Liver Disease

Some Critical Notices Should Knowing When Using Warfarin

June 30, 2017 Anticoagulant Therapy, Hematology, Laboratory Medicine No comments , , , , , , , , , , , ,

PT/INR and Anticoagulation Status

For the vast majority of patients        , monitoring is done using the prothrombin time with international normalized ratio (PT/INR), which reflects the degree of anticoagulation due to depletion of vitamin K-dependent coagulation. However, attention must be paid that the PT/INR in a patient on warfarin may note reflect the total anticoagulation status of the patient in certain settings:

  • First few day of warfarin initiation

The initial prolongation of the PT/INR during the first one to three days of warfarin initiation does not reflect full anticoagulation, because only the factor with the shortest half-life is initially depleted; other functional vitamin K-dependent factors with longer half-lives (e.g., prothrombin) continues to circulate. The full anticoagulation effect of a VKA generally occurs within approximately one week after the initiation of therapy and results in equilibrium levels of functional factors II, IX, and X at approximately 10 to 35 percent of normal.

  • Liver disease

Individuals with liver disease frequently have abnormalities in routine laboratory tests of coagulation, including prolongation of the PT, INR, and aPTT, along with mild thrombocytopenia, elevated D-dimer, especially when liver synthetic function is more significantly impaired and portal pressures are increased. However, these tests are very poor at predicting the risk of bleeding in individuals with liver disease because they only reflect changes in procoagulant factors.

  • Baseline prolonged PT/INR

Some patients with the antiphospholipid antibody syndrome (APS) have marked fluctuations in the INR that make monitoring of the degree of anticoagulation difficult.

Time in the Therapeutic Range (TTR)

For patients who are stably anticoagulated with a VKA, the percentage of time in the therapeutic range (TTR) is often used as a measure of the quality of anticoagulation control. TTR can be calculated using a variety of methods. The TTR reported depends on the method of calculation as well as the INR range considered “therapeutic.” A TTR of 65 to 70 percent is considered to be a reasonable and achievable degree of INR control in most settings.

Factors Affecting the Dose-Response Relationship Between Warfarin and INR

  • Nutritional status, including vitamin K intake
  • Medication Adherence
  • Genetic variation
  • Drug interactions
  • Smoking and alcohol use
  • Renal, hepatic, and cardiac function
  • Hypermetabolic states

In addition, female sex, increased age, and previous INR instability or hemorrhage have been associated with a greater sensitivity to warfarin and/or an increased risk of bleeding.

Dietary Factors

Vitamin K intake – Individuals anti coagulated with warfarin generally are sensitive to fluctuations in vitamin K intake, and adequate INR control requires close attention to the amount of vitamin K ingested from dietary and other sources. The goal of monitoring vitamin K intake is to maintain a moderate, constant level of intake rather than to eliminate vitamin K from the diet. Specific guidance from anticoagulation clinics may vary, but a general principle is that maintaining a consistent level of vitamin K intake should not interfere with a nutritious diet. Patients taking warfarin may wish to be familiar with possible sources of vitamin K (in order to avoid inconsistency).

Of note, intestinal microflora produce vitamin K2, and one of the ways antibiotics contribute to variability in the prothrombin time/INR is by reducing intestinal vitamin K synthesis.

Cranberry juice and grapefruit juice have very low vitamin K content but have been reported to affect VKA anticoagulation in some studies, and some anticoagulation clinics advise patients to limit their intake to one or two servings (or less) per day.

Medication Adherence

Medication adherence for vitamin K antagonists can be challenging due to the need for frequent monitoring and dose adjustments, dietary restrictions, medication interactions, and, in some cases, use of different medication doses on different days to achieve the optimal weekly intake. Reducing the number of medications prescribed may be helpful, if this can be done safely.

Drug Interactions

A large number of drugs interact with vitamin K antagonists by a variety of mechanisms, and additional interacting drugs continue to be introduced. Determine clinically important drug interactions is challenging because the evidence substantiating claims for some drug is very limited; in other cases, the evidence is strong but the magnitude of effect is small. Patients should be advised to discuss any new medication or over-the-counter supplement with the clinician managing their anticoagulation, and clinicians are advised to confirm whether a clinically important drug-drug interaction has been reported when introducing a new medication in a patient anticoagulated with a VKA.

Smoking and Excess Alcohol

The effect of chronic cigarette smoking on warfarin metabolism was evaluated in a systematic review and that included 13 studies involving over 3000 patients. A meta-analysis of the studies that evaluated warfarin dose requirement found that smoking increased the dose requirement by 12 percent, corresponding to a requirement of 2.26 additional mg of warfarin per week. However, two studies that evaluated the effect of chronic smoking on INR control found equivalent control in smokers and non-smokers.

The mechanisms by which cigarette smoking interacts with warfarin metabolism is by causing enhanced drug clearance through induction of hepatic cytochrome P-450 activity by polycyclic aromatic hydrocarbons in cigarette smoke. Nicotine itself is not thought to alter warfarin metabolism.

The interaction between excess alcohol use and warfarin anticoagulation was evaluated in a case-control study that compared alcohol use in 265 individuals receiving warfarin who had major bleeding with 305 controls from the same cohort receiving warfarin who did not have major bleeding. The risk of major bleeding was increased with moderate to severe alcohol use and with heavy episodic drinking.

Mechanism by which alcohol use interacts with warfarin anticoagulation are many, and the contribution of various factors depends greatly on the amount of intake and the severity of associated liver disease. Excess alcohol consumption may interfere with warfarin metabolism. Severe liver disease may also be associated with coagulopathy, thrombocytopenia, and/or gastrointestinal varices, all of which increase bleeding risk independent of effects on warfarin metabolism.


The major comorbidities that affect anticoagulation control are hepatic disease, renal dysfunction, and heart failure. In addition, other comorbidities such as metastatic cancer, diabetes, or uncontrolled hyperthyroidism may also play a role.

The liver is the predominant site of warfarin metabolism. It is also the source of the majority of coagulation factors. Thus, liver disease can affect warfarin dosage, INR control, and coagulation in general. Importantly, individuals with severe liver disease are not “auto-anticoagulated,” because they often have a combination of abnormalities that both impair hemostasis and increase thrombotic risk.

Warfarin undergoes partial excretion in the kidney. Patients with kidney disease can receive warfarin, and management is generally similar to the population without renal impairment; however, dose requirement may be lower.

Heart failure has been shown to interfere with INR stabilization.

Acute illnesses may alter anticoagulation through effects on vitamin K intake, VKA metabolism, and medication interactions, especially infections and gastrointestinal illnesses.

Genetic Factors

Genetic polymorphisms have been implicated in altered sensitivity to warfarin and other vitamin K antagonists.

Factors Affecting Metabolism

March 30, 2016 Medicinal Chemistry No comments , , , , , , , ,

Drug therapy is becoming oriented more toward controlling metabolic, genetic, and environmental illnesss rather than short-term therapy associated with infectious disease. In most cases, drug therapy lasts for months or even years, and the problems of drug-drug interactions and chronic toxicity from long-term drug therapy have become more serious. Therefore, a greater knowledge of drug metabolism is essential. Several factors influencing xenobiotic metabolism include:

1.Genetic factors. Individual differences in drug effectiveness (drug sensitivity or drug resistance), drug-drug interactions, and drug toxicity can depend on racial and ethnic characteristics with the population frequencies of the many polymorphic genes and the expression of the metabolizing enzymes. Pharmacogenetics focuses primarily on genetic polymorphisms (mutations) responsible for interindividual differences in drug metabolism and disposition. Genotype-phenotype correlation studies have validated that inherited mutations result in two or more distinct phenotypes causing very different responses following drug administration. The genes encoding for CYP2A6, CYP2C9, CYP2C19, and CYP2D6 are functionally polymorphic; therefore, at least 30% of P450-dependent metabolism is performed by polymorphic enzymes. For example, mutations in the CYP2D6 gene result in poor, intermediate, or ultrarapid metabolizers of more than 30 cardiovascular and central nervous system drugs. Thus, each of these phenotypic subgroups experiences different responses to drugs extensively metabolized by CYP2D6 pathway ranging from severe toxicity to complete lack of efficacy. For example, ethnic specificity has been observed with the sensitivity of the Japanese and Chinese to ethanol as compared to Caucasians, CYP2C19 polymorphism (affects ~20% of Asians and ~3% of Caucasians) and the variable metabolism of omeprazole (proton pump inhibitor) and antiseizure drugs, and the polymorphic paraoxonase-catalyzed hydrolysis of the neurotoxic organophosphates and lipid peroxides (atherosclerosis).

2.Physiologic factors. Age is a factor as both very young and old have impaired metabolism. Hormones, sex differences, pregnancy, changes in intestinal micro-flora, diseases (espeically those involving the liver), and nutritional status can also influence drug and xenobiotic metabolism.

Beause the liver is the principal site for xenobiotic and drug metabolism, liver disease can modify the pharmacokinetics of drugs metabolized by the liver. Several factors identified as major determinants of the metabolism of a drug in the diseased liver are:

  • the nature and extent of liver damage
  • hepatic blood flow
  • the drug involved
  • the dosage regimen
  • the degree of participation of the liver in the pharmacokinetics of the drug

Liver disease affects the elimination half-life of some drugs but not of others, although all undergo hepatic biotransformation. Some results have shown that the capacity for dug metabolism is impaired in chronic liver disase, which could lead to drug overdosage. Consequently, as a result of the unpredictability of drug effects in the presence of liver disorders, drug therapy in these circumstances is complex, and more than usual caution is needed.

Substances influencing drug and xenobiotic metabolism (other than enzyme inducers) include lipids, proteins, vitamins, and metals. Dietary lipid and protein deficiencies diminish microsomal drug-metabolizing activity. Protein deficiency leads to reduced hepatic microsomal protein and lipid metabolism; oxidative metabolism is decreased due to an alteration in endoplasmic reticulum (ER) membrane permeability affecting electron transfer. In terms of toxicity, protein deficiency would increase the toxicity of drugs and xenobiotics by reducing their oxidative microsomal metabolism and clearance from the body.

3.Pharmacodynamic factors. Dose, frequency, and route of administration, plus tissue distribution and protein binding of a drug, affect its metabolism.

4.Environmental factors. Competition of ingested environmental substances with other drugs and xenobiotics for metabolizing enzymes, and poisoning of enzymes by toxic chemicals such as carbon monoxide or pesticide synergists alter metabolism. Induction of enzyme expression (in which the number of enzyme molecules is increased, while the activity is constant) by other drugs and xenobiotics is another consideration.

Such factors (genetic, physiologic, pharmacodynamic, and environmental factors) can change not only the kinetics of an enzyme reaction but also the whole pattern of metabolism, thereby altering bioavailability, pharmacokinetics, pharmacologic activity, or toxicity of a xenobiotic.