**6. Drawbacks and side-effects**

*Phytochemicals in Human Health*

**5. Indications and contraindications**

(factor II) and the structurally related serine proteases known as factors VII, IX, and X in the liver cells [27]. Decreasing the biological availability of vitamin K inhibits the synthesis of these essential factors and eventually leads to inhibition of the coagulation process. This means that this compound affects both the intrinsic as well as the extrinsic cascade of coagulation since prothrombin plays a central role in both of these pathways [28] and renders it a highly effective anticoagulant drug.

Hemostasis is an essential process to prevent significant external as well as internal blood loss after injury. However, under certain circumstances, it is not desirable to activate or continue this homeostatic process like in disorders with spontaneous thrombosis such as deep venous thrombosis in the legs often resulting in pulmonary embolism [39]. In addition, there are conditions that are prone to a reasonable chance of forming a blood clot during stasis of the blood circulation like in atrial fibrillation and in the limbs of patients with prolonged immobility after surgery [39]. Moreover, conditions like myocardial infarction or ischemic stroke form a preventable group of disorders with inhibition of the thrombotic process [5]. Based on its anticoagulant properties, warfarin is thus an ideal compound for the

Based on the pharmacokinetic properties and the challenges they present, dosing of warfarin is not simple, and a careful approach is necessary. On one hand, a low plasma concentration will not achieve the effect of sufficient anticoagulation and, on the other side of the spectrum, there is the constant chance of overdosing with potential lethal internal or external bleeding. Another problem is the great variety of absorption, body distribution, and metabolism of the agent with individual patients based on the pharmacokinetic properties of warfarin [30]. Frequent monitoring of therapeutic efficiency with adequate laboratory tools like prothrombin time (PT) or international normalized ratio (INR) is absolutely necessary [40, 41] and a fixed or constant dose is close to impossible. Nevertheless, warfarin is highly effective in anticoagulation regiments when carefully dosing and assessing the potential bleeding sites as well as other potential side effects. Warfarin is initially dosed at 5–10 mg daily [42]. Subsequent doses depend on the international normalized ratio, with a therapeutic value between 2 and 4. Concomitant administration of heparins like fraxiparine is necessary when fast anticoagulant activity is

Warfarin is not an ideal agent in conditions when immediate treatment of thromboembolism is imminent due to the long time of onset. In cases of pulmonary embolism and acute ischemic stroke, it is desirable to start with both the oral anticoagulant and fast-acting agent like heparins [44]. The long duration of action harbors another challenge. When acute termination of anticoagulation is necessary with unwanted bleeding like in menstruating women and after blunt and sharp trauma leading to hemorrhage, it could take days before the process of coagulation completely restores after quitting oral administration [27, 30] due to the depletion of coagulant factors in liver and blood. In these cases, intravenous administration of prothrombin complex, fresh frozen plasma with coagulation factors, and high doses

Warfarin readily passes the placenta and may result in spontaneous abortion due to retroplacental bleeding [46], as well as prematurity [47], fetal deformity [48], stillbirth [48], and fetal cranial bleeding [49]. Administration during the first trimester of pregnancy has a high risk of embryopathy [50]. This is accompanied by deformities of bone and cartilage [51], blindness, mental retardation, and other

treatment and prevention of these thromboembolic conditions [5].

**94**

desirable [43].

of vitamin K may be helpful [45].

To say that anticoagulant coumarins have only a few side effects is an absolute understatement. Warfarin is one of the leading drugs with adverse effects requiring hospital admission [59]. Most of all, there is the constant chance of severe bleeding [60]. This can include internal hemorrhagic conditions in the head, gastrointestinal tract, female genitalia, the bladder and urethra or skeletal joints and muscles [40, 61]. They generally present as severe headache, stomach pain, and black or bloody stool, heavier than normal menstrual bleeding, discoloration of urine, and pain and swelling of the joints or muscles. Prolonged bleeding from external sharp or blunt wounds is always present [61]. All these conditions are the result of inability of the affected tissues to initiate and continue the process of hemostasis after damage to the epithelial barrier [62].

Patients suffering from hypertension, disorders of the liver, bleeding lesions, and the elderly and patients using drugs and substances that affect coagulation are at higher risk to suffer from bleeding when using warfarin [63]. Hypertension poses mechanical defects in the blood vessels, especially the arteries. Disorders of the liver reduce the ability of the body to eliminate the warfarin and thus make it more biologically available. In bleeding lesions, warfarin inhibits hemostasis. Among substances that can lead to bleeding when used with warfarin are steroidal and non-steroidal anti-inflammatory drugs, antibiotics, and alcohol. These potentiate the activity, interfere with the protein binding, and reduce the metabolism of warfarin, respectively [63]. Other side effects include injury to the kidneys with potential nephritis [64–66], inflammation of the skin [67] and blood vessels [66], and potentiation of rhabdomyolysis by simvastatin [64].

Due to resistance of rodents against warfarin, superwarfarins have been created [68]. These have a much longer time of activity and hence need only to be consumed once by the rodents, contrary to warfarin. The result however is that their effect persists much longer when deliberately or accidently consumed by humans [69] and treatment of this intoxication is a more challenging enterprise.
