Warfarin

In the early 1920s, an outbreak of a previously undetected cow disease occurred in the northern territories of the USA and Canada . Cows bleeding after small procedures, and in some cases spontaneously. For example, 21 out of 22 cows died after removing horns, and 12 out of 25 bulls died after castration. The cause of death of all these animals was the loss of blood. ^[one]

In 1921, Frank Schofield, a Canadian pathologist veterinarian, determined that cows ate moldy silage from sweet clover (“sweet clover”), which is a powerful anticoagulant . Only spoiled hay from clover led to the disease ^[2] . Schofield separated normal and spoiled clover stalks from one haystack and gave them to different rabbits. The condition of the rabbit that ate the normal stems did not change, but the rabbit that received the damaged stems was dying from multiple bleeding. Repeated experiment with other samples of clover gave a similar result ^[1] . In 1929, a North Dakota veterinarian, Roderick L. M., demonstrated that such a condition is associated with insufficient functioning of prothrombin ^[3] .

The anticoagulating substance in the corrupted clover could not be detected until 1940. In 1933, a group of chemists working in the laboratory of the University of Wisconsin under the leadership of Karl Paul Link, intended to isolate bleeding from hay and describe the substance. It took 5 years for Link's student Harold Campbell to receive 6 mg of crystalline anticoagulant. Next, Link's student Mark Stachmann began a project to extract 1.8 g of recrystallized anticoagulant for about 4 months. This material was sufficient to verify the results of Campbell's work and describe in detail the resulting compound. It was found that it was 3,3'-methylenebis- (4-hydroxycoumarin), which was later called dicumarol . These results were confirmed by the synthesis of dicumarol and proof of its identity with a natural agent that caused bleeding ^[4] .

Dicumarol was a product of the plant molecules of coumarin . Coumarin, as it is now known, is present in many plants and causes a sweet smell of freshly cut grass or hay, as well as some plants, such as aromatic bison . In fact, the sweet clover got the name “sweet clover” because of the sweet smell due to the high content of coumarin in its composition, and not for its bitter taste ^[1] . Coumarins, in particular, are present in the fragrant bedstraw and, to a lesser extent, in licorice , lavender, and various other types. However, coumarin itself does not affect blood coagulation, but can be first metabolized by various fungi to compounds, such as 4-hydroxycoumarin , and then (in the presence of natural formaldehyde) to dicumarol, which has anticoagulant properties. Damage and death of clover stems under the influence of fungi explains the presence of an anticoagulant only in damaged clover silo. Dicumarol is considered a fermentation product and mycotoxin . ^[5]

Over the next few years, numerous similar substances (for example, 4-hydroxycoumarins) showed the same anticoagulant properties. The first drug from the class of anticoagulants was dicumarol itself, patented in 1941 and then used as a pharmacological agent. Karl Link continued to develop more powerful coumarin-like anticoagulants for use as rodent venom , resulting in the synthesis of warfarin in 1948. The name “warfarin” (eng. Warfarin ) comes from the abbreviation WARF (eng. W isconsin A lumni R esearch F oundation) + ending -arin , indicating a connection with coumarin. Warfarin was first registered as a rodent venom in the United States in 1948 and immediately became popular. ^[6]

After the event in 1951, when a US Army conscript tried unsuccessfully to commit suicide by taking several doses of warfarin as part of rodent poison and fully recovered in a hospital where he was given vitamin K (already known as a specific antidote) ^[6] , they started studies on the use of warfarin as a therapeutic anticoagulant. It was found that it is superior in effectiveness to dicumarol, and in 1954 was approved for medical use in humans. One of the first known people to receive warfarin was US President Dwight Eisenhower , who was appointed warfarin after a heart attack in 1955 ^[6] .

The exact mechanism of action remained unknown until in 1978 it was demonstrated that warfarin inhibits the enzyme epoxide reductase and, therefore, disrupts the metabolism of vitamin K ^[7] .

A hypothesis published in 2003 claims that Lavrenty Beria , Nikita Khrushchev and others entered into a conspiracy to use warfarin to poison Joseph Stalin . Warfarin is tasteless and colorless and causes symptoms that appeared in Stalin. ^[8]

Warfarin contains a stereo center and consists of two enantiomers. This is a racemate , i.e., a mixture of 1: 1 ( R ) - and ( S ) - form: ^[9]

Pharmacological action

Indirect anticoagulant. The optimal anticoagulant effect is observed on 3-5 days from the start of use and stops 3-5 days after the last dose. Warfarin suppresses vitamin K-dependent synthesis of biologically active forms of calcium-dependent coagulation factors II , VII , IX and X , as well as proteins C , S and Z in the liver ^{[10] [11]} . Warfarin may also affect other proteins that are not involved in blood coagulation, such as osteocalcin or Gla protein.

Precursors of these factors require carboxylation of their glutamic acid residues so that coagulation factors bind to the phospholipid surface of the blood vessel endothelium . Gamma-glutamyl carboxylase is an enzyme that carries out carboxylation of glutamic acid. The carboxylation reaction will continue only if the carboxylase is able to convert the oxidized form of vitamin K (vitamin K hydroquinone) to vitamin K epoxide. Vitamin K epoxide, in turn, is converted back to vitamin K and vitamin K hydroquinone by the action of the vitamin K epoxide reductase enzyme (VKOR, from English V itamin K ep o xide r eductase ). Warfarin inhibits epoxide reductase ^[7] (in particular the VKORC1 subunit ^{[12] [13]} ), thereby reducing the availability of vitamin K and vitamin K hydroquinone in tissues that inhibit the carboxylating activity of glutamyl carboxylase. When this happens, certain glutamic acid residues are no longer carboxylated in the precursors of coagulation factors and coagulation factors are not able to bind to the endothelial surface of blood vessels, thereby becoming biologically inactive. When the reserves of active factors in the body decrease (within a few days) and are replaced by inactive factors, an anticoagulant effect is manifested. Coagulation factors are formed, but their functionality is reduced due to the lack of decarboxylation; these proteins are collectively referred to as PIVKA (eng. p roteins i nduced [by] v itamin K a bsence / a ntagonism - proteins induced by the absence / antagonism of vitamin K). Each such coagulation factor is called PIVKA-x, where x is the number (for example, PIVKA-II ). Thus, ultimately, the use of warfarin reduces blood coagulation in a patient.

Pharmacokinetics

Warfarin is a racemic mixture of two active enantiomers - R- and S- forms, each of which is eliminated from the body in different ways. S-warfarin is five times stronger than the R-isomer in relation to antagonism to vitamin K. ^[14]

Warfarin is slower than heparin , although it has several advantages. Heparin should be injected while warfarin is available in tablet form. Warfarin has a long half-life and is taken only once a day. Heparin can also lead to a prothrombotic state, heparin-induced thrombocytopenia , which increases the risk of thrombosis . The therapeutic effect is achieved only a few days after the start of warfarin. Also, the appointment of warfarin at the beginning without additional anticoagulant therapy may increase the risk of thrombosis (see below). For these main reasons, hospitalized patients are usually given heparin with warfarin at the beginning of treatment, heparin is prescribed for 3-5 days and then gradually withdrawn over several days.

Absorption is complete. Communication with plasma proteins - 97-99%. The therapeutic plasma concentration is 1-5 μg / ml (0.003-0.015 mmol / l). Penetrates through the placenta , but is not secreted with breast milk . The drug is metabolized by the CYP2C9 enzyme system with the formation of inactive and weakly active metabolites that are reabsorbed from bile , while the S-isomer is metabolized faster. T _{1/2 of} racemic warfarin - 40 hours. Excreted by the kidneys .

Pharmacogenomics

Warfarin activity is partially determined by genetic factors. The US Food and Drug Administration (FDA) “emphasizes the possibility that healthcare professionals use genetic tests to improve the selection of the initial dose of warfarin for a particular patient” ^[15] . Polymorphisms in two genes (VKORC1 and CYP2C9) are especially important.

VKORC1 polymorphisms account for 30% of dose variations between patients: ^[16] in particular, mutations make VKORC1 less susceptible to warfarin suppression. ^[13] There are two main haplotypes that account for 25% of the variations: a low-dose haplotype of group (A) and a high-dose haplotype of group (B). ^[17] VKORC1 polymorphisms explain why African Americans are on average relatively resistant to warfarin (a high proportion of the haplotype group B), while Asians are generally more sensitive (a high proportion of group A haplotypes). ^[17] Groups A VKORC1 polymorphisms lead to faster achievement of the target level of the international normalized ratio (INR), but an INR of more than 4 is also achieved faster, which is associated with bleeding. ^[eighteen]

CYP2C9 polymorphisms account for 10% of dose variations between patients. ^[16] These CYP2C9 polymorphisms do not affect the time to reach the target INR level, unlike VKORC1, but reduce the time to reach INR> 4. ^[18]

Antagonism

The effects of warfarin can be canceled by the use of vitamin K. For quick cancellation (for example, with severe bleeding), freshly frozen plasma or a prothrombin complex concentrate (contains only factors inhibited by warfarin) in addition to the intravenous administration of vitamin K. Patients with INR from 4.5 to 10.0 is sufficient for oral administration of small doses of vitamin K. ^[19]

Interaction with other drugs

Warfarin interacts with many commonly used drugs and the warfarin metabolism varies greatly in patients. It is reported that some foods also interact with warfarin. ^[20] In addition to metabolic interactions, drugs that bind well to proteins can displace warfarin from serum albumin and cause an increase in INR. ^[21] This makes it difficult to select the right dosage and emphasizes the need for monitoring INR; when treatment begins with a drug that is known to interact with warfarin (for example, simvastatin ), the INR control is increased or the dose adjusted until a new ideal dosage is found.

Many widely used antibiotics, such as metronidazole or macrolides , significantly increase the effect of warfarin by reducing the metabolism of this anticoagulant in the body. Other broad-spectrum antibiotics can reduce the amount of normal bacterial flora in the gut that produces large amounts of vitamin K, which enhances the effect of warfarin. ^[22] In addition, foods that are high in vitamin K reduce the effects of warfarin. ^[20] Thyroid activity also affects the effectiveness of warfarin; ^[23] hypothyroidism (decreased thyroid function) makes patients less susceptible to warfarin treatment, ^[24] while hyperthyroidism (overactive thyroid gland) increases the effect of the anticoagulant. ^[25] Several mechanisms of this effect are suggested, including changes in the rate of breakdown of blood coagulation factors and changes in the metabolism of warfarin. ^{[23] [26]}

Patients should avoid excessive consumption of alcoholic beverages while taking warfarin, as this affects its metabolism and can increase the level of INR ^[27] .

Warfarin interacts with many herbs and spices ^[28] used in food (for example, ginger and garlic ) or exclusively for medical purposes (for example, ginseng and ginkgo ).

In medicine

Warfarin is prescribed to patients with an increased tendency to thrombosis, as well as for primary prophylaxis to persons at risk of thrombosis or embolism or as a secondary prophylaxis (prevention of subsequent episodes) to persons who have already developed a thrombus .

The main clinical indications for the use of warfarin are atrial fibrillation , the presence of artificial heart valves , deep vein thrombosis and pulmonary embolism . It is also used in the treatment of antiphospholipid syndrome . It can sometimes be used after myocardial infarction , but it is much less effective in preventing new thrombosis in the coronary arteries. Prevention of thrombosis in arteries is usually carried out in combination with antiplatelet drugs (for example, aspirin , clopidogrel ), which have a different mechanism of action than that of warfarin (which usually does not affect platelet function). ^[fourteen]

Dosage of warfarin is complicated by the fact that it interacts with many widely used drugs and even with chemicals that may be present in some foods ^[20] . These interactions can enhance or weaken the anticoagulant effect of warfarin. In order to optimize the therapeutic effect without the risk of dangerous side effects such as bleeding , a blood test is required to monitor the degree of anticoagulation ( INR control is an international normalized ratio). At the initial stage of treatment, control can be carried out every day; the time intervals between blood tests for INR can be increased if the patient manages to achieve a stable proper level of INR with a constant dose of warfarin. ^{[14] The} target level of INR will vary from case to case depending on clinical indications, but in most cases is 2-3. In particular, the target INR values ​​may be 2.5-3.5 (or even 3.0-4.5) in patients with one or more artificial heart valves. ^[29]

In some countries, other coumarins may be used instead of warfarin, such as acenocoumarol and fenprocoumone . They have a shorter (acenocoumarol) or longer (fenprocoumon) half-life and are not completely interchangeable with warfarin. The oral anticoagulant ximelagatran was expected to significantly replace warfarin, but reports of its hepatotoxicity prompted the manufacturer to withdraw it from development. There are other drugs similar to the effectiveness of warfarin without the need for INR control, such as dabigatran and rivaroxaban . ^[thirty]

As Rodenticide

To this day, the so-called "coumarins" (4-hydroxycoumarin derivatives) are used as rodenticides to kill rats and mice in residential, industrial and agricultural areas. Warfarin has no taste or smell and is effective when mixed with food as a bait , because rodents return to the bait and continue to eat poison during the day until a deadly dose accumulates in their body (1 mg / kg / day for about six days ) It can also be mixed with talcum powder , which settles on the skin and fur of an animal and is subsequently consumed by it during cleaning / personal care. LD ₅₀ - 50-500 mg / kg. IDLH is 100 mg / m³. ^[31]

Currently, warfarin is used less frequently as rat poison, since many rat populations have developed resistance to it and more effective poisons are available. Other 4-hydroxycoumarins used as rodenticides include coumatetralil and brodifacum , which are sometimes called “super-warfarins,” since they are more powerful, long-acting and more effective in killing populations of rats and mice, even those resistant to warfarin. Unlike warfarin, which is easily excreted from the body, new anticoagulant poisons accumulate in the liver and kidneys after their use. ^[32]

Hypersensitivity, acute bleeding, severe liver or kidney disease, severe arterial hypertension , acute DIC , protein deficiency C and S, hemorrhagic diathesis , thrombocytopenia , peptic ulcer of the stomach and 12 duodenal ulcer , cerebral hemorrhage , alcoholism , renal failure .

Pregnancy

Warfarin is contraindicated during pregnancy, as it passes through the placental barrier and can cause bleeding in the fetus. The use of warfarin during pregnancy is usually associated with the occurrence of miscarriages , stillbirths, neonatal mortality and premature birth. ^[33] Coumarins (including warfarin) also have teratogenic properties, that is, they cause birth defects ; the incidence of birth defects in children exposed to intrauterine warfarin is about 5%, although higher numbers (up to 30%) have been reported in some studies. ^[34] Depending on how long the pregnancy occurs, two different combinations of congenital malformations may occur. ^[33]

When warfarin (or another 4-hydroxycoumarin derivative) is given during the first trimester (especially between the sixth and ninth weeks of pregnancy), a group of birth defects may occur that are known differently as fetal warfarin syndrome (FVS), warfarin embryopathy, or coumarin embryopathy. PFD is characterized mainly by skeletal defects, which include nasal hypoplasia, drooping or narrowing of the nasal dorsum, scoliosis and calcification in the spine , femur and calcaneus . Anomalies of the limbs, such as brachidactyly (unusually short fingers and toes) or underdeveloped limbs, can also occur. ^{[33] [34]}

The use of warfarin in the second and third trimesters is much less likely to lead to birth defects and, when they occur, are significantly different from fetal warfarin syndrome. During this period, CNS disorders may occur, including cramping, epileptic seizures and eye defects. ^{[33] [34]} As a rule, warfarin is not used in the first trimester and is replaced by low molecular weight heparin, such as enoxaparin . With heparin, the risk of maternal bleeding and other complications is higher, but heparins do not pass through the placental barrier and therefore do not cause birth defects. ^[34]

Inside, in one go, at the same time of day. The initial dose is 2.5-5 mg / day. A further dosing regimen is set individually depending on the results of determining prothrombin time or international normalized ratio (INR) . Prothrombin time should be increased 2-4 times from the original, and INR should reach 2.2-4.4 depending on the disease, the risk of thrombosis, the risk of bleeding and the individual characteristics of the patient. When evaluating prothrombin time (PTV) and prothrombin index (PTI), the international thromboplastin sensitivity index (MIC) should be taken into account and this indicator should be used as a correction factor. The INR indicator compares favorably with the PTV and IPT in that its calculation takes into account the MIC. Elderly and debilitated patients are usually prescribed lower doses of the drug. Перед предстоящим хирургическим вмешательством (при высоком риске тромбоэмболических осложнений) лечение начинают за 2-3 дня до операции. В случае острого тромбоза лечение проводят в комбинации с гепарином до того момента, пока полностью не проявится эффект от пероральной антикоагулянтной терапии (не ранее чем на 3-5 сут лечения). При протезировании клапанов сердца, остром венозном тромбозе вен или тромбоэмболии (на начальных этапах), тромбозе левого желудочка и для профилактики ишемии миокарда нужно стремиться к эффективному действию, отмечающемуся при МНО — 2.8-4. В случае мерцания предсердий и при проведении поддерживающей терапии при тромбозе вен и тромбоэмболии добиваются умеренного противосвертывающего эффекта ( МНО 2.8-3). При совместном применении варфарина с аспирином показатель МНО должен находиться в пределах 2-2.5. Продолжительность лечения зависит от состояния больного. Лечение можно отменять сразу.

Наиболее часто — кровотечения. Редко — диарея , повышение активности «печеночных» трансаминаз , экзема , некроз кожи ; васкулиты , выпадение волос.

Кровотечения

Кровотечение — наиболее частый побочный эффект варфарина. Риск тяжёлого кровотечения небольшой, но определённый (в среднем в год от 0,9 до 2,7 % ^[35] ) и польза от лечения должна перевешивать этот риск, когда рассматривается назначение варфарина.

Риск кровотечения увеличивается при сочетании варфарина с антитромбоцитарными препаратами, такими как клопидогрел , аспирин или другие нестероидные противовоспалительные препараты ^[36] . Риск также может быть повышен у пожилых пациентов ^[37] и у больных на гемодиализе ^[38] .

Варфариновый некроз

Варфариновый некроз — редкое, но серьёзное осложнение лечения варфарином. Он чаще встречается вскоре после начала лечения у пациентов с дефицитом протеина С . Протеин C — врождённый антикоагулянт, который как прокоагулянтный фактор ингибирует варфарин. Так как варфарин вначале снижает уровень протеина C быстрее, чем факторов свёртывания крови, то в начале лечения возможно парадоксальное увеличение свёртывающих свойств крови (для предупреждения этого многие пациенты в начале лечения варфарином также получают гепарин ). Поэтому возможно возникновение массивных тромбозов с некрозом кожи и гангреной конечностей. ^[39]

Остеопороз

После первых сообщений о том, что варфарин может снизить минеральную плотность кости, были проведены исследования, которые показали, что существует связь между применением варфарина и остеопорозом . В исследовании 1999 года у 572 женщин, принимавших варфарин при глубоком венозном тромбозе, риск перелома позвоночника и рёбер был повышен; другие виды переломов возникали реже ^[40] . Рандомизированное исследование 2002 года у 1523 пациентов с остеопоротическим переломом не обнаружило повышенное влияние антикоагулянтов по сравнению с контрольной группой, а также не удалось определить зависимость склонности к переломам от длительности антикоагулянтной терапии ^[41] .

В ретроспективном исследовании 2006 года 14564 пациентов, принимавших препарат, показало, что применение варфарина более 1 года было связано с повышением риска переломов, связанных с остеопорозом, на 60 % у мужчин; подобная связь у женщин не была обнаружена. Такую связь объясняют снижением поступления витамина K в организм и ингибированием варфарином витамин K-опосредованного карбоксилирования некоторых белков костей, нарушая их функцию ^[42] .

Синдром фиолетового пальца

Синдром фиолетового пальца — другое редкое осложнение, которое может произойти во время раннего лечения варфарином (обычно в пределах от 3 до 8 недель от начала). Как полагают, это состояние возникает в результате мелких отложений холестерина в кровеносных сосудах кожи ног. При этом кожа приобретает голубовато-фиолетовый цвет и может быть болезненной.

Обычно, поражается большой палец ноги, но могут поражаться и другие части нижних конечностей, включая нижнюю часть стопы (подошвенную поверхность). При возникновении синдрома фиолетового пальца может потребоваться прекращение приёма варфарина. ^[43]

Overdose

В случае, если протромбиновое время составляет более чем 5 % и нет других возможных источников кровотечения ( нефроуролитиаз и др.), коррекции режима дозирования не требуется. При незначительных кровотечениях необходимо снизить дозу препарата или прекратить лечение на короткий срок. В случае развития тяжёлого кровотечения — витамин К до восстановления коагулянтной активности. При угрожающих кровотечениях — переливание концентратов факторов протромбинового комплекса или свежезамороженной плазмы, или цельной крови . Риск кровотечения увеличивается, если МНО выше допустимых значений (в результате случайной или преднамеренной передозировки или из-за взаимодействия с другими веществами), и может вызвать кровохарканье , выраженные кровоподтёки, кровотечение из носа и дёсен или кровь в моче или стуле.

Перед началом терапии определяют показатель МНО (соответственно протромбиновому времени с учётом коэффициента чувствительности тромбопластина). В дальнейшем проводят регулярный (каждые 2-4-8 нед) лабораторный контроль. Препарат не следует назначать беременным женщинам в связи с выявленным тератогенным действием , развитием кровотечений у плода и гибелью плода. Варфарин выводится с материнским молоком в незначительном количестве и практически не оказывает влияния на свёртываемость крови у ребёнка, поэтому препарат можно применять в период лактации , однако желательно воздержаться от кормления грудью в первые 3 дня терапии варфарином. В период лечения необходимо воздерживаться от употребления этанола (риск развития гипопротромбинемии и кровотечений).

НПВП, дипиридамол , вальпроевая кислота , ингибиторы цитохрома P450 , циметидин , хлорамфеникол повышают риск развития кровотечений. Следует избегать сочетанного применения этих лекарственных средств и варфарина (циметидин можно заменить на ранитидин или фамотидин ). При необходимости лечения хлорамфениколом антикоагулянтную терапию следует временно прекратить. Диуретики могут снижать действие антикоагулянтов (в случае выраженного гиповолемического действия, которое может привести к увеличению концентрации факторов свёртывания крови).

Ослабляют действие

Барбитураты , витамин К, глутетимид , гризеофульвин , диклоксациллин , карбамазепин , миансерин , ретиноиды , рифампицин , сукральфат , феназон , колестирамин , кофермент Q10.

Усиливают

Аллопуринол , амиодарон , анаболические стероиды ( алкилированные в положении C17), АСК и др. НПВП, гепарин , глибенкламид , глюкагон , даназол , диазоксид , дизопирамид , дисульфирам , изониазид , кетоконазол , кларитромицин , клофибрат , левамизол , метронидазол , миконазол , налидиксовая кислота , нилутамид, омепразол , пароксетин , прогуанил , пероральные гипогликемические лекарственные средства — производные сульфаниламидов, симвастатин , сульфаниламиды , тамоксифен , тироксин , хинин , хинидин , флувоксамин , флуконазол , фторурацил , хинолоны , хлоралгидрат , хлорамфеникол , цефалоспорины , циметидин , эритромицин , этакриновая кислота , этанол. В случае сочетанного применения варфарина с вышеперечисленными препаратами необходимо проводить контроль МНО в начале и в конце лечения и по возможности через 2-3 недели от начала терапии. При использовании лекарственных средств (например слабительные лекарственные средства), которые могут повысить риск развития кровотечений из-за снижения нормальной коагуляции (ингибирование факторов свёртывания крови или ферментов печени), стратегия антикоагулянтной терапии должна определяться возможностью проведения лабораторного контроля. Если возможен частый лабораторный контроль, то при необходимости терапии подобными лекарственными средствами дозу варфарина можно уменьшить на 5-10 %. Если проведение лабораторного контроля затруднено, то в случае необходимости назначения указанных лекарственных средств варфарин следует отменить.

Список А .В оригинальной упаковке при температуре не выше 25°

• Варфарин (Warfarin) - Энциклопедия лекарств и товаров аптечного ассортимента . Radar Patent. - Instruction, application and formula.
• Варфарин (Warfarin) - Энциклопедия лекарств и товаров аптечного ассортимента . Radar Patent. - Active substance.

• Site for calculating the dosage of warfarin
• Analysis of the direct costs associated with the use of warfarin in patients with atrial fibrillation
• More on the interaction of warfarin and food