Warfarin therapeutic index

Warfarin has been the primary oral anticoagulant used in the United States for the past 60 years. Warfarin is the anticoagulant of choice when long-term or extended anticoagulation is required. Warfarin is FDA-approved for the prevention and treatment of VTE, as well as the prevention of thromboembolic complications in patients with myocardial infarction, atrial fibrillation, and heart valve replacement. While very effective, warfarin has a narrow therapeutic index, requiring frequent dose adjustments and careful patient monitoring.15,29... 

Is the drug likely to he co-prescribed with a drug of narrow therapeutic index For example, a drug for angina, cardiac failure or an antiarrhythmic agent is likely to be co-prescribed with warfarin. If there is any evidence of enzyme induction or inhibition, a clinical study with warfarin may be required. 

There are small changes in serum albumin concentration with age, with concomitant small effects on protein binding of some highly bound drugs such as naproxen, salicylate, and warfarin. For such drugs the free concentration rather than the total plasma concentration is a better predictor of drug dose requirements, particularly for drugs with low therapeutic index (difference between the therapeutic... 

Drugs with a narrow therapeutic index are candidates for therapeutic drug monitoring, as in the case of the anticoagulant warfarin. The adverse effect of warfarin, namely excessive anticoagulation that can result in fatal hemorrhaging, is an extension of its pharmacological effect (inhibition of the synthesis of... 

The therapeutic index is determined by measuring the frequency of desired response and toxic response at various doses of drug. For example, Figure 2.9 shows the response to warfarin (see p. 199), an oral anticoagulant with a narrow therapeutic index, and penicillin (see p. 297), an antimicrobial drug with a large therapeutic index. 

Warfarin (example of a drug with a small therapeutic index) As... 

Toxicity as an extension of therapeutic action is usually associated with a small therapeutic index, which is simply the ratio of the toxic plasma concentration over the therapeutic plasma concentration. It should be apparent that drugs with a small therapeutic index require the most attention and alertness with respect to variations in metabolism and elimination. Such variations may easily cause the concentration within the body to either exceed the toxicity threshold, or drop below the minimum amount required for the therapeutic effect. Accordingly, in our example, patients receiving warfarin treatment need to have their blood clotting function measured at regular, frequent intervals. 

During the hyperthyroid state, other drugs that are metabolized by the liver or eliminated renally may need to be adjusted because metabolism may be increased. Patients using drugs with a narrow therapeutic index such as digoxin, warfarin, and phenytoin should be monitored carefully because dosing adjustments will be necessary as the hyperthyroidism or hypermetabolic state resolves. 

The most widely prescribed anticoagulant in North American is warfarin sodium (Coumadin). It was discovered serendipitously in the early 1940s at the University of Wisconsin after hemorrhagic deaths occurred in cattle eating spoiled sweet clover. Warfarin is approved by the FDA for the prevention and treatment of VTE as well as for the prevention of thromboembolic complications associated with atrial fibrillation, heart valve replacement, and myocardial infarction. Because of its narrow therapeutic index, predisposition to drug and food interactions, and propensity to cause hemorrhage, warfarin requires... 

Alternative medicine therapies have become increasingly popular, and it has been estimated that one-third of all Americans use herbal products. In 1997, herbal medicine sales increased nearly 59%, reaching an estimated total of 3.24 billion. One particular safety concern is potential interactions of alternative medicine products with prescription medications. This issue is especially important with respect to drugs with narrow therapeutic indexes, such as warfarin. More food and drug interactions have been... 

Potentially clinically significant interactions include the tendency for fluvoxamine to increase circulating concentrations of oxidatively metabolized benzodiazepines, clozapine, theophylline, and warfarin. Sertraline and fluoxetine can increase levels of benzodiazepines, clozapine, and warfarin. Paroxetine increases levels of clozapine, theophylline, and warfarin. Fluoxetine also potentiates tricyclic antidepressants and some class 1C antiarrhythmics with a narrow therapeutic index (including encainide, flecainide, and propafenone). Nefazodone potentiates benzodiazepines other than lorazepam and oxazepam. 

Colesevelam appears to be less likely to interfere with the absorption of concurrently administered drugs. No significant decreases in absorption were seen when colesevelam was coadministered with either digoxin, lovastatin, warfarin, metoprolol, quinidine, or valproic acid. Because of potential interactions, especially for drugs with a low therapeutic index, the administration of drugs that have not been directly studied in combination with colesevelam should be spaced accordingly, as described above tor cholestryamine and colestipol (7,15). 

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