels in the skin of the feet, which causes a blueish purple colour and may be painful.
       It is typically thought to affect the big toe, but it affects other parts of the feet as well, including the bottom of the foot (plantar surface). The occurrence of purple toe syndrome may require discontinuation of warfarin.
Calcification of Valves and Arteries
       Several epidemiological studies have also implicated warfarin use in valvular and vascular calcification. No specific treatment is currently available, but some modalities are under investigation.