Pharmacology and Pathophysiology

Questions: 1. Outline the mechanism of action of the drug on the body. How does the drug achieve a therapeutic effect? 2. How is the therapeutic effect monitored? 3. What are the optimal value ranges for these measures? 4. There is a long list of drug interactions given for warfarin. What are the three main reasons for the length of this list? 5. A person known to have coeliac disease is noted to be vitamin K deficient. If prescribed warfarin, how would this influence the therapeutic effect of the drug? 6. How does liver disease impact the therapeutic effect of warfarin? Would the dose need to be increased or decreased? 7. The Full Product Information Sheet (PI) indicates elderly patients who have experienced falls should only be prescribed this drug with caution. What is the rationale for this warning? 8. Pregnancy is a contraindication for the prescribing of warfarin. Explain the rationale for this contraindication? 9. A person is prescribed an antimicrobial drug from the cephalosporin drug group. This person has been taking warfarin for the last 6 months. Why might this prove problematic? 10. A person who is heterozygous for the CYP2C9*2 allele is prescribed warfarin. Outline why knowing this piece of information may be helpful in this persons care? 11. Warfarin is contraindicated in those with severe uncontrolled hypertension. Outline the rationale for this contraindication? Answers: 1.Warfarin is a drug used as a blood thinner for treating blood clots like pulmonary embolism and deep vein thrombosis for the prevention of stroke in people who have artificial heart valves, valvular heart disease or atrial fibrillation. It acts as a vitamin K antagonist. Warfarin also prevents recurrent transient ischemic attacks and reduces the chances of recurrent myocardial infarction. The common route of administration is oral; however, it may also be injected into the veins. Warfarin is a monomer as there is no effect on the viscosity of blood. The drug acts by inhibiting the synthesis of clotting factors II, VII, IX and X that is dependent on Vitamin-K. The clotting factors are highly calcium-dependent and biologically active. Warfarin is also responsible for inhibiting the synthesis of regulatory factors protein C, protein S and protein Z. However, the impact may also be on other proteins that do not have any involvement in the process of blood clotting, like matrix Gla prot ein and osteocalcin. The precursors of the clotting factors need gamma carboxylation of the glutamic acid residues in order to let the coagulation factors bind to the phospholipid surfaces of the inner side of blood vessels. Gamma-glutamyl carboxylase enzyme is responsible for the carboxylation reaction of the glutamic acid. This reaction is only allowed in case the carboxylase enzyme can bring about the conversion of reduced form of vitamin K to vitamin K epoxide simultaneously. The enzyme vitamin K epoxide reductase (VKOR) then gives rise to vitamin K and vitamin K hydroquinone from vitamin K epoxide through a recycling process. The drug is responsible for inhibiting epoxide reductase that subsequently diminishes the amount of available vitamin K and vitamin K hydroquinone in the tissues. The carboxylation activity is thereby exhibited by the glutamyl carboxylase. At this time the coagulation factors are not carboxylated at glutamic acid residues. As a result the binding to the en dothelial surface of blood vessels is not fostered. The coagulation factors, therefore, become biologically inactive. The existing active factors degrade soon over the next few days, and the inactive factors replace them. The anticoagulation effect is, therefore, apparent. The factors have reduced functionality as a result of undercarboxylation. The end result is diminished blood clotting in the body of the patient (Satoskar et al., 2015). The initial phase of warfarin therapy may be challenging as the pharmacodynamic response is difficult for prediction. Since the half-life of prothrombin is 50 hours, the initial doses may have limited value. During the initial phase of warfarin application, clot formation may be promoted temporarily. The reason is that the activity of vitamin K influences the level of protein S and protein C. The action leads to a decline in the levels of protein C in the first 36 hours. In addition, reduction in the level of protein S causes a reduction in protein C activity. With administration of warfarin rapidly at a dose of more than 5 mg in a day, an anticoagulant heparin is to be administered (Andersson 2014). 2. The goal of therapy with warfarin is to bring a reduction in the tendency to clot but not to prevent complete clotting of blood. Thus, the clotting ability of the blood in a patient is to be monitored carefully when warfarin is administred to a patient. Warfarin dose is adjusted for maintaining suitably the clotting time within range. Twp periodic tests can be conducted for this purpose- Prothrombin time (PT) and international normalised ratio (INR). Prothrombin time (PT)- this particular test is used for the measurement of the impact of warfarin. The test is performed in the laboratory for measuring the time taken for clot formation. It is sensitive to the clotting factors upon which warfarin makes an effect. The test is also carried out for computing the measure used for adjusting the dose of warfarin, called the international normalised ratio (INR). An administration of a lowest effective dose of the drug for maintaining the target international normalised ratio is the target in warfarin therapy. International Normalised Ratio (INR)- INR is a means of expressing the PT is a standard way through comparison with a reference value. The purpose is to make sure that the results received from different laboratories can be compared effectively (Lehne Rosenthal, 2014). 3.The measurement of PT is done in seconds. The result of PT is given in terms of INR. If a person is not taking warfarin or any other blood thining drug, the normal range of PT is 11 to 13.5 seconds, and the nomal range of INR is 0.8 to 1.1. In case a person is taking warfarin the INR has to be between 2.0 and 3.0 (Reznik et al., 2016). 4. 1. There is a high chance of interference with platelet function 2. Injury to the gastrointestinal mucosa is common 3. Interference with warfarin metabolism, predominantly by CYP2C9 inhibitors or inducers, is found to take place frequently (Scheife et al., 2015). 5. Celiac disease is a form of malabsorption. If a person having such disease is a deficit in vitamin K and warfarin is administred, the therapeutic effect of the drug would increase. Excessive anticoagulation would take place with warfarin administration (Pietzak, 2014). 6. Anticoagulants like Warfarin are basically metabolised by the liver. Patients who suffer from liver diseases that is hepatic impairment, have a heightened response to the medication as a result of decreased clearance of the drug and defective hemostasis related to impaired clotting factor synthesis taking place in the liver. The use of warfarin is contradicted in patients with liver disease also due to vitamin k deficiency and abnormalities in the function of the fibrinogen and platelets. Therapy is to be administred with caution for such patients. The dose needs to be decreased. The INR is to be monitored well, and side effects are to be reported promptly (Brenner Stevens, 2013). 7. Since warfarins application is through the prevention of blood clots, older patients who have a tendency to suffer falls and get cuts and bruises must avoid the medication, or it must be prescribed with caution. Improper use of warfarin may lead to unnecessary prevention of blood clot in case of injuries suffered due to falls (Coleman et al., 2016). 8. Warfarin is contraindicated in pregnant women as the medication can lead to fetal harm. Exposure to the medicine during thee first trimester of pregnancy is a reason for patterns of congenital malformation. Warfarin can cross the placenta and lead to fetal bleeding as well as teratogenecity. Maternal complications are also marked as a use of warfarin during pregnancy. Major bleeding takes place in case of a patient who is treated with unfractionated heparin (UFH) therapy. Herapin-induced thrombocytopenia is another major complication suffered by pregnant women as a result of using warfarin. Considerable reduction in the density of bonnes is also a negative impact on the womens body. 9. Cephalosporins have the tendency to increase the impact of the drug Warfarin through the inhibition of vitamin K-dependent clotting factors production. The INR therefore increases due to the interference between the antimicrobial agent and the anticoagulant (Herz, 2011). 10. The CYP2C9 genotype is used for determining the optimal starting dose of warfarin. This particular gene encodes an important enzyme that is related to warfarin metabolism. Patients who have at least one copy of such gene have reduced metabolism and a higher concentration of warfarin (Brenner Stevens 2013). 11. Warfarin increases blood pressure by preventing clotting and thinning the blood present in the body. Severe hypertension contradicts the use of warfarin (Herz, 2011). References Andersson, K. E. (2014). Relevant Anatomy, Physiology, and Pharmacology. InBladder Dysfunction in the Adult(pp. 3-18). Springer New York. Brenner, G. Stevens, C. (2013).Pharmacology. 1st ed. Philadelphia, PA: Elsevier/Saunders. Coleman, J., Baldawi, M., Heidt, D. (2016). 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