patient on amiodarone, glipizide, and warfarin was just diagnosed with clostridium difficile infection. what drug interactions might be seen?
Interactions between your selected drugs
amiodarone ↔ warfarin
Applies to: amiodarone, warfarin
MONITOR CLOSELY: Amiodarone may increase the pharmacologic effects of warfarin by inhibiting CYP450 2C9 hepatic metabolism of S-warfarin. Similar effects may also occur with other oral anticoagulants, resulting in significant hypoprothrombinemia and bleeding. When amiodarone is added to an anticoagulant regimen, increased anticoagulant effects may become apparent within one to several weeks and may persist for months after the amiodarone is discontinued. The effects of this interaction are highly variable - while some patients are asymptomatic, serious and life-threatening bleeding complications have been reported in others. Patients who are poor CYP450 2C9 metabolizers may have a higher risk of bleeding and a faster onset of the interaction.
MANAGEMENT: An empiric 30% to 50% reduction in anticoagulant dosage has been recommended, in addition to frequent monitoring of the patient and the prothrombin time or International Normalized Ratio (INR). Patients should be advised to notify their physician promptly if they experience any signs of excessive anticoagulation such as unusual or prolonged bleeding, bruising, vomiting, change in stool or urine color, headache, dizziness, or weakness.
warfarin ↔ metronidazole
Applies to: warfarin, metronidazole
MONITOR CLOSELY: Coadministration with metronidazole may increase the plasma concentrations and hypoprothrombinemic effect of warfarin. The proposed mechanism is metronidazole inhibition of CYP450 2C9, the isoenzyme responsible for the metabolic clearance of the more active S(-) enantiomer of warfarin. The interaction was associated with significant bleeding and elevation of prothrombin time in two case reports. No data are available for other oral anticoagulants, although at least one other coumarin derivative is known to be metabolized by CYP450 2C9.
MANAGEMENT: Given the potential for interaction and the high degree of interpatient variability with respect to warfarin metabolism, patients should be closely monitored during concomitant therapy with metronidazole. The INR should be checked frequently and warfarin dosage adjusted accordingly, particularly following initiation or discontinuation of metronidazole in patients who are stabilized on their warfarin regimen. The same precaution may be applicable during therapy with other oral anticoagulants, although clinical data are lacking. Patients should be advised to promptly report any signs of bleeding to their physician, including pain, swelling, headache, dizziness, weakness, prolonged bleeding from cuts, increased menstrual flow, vaginal bleeding, nosebleeds, bleeding of gums from brushing, unusual bleeding or bruising, red or brown urine, or red or black stools.
amiodarone ↔ metronidazole
Applies to: amiodarone, metronidazole
MONITOR: QT interval prolongation and torsade de pointes have been reported with the coadministration of metronidazole and amiodarone. A 71-year-old woman developed marked QTc prolongation (625 ms) and torsade de pointes ventricular tachycardia when she received both metronidazole and amiodarone for the treatment of pseudomembranous colitis and paroxysmal atrial fibrillation. The patient recovered following defibrillation and withdrawal of both medications. An interaction was suspected based on the strong temporal relation between administration of the two drugs and development of the arrhythmia. The authors suggest inhibition of CYP450 3A4 metabolism by metronidazole as a possible mechanism of interaction. However, some studies have found no effect of metronidazole on CYP450 3A4 activity.
MANAGEMENT: Until more information is available, it may be appropriate to monitor QT interval on the ECG if amiodarone is used in combination with metronidazole. Patients treated on an outpatient basis should be advised to seek medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, palpitations, or syncope.
warfarin ↔ glipizide
Applies to: warfarin, glipizide
MONITOR: Oral sulfonylureas may enhance or reduce the hypoprothrombinemic response to oral anticoagulants. The mechanism may be related to displacement from plasma protein binding sites. In addition, coumarin anticoagulants may cause an increase in blood levels of hypoglycemic agents, possibly by inhibiting their hepatic metabolism. Clinical data have been highly variable.
MANAGEMENT: The patient should be monitored for altered anticoagulation (PT/INR) and altered glycemic effect when either of these drugs is added to or removed from a patient's regimen. Patients should be advised to regularly monitor their blood sugar, counseled on how to recognize and treat hypoglycemia (e.g., headache, dizziness, drowsiness, nausea, tremor, hunger, weakness, or palpitations), and to promptly report any signs of bleeding (pain, swelling, headache, dizziness, weakness, prolonged bleeding from cuts, vaginal bleeding, nosebleeds, bleeding of gums from brushing, red or brown urine, or red or black stools) to their physician.
No other interactions were found between your selected drugs.
Note: this does not necessarily mean no interactions exist. ALWAYS consult with your doctor or pharmacist.
Other drugs that your selected drugs interact with
amiodarone interacts with more than 400 other drugs.
glipizide interacts with more than 300 other drugs.
metronidazole interacts with more than 100 other drugs.
warfarin interacts with more than 400 other drugs.
Interactions between your selected drugs and food
amiodarone ↔ food
Applies to: amiodarone
GENERALLY AVOID: Grapefruit juice may significantly increase the plasma concentrations of orally administered amiodarone. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. In 11 nonsmoking, healthy volunteers, grapefruit juice (300 mL with drug administration, then 3 hours and 9 hours later) increased the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of amiodarone (17 mg/kg single dose) by 84% and 50%, respectively, compared to water. Formation of the pharmacologically active metabolite, N-desethylamiodarone (N-DEA), was completely inhibited. Clinically, this interaction can lead to altered efficacy of amiodarone, since antiarrhythmic properties of amiodarone and N-DEA appear to differ. In the study, mean increases in PR and QTc intervals of 17.9% and 11.3%, respectively, were observed 6 hours postdose with water, while increases of 10.2% and 3.3%, respectively, were observed after administration with grapefruit juice.
ADJUST DOSING INTERVAL: Food increases the rate and extent of absorption of amiodarone. The mechanism appears to involve the effect of food-induced physiologic changes on drug release from its formulation. In 30 healthy volunteers, administration of a single 600 mg dose of amiodarone following a high-fat meal resulted in a Cmax and AUC that were 3.8 and 2.4 times the respective values under fasting conditions. The time to reach peak plasma concentration (Tmax) was decreased by 37%, indicating an increased rate of absorption. Mean Cmax and AUC for the active metabolite, N-DEA, also increased by 32% and 55%, respectively, but there was no change in the Tmax.
MANAGEMENT: Patients treated with oral amiodarone should avoid consumption of grapefruits and grapefruit juice. In addition, oral amiodarone should be administered consistently with regard to meals.
warfarin ↔ food
Applies to: warfarin
MONITOR: Vitamin K may antagonize the hypoprothrombinemic effect of oral anticoagulants. Vitamin K is a cofactor in the synthesis of blood clotting factors that are inhibited by oral anticoagulants, thus intake of vitamin K through supplements or diet can reverse the action of oral anticoagulants. Resistance to oral anticoagulants has been associated with consumption of foods or enteral feedings high in vitamin K content. Likewise, a reduction of vitamin K intake following stabilization of anticoagulant therapy may result in elevation of the INR and bleeding complications. Foods rich in vitamin K include green, leafy vegetables, avocados, soy beans, and green tea. Lesser amounts are found in liver, bacon, cheese, butter, cauliflower, and coffee. Snack foods containing the fat substitute, olestra, are fortified with 80 mcg of vitamin K per each one ounce serving so as to offset any depletion of vitamin K that may occur due to olestra interference with its absorption. Whether these foods can alter the effect of oral anticoagulants has not been extensively studied. One small study found that moderate consumption (1.5 servings/day) does not significantly affect the INR after one week in patients receiving long-term anticoagulation.
Consumption of large amounts of mango fruit has been associated with enhanced effects of warfarin. The exact mechanism of interaction is unknown but may be related to the vitamin A content, which may inhibit metabolism of warfarin. In one report, thirteen patients with an average INR increase of 38% reportedly had consumed one to six mangos daily 2 to 30 days prior to their appointment. The average INR decreased by 17.7% after discontinuation of mango ingestion for 2 weeks. Rechallenge in two patients appeared to confirm the interaction.
Limited data also suggest a potential interaction between warfarin and cranberry juice resulting in changes in the INR and/or bleeding complications. The mechanism is unknown but may involve alterations in warfarin metabolism induced by flavonoids contained in cranberry juice. At least a dozen reports of suspected interaction have been filed with the Committee on Safety of Medicines in the U.K. since 1999, including one fatality. In the fatal case, the patient's INR increased dramatically (greater than 50) six weeks after he started drinking cranberry juice, and he died from gastrointestinal and pericardial hemorrhage. However, the patient was also taking cephalexin for a chest infection and had not eaten for two weeks prior to hospitalization, which may have been contributing factors. Other cases involved less dramatic increases or instabilities in INR following cranberry juice consumption, and a decrease was reported in one, although details are generally lacking. In a rare published report, a 71-year-old patient developed hemoptysis, hematochezia, and shortness of breath two weeks after he started drinking 24 ounces of cranberry juice a day. Laboratory test results on admission revealed a decrease in hemoglobin, an INR greater than 18, and prothrombin time exceeding 120 seconds. The patient recovered after warfarin doses were withheld for several days and he was given packed red blood cells, fresh-frozen plasma, and subcutaneous vitamin K. It is not known if variations in the constituents of different brands of cranberry juice may affect the potential for drug interactions.
Soy protein in the form of soy milk was thought to be responsible for a case of possible warfarin antagonism in an elderly male stabilized on warfarin. The exact mechanism of interaction is unknown, as soy milk contains only trace amounts of vitamin K. Subtherapeutic INR values were observed approximately 4 weeks after the patient began consuming soy milk daily for the treatment of hypertriglyceridemia. No other changes in diet or medications were noted during this time. The patient's INR returned to normal following discontinuation of the soy milk with no other intervention.
An interaction with chewing tobacco was suspected in a case of warfarin therapy failure in a young male who was treated with up to 25 to 30 mg/day for 4.5 years. The inability to achieve adequate INR values led to eventual discontinuation of the chewing tobacco, which resulted in an INR increase from 1.1 to 2.3 in six days. The authors attributed the interaction to the relatively high vitamin K content in smokeless tobacco.
MANAGEMENT: Intake of vitamin K through supplements or diet should not vary significantly during oral anticoagulant therapy. The diet in general should remain consistent, as other foods containing little or no vitamin K such as mangos and soy milk have been reported to interact with warfarin. Patients should also consider avoiding or limiting the consumption of cranberry juice or other cranberry formulations (e.g., encapsulated dried cranberry powder).
All the best and take care.-
If Maso's post isn't clear: there are seven drugs that show a major interaction with metronidazole. Please type the medication into the search window on this page and scroll down until you see drug interactions. It will list and explain all interactions both major, moderate, and minor as well as food interactions, if any.
Hope this helps,
- Metronidazole Information for Consumers
- Metronidazole Information for Healthcare Professionals (includes dosage details)
- Side Effects of Metronidazole (detailed)
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