Question 1

Warfarin works as a Vitamin K antagonist and is a racemic mixture of two isomers, R and S (Jeske, 2019). Of these two, the S enantiomer is more biologically active but has a shorter half-life than the R isomer. Existence in two isomeric forms provides for improved overall half-life of the drug. The fast acting isomer gets cleared from the body very fast leaving behind the less biologically active isomer; which continues displaying the desired outcome. The compound derived from plant-based molecules.

Figure 1. Warfarin structure

The molecule has a chiral carbon centre that allows for flexibility thus the display of stereoisomerism. The chiral carbon enables the molecule to bind to receptors or plasma protein. The drug can form pi-pi interactions via hydrogen bonding and Van der Waals forces of attraction. The Warfarin molecule is very stable because of the resonance that occurs at an intramolecular level because of the sp2 hybridizing of its carbon atoms. During ionization stage, Warfarin loses a hydrogen ion from the hydroxyl group to form a conjugate base of the compound.

Figure 2. Formation of conjugate base of Warfarin

The conjugate base is highly stable because of resonance that occurs between negatively charged oxygen atom and the oxygen that is bonded to a benzene ring carbon atom with a double covalent bond. The negative charge is, therefore, shared between the two oxygen atoms.

Figure 3. Resonance of negative charge

The compound is similar to carboxylic acid in that it has pKa value of 5 indicating that it is weakly acidic. With a physiological pH of 7.4 and a Log D value of 1, Warfarin is distributed effectively in both aqueous and fatty phases.

Question 2

The Warfarin molecule contains significant amounts of organic material that make it hydrophobic with poor solubility in water. Instead, the compound is lipophilic and has high solubility in fat or octanol. At physiological pH of 7.4, Warfarin dissolves equally in both fatty and aqueous phases and is almost completely ionized. The high level of ionization increases solubility in aqueous phase as hydrogen bonds are formed between the drug and water molecules.

The absorption of Warfarin in the gastrointestinal tract occurs rapidly and almost completely. In the stomach, the drug exists predominantly in unionized form. Since the Log P of the drug is 3.4, the unionized version is 3.4 times lipophilic than it is hydrophilic. Consequently, when Warfarin is in an aqueous environment, it is more likely to be bound to plasma proteins such as Albumin when it leaves the small intestines and enters the hepatic portal blood.

Warfarin has moderate permeability. As it traverses the cell membrane lipid barrier, it should be in unionized and unbound state. Since the bound and unbound states of Warfarin are in equilibrium in the small intestines, the drug will be able to permeate the barrier. However, the lipophilic drug molecules do not entirely pass through the lipid bilayer and remain bound within the walls of the small intestines. Warfarin has low clearance levels because it has up to 99% protein binding in plasma. The clearance is mainly renal but some studies have indicated an interaction between Warfarin and the ABCB1 transporter found in the liver.

Question 3

Various proteins and enzymes are involved in the thrombus formation process. Targeting a specific component of the above process will disrupt thrombus formation hence have an anticoagulation effect.

Figure 4. Thrombus formation process

The target of action by Warfarin is inhibition of the vitamin K epoxide reductase (VKOR) complex 1 (PharmGKB, 2020). To this end, S-Warfarin is upto 5 times more potent than R-Warfirin. VKOR inhibition interferes with activation of Factor Xa precursors and as a result, prothrombin is not converted to thrombin. Warfarin depletes functional vitamin K reserves reducing synthesis of active clotting factors (Patel, Singh, Preuss, & Patel, 2019).

Enoxaparin is a Low Molecular Weight Heparin (LMWH) which acts as an indirect anticoagulant. Indirect anticoagulants require antithrombin (AT) produced by the liver for it to function. They bind to AT through a pentasaccharide sequence. Like other LMWHs, it prevents the propagation and growth of existing thrombi but does not breakdown existing clots (Nutescu, Burnett, Fanikos, Spinler, & Wittkowsky, 2016). The drug is specifically active against factor Xa and thrombin (Willihnganz, Gurevitz, & Clayton, 2019).

Figure 5. Enoxaparin

Enoxaparin is a complex mixture of oligosaccharides varying in structure and size (U.S. FDA, 2018). Its chemical properties are determined by heparin properties and the chemical processes undertaken in breaking the heparin into short chains of the enoxaparin. Made from heparin, enoxaparin lasts longer in the body thus it is administered subcutaneously (U.S. FDA, 2018).

Warfarin takes between 24 and 72 hours after administration for its action to start and peak therapeutic effect 5 to 7 days after initiation. However, it has two main benefits: being rapidly and completely absorbed, and 99% protein binding (Patel, Singh, Preuss, & Patel, 2019). For these two reasons, it is appropriate for oral administration. Additionally, 92% of Warfarin is excreted in urine through glomerular filtration in the kidney.

Both of these drugs have contraindications that should be considered before prescription. The high absorption rate of Warfarin is disadvantageous to pregnant women because it traverses the placental barrier causing fetal plasma levels to rise to be the same with maternal levels (Patel, Singh, Preuss, & Patel, 2019). When used in the first trimester, it is likely to cause spontaneous abortion in a condition referred to as Fetal Warfarin Syndrome (FWS). Warfarin also has the associated risk of bleeding and significant haemorrhage dependent on patient susceptibility and intensity of anticoagulation. The risk is especially significant after high-risk procedures like polypectomy and remains high for several days (Lee, Ross, Rivadeneira, Steele, & Feingold, 2017). Enoxaparin does not cross the placental barrier, thus is used instead of Warfarin in pregnancy. Even so, if the woman has renal impairment, specific advice should be given because Enoxaparin exits the body through renal excretion (Nottinghamshire Area Prescribing Committee, 2019). If the woman has normal renal functioning, the dosage is based on early pregnancy weight.