**3. Physiology of hemostasis**

Hemostasis in mammals and humans is the result of three sequential processes. The first of these is the acute vasoconstriction within seconds after damaged arteries and veins, by local activity of the potent vasoconstrictor thromboxane among others [26]. The second step is the formation of a blood clot through the entrapment of platelets by fibrin within hours and finally followed by the organization of the fibrin mesh into an adhesive structure on the vessel wall [27]. In one of the last steps of the coagulation, prothrombin converts to thrombin, an enzyme that converts the plasma protein fibrinogen to fibrin monomers and activates factor XIII of the coagulation cascade. Activated factor XIII synthesizes fibrin from these monomers. The acquired fibrin molecules then trap the platelets and eventually form the blood clot [27, 28]. The coagulation process has both an intrinsic and an extrinsic pathway. The difference is that the intrinsic pathway only requires ionized calcium to be activated while the extrinsic pathway requires both calcium and tissue factor that

**93**

*From Rat Poison to Medicine: Medical Applications of Coumarin Derivatives*

is released with trauma [28]. **Figure 1** gives an overview of the coagulation process

Warfarin is highly lipid soluble [29–31]. Between 70 and 100% of the oral intake is rapidly absorbed by the intestines with a maximum plasma concentration within 2 h after oral intake [30]. The half-life of the drug is generally more than 20 h, with a large individual variety [32]. Due to the overt lipid solubility, the major part of the drug is protein bound with less than 3% being biologically available [29]. Consequently, the agent has a slow onset of action and a long duration of activity [33]. In fact, the optimal effect is delayed for a few days, until all remaining activated factors II, VII, IX, and X are depleted from the liver and the circulation [33]. Warfarin accumulates in the liver where it exerts its effect and is inactivated through oxidative metabolism by cytochromes P450 to several isomers of water-soluble hydroxywarfarin with negligible anticoagulant activity [34, 35]. These metabolites are almost completely cleared by the kidneys [36]. The hepatic accumulation and relative easy absorption in the intestines result in an enterohepatic circulation of the drug [37]. Enterohepatic circulation is a process in which substances are secreted by the liver with bile to the intestines and subsequently absorbed again by the latter [28]. This results in recycling of the product with very little elimination.

Warfarin inhibits the enzyme vitamin K epoxide reductase that recycles oxidized vitamin K [38]. Vitamin K activates the coagulating factors prothrombin

*DOI: http://dx.doi.org/10.5772/intechopen.89765*

along with the interference sites of warfarin.

*Overview of the coagulation process along with the interference sites of warfarin.*

**4. Pharmacology**

**Figure 1.**

**4.1 Pharmacokinetics**

**4.2 Mechanism of action**

*From Rat Poison to Medicine: Medical Applications of Coumarin Derivatives DOI: http://dx.doi.org/10.5772/intechopen.89765*

**Figure 1.**

*Phytochemicals in Human Health*

as important anticoagulant agents.

membranaeous potassium channels [15].

clinical settings [23–25].

**3. Physiology of hemostasis**

**2. History**

blood clots leading to myocardial infarction, pulmonary embolism, and ischemic stroke among others. This chapter gives an overview of medical applications of coumarins, in particular the history and evolution of warfarin and related compounds

The medical application of plants containing coumarins probably started long before the isolation of this chemical compound from the Tonka bean in 1820 by Nicholas Jean Baptiste Gaston Guibourt [6]. Ancient Romans produced a cough syrup from the marshmallow (*Althea officinalis*) [7], which contains the coumarin scopoletin [8]. This coumarin demonstrated inhibition of leucocyte migration in mice [9], a process that can be linked to the alleged antitussive effect. Cough is a result of the reaction of the airways to leukotrienes and other factors secreted by leucocytes [10–12]. Inhibition of the migration of these to the affected region consequently reduces the availability of these paracrine factors. In addition, at least one of the herbs mentioned by the famous Roman General Pliny in his pharmacopeia [13] contain coumarins with proven action. For example, the extracts of the common rue or herb-of-grace *Ruta graveolens* contain xanthotoxin [14], a coumarin that reduces the mobility of human spermatozoa possibly through inhibition of

The application of coumarin and its derivatives in current western medicine dates to the fifties of the past century with the clinical recognition of coumarins as anticoagulant agents. This event was the result of observations of poisoning of animals with coumarin derivatives that led to massive internal organ bleeding [16]. Soon it became clear that the substance that was responsible for the deadly internal bleeding of cattle was dicoumarol [17]. Shortly after this, the proposal was made to develop a coumarin derivative with rodent killing ability and gradually warfarin found its application as a potent rodenticide [18]. When it became clear that this substance also led to bleeding disorders after poisoning in human beings [19], its application as a therapeutic anticoagulant found its way in medicine [20, 21]. Seven decades later, warfarin is still in use as an anticoagulant [22]. In the meantime, several other coumarins with anticoagulant properties like acenocoumarol, phenprocoumon, and fluindione have been developed, and they are used in a variety of

Hemostasis in mammals and humans is the result of three sequential processes. The first of these is the acute vasoconstriction within seconds after damaged arteries and veins, by local activity of the potent vasoconstrictor thromboxane among others [26]. The second step is the formation of a blood clot through the entrapment of platelets by fibrin within hours and finally followed by the organization of the fibrin mesh into an adhesive structure on the vessel wall [27]. In one of the last steps of the coagulation, prothrombin converts to thrombin, an enzyme that converts the plasma protein fibrinogen to fibrin monomers and activates factor XIII of the coagulation cascade. Activated factor XIII synthesizes fibrin from these monomers. The acquired fibrin molecules then trap the platelets and eventually form the blood clot [27, 28]. The coagulation process has both an intrinsic and an extrinsic pathway. The difference is that the intrinsic pathway only requires ionized calcium to be activated while the extrinsic pathway requires both calcium and tissue factor that

**92**

*Overview of the coagulation process along with the interference sites of warfarin.*

is released with trauma [28]. **Figure 1** gives an overview of the coagulation process along with the interference sites of warfarin.
