Dangerous Liaisons: Drug-drug, drug-nutrient interactions. Disclosure

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1 Dangerous Liaisons: Drug-drug, drug-nutrient interactions Monica Tombasco, MS, MSNA, FNP-BC, CRNA Senior Lecturer, Fitzgerald Health Education Associates, LLC North Andover, MA Emergency Medicine Nurse Practitioner Huggins Hospital, Wolfeboro, NH Certified Registered Nurse Anesthetist Catholic Medical Center, Manchester, NH Developed by: Margaret A. Fitzgerald, DNP, FNP-BC, NP-C, FAANP, CSP, FAAN, DCC, FNAP President, Fitzgerald Health Education Associates, LLC, North Andover, MA Disclosure No real or potential conflict of interest to disclose No off-label, experimental or investigational use of drugs or devices will be presented. Fitzgerald Health Education Associates, LLC 1 Fitzgerald Health Education Associates, LLC 2 Objectives Having completed the learning activities, the participant will be able to: Identify mechanisms of common drugdrug, drug-nutrient interactions. Describe commonly encountered and potential hazardous drug-drug, drugnutrient interactions. Develop strategies to avoid the abovementioned interactions. Is this what you think about when considering drug interactions? Fitzgerald Health Education Associates, LLC 3 Fitzgerald Health Education Associates, LLC 4 How do drug interactions occur? Drug-drug Drug-food Drug-herb Pharmacodynamics (PD) Study of biochemical and physiological effects of drugs What the drug does to the body and/or disease Fitzgerald Health Education Associates, LLC 5 Fitzgerald Health Education Associates, LLC 6

2 Pharmacodynamics True or false? The pharmacodynamic profile of a medication is unchanged over the lifespan. Pharmacokinetics (PK) What the body does to the drug Includes Absorption Distribution Biotransformation (metabolism) Excretion of drugs Fitzgerald Health Education Associates, LLC 7 Fitzgerald Health Education Associates, LLC 9 Age and gender significantly impact a medication s pharmacokinetics. Pharmacokinetics True or false? Case Example of PD Drug Interaction 38-year-old woman Propranolol for migraine headache prophylaxis β 1, β 2 blockade Develops acute bronchitis with bronchospasm The albuterol is not doing anything. β 2 agonism (activation) Fitzgerald Health Education Associates, LLC 10 Fitzgerald Health Education Associates, LLC 12 What is etiology of the problem? Receptor site blockage prevents receptor site activation. Bronchodilator in β-blockade Ipratropium bromide (Atrovent ) Acts at cholinergic receptor sites Onset of action=1 h Duration of action=4 6 h Monitor carefully during 3 5 halflives (T½) of beta blocker withdrawal Fitzgerald Health Education Associates, LLC 14

3 Chemical/Pharmacokinetic DI 62-year-old woman with longstanding hypothyroidism On levothyroxine 0.1 mg daily TSH=1.2 mcg/ml Placed on iron after significant intraop bleed TSH=10.3 mcg/ml ( mcg/ml) Fitzgerald Health Education Associates, LLC 15 TSH Level, μiu/ml Iron Ingestion and Levothyroxine Therapy Ferrous sulfate effect on TSH levels in patients with hypothyroidism P<0.001 Before Ingestion After Ingestion Fitzgerald Campbell Health Education NR, et Associates, al. Ann Intern LLC Med. 1992;117: Levothyroxine (LT4) Interactions Great Resource Iron Calcium Aluminum Soy milk Sucralfate Formation of inactive drug compound Separate 2 h Empty stomach Same time each day Dietary Supplement Fact Sheet /Calcium-HealthProfessional/ Fitzgerald Health Education Associates, LLC 17 Fitzgerald Health Education Associates, LLC 18 Chemical/Pharmacokinetic DI 48-year-old woman with IDA Taking oral ferrous sulfate Develops UTI Placed on oral ciprofloxacin Remains symptomatic at 72 hours into treatment Results=Urine culture=e. coli sensitive to ciprofloxacin Inactivation of Antimicrobial Effect via Chelation 60 70% reduction in -floxacin dose When taken with metals such as iron, calcium (potential with dairy products), magnesium, aluminum Separate in stomach from metals by 2 hours Source: Fitzgerald Health Education Associates, LLC 19 Fitzgerald Health Education Associates, LLC 20

4 True or false? The warning about drug interaction potential when taken metals and cations extends to all antimicrobials with the -floxacin suffix. Are other antimicrobials similarly impacted? Tetracycline forms including doxycycline, minocycline When taken with metals such as iron, calcium (potential with dairy products), magnesium, aluminum Separate in stomach from metals by 2 hours Source: s005lbl.pdf Fitzgerald Health Education Associates, LLC 23 Examples Medications Labeled to Take with Food Taking Medications with Food: Is this simply to avoid stomach upset? To avoid GI upset Amoxicillin/clavulanate NSAIDs Iron forms Recognizing that there will be some iron dose lost, best taken on an empty stomach but many will not tolerate Fitzgerald Health Education Associates, LLC 25 Examples Medications Labeled to Take with Food (continued) To enhance drug absorption Nitrofurantoin (Macrodantin, Macrobid ) % increase in drug absorbed due to delayed emptying, increased time to dissolve Sertraline (Zoloft ) ~33% increase in dose absorbed when taken with food Source: Examples Medications Labeled to Take with Food (continued) To minimize risk of adverse effect Carvedilol (Coreg ), alpha-beta blocker Take with food in immediate-release formulation to slow absorption and minimize risk of orthostasis Source: Fitzgerald Health Education Associates, LLC 26 Fitzgerald Health Education Associates, LLC 27

5 Drug-food Interactions: Potential for Decreased Drug Absorption Enteral feedings Contains Ca+, other metals, protein Binds to components of feeding Potential Decreased absorption Chelation Source: Article by M. Fitzgerald available at Medications Given with Enteral Feedings Phenytoin suspension 71.6% dose absorption reduction w/ continuous feeding If continuous feeding required Increase dose accordingly. Alternative Hold feeding for 2 h before and 2 h after phenytoin dose; flush feeding tube with 60 ml water after phenytoin dose. Fitzgerald Health Education Associates, LLC 28 Fitzgerald Health Education Associates, LLC 29 Medications Given with Enteral Feedings (continued) FQ antimicrobials 27 67% reduction in mean bioavailability Increased risk of treatment failure Optimally, hold feeding for 1 h before and 2 h after FQ dose; flush feeding tube with 60 ml water after FQ dose. Might not apply to moxifloxacin Avoid use of liquid ciprofloxacin due to tube occlusion risk. Fitzgerald Health Education Associates, LLC 30 With drug-drug interactions, what drugs are most worrisome? Narrow therapeutic index (NTI) vs. wide therapeutic index (WTI) medications Source: cist/faq_ntidrugs.htm Fitzgerald Health Education Associates, LLC 31 What is a drug s therapeutic index? Drug s therapeutic index Ratio of dose that produces toxicity to the dose that produces clinically desired or effective response in a population of individuals How is drug s therapeutic index calculated? TD50 Dose of drug that causes a toxic response in 50% of population ED50 Dose of drug that is therapeutically effective in 50% of population Therapeutic index=td50/ed50 Fitzgerald Health Education Associates, LLC 32 Fitzgerald Health Education Associates, LLC 33

6 Narrow Therapeutic Index (NTI) Medications Defined: Any pharmaceutical which has a <2-fold difference between the minimum toxic concentration and minimum effective blood concentration NTI Medications How can you tell? Need to check a therapeutic level? Of the medication? Theophylline, digoxin, TCA (when given in full antidepressant dose), carbamazepine Of the medication s effect? Levothyroxine (TSH), warfarin (INR), heparin (PTT) Fitzgerald Health Education Associates, LLC 35 Wide Therapeutic Index (WTI) Medications Typically Have wide dose ranges Fluoxetine mg Atorvastatin mg No requirement for periodic drug monitoring of the medication What does the body want to do to drugs? Hang on to these foreign substances? Get rid of the invader as quickly as possible? Fitzgerald Health Education Associates, LLC 36 Fitzgerald Health Education Associates, LLC 37 Biotransformation Lipophilic vs. Hydrophilic Metabolism (biotransformation) The process by which the body modifies or alters the chemical structure of the drug Often to allow for urinary excretion Prodrug (inactive compound) is transformed to active metabolite. Most drugs are designed to be lipophilic to allow for absorption and cell membrane penetration. These products must be changed to a hydrophilic metabolite to allow for excretion. Fitzgerald Health Education Associates, LLC 38 Fitzgerald Health Education Associates, LLC 39

7 CYP450 Drug Metabolism The major process in which drugs are converted from lipophilic to hydrophilic. This is also a common source of drug-drug interactions. Biotransformation Sites via CYP450 Liver Kidney Placenta Lung Plasma Intestinal mucosa Fitzgerald Health Education Associates, LLC 40 Fitzgerald Health Education Associates, LLC 41 Cytochromes P450 (CYP) Important to drug metabolism CYP1A2 CYP2C9 CYP2C19 CYP2D6 CYP2E1 CYP3A4 A source of pharmacokinetic DI Proportion of Medications Metabolized by Select CYP450 Isoenzymes CYP1A2 CYP2C9/19 CYP2D6 13% 15% 25% 47% CYP3A4 Michalets EL. Pharmacotherapy. 1998;18: Katzung, Fitzgerald Health Education Associates, LLC 42 Fitzgerald Health Education Associates, LLC 43 CYP450 Drug-metabolizing Isoenzymes: A Potential Source of Drug-drug Interactions Fitzgerald Health Education Associates, LLC 45

8 Medications Parent Drug to Metabolite Amitriptyline ---> nortriptyline Codeine ---> morphine Primidone ---> phenobarbital Valacyclovir ---> acyclovir Clopidogrel Activation Fitzgerald Health Education Associates, LLC 46 Fitzgerald Health Education Associates, LLC 47 CYP450 Drug-metabolizing Isoenzymes: A Potential Source of Drug-drug Interactions Substrate Utilizes a specific enzymatic pathway. Inhibitor Blocks a specific enzymatic pathway, keeps substrate from exiting. Inducer Pushes the substrate out the exit pathway. CYP450 3A4 substrates: Sildenafil (Viagra ), atorvastatin, simvastatin, venlafaxine (Effexor ), alprazolam (Xanax ), many others About 50% of all prescription medications are CYP450 3A4 substrates CYP450 3A4 substrates: Sildenafil (Viagra ), atorvastatin, simvastatin, venlafaxine (Effexor ), alprazolam (Xanax ), many others About 50% of all prescription medications are CYP450 3A4 substrates Erythro-, clarithromycin=cyp450 3A4 inhibitors Concomitant use of one of these antibiotics with any of the aforementioned CYP450 3A4 substrates (sildenafil, atorvastatin, simvastatin, venlafaxine, alprazolam, many others) results in an increase in substrate levels, potentially leading to substrateinduced toxicity St. John s wort=cyp450 3A4 inducer Concomitant use of St. John s wort and 3A4 substrate can lead to reduced target drug levels and diminished therapeutic effect, possible treatment failure Medications of particular concern include select antiretrovirals, oral contraceptives, and cyclosporine Fitzgerald Health Education Associates, LLC Fitzgerald Health Education Associates, LLC 49 CYP450 Drug-metabolizing Isoenzymes: A Potential Source of Drug-drug Interactions Substrate Utilizes a specific enzymatic pathway. Erythro-, clarithromycin=cyp450 3A4 inhibitors CYP450 3A4 substrates: Sildenafil (Viagra ), atorvastatin, simvastatin, venlafaxine (Effexor ), alprazolam (Xanax ), many others About 50% of all prescription medications are CYP450 3A4 substrates Erythro-, clarithromycin=cyp450 3A4 inhibitors Inhibitor Concomitant use of one of these Concomitant use of one of these antibiotics with any of the aforementioned CYP450 3A4 substrates (sildenafil, atorvastatin, simvastatin, venlafaxine, alprazolam, many Blocks a specific antibiotics with any of the others) results in an increase in substrate levels, potentially leading to substrateinduced toxicity enzymatic pathway, aforementioned CYP450 3A4 keeps substrate substrates (sildenafil, atorvastatin, from exiting. simvastatin, venlafaxine, alprazolam, Inducer St. John s wort=cyp450 3A4 inducer Pushes the substrate out the exit Concomitant use of St. John s wort and 3A4 substrate can lead to reduced target many others) results in increase pathway. drug levels and diminished therapeutic effect, possible treatment failure Medications of particular concern include select antiretrovirals, oral contraceptives, in substrate levels, potentially and cyclosporine leading to substrate-induced toxicity Additional CYP450 3A4 Inhibitors Select HIV antivirals Indinavir, nelfinavir, ritonavir Select systemic antifungals Itraconazole, ketoconazole Grapefruit juice NonDHP CCB verapamil, diltiazem Source: P450 Drug Interaction Table: Abbreviated "Clinically Relevant" Table, available at Fitzgerald Health Education Associates, LLC 50 Fitzgerald Health Education Associates, LLC 51

9 Caution: DI of Select Statins and Clarithromycin Clarithromycin significantly (p <0.001) increased the AUC and C max of all 3 statins (atorvastatin, lovastatin, simvastatin {CYP 3A4 substrates}), most markedly simvastatin (approximately 10-fold increase in AUC)... Source: Jacobson TA. Am J Cardiol. (2004) 94: What about statin choices if one of aforementioned meds is needed? Fitzgerald Health Education Associates, LLC 52 CYP450 Substrates CYP1A2 CYP450 3A4 Atorvastatin Lovastatin Simvastatin CYP450 2C9 Pitavastatin Rosuvastatin Not metabolized by CYP450 Pravastatin 70-year-old woman with UTI On ciprofloxacin CYP1A2 inhibitor Feeling better but cannot sleep The antibiotic is keeping me awake. Drinks 4 5 cups ( L) of coffee/d Caffeine=CYP1A2 substrate Fitzgerald Health Education Associates, LLC 54 Fitzgerald Health Education Associates, LLC 55 CYP450 Drug-metabolizing Isoenzymes: A Potential Source of Drug-drug Interactions Substrate Utilizes a specific enzymatic pathway. Inhibitor Blocks a specific enzymatic pathway, keeps substrate from exiting. Inducer Pushes the substrate out the exit pathway. CYP450 3A4 substrates: Sildenafil (Viagra ), atorvastatin, simvastatin, venlafaxine (Effexor St. John s ), alprazolam (Xanax wort=cyp450 ), many others 3A4 inducer About 50% of all prescription medications are CYP450 3A4 substrates Concomitant use of St. John s wort and 3A4 substrate can lead to Erythro-, clarithromycin=cyp450 3A4 inhibitors Concomitant use of one of these antibiotics with any of the aforementioned CYP450 3A4 substrates reduced (sildenafil, target atorvastatin, simvastatin, drug venlafaxine, levels alprazolam, and many others) results in an increase in substrate levels, potentially leading to substrate-induced toxicity diminished therapeutic effect, possible treatment failure Medications of particular concern St. John s wort=cyp450 3A4 inducer Concomitant use of St. John s wort and 3A4 substrate can lead to reduced target drug levels and diminished therapeutic effect, possible treatment failure Medications include of particular select concern antiretrovirals, include select oral contraceptives, and cyclosporine combined oral contraceptives, and cyclosporine Fitzgerald Health Education Associates, LLC 56 Fitzgerald Health Education Associates, LLC 57

10 CYP450 3A4 Inducer St. John s wort Cyclosporine Result Transplanted organ rejection Digoxin Decreased digoxin levels by day 10 Source: Clinical Pharm Therapy, 1999, 66:338. Clinically relevant table of drug interactions, available at But that St. John s wort really works...states the 70-year-old man with heart failure who is taking digoxin. Has been taking two capsules of St. John s wort per day for the past 5 years with no evidence of loss of digoxin effect. Fitzgerald Health Education Associates, LLC 58 Fitzgerald Health Education Associates, LLC 59 But that St. John s wort really works (continued) What advice should you give? A. Stop the St. John s wort immediately. B. Taper the St. John s wort over the next 2 weeks. C. Continue to take the St. John s wort with certain additional advice. CYP450 1A2 A cigarette smoker Nicotine as a CYP450 1A2 inducer Takes theophylline CYP450 1A2 substrate Cuts down on smoking due to a bad cold Feels jittery and nauseated Fitzgerald Health Education Associates, LLC 60 Fitzgerald Health Education Associates, LLC year-old with Genetically-based Coagulopathy Goal INR , average warfarin weekly dose=56 mg INR 7 d ago=3.2 Today=5.6 Denies Increased leafy greens, new meds, extra warfarin doses, alcohol, etc. 35-year-old with Genetically-based Coagulopathy Admits to going away for the weekend and smoking some weed, something I hardly ever do. Fitzgerald Health Education Associates, LLC 63 Fitzgerald Health Education Associates, LLC 64

11 Warfarin-Marijuana Interaction Theoretically, marijuana might increase the risk of bleeding when used concomitantly with anticoagulant/ antiplatelet drugs. Aspirin, clopidogrel (Plavix ) nonsteroidal anti-inflammatory drugs (NSAIDs), dalteparin (Fragmin ) enoxaparin (Lovenox ) heparin, warfarin (Coumadin ); and others. Sourcehttp://naturaldatabase.therapeuticresearch.com/nd/Search.aspx?cs=PEERREVIEW&s=ND&pt=100&id=947 &fs=prl&searchid= Fitzgerald Health Education Associates, LLC 65 Warfarin-Marijuana Interaction Concomitant use with marijuana may decrease warfarin metabolism or decrease the amount of warfarin bound to plasma proteins and increase warfarin effects. In one report, smoking marijuana grams in a week resulted in an increase in international normalized ratio (INR). Sourcehttp://naturaldatabase.therapeuticresearch.com/nd/Search.aspx?cs=PEERREVIEW&s=ND&pt =100&id=947&fs=PRL&searchid= Fitzgerald Health Education Associates, LLC 66 Marijuana Use, Drug Interaction Potential Potential inhibitor cytochrome P450 3A4 (CYP3A4) Based on in vitro evidence CYP3A4 substrates include lovastatin (Mevacor ), clarithromycin (Biaxin ), cyclosporine, diltiazem (Cardizem ), estrogens, indinavir (Crixivan ), triazolam (Halcion ), approx ~50% Rx medications Does the no statin with grapefruit juice warning extend to all in the class? Fitzgerald Health Education Associates, LLC 67 Fitzgerald Health Education Associates, LLC 68 Simvastatin: When Compared to Ingestion with Water as Control With grapefruit juice C max and AUC increased 12.0-fold (P<0.001) and 13.5-fold (P<0.001) 24 hours after last grapefruit juice C max and AUC increased 2.4-fold (P<0.01) and 2.1-fold (P<0.001) 7 days after last grapefruit juice dose No change Source: Fitzgerald Health Education Associates, LLC 69 CYP450 3A4 Atorvastatin Lovastatin Simvastatin CYP450 Substrates CYP450 2C9 Pitavastatin Rosuvastatin Not metabolized by CYP450 Pravastatin Fitzgerald Health Education Associates, LLC 70

12 Statin vs. Statin LDL Lowering at Various Doses ( Lova 20 mg=29% 40 mg=31% 80 mg=48% Mevacor Prava 10 mg=19% 20 mg=29% 40 mg=34% 80 mg=48% Pravachol Simva 10 mg=28% 20 mg=35% 40 mg=40% 80 mg=48% Zocor Fluva 20 mg=17% 40 mg=23% 80 mg=33% Lescol Atorva 10 mg=38% 20 mg=46% 40 mg=51% 80 mg=54% Lipitor Rosuva Crestor 5 mg=43% 10 mg=50% 20 mg=53% 40 mg=62% Pitava Livalo 1 mg=30% 2 mg=36% 4 mg=45% Fitzgerald Health Education Associates, LLC 71 Resources for Ongoing Information, Updates Indiana University School of Pharmacy s work on the most important DI al-table/ AZCert s website on drugs that potentially prolong the QT interval Fitzgerald Health Education Associates, LLC 72 Conclusions Polypharmacy is a reality. Avoid drug interactions and you will avoid problems for you and your patients. End of Presentation Thank you for your time and attention. fhea.com cs@fhea.com Fitzgerald Health Education Associates, LLC 73 Fitzgerald Health Education Associates, LLC 74 References Katzung, BG. (2014) Basic and Clinical Pharmacology (13th ed.) New York, NY: Lange Medical Books/McGraw-Hill. Stringer, J. (2011) Basic Concepts in Pharmacology: All you need to know for each drug class (4th edition). New York, NY: McGraw-Hill. Images/Illustrations: Unless otherwise noted, all images/illustrations are from open sources, such as the CDC or Wikipedia or property of FHEA or author. All websites listed active at the time of publication. Fitzgerald Health Education Associates, LLC 75 Fitzgerald Health Education Associates, LLC 76

13 Copyright Notice Copyright by Fitzgerald Health Education Associates, LLC All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording or any information storage and retrieval system, without permission from Fitzgerald Health Education Associates, LLC Requests for permission to make copies of any part of the work should be mailed to: Fitzgerald Health Education Associates, LLC 85 Flagship Drive North Andover, MA Statement of Liability The information in this program has been thoroughly researched and checked for accuracy. However, clinical practice and techniques are a dynamic process and new information becomes available daily. Prudent practice dictates that the clinician consult further sources prior to applying information obtained from this program, whether in printed, visual or verbal form. Fitzgerald Health Education Associates, LLC disclaims any liability, loss, injury or damage incurred as a consequence, directly or indirectly, of the use and application of any of the contents of this presentation. Fitzgerald Health Education Associates, LLC 77 Fitzgerald Health Education Associates, LLC 78 Fitzgerald Health Education Associates, LLC 85 Flagship Drive North Andover, MA Fax Website: fhea.com Learning & Testing Center: fhea.com/npexpert Fitzgerald Health Education Associates, LLC 79