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The Knowledge of Drug Interactions Can Lead to Better Outcomes

Per the Oxford Languages, an interaction is the communication or direct involvement with someone or something. In aviation, an interaction is how the pilot reacts to him/herself, the airplane, the environment, and external pressures.

A drug-related problem (DRP) is defined as an event or circumstance that involves a patient’s drug treatment that actually or potentially interferes with the achievement of an optimal outcome. A drug-related problem can be inappropriate medication selection. An improper medication selection is a prescribed medication that could harm the patient. Other drug-related problems that may be inappropriate for the patient are adverse drug reactions, an untreated disease state, wrong dosage of medication, non-compliance, and drug interactions. In the United States, estimates suggest that DRPs account for 17 million emergency department visits and 8.7 million hospital admissions annually (Saudi Pharm J.2014;22(1):17–25).

A drug-related problem study was conducted in 2012 in the emergency department at a university hospital. The study collected information on 143,833 patients. Two hundred and fifty-three patients (4.5%) were due to DRPs. Almost 20% of the patients admitted fell into the category of drug-drug interactions (J Family Community Med. 2015 Jan-Apr; 22(1): 44-48).

Drug interactions are a patient safety issue. A drug-drug interaction (DDI) is the effect of one medication that changes (enhances, diminishes, or modifies) another administered medication. There are three different types of drug interactions: drug-drug, drug-food, and drug-condition. Drug-drug interactions are the most common. DDIs are especially prevalent in hospitalized elderly patients who are on six or more medications. The range of drug interactions observed in the elderly ranges from eight to one hundred percent and may compromise patient safety.

Two primary mechanisms play a role in drug-drug interactions: pharmacodynamics and pharmacokinetics. Pharmacodynamics is the effect medications have on the physiology of the body. An example is a patient who had taken sildenafil (Viagra Ô) and was prescribed isosorbide dinitrate for angina. Each of these medications is a vasodilator and may cause a precipitous drop in blood pressure. Pharmacokinetics is how a medication is absorbed, distributed, metabolized, and excreted. The majority of significant drug interactions occur at the site of metabolism. A majority of medications will be metabolized in the liver. A simple term when describing the metabolism process to patients is the “breaking down” of the medicine into inactive or active drugs. The active drug metabolites can have an additive effect on the patients. The enzymes involved in metabolizing medications in the liver are substances known as cytochrome P450 (CYP450). A specific CYP450 can induce metabolism or inhibit the metabolism of a medication. A CYP450 inducer may cause a decrease in medication effect and not provide any benefit to the patient. On the other hand, a CYP450 inhibitor may cause an added effect of the medication that may lead to an adverse effect, thus increasing the risk to the patient.

The physician, PA, NP, pharmacist, and patient must also be aware of possible drug interactions when over-the-counter (OTC) medications and supplements are administered with prescription medications. Many, if not all, OTCs were prescription medications at one time. Every patient must share all OTC medication and supplement use with their caregivers. Omeprazole (Prilosec Ô) is a GI medication that is administered orally for gastrointestinal problems like gastroesophageal reflux disease (heartburn) and ulcers. A patient who has had a recent heart attack is often prescribed two antiplatelet medications, aspirin and clopidogrel, to prevent future cardiovascular events. The combination of aspirin and clopidogrel may increase the risk of GI bleeding. Omeprazole is either prescribed or can be purchased at a pharmacy. The indication for omeprazole is to protect the gut and decrease the risk of a GI bleed from the combination of aspirin and clopidogrel. Omeprazole may inhibit CYP2C19, which is needed to metabolize clopidogrel to its active form. The active metabolite of clopidogrel inhibits the clotting mechanism and prevents future heart attacks when omeprazole is not part of the patient’s medication regimen. If the clopidogrel is prevented from becoming the active form, the risk of subsequent myocardial infarction (MI) increases.

In my 43 years of experience, the most common drug interactions are with an anticoagulant called warfarin (Coumadin Ô). Warfarin is an anticoagulant for stroke prevention in atrial fibrillation and to prevent future clotting in patients with deep vein thrombosis (DVT) and pulmonary embolism (PE). There are 635 drugs known to interact with warfarin, along with eight disease interactions and five alcohol/food interactions. The totality of drug interactions with warfarin includes 141 listed as major, 424 as moderate, and 70 as minor. The major adverse effects caused by warfarin drug interactions are massive GI and cranial (brain) bleeding.

Antibiotics are the primary culprits of significant drug interactions with warfarin. Antibiotics inhibit CYP450, change how warfarin binds to proteins, and decrease vitamin K absorption in the gut. The top antibiotics causing this drug interaction are sulfamethoxazole/trimethoprim (Bactrim DSÔ), metronidazole (Flagyl Ô), and fluconazole (Diflucan Ô). Another medication to be aware of, drug interaction-wise, is amiodarone (Cordarone Ô). Amiodarone is an antiarrhythmic prescribed for rhythm control in atrial fibrillation and ventricular arrhythmias. Amiodarone plus warfarin inhibits CYP2C9, increases the amount of warfarin in the blood, and increases bleeding risk. The warfarin dose must be cut in half or adjusted down if given with amiodarone. Lovastatin (Mevacor Ô), rosuvastatin (Crestor Ô), and simvastatin (Zocor Ô) inhibit CYP2C9, leading to an increased risk of bleeding. The most recent anticoagulants on the medication market, dabigatran (Pradaxa Ô), rivaroxaban (Xarelto Ô), apixaban (Eliquis Ô), and edoxaban (Savaysa Ô) have drug interactions with medications that inhibit CYP3A4, which includes: ketoconazole (antifungal), ritonavir (HIV), fluconazole (antifungal), and amiodarone. The drug interaction may increase the bleeding risk. Mixing fluoroquinolone antibiotics, levofloxacin, or ciprofloxacin with antiarrhythmics, amiodarone, or dofetilide (Tikosyn Ô) may increase the risk of QT prolongation. This combination changes the electrical conduction in the heart and could cause ventricular tachycardia. Ventricular tachycardia, if not fixed quickly, could lead to mortality.

A few drug-food interactions to be aware of are lovastatin, simvastatin, and atorvastatin, plus grapefruit juice and warfarin, with the intake of vitamin K-rich food. The statins and grapefruit juice are due to furanocoumarins in grapefruit that inhibit CYP3A4. This mechanism will reduce statin metabolism and increase the risk of myalgias (muscle pain). Warfarin inhibits vitamin K-dependent blood factors. Warfarin puts the blood factors to sleep and decreases clotting. If a warfarin patient eats foods rich in vitamin K, the opposite effect happens, and the blood factors wake up. Vitamin K is administered to reverse bleeding when a patient is experiencing warfarin toxicity.

Please be an informed consumer of the medications you are prescribed. Be aware of the benefits and possible risks of all your prescribed and OTC medications. Read the printed information, which includes drug interactions, given to you by your healthcare provider and pharmacist. The pharmacist’s mission is to ensure efficacy and safety with positive outcomes. Ask the pharmacist if there are any significant drug interactions that may occur with your medication therapy. There also are drug interaction applications available to keep patients informed. Fly safe, and Happy Holidays to you and your loved ones.

Larry M. Diamond, PharmD, CFII

Larry Diamond has a Doctor of Pharmacy Degree and has been a pharmacist for 37 years. Larry’s pharmacy practice has been as a Clinical Pharmacy Specialist in Cardiology, Orthopedic Surgery Specialist and most recently Clinical Pharmacy Coordinator. He is a CFII, a pilot for 33 years and has been an AOPA member since 1984.

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