Warfarin

Drug Interactions to Warfarin

March 22, 2017 Drug Informatics, Drug Interactions, Pharmacodynamics, Pharmacokinetics No comments , , , , , , ,

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Drugs may interact with warfarin sodium through pharmacodynamic or pharmacokinetic mechanisms. Pharmacodynamic mechanisms for drug interactions with warfarin sodium are synergism (impaired hemostasis, reduced clotting factor synthesis), competitive antagonism (vitamin K), and alteration of the physiologic control loop for vitamin K metabolism (hereditary resistance). Pharmacokinetic mechanisms for drug interactions with warfarin sodium are mainly enzyme induction, enzyme inhibition, and reduced plasma protein binding. It is important to note that some drugs may interact by more than one mechanism.

Pharmacodynamic:

  • Synergism
  • Competitive antagonism
  • Alteration of vitamin K cycle and metabolism

Pharmacokinetic:

  • Enzyme induction
  • Enzyme inhibition
  • Reduced plasma protein binding

CYP450 Interactions

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CYP450 isozymes involved in the metabolism of warfarin include CYP2C9, 2C19, 2C8, 2C18, 1A2, and 3A4. The more potent warfarin S-enantiomer is metabolized by CYP2C9 while the R-enantiomer is metabolized by CYP1A2 and 3A4.

  • Inhibitors of CYP2C9, 1A2, and/or 3A4 have the potential to increase the effect (increase INR) of warfarin by increasing the exposure of warfarin.
  • Inducers of CYP2C9, 1A2, and/or 3A4 have the potential to decrease the effect (decrease INR) of warfarin by decreasing the exposure of warfarin.

Examples of inhibitors and inducers of CYP2C9, 1A2, and 3A4 are below in Table 2; however, this list should not be considered all-inclusive.

Drugs that Increase Bleeding Risk

Examples of drugs known to increase the risk of bleeding are presented in Table 3. Because bleeding risk is increased when these drugs are used concomitantly with warfarin, closely monitor patients receiving any such drug with warfarin.

Antibiotics and Antifungals

There have been reports of changes in INR in patients taking warfarin and antibiotics or antifungals, but clinical pharmacokinetic studies have not shown consistent effects of these agents on plasma concentrations of warfarin.

Botanical (Herbal) Products and Foods

More frequent INR monitoring should be performed when starting or stopping botanicals.

Few adequate, well-controlled studies evaluating the potential for metabolic and/or pharmacologic interactions between botanicals and warfarin sodium exist. Due to a lack of manufacturing standardization with botanical medicinal preparations, the amount of active ingredients may vary. This could further confound the ability to assess potential interactions and effects on anticoagulation.

Some botanicals may cause bleeding events when taken alone and may have anticoagulant, antiplatelet, and/or fibrinolytic properties. These effects would be expected to be additive to the anticoagulant effects of warfarin sodium. Conversely, some botanicals may decrease the effects of warfarin sodium. Some botanicals and foods can interact with warfarin sodium through CYP450 interactions (e.g., echinacea, grapefruit juice, ginkgo, goldenseal, St. John’s wort).

The amount of vitamin K in food may affect therapy with warfarin sodium. Advise patients taking warfarin sodium to eat a normal, balanced diet maintaining a consistent amount of vitamin K. Patients taking warfarin sodium should avoid drastic changes in dietary habits, such as eating large amounts of green leafy vegetables.

Nine agents in one Rx. and twenty drug interactions found (Not finished)

July 20, 2012 Anticoagulant Therapy, Cardiology, Drug Interactions 2 comments , , , ,

This afternoon I met a perscription that consist of nine different agents, which have twenty drug interactions. Many of them are cardiovascular drugs. They are  Beta-Blockers, Electrolytes, Statins, ARBs, Inotropic Agents, Thiazide, Calcium Channel Blockers, and Benzodiazepines. I list them and their dosage below.

  1. Alprazolam 0.4 mg po Qd
  2. Metoprolol 12.5 mg po Bid
  3. Potassium Chloride 1 g po Bid
  4. Simvastatin 20 mg po Qn
  5. Irbesartan 0.15 g po Qd
  6. Irbesartan/Hydrochlorothiazide 1 tablet po Qd
  7. Digoxin 0.125 mg po Qd
  8. Amlodipine 5 mg po Qd
  9. Warfarin 2.5 mg po Qd

I check these nine drug in Multi-Dug Interaction Chechker and find there are twenty drug interactions between these nine drugs. They are:

Serious – Use alternative

Amlodipine + Simvastatin. Amlodipine increases levels of simvastatin by Other (See comment). Possible serious or life-threatening interaction. Monitor closely. Use alternatives if available. Comment: Benefits of combination therapy should be carefully weighed against the  potential risks of combination. Potential for increased risk of myopathy/rhabdomyolysis. Limit simvastatin dose to no more than 20 mg/day when used concurrently.

Significant – Monitor Closely

Hydrochlorothiazide + Digoxin. Hydrochlorothiazide increases effects of digoxin by pharmacodynamic synergism. Significant interaction possible, monitor closely. Hypokalemia increases digoxin effects.

Potassium Chloride + Hydrochlorothiazide. Potassium chloride increases and hydrochlorothiazide decreases serum potassium. Effect of interaction is not clear, use caution. Potential for dangerous interaction. Use with caution and monitor closely.

Simvastatin + Warfarin. Simvastatin, warfarin. Either increases effects of the other by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Significant – Monitor Closely. Competition by each drug for CYP3A4-mediated metabolism may result in increased INR and increased risk of rhabdomyolysis.

Simvastatin + Digoxin. Simvastatin will increase the level or effect of digoxin by P-glycoprotein (MDR1) efflux transporter. Significant – Monitor Closely.

Digoxin + Hydrochlorothiazide. Digoxin will increase the level or effect of hydrochlorothiazide by basic (cationic) drug competition for renal tubular clearance. Significant – Monitor Closely.

Metoprolol + Irbesartan. Metoprolol, irbesartan. Mechanism: pharmacodynamic synergism. Significant – Monitor Closely. Risk of fetal compromise if given during pregnancy.

Alprazolam + Digoxin. Alprazolam increases levels of digoxin by unknown mechanism. Significant – Monitor Closely.

Metoprolol + Digoxin. Metoprolol increases effects of digoxin by pharmacodynamic synergism. Significant – Monitor Closely. Enhanced bradycardia.

Metoprolol + Amlodipine. Metoprolol and amlodipine both increase anti-hypertensive channel blocking. Significant – Monitor Closely.

Irbesartan + Potassium Chloride. Irbesartan and potassium chloride both increase serum potassium. Significant – Monitor Closely.

Metoprolol + Potassium Chloride. Metoprolol and potassium chloride both increase serum potassium. Significant – Monitor Closely.

Potassium Chloride + Digoxin. Potassium chloride and digoxin both increase serum potassium. Significant – Monitor Closely.

Irbesartan + Metoprolol. Irbesartan and metoprolol both increase serum potassium. Significant – Monitor Closely.

Irbesartan + Digoxin. Irbesartan and digoxin both increase serum potassium. Significant – Monitor Closely.

Irbesartan + Hydrochlorothiazide. Irbesartan increases and hydrochlorothiazide decreases serum potassium. Effect of interaction is not clear, use caution. Significant – Monitor Closely.

Metoprolol + Digoxin. Metoprolol and digoxin both increase serum potassium. Significant – Monitor Closely.

Metoprolol + Hydrochlorothiazide. Metoprolol increases and hydrochlorothiazide decreases serum potassium. Effect of interaction is not clear, use caution. Significant – Monitor Closely.

Digoxin + Hydrochlorothiazide. Digoxin increases and hydrochlorothiazide decreases serum potassium. Effect of interaction is not clear, use caution. Significant – Monitor Closely.

Irbesartan + Irbesartan/Hydrochlorothiazide (Not listed in the multi-drug interaction checker. I add this interaction by myself). Both Irbesartan and Irbesartan/Hydrochlorothiazide increase the level or effects of each other. The combination use of these two drugs is repeated administration and may enhance adverse effects of Irbesartan. I think this combination use should be avoid absolutely.

I alysis these twenty drug interactions. These twenty drug interactions include ten refered to  potassium disorder, three refered to pharmacodynamic synergism, one refered to myopathy/rhabdomyolysis, one hepatic/instestinal enzyme, one MDR1 (P-gp), one renal tubular excretion, one unknown, one anti-hypertension channel, and one repeated administration.

I think the next thing to do is to modify this pharmacotherapy regimen as there are many drug interactions in this regimen.

A serious drug interaction was found last week in 416 Hospital

May 2, 2012 Anticoagulant Therapy, Cardiology, Clinical Cases, Drug Interactions, Therapeutics 1 comment , , , ,

Fluoxetine Capsule.

Last week, before the “May 1st Labor Festival” an old man came to outpatient pharmacy to take his medications. Someone doctor (Neurology Clinics of 416 Hospital) prescribled the drug – Fluoxetine Capsule – to the old man.

When I was dispensing the fluoxetine capsule (Dosage and frequency : 20mg po Qd) to the lovely old man, he told me that he had taken a heart surgery not long ago and he was taking warfarin to prevent cardiac incidents such as acute myocardial infarction.

He didn’t tell me what kind of heart surgery he had taken and the dosage and frequency of warfarin. But I speculated that there might be some cardiac diseases with him and some device such as mechanical valve had been implanted into his heart. So he needs to take anticoagulant to prevent cardiac incidents such as acute myocardial infarction and so on.

The old man inquired me wheth he could take warfarin and fluoxetine in combination. So I checked the two agents in Medscape Multi-Drug Interaction Checker on my android phone and three drug interactons was found among which one was serious and two were significant. They are:

1. Serious: fluoxetine increases levels of warfarin by decreasing metabolism. This drug interaction possibly is serious or life-threatening. It is recommended to use alternatives if available or monitor closely.

2. Significant: fluoxetine will increase the level or effect of warfarin by affecting hepatic enzyme CYP2C19 metabolism. Significant interaction. To monitor closely.

3. Significant: fluoxetine will increase the level or effect of warfarin by affecting hepatic enzyme CYP2C9/10 metabolism. Potential for interaction. To monitor.

So I was hesitant to dispense fluoxetine capsule to him and I warned him to avoid the combination use of these two drugs. If there were no alternatives and he must take fluoxetine I recommended him to monitor his INR twice weekly at least. If the INR exceeds the normal range or the symptom of haemorrhage turns up, the dosage of these two drugs must be adjusted, or the combination use must be stopped.

Discussion:

Fluoxetine and warfarin are different drugs. But they have a same point that they both are metabolise by the same hepatic enzymes such as CYPC19, CYP2C9, CYP2C10. So when one drug is being metabolized, the other one can play a role as antagonist. The result is that the levels of both two drugs are enhanced by each other, espically both two drugs are long-term administered. Because both levels are increased so the rate of adverse drug reactions increases too. For fluoxetine patients may have the adverse drug reactions such as headache, nausea, insomnia and so on. For warfarin patients may have ADRs such as cholesterol embolus syndrome, tissue necrosis, and the most serious – hemorrhage.

Above is the clinical case of drug interaction I met last week. Hope it will be useful for our clinical pharmacists.