Mechanism Of Action Of Warfarin Biology Essay

Mechanism Of Action Of Warfarin Biology Essay Warfarin is an anticoagulant medication that is used to prevent thrombosis (clots) and embolism in many disorders. Warfarin activity has to be monitored by frequent blood testing for the International Normalized Ratio (INR). Warfarin is a synthetic derivative of coumarin, a chemical found naturally in many plants it decreases blood coagulation by interfering with vitamin K metabolism. Mechanism of Action of Warfarin Warfarin is vitamin K antagonist that produce its anticoagulant effect by interfering with the cyclic interconversion of vitamin K and its 2,3 epoxide (vitamin K epoxide). Vitamin K is a cofactor for the posttranslational carboxylation of glutamate residues to ÃŽÂ ³-carboxyglutamates on the N-terminal regions of vitamin K-dependent proteins (Whitlon, et al., 1978; Fasco, et al., 1982) .123456 These coagulation factors (factors II, VII, IX, and X) require ÃŽÂ ³-carboxylation for their biological activity. Coumarins produce their anticoagulant effect by inhibiting the vitamin K conversion cycle, thereby causing hepatic production of partially carboxylated and decarboxylated proteins with reduced procoagulant activity.78 In addition to their anticoagulant effect, the vitamin K antagonists inhibit carboxylation of the regulatory anticoagulant proteins C and S and therefore have the potential to exert a procoagulant effect. In the presence of calcium ions, carboxylation causes a conformational change in coagulation proteins91011 that promotes binding to cofactors on phospholipid surfaces. The carboxylation reaction requires the reduced form of vitamin K (vitamin KH2), molecular oxygen, and carbon dioxide, and is linked to the oxidation of vitamin KH2 to vitamin K epoxide. Vitamin K epoxide is then recycled to vitamin KH2 through two reductase steps. The first, which is sensitive to vitamin K antagonists,123 reduces vitamin K epoxide to vitamin K1 (the natural food form of vitamin K1), while the second, which is relatively insensitive to vitamin K antagonists, reduces vitamin K1 to vitamin KH2. Treatment with vitamin K antagonists leads to the depletion of vitamin KH2, thereby limiting the ÃŽÂ ³-carboxylation of the vitamin K-dependent coagulant proteins. The effect of coumarins can be counteracted by vitamin K1 (either ingested in food or administered therapeutically) because the second reductase ste p is relatively insensitive to vitamin K antagonists (Fig 1). Patients treated with a large dose of vitamin K1 can also become warfarin resistant for up to a week because vitamin K1 accumulates in the liver and is available to the coumarin-insensitive reductase. Pharmacokinetics and Pharmacodynamics of Warfarin Warfarin is a racemic mixture of two optically active isomers, the R and S forms in roughly equal proportion. It has high bioavailability,1920 is rapidly absorbed from the GI tract, and reaches maximal blood concentrations in healthy volunteers in 90 min after oral administration.1921 Racemic warfarin has a half-life of 36 to 42 h, circulates bound to plasma proteins (mainly albumin), and accumulates in the liver where the two isomers are metabolically transformed by different pathways.22 The dose-response relationship of warfarin is influenced by genetic and environmental factors, including a recently identified common mutation in the gene coding for one of the common cytochrome P450 enzymes (2C9), the hepatic enzyme responsible for oxidative metabolism of the warfarin S-isomer.2324 This mutation likely contributes to the variability in dose response to warfarin among healthy subjects.25 In addition to known and unknown genetic factors, various disease states, drugs, and dietary fac tors can interfere with the response to warfarin. The anticoagulant response to warfarin is influenced by pharmacokinetic factors, including drug interactions that affect the absorption or metabolic clearance of warfarin, and pharmacodynamic factors that alter the hemostatic response to given concentrations of the drug. Variability in anticoagulant response also occurs as a result of inaccuracies in laboratory testing, patient noncompliance, and miscommunication between patient and physician. Other drugs may influence the pharmacokinetics of warfarin by reducing GI absorption or by disrupting its metabolic clearance. For example, the anticoagulant effect of warfarin is reduced by cholestyramine, which impairs its absorption, and is potentiated by drugs that inhibit warfarin clearance through stereoselective or nonselective pathways.252627 Stereoselective interactions affect oxidative metabolism of either the S-isoner or R-isomer of warfarin.2627 Inhibition of S-warfarin metabolism is more important clinically because this isomer is five times more potent as a vitamin K antagonist than the R-isomer.2627 Clearance of S-isomer warfarin is inhibited by phenylbutazone,2829 sulfinpyrazone,30 metronidazole,31 and trimethoprim- sulfamethoxazole,32 each of which potentiates the effect of warfarin on the prothrombin time (PT). In contrast, drugs such as cimetidine and omeprazole that inhibit clearance of the R-isomer have only moderate potentiating effects on the PT in patients treated with warfarin.272833 Amiodarone inhibits the metabolic clearance of both the S-isomer and R-isomer and potentiates the anticoagulant effect of warfarin.34 The anticoagulant effect is inhibited by barbiturates,32 rifampicin,34 and carbamazepine,32 which increase its metabolic clearance by inducing hepatic mixed oxidase activity. Although long-term alcohol use has a potential to increase the clearance of warfarin through a similar mechanism, consumption of even relatively large amounts of wine was shown in one study29 to have little influen ce on PT in subjects treated with warfarin. For a more thorough discussion of the effect of enzyme induction on warfarin therapy, the reader is referred to a critical review (Table 2 ).35 The pharmacodynamics of warfarin are subject to genetic and environmental variability. Hereditary resistance to warfarin occurs in rats36 as well as in human beings.3738 Patients with genetic warfarin resistance require doses fivefold to 20-fold higher than average to achieve an anticoagulant effect. This disorder is attributed to altered affinity of the receptor for warfarin since the plasma warfarin levels required to achieve an anticoagulant effect are increased. Two mis-sense mutations in the factor IX propeptide have been described394041 that cause bleeding without excessive prolongation of PT. When affected individuals are treated with coumarin drugs, factor IX activity decreases to about 1 to 3%, while levels of other vitamin K-dependent coagulation factors decrease to 30 to 40% of normal. These mutations are uncommon and have been estimated to occur in Subjects receiving long-term warfarin therapy are sensitive to fluctuating levels of dietary vitamin K,4243 which is provided predominantly by phylloquinone in plant material.43 The phylloquinone content of a wide range of foodstuffs has been listed by Sadowski and associates.44 Phylloquinone acts through the warfarin-insensitive reductase reaction.45 Important fluctuations in vitamin K intake occur in both apparently healthy and sick subjects.46 Increased intake of dietary vitamin K sufficient to reduce the anticoagulant response to warfarin42 occurs in patients on weight-reduction diets consuming green vegetables or receiving vitamin K-containing supplements, and in patients treated with IV supplements containing vitamin K. Reduced dietary vitamin K1 intake potentiates the effect of warfarin in sick patients treated with antibiotics and IV fluids without vitamin K supplementation and in states of fat malabsorption. Hepatic dysfunction potentiates the response to warfarin through im paired synthesis of coagulation factors. Hypermetabolic states produced by fever or hyperthyroidism increase warfarin responsiveness, probably by increasing the catabolism of vitamin K-dependent coagulation factors.4748 Drugs may influence the pharmacodynamics of warfarin by inhibiting synthesis or increasing clearance of vitamin K-dependent coagulation factors or by interfering with other pathways of hemostasis (Table 3 ). The anticoagulant effect of warfarin is augmented by the second-generation and third-generation cephalosporins, which inhibit the cyclic interconversion of vitamin K,4950 by thyroxine, which increases the metabolism of coagulation factors,48 and by clofibrate, through an unknown mechanism.51 Doses5253 of salicylates > 1.5 g/d also augment the anticoagulant effect of warfarin,54 possibly because these drugs have warfarin-like activity. Acetaminophen has also been reported to augment the anticoagulant effect of warfarin,52 although this contention has been challeng ed (see below). Although heparin potentiates the anticoagulant effect of warfarin, in therapeutic doses, it produces only slight prolongation of the PT. Drugs such as aspirin,55 nonsteroidal anti-inflammatory drugs,56 high doses of penicillins,5758 and moxolactam50 increase the risk of warfarin-associated bleeding by inhibiting platelet function. Of these, aspirin is the most important because of its widespread use and prolonged effect.59 Aspirin and nonsteroidal anti-inflammatory drugs can also produce gastric erosions that increase the risk of upper-GI bleeding.58 The risk of clinically important bleeding is heightened when high doses of aspirin are taken in combination with high-intensity warfarin therapy (INR, 3.0 to 4.5).5560 In two studies, one study61 in patients with prosthetic heart valves and the other study62 in asymptomatic individuals at high risk of coronary artery disease, low doses of aspirin (100 mg/d and 75 mg/d, respectively) were also associated with increased rates of minor bleeding when combined with moderate-intensity and low-intensity warfarin anticoagulation. The mechanisms by which erythromycin63 and some anabolic steroids64 potentiate the anticoagulant effect of warfarin are unknown. Sulfonamides and several broad-spectrum antibiotic compounds may augment the anticoagulant effect of warfarin by eliminating bacterial flora and aggravating vitamin K deficiency in patients whose diet is deficient of vitamin K.65 Wells and associates66 performed a critical analysis of articles reporting possible interaction between drugs or foods and warfarin. Studies were assigned to one category if the interaction was considered highly probable, to a second category if interaction was probable, to a third level if judged possible, and to a fourth level if doubtful. Of 751 citations retrieved, pertinent results from 172 original articles are summarized in Table 3. Strong evidence of interaction was found for 39 of the 81 different drugs and foods appraised; 17 potentiate warfarin effect, 10 inhibit, and 12 produce no effect. Many other drugs have been reported to either interact with oral anticoagulants or alter the PT response to warfarin,6768 but convincing evidence of a causal association is lacking. In a case-control study,52 low to moderate doses of acetaminophen (nine or more tablets per week) were reported to be associated with excessively prolonged INR values. The presence of a causal association bet ween acetaminophen use and potentiation of a warfarin effect is uncertain. The article52 was supported by an editorial,53 but has been challenged by personal experiences (case series) cited in two letters6970 and by the results of a prospective study71 in normal volunteers. However, until more information is presented, it would be prudent to monitor the INR more frequently when acetaminophen is used in this quantity by patients during warfarin therapy. Indeed, it would be reasonable to monitor the PT more frequently when any drug therapy is added or withdrawn from the regimen of a patient treated with an oral anticoagulant. DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any drug, vitamin, or herbal product without checking with your doctor or pharmacist first.Warfarin interacts with many prescription, nonprescription, vitamin, and herbal products. This includes medications that are applied to the skin or inside the vagina or rectum. The following interactions listed do not contain all possible drug interactions. The interactions with warfarin usually result in an increase or decrease in the blood-thinning (anticoagulant) effect. Your doctor or other health care professional should closely monitor you to prevent serious bleeding or clotting problems. While taking warfarin, it is very important to tell your doctor or pharmacist of any changes in medications, vitamins, or herbal products that you are taking.This drug should not be used with the following medications because v ery serious interactions may occur: imatinib, mifepristone.If you are currently using any of these medications listed above, tell your doctor or pharmacist before starting warfarin.Aspirin and aspirin-like drugs (salicylates) and nonsteroidal anti-inflammatory drugs (NSAIDs such as ibuprofen, naproxen, celecoxib) may have effects similar to warfarin. These drugs may increase the risk of bleeding problems if taken during treatment with warfarin. Carefully check all prescription/nonprescription product labels (including drugs applied to the skin such as pain-relieving creams) since the products may contain NSAIDs or salicylates. Talk to your doctor about using a different medication (such as acetaminophen) to treat pain/fever. Low-dose aspirin and related drugs (such as clopidogrel, ticlopidine) should be continued if prescribed by your doctor for specific medical reasons such as heart attack or stroke prevention. Consult your doctor or pharmacist for more details.Many herbal medicati ons have blood-thinning or blood-clotting effects, and some may directly affect warfarin. Tell your doctor before taking any herbal products, especially bromelains, coenzyme Q10, cranberry, danshen, dong quai, fenugreek, garlic, ginkgo biloba, ginseng, goldenseal, and St. Johns wort, among others.This medication may interfere with a certain laboratory test to measure theophylline levels, possibly causing false test results. Make sure laboratory personnel and all your doctors know you use this drug.This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist

Characteristic of an Effective Teacher Essay

1. A ‘Calling’ for the profession This is supposed to be the most important. And this is what is causing me the most headache at the moment. To accept the fact that someone might be doing this job as a job for the perks and the advantages without a real commitment is a real hindrance in achieving my aim of helping teachers become better professionals. How do you train teachers to develop a calling for the profession? Is this something I can possibly aim at? 2. Professional knowledge I tend to feel that a lot of what is considered professional knowledge is in easy-to-assess tests, like TKT or CELTA. Does he know the different kinds of assessments, and the present perfect? Yes, great, then he’s good. Professional knowledge is a matter of pride among teachers. Local teachers make a lot of effort to speak better English and expect ‘native teachers’ to explain random weird ideas they learnt 30-40 years before. I personally attribute little importance to this aspect. Long gone are the days when a clever teacher taught a stupid child about the big-big world. 3. Personal qualities Yeah, yeah. Here we go again: the teacher as the frustrated (failed) actor, the clown, the village idiot†¦ Well actually no, I think there are much more important personal qualities we tend to ignore these days and we shouldn’t: honesty, emotions, intelligence, reliability, enthusiasm, curiosity. These are all characteristics we use to define effective learners, but the more these qualities are shared by their teachers, the more likely it is that they get what they want. It’s always going to be more entertaining to watch Friends, or whatever it is teenagers watch these days, than to attend an English class. So, why compete? Establishing an efficient and mutually beneficial working environment is much more helpful I believe†¦. 4. With-it-ness (McEwan, E K 2002. How to survive and strive in the first three weeks of school) This is an exciting addition to the list. The essential skill of being able to envisage possible classroom and curriculum events. Planning with an awareness of the objectives and the conditions. This is definitely an acquired skill that you can get better with every new year, school and group. This is why every employer should be wary of teachers who do a year or so and then move on regularly. They will not have this understanding of their actions within the bigger picture. It’s arguable of course how important this is, but if we see education – especially public schools – as a continuum with precise expectations, it is important to have teachers who understand them. This is especially true if we want to liberate teachers from prescribed teaching materials and expect them to develop customised tasks for their students. 5. Instructional Effectiveness To be an effective teacher you have to teach well. Hard to argue. The interesting thing about this is that this demands again a very high level of flexibility and a wide range of expertise from the teacher, since something that may be a piece of cake with one group of students can prove to be an absolute nightmare with another. Even if I planned the same lesson for two different groups, they could and they should never be the same. So, this is again a hunch, not more. This seems to work with this group so let’s go with it, but heaven forbid I would try it with the other group. 6. Good communicator Well, this is pretty obvious, and necessary not only with students, but with teachers, managers and parents. Communication is not always direct, which is difficult. Other teachers and management hear about you from students and parents. It’s all a vicious circle, and to communicate your message well in all directions is a bit of a juggling act. 7. Street smart Know about who you teach. This is sometimes perceived as the great advantage of having local teachers or teachers who come from the same-similar context. While I admit that this has its advantages, I think it has just as many disadvantages. There is a false sense of mutuality between the local teachers and students against the foreign teacher in the school. All those dismissive nods from the colleagues and students are the same, really. Sometimes blowing up a little bit of a bomb with a completely innocent face can be very helpful. I’ll never forget the conversation I had with my students about respecting women and giving them rights and me doing the cooking and the washing up. I loved it. In many situations you are expected to be the foreigner. Embracing your foreignness is one way of being successful. You are not expected to be one of them. Why try? Clearly, you don’t want to be rude or hurt anyone but there are several stages between the extremes. Don’t do any thing that would offend you if it was the other way round but don’t expect them to eat the goulash as you serve it, what’s more, they can even be allowed not to like goulash. 8. Willing to go the extra mile This is closely linked to the first one. If you follow a calling, you will go the extra mile. Otherwise you won’t. There is no way of making someone do more than what they are paid to. 9. Lifelong learner The excitement of Amazon delivering yet another book about ELT, Russell Tarr recommending another mindboggingly good link. A conference near you, a conference on the web, all the tweets from last night. If you are still excited about any of these things, we’re talking about you. If you watch a movie and 2 minutes into the film you start thinking about how you could use this in class, this is about you. Most teachers start forgetting what they learn when they start their education, and will have forgotten why they are standing in front of a class by the time they have finished. They are the life-long forgetters. Heaven save students from them. This is not about the ‘best method’ the ‘best book’ ’the greatest author’, ‘the best publisher’, it’s about you and where you are in the wonderful process of your professional development 10 Life outside the classroom Your life outside the classroom is the bread and butter you bring to your students and re-contextalise to feed their learning appetite.

Can This Marriage Be Saved - 804 Words

Can This Marriage Be Saved - Answers You Need to Hear By Catherine R King | Submitted On February 22, 2014 Recommend Article Article Comments Print Article Share this article on Facebook Share this article on Twitter Share this article on Google+ Share this article on Linkedin Share this article on StumbleUpon Share this article on Delicious Share this article on Digg Share this article on Reddit Share this article on Pinterest Expert Author Catherine R King Divorce happens, this we know. About half of all marriages will end because of irreconcilable differences, and that is a well known statistic that we dread. Sometimes it may feel hopeless, as you try to ignore your suspicions but only face one disappointment after another. Maybe it seems as if your partner is unwilling to work with you. It feels like you re battling the inevitable. Can this marriage be saved is certainly the resounding thought in your mind. How It Used to Work Back in the Old Days You want things the way they used to be, that is quite understandable. Like most of us, you probably heard your parents or grandparents say, Till death do us part. Back in the day, people tried harder to stay together. Today social norms have changed; there are more divorces in the modern age than there ever were in previous decades. It s not a question of can this marriage be saved; anything could be forced to work. It s should it be saved? Relationships that involve physical violence or emotionalShow MoreRelatedThe Moral View Of Homosexuality1708 Words   |  7 Pagesin existence. This argument has been viewed by philological experts and people all over the world for centuries and it continues to be a major argument today. 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Essay about Critical Thinking - 769 Words

Critical Thinking Application Critical thinking is the art of thinking in a manner that is critical. This means that prior to making a decision one must be informed about possible repercussions and/or outcomes, this is particularly true in the case of both employers and an employees. A decision maker must be willing to â€Å"choose how to respond to opportunities and problems on the basis of a simplified and approximate account of the situation† (George Jones, 2005, pg 475), while a stakeholder (in this case an employee) must be willing and able to complete any task that is put before him or her. The stakeholder must also make an informed decision based on their personal code of ethics. Based on that belief it becomes evident†¦show more content†¦We use reCon in a three tiered, interconnected manner: maintaing an in-depth contact index, for keeping track of what is going on in properties in our market, and as an invoice and voucher system. 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