MEDICINAL CHEMISTRY PRINCIPLES IN THE USE OF WARFARIN AND ENOXAPARIN AS ANTI-COAGULANTS
MEDICINAL CHEMISTRY PRINCIPLES IN THE USE OF WARFARIN AND ENOXAPARIN AS ANTI-COAGULANTS
CfP1 2020 Integrated Assignment
1). Examining the data given below for WARFARIN, examine and explain how the key physiochemical properties can be related to the chemical structure and structural features of warfarin.
(25 marks)
Warfarin
Enoxaparin
pKa
5
–2, –2, –2, 2.9 per repeating unit
MW
310
~5000 (typically ~16 repeating units)
Log P
3.4
< –4 per repeating unit Log D7.4 1 < –8 per repeating unit HBD’s 1 >20 in total
Stereoisomerism
Enantiomers
Many stereocentres
[WRITE YOUR ANSWER HERE]
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 comprises of two benzene rings, a hydroxyl group, three oxygen atoms, and a methyl substituent group.
Figure 1. Warfarin structure
The molecule additionally has a chiral carbon centre that allows for flexibility and as a consequence, 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 also 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.
2). Explain how the structure and molecular properties of WARFARIN determines and influences its pharmacokinetic properties such as solubility, permeability, clearance, plasma protein binding and volume of distribution as displayed below.
(30 marks)
Warfarin
Enoxaparin
Solubility
Very high
Very high
Permeability
Moderate
Very low
Clearance
Low
‘Natural rate’
Plasma Protein binding
99%
80%
Volume of distribution
8L (low)
4L (low)
[WRITE YOUR ANSWER HERE]
The Warfarin molecule contains significant amounts of organic material that make it hydrophobic and as a result, it has 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 which has minimal solubility in solution. 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. Since Warfarin has a significant protein binding percentage of up to 99% in plasma,its clearance levels are low.
Clearance of Warfarin from the body involves metabolism of S-Warfarin by using CYP2C9 and metabolism of R-Warfarin by predominantly CYP3A4. The clearance is mainly renal but some studies have indicated an interaction between Warfarin and the ABCB1 transporter found in the liver. While is has been established that the enantiomers are metabolized by different phase 1 enzymes, phase 2 metabolism is yet to be extensively studied and understood.
3) For WARFARIN and ENOXAPARIN, explain and compare how the above physiochemical and pharmacokinetic properties impact on the administration, clinical use and effects of these drugs. Please include an explanation of any differences in usage during pregnancy and how these relate to the drug’s properties (10 marks).
(40 marks in total)
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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 is able to deplete reserves of functional vitamin K causing a reduction in the 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). Therefore, it prevents the coagulation cascade from going to completion.
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, in contrast, has the advantage of reduced likelihood of haemorrhage. 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.
References
Jeske, A. H. (2019). Contemporary Dental Pharmacology: Evidence-Based Considerations. Berlin: Springer.
Lee, S. W., Ross, H. M., Rivadeneira, D. E., Steele, S. R., & Feingold, D. L. (2017). Advanced Colonoscopy and Endoluminal Surgery. Berlin: Springer.
Nottinghamshire Area Prescribing Committee. (2019, March). Information sheet for Enoxaparin for Primary Care Prescribers. Retrieved from NHS Trust: https://www.nottsapc.nhs.uk/media/1080/enoxaparin-info-sheet.pdf
Nutescu, E. A., Burnett, A., Fanikos, J., Spinler, S., & Wittkowsky, A. (2016). Pharmacology of anticoagulants used in the treatment of venous thromboembolism. Journal of Thrombosis and Thrombolysis, 15–31.
Patel, S., Singh, R., Preuss, C. V., & Patel, N. (2019, October 29). Warfarin. Retrieved from StatPearls Publishing LLC: https://www.ncbi.nlm.nih.gov/books/NBK470313/
PharmGKB. (2020). Warfrin. Retrieved from PharmGKB: https://www.pharmgkb.org/chemical/PA451906
Royal Cornwall Hospitals. (2018, October). Anticoagulation Related Bleeding – Guideline Summary. Retrieved from NHS Trust: https://doclibrary-rcht.cornwall.nhs.uk/DocumentsLibrary/RoyalCornwallHospitalsTrust/Clinical/AnticoagulationAndThrombosis/AnticoagulationRelatedBleedingGuidelineSummary.pdf
U.S. FDA. (2018, February 6). Generic Enoxaparin Questions and Answers. Retrieved from U.S. FDA: https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/generic-enoxaparin-questions-and-answers
