Warfarin and Its Therapeutic Mechanisms
Types of Nutrient Drug Interactions Associated with Warfarin
Warfarin Interaction with Vitamin E
Warfarin Interaction with Fish Oil
In practice, nutritional components are known to influence the efficacy of therapeutic agents. Some nutrients improve the efficacy of some drugs, whereas others reduce their therapeutic potency. As such, it is critical to understand the nutritional interactions between drugs and the nutritional components in the diet. Diets which interfere with the activity of certain drugs should be avoided during the treatment period. This prevents nutritional interactions which may result into adverse reactions. The same precaution applies to nutritional supplements. Over the past few decades, nutritional supplements have flooded the market. However, these supplements raise safety concerns, especially on dosage, efficacy and side effects. Despite the safety concerns, it is worth noting that some nutritional components such as vitamins and fatty acids have been found to have clinical significance. They are used for the treatment of different health conditions and illnesses, especially when combined with therapeutic agents. For instance, vitamin E and Omega-3 fatty acids have gained immense acceptance in clinical practice. However, their use should be guided by their interactions with drugs. Warfarin, an antithrombotic agent, is one of the drugs which exhibit interactions with vitamin E and fish oil. This drug is used for the prevention and treatment of arterial and venous thrombotic disease since its development. However, dietary interactions have always complicated its safe use (Murphy 2011, p. 351). Therefore, this paper will provide a comprehensive assessment of warfarin and its nutritional interactions, primarily vitamin E and fish oil.
Warfarin and Its Therapeutic Mechanisms
Biologically, the antithrombotic effect of warfarin depends on the drug’s pharmacodynamics and pharmacokinetics factors. This implies that an extensive understanding of these factors plays a key role in improving the effectiveness and safety of warfarin therapy (Murphy 2011, p. 351). In addition, it is worth noting that the pharmacokinetics and pharmacodynamics of warfarin differ between the R and S enantiomers. Studies indicate that S-warfarin exhibits more potency than R-warfarin (Paterson et al. 2006). This aspect is attributable to their biological properties, primarily receptor affinity to the key enzymes involved in the synthesis of vitamin K-dependent clotting factors (Murphy 2011, p. 353).
Overall, warfarin is readily absorbable with a 100% bioavailability after an oral administration. Studies indicate that similar pharmacokinetic features are experienced for both intravenous and oral formulations. Following administration, warfarin reaches the peak plasma concentration within 0.3 to 4 hours. However, it is worth noting that the rate of absorption is decreased by food interaction, but this does not influence the extent of the drug’s absorption (Murphy 2011, p. 353). Regarding the distribution of warfarin, the volume of distribution is similar to that of albumin with an average volume of 0.15 L/kg. However, warfarin’s distribution depends on its protein binding capacity. Studies indicate that more than 98% of warfarin binds to plasma proteins. As a result, only a small percentage of the drug remains free. This implies that the unbound concentration is available for pharmacological activity. Therefore, the concentration of the free warfarin in the plasma increases as plasma albumin concentrations decrease, leading to an increased plasma clearance. On the other hand, the metabolism of warfarin exhibits stereoselectivity. Its elimination occurs almost entirely through metabolism in which hepatic cytochrome P-450 microsomal enzymes catalyze the inactivation of warfarin metabolites. In turn, the hydroxylated metabolites are reduced into warfarin alcohols (hydroxyl warfarins) by reductases. These alcohol derivatives and inactive oxidative residues are eliminated through urinary excretion.
Overall, warfarin is known to exert its thrombotic effect through interfering with blood clotting process. It interferes with the synthesis of the key clotting factors, primarily those whose synthesis depends on the availability of vitamin K. For instance, clotting factors II, VII and IX are synthesized in the hepatic system under the influence of vitamin K. The hepatic synthesis of clotting factor X is also vitamin K-dependent. Biologically, warfarin reduces the levels of vitamin K-dependent clotting factors through inhibiting the activity of the core enzymes, vitamin K1 reductase and vitamin K epoxide reductase (VKOR), which are involved in the synthesis. These enzymes play integral roles in the formation of active clotting factors from their precursor proteins. The mechanism involves gamma-carboxylation of the glutamic acid residues of the clotting factors precursor molecules, primarily at the NH2-terminal to form biologically active clotting factors. During the process of gamma-carboxylation, a reduced form of vitamin K (vitamin KH2) becomes oxidized to form an inactive form, vitamin KO. In order to recycle, VKOR and vitamin K1 reductase convert vitamin KO into vitamin KH2 required for the synthesis of clotting factors. Therefore, warfarin interferes with this hepatic recycling process of vitamin K resulting to low supply of biologically active vitamin K (Ansell et al. 2008). In turn, the inadequate supply of vitamin K leads to a significant decrease in vitamin K-dependent clotting factors, thus preventing blood clotting in the arteries and veins. However, it is worth noting that the biologic effects of warfarin are experienced after the depletion all the previously activated clotting factors in accordance to their half-lives. This is why it takes at least 3 days for its effects to occur after the initiation of therapy.
Another mechanism through which warfarin exerts its antithrombotic effect is the interference with the synthesis of anticoagulant proteins. Clinical studies indicate that warfarin causes interference with the biosynthesis of proteins S and C.
Types of Nutrient Drug Interactions Associated with Warfarin
In understanding the aspect of nutritional interaction of warfarin, it is worth defining the types of drug interactions associated with warfarin. Ordinarily, there are two types of drug interactions, categorized as either pharmacodynamics or pharmacokinetic interactions. Pharmacodynamics interactions are known to enhance or counteract the pharmacologic effect in the body. In the case of warfarin, these interactions result into changes in platelet function or homeostasis. On the other hand, pharmacokinetic interactions alter the drug’s absorption and its distribution in the body. They also alter its metabolism, as well as elimination, thus the drug’s pharmacological activity is influenced, significantly. Therefore, pharmacokinetic interactions cause changes in serum warfarin concentration. In this context, the interaction between warfarin and nutrients, primarily vitamin E and Fish oil are pharmacodynamics interactions. For instance, vitamin E is known to potentiate the risk of bleeding among patients who are on warfarin therapy (Liu & Stumpo 2007).
From a clinical perspective, the modes of action of warfarin, vitamin E and fish oil exhibit significant differences and similarities. Therefore, these aspects influence the interaction between warfarin and the two nutrients. This implies that understanding warfarin’s nutrients interaction requires a brief comparison on their respective modes of action. One of the main similarities among warfarin, vitamin E and fish oil, primarily omega-3 fatty acids is that they are heart protective. As such, they are useful for the prevention, treatment and the management of cardiovascular disease in humans.
As discussed earlier, warfarin exerts its pharmacologic effect by inhibiting the synthesis of anticoagulant proteins and vitamin K-dependent clotting factors. Therefore, the antithrombotic effect of warfarin accounts for its heart protective capacity.
On the other hand, vitamin E exerts its heart protective effect through inhibiting oxidative reactions on cell membranes. Biologically, vitamin E contains α-Tocopherol, a lipid-soluble antioxidant which plays critical antioxidative functions through the glutathione peroxidase pathway. In atherosclerosis, vitamin E prevents the oxidation of LDL cholesterol which contains oxidative –sensitive fatty acids, thus preventing plaque formation in blood vessels. Therefore, it is believed that adequate concentration of vitamin E stabilizes formed plaques in cardiovascular disease and prevents the development of atherosclerosis (Simon et al. 2001). This implies that vitamin E plays some biological roles in the synthesis of vitamin K-dependent clotting factors which is inhibited by warfarin. As such, vitamin E potentiates the effects of warfarin.
Fish oil contains biologically active fatty acids, primarily the omega 3 and omega 6 fatty acids (Calder 2012, p. 1S). Over the decades, fish oil has gained acceptance for medical purposes. The acceptance of fish oil is attributable to its potential health benefits. Some of the physiological roles of fish oil-derived long-chain fatty acids include the regulation of blood pressure, platelet function, blood coagulation, plasma TG concentrations, heart rate, and cardiac function. Therefore, adequate concentrations of fish oil decreases blood pressure and the likelihood of thrombosis. They also increase vascular reactivity and heart rate variability. As such, fish oil helps in the prevention of hypertension, thrombosis, cardiovascular disease, and hypertriglyceridemia (Calder 2012, p. 3S). Contrary to the mechanism of warfarin, long-chain fatty acids in fish oil exhibit a multifactorial mechanism of action. Overall, fish oil-derived omega-3 fatty acids exert their physiological effects in four general mechanisms. First, they influence hormone or metabolite concentration. Through this mechanism, they can influence tissue or cell behaviour. Second, the fatty acids cause direct effects on cell behaviour through fatty acid receptors (Oh et al. 2010). Third, omega-3 fatty acids act by influencing other factors such as oxidative stress and oxidation of LDL. Changes in these factors lead to influences on cell and tissue behaviour. Finally, these fatty acids cause their physiological effects through changes in cell membrane phospholipids-mediated cell behaviour (Calder 2012, p. 3S). In comparison to warfarin, especially based on the antithrombotic effect, fish oil decreases platelet function and blood coagulation the same roles played by warfarin but their mechanisms of action are different. In general, fish oil potentiates the effects of warfarin.
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- Patrick Kimuyu (Author), 2018, Drug Nutrient Interactions. The Case for Warfarin’s Interaction with Vitamin E and Fish Oil, Munich, GRIN Verlag, https://www.grin.com/document/411954