Upload
dinhkiet
View
227
Download
2
Embed Size (px)
Citation preview
Dangerous Liaisons: Drug-drug, drug-nutrient interactions
Monica Tombasco, MS, MSNA, FNP-BC, CRNASenior Lecturer, Fitzgerald Health Education Associates, LLC
North Andover, MAEmergency Medicine Nurse Practitioner Huggins Hospital,
Wolfeboro, NHCertified 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, MAFitzgerald Health Education Associates, LLC 1 Fitzgerald Health Education Associates, LLC 2
• No real or potential conflict of interest to disclose
• No off-label, experimental or investigational use of drugs or devices will be presented.
Disclosure
Objectives• Having completed the learning
activities, the participant will be able to:– Identify mechanisms of common drug-
drug, drug-nutrient interactions. – Describe commonly encountered and
potential hazardous drug-drug, drug-nutrient interactions.
– Develop strategies to avoid the above-mentioned interactions.
Fitzgerald Health Education Associates, LLC 3
Is this what you…
• …think about when considering drug interactions?
Fitzgerald Health Education Associates, LLC 4
How do drug interactions occur?
• Drug-drug• Drug-food• Drug-herb
Fitzgerald Health Education Associates, LLC 5
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 6
Pharmacodynamics True or false?
• The pharmacodynamic profile of a medication is unchanged over the lifespan.
Fitzgerald Health Education Associates, LLC 7
Pharmacokinetics (PK)
• What the body does to the drug• Includes
– Absorption– Distribution– Biotransformation (metabolism)– Excretion of drugs
Fitzgerald Health Education Associates, LLC 9
PharmacokineticsTrue or false?
• Age and gender significantly impact a medication’s pharmacokinetics.
Fitzgerald Health Education Associates, LLC 10
Case Example ofPD Drug Interaction
• 38-year-old woman– Propranolol for migraine headache
prophylaxis• β1, β2 blockade
– Develops acute bronchitis with bronchospasm
• “The albuterol is not doing anything.”• β2 agonism (activation)
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 half-lives (T½) of beta blocker withdrawal
Fitzgerald Health Education Associates, LLC 14
Chemical/Pharmacokinetic DI
• 62-year-old woman with long-standing hypothyroidism– On levothyroxine 0.1 mg daily
• TSH=1.2 mcg/mL
– Placed on iron after significant intraop bleed• TSH=10.3 mcg/mL (0.3−4.0 mcg/mL)
Fitzgerald Health Education Associates, LLC 15
Iron Ingestion and Levothyroxine Therapy
Campbell NR, et al. Ann Intern Med. 1992;117:1010-1013.
Ferrous sulfate effect on TSH levels in patients with hypothyroidism
P<0.001
0123456
TSH
Lev
el, μ
IU/m
L
Before Ingestion After IngestionFitzgerald Health Education Associates, LLC 16
Levothyroxine (LT4) Interactions
• Iron• Calcium• Aluminum • Soy milk• Sucralfate
• Formation of inactive drug compound– Separate ≥2 h– Empty stomach– Same time each day
Fitzgerald Health Education Associates, LLC 17
Great Resource
• Dietary Supplement Fact Sheet– https://ods.od.nih.gov/factsheets
/Calcium-HealthProfessional/
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
Fitzgerald Health Education Associates, LLC 19
Inactivation of AntimicrobialEffect 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: http://www.drugs.com/pro/cipro.html
Fitzgerald Health Education Associates, LLC 20
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: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/050795s005lbl.pdf
Fitzgerald Health Education Associates, LLC 23
Taking Medications with Food: Is this simply to avoid stomach upset?
Examples Medications Labeled to Take with Food
• 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
• To enhance drug absorption– Nitrofurantoin (Macrodantin®, Macrobid®)
• 200−400% increase in drug absorbed due to delayed emptying, increased time to dissolve
– Sertraline (Zoloft®)• ~33% increase in dose absorbed when taken
with food– Source: http://www.globalrph.com/drugfoodrxn.htm
Examples Medications Labeled to Take with Food
(continued)
26Fitzgerald Health Education Associates, LLC
• 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: http://www.globalrph.com/drugfoodrxn.htm
Fitzgerald Health Education Associates, LLC 27
Examples Medications Labeled to Take with Food
(continued)
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 http://www.medscape.com/viewarticle/498270, http://www.medscape.com/viewarticle/585397_9
Fitzgerald Health Education Associates, LLC 28
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 29
• 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
Medications Given with Enteral Feedings
(continued)
With drug-drug interactions, what drugs are most worrisome?
• Narrow therapeutic index (NTI) vs. wide therapeutic index (WTI) medications
– Source: http://www.ncbop.org/faqs/Pharmacist/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
Fitzgerald Health Education Associates, LLC 32
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 33
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 10−80 mg• Atorvastatin 10−80 mg
– No requirement for periodic drug monitoring of the medication
Fitzgerald Health Education Associates, LLC 36
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 37
Biotransformation
• 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.
Fitzgerald Health Education Associates, LLC 38
Lipophilic vs. Hydrophilic
• 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 39
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.
Fitzgerald Health Education Associates, LLC 40
Biotransformation Sites via CYP450
• Liver• Kidney• Placenta• Lung• Plasma• Intestinal mucosa
Fitzgerald Health Education Associates, LLC 41
Cytochromes P450 (CYP)
• Important to drug metabolism– CYP1A2– CYP2C9– CYP2C19– CYP2D6– CYP2E1– CYP3A4
• A source of pharmacokinetic DI
Fitzgerald Health Education Associates, LLC 42
Michalets EL. Pharmacotherapy. 1998;18:84-112. Katzung, 2014.
Proportion of Medications Metabolized by Select CYP450 Isoenzymes
Fitzgerald Health Education Associates, LLC 43
CYP3A4
CYP2D6
CYP1A2
CYP2C9/19 47%
25%
15%
13%
CYP450 Drug-metabolizing Isoenzymes: A Potential Source of Drug-drug Interactions
Fitzgerald Health Education Associates, LLC 45
MedicationsParent Drug to Metabolite
• Amitriptyline ---> nortriptyline • Codeine ---> morphine • Primidone ---> phenobarbital• Valacyclovir ---> acyclovir
Fitzgerald Health Education Associates, LLC 46
Clopidogrel Activation
Fitzgerald Health Education Associates, LLC 47
CYP450 Drug-metabolizing Isoenzymes: A Potential Source of Drug-drug Interactions
SubstrateUtilizes a specific
enzymatic pathway.
CYP450 3A4 substrates: Sildenafil (Viagra®), atorvastatin, simvastatin, venlafaxine (Effexor®), alprazolam (Xanax®), many others About 50% of all prescription medications are CYP450 3A4 substrates
Inhibitor
Blocks a specific enzymatic pathway, keeps substrate from exiting.
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 substrate-induced toxicity
Inducer
Pushes the substrate out the exit pathway.
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 failureMedications of particular concern include select antiretrovirals, oral contraceptives, and cyclosporine
Fitzgerald Health Education Associates, LLC 48
CYP450 3A4 substrates: Sildenafil (Viagra®), atorvastatin, simvastatin, venlafaxine (Effexor®), alprazolam (Xanax®), many others About 50% of all prescription medications are CYP450 3A4 substrates
48 Fitzgerald Health Education Associates, LLC 49
CYP450 Drug-metabolizing Isoenzymes: A Potential Source of Drug-drug Interactions
Substrate
Utilizes a specific enzymatic pathway.
CYP450 3A4 substrates: Sildenafil (Viagra®), atorvastatin, simvastatin, venlafaxine (Effexor®), alprazolam (Xanax®), many others About 50% of all prescription medications are CYP450 3A4 substrates
InhibitorBlocks a specific
enzymatic pathway, keeps substrate
from exiting.
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 substrate-induced toxicity
Inducer
Pushes the substrate out the exit pathway.
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 failureMedications of particular concern include select antiretrovirals, oral contraceptives, and cyclosporine
Fitzgerald Health Education Associates, LLC 50
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 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 http://medicine.iupui.edu/clinpharm/ddis/clinicalTable.aspx
Fitzgerald Health Education Associates, LLC 51
Fitzgerald Health Education Associates, LLC 52
Caution: DI of Select Statins and Clarithromycin
• “Clarithromycin significantly (p <0.001) increased the AUC and Cmaxof 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) 94:1140-6.
What about statin choices if one of aforementioned meds is needed?
CYP450 Substrates
• CYP450 3A4– Atorvastatin– Lovastatin– Simvastatin
• CYP450 2C9– Pitavastatin– Rosuvastatin
• Not metabolized by CYP450 – Pravastatin
Fitzgerald Health Education Associates, LLC 54
CYP1A2
• 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 (0.95−1.18 L) of coffee/d • Caffeine=CYP1A2 substrate
Fitzgerald Health Education Associates, LLC 55
Fitzgerald Health Education Associates, LLC 56
CYP450 Drug-metabolizing Isoenzymes: A Potential Source of Drug-drug Interactions
Substrate
Utilizes a specific enzymatic pathway.
CYP450 3A4 substrates: Sildenafil (Viagra®), atorvastatin, simvastatin, venlafaxine (Effexor®), alprazolam (Xanax®), many others About 50% of all prescription medications are CYP450 3A4 substrates
Inhibitor
Blocks a specific enzymatic pathway, keeps substrate from
exiting.
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 substrate-induced toxicity
InducerPushes the
substrate out the exit pathway.
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 failureMedications of particular concern include select antiretrovirals, oral contraceptives, and cyclosporine
Fitzgerald Health Education Associates, LLC 57
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 failureMedications of particular concern include select antiretrovirals, combined oral contraceptives, and cyclosporine
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
http://medicine.iupui.edu/clinpharm/ddis/main-table
Fitzgerald Health Education Associates, LLC 58
“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 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.
Fitzgerald Health Education Associates, LLC 60
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 62
35-year-old with Genetically-based Coagulopathy
• Goal INR– 2.5-3.5, 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.
Fitzgerald Health Education Associates, LLC 63
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 64
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.”
– Source-http://naturaldatabase.therapeuticresearch.com/nd/Search.aspx?cs=PEERREVIEW&s=ND&pt=100&id=947&fs=PRL&searchid=56572678
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 2‒2.5 grams in a week resulted in an increase in international normalized ratio (INR).”
• Source-http://naturaldatabase.therapeuticresearch.com/nd/Search.aspx?cs=PEERREVIEW&s=ND&pt=100&id=947&fs=PRL&searchid=56572678
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
Fitzgerald Health Education Associates, LLC 67
• Does the “no statin with grapefruit juice” warning extend to all in the class?
Fitzgerald Health Education Associates, LLC 68
Simvastatin: When Compared to Ingestion with Water as Control
• With grapefruit juice– Cmax and AUC increased 12.0-fold
(P<0.001) and 13.5-fold (P<0.001)
• 24 hours after last grapefruit juice– Cmax 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: http://cat.inist.fr/?aModele=afficheN&cpsidt=795058
Fitzgerald Health Education Associates, LLC 69
CYP450 Substrates
• CYP450 3A4– Atorvastatin– Lovastatin– Simvastatin
• CYP450 2C9– Pitavastatin– Rosuvastatin
• Not metabolized by CYP450 – Pravastatin
Fitzgerald Health Education Associates, LLC 70
Statin vs. StatinLDL Lowering at Various Doses
(www.prescribersletter.com)
LovaMevacor®
20 mg=29% 40 mg=31% 80 mg=48%
PravaPravachol®
10 mg=19% 20 mg=29% 40 mg=34% 80 mg=48%
SimvaZocor®
10 mg=28% 20 mg=35% 40 mg=40% 80 mg=48%
FluvaLescol®
20 mg=17% 40 mg=23% 80 mg=33%
AtorvaLipitor®
10 mg=38% 20 mg=46% 40 mg=51% 80 mg=54%
RosuvaCrestor®
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– http://medicine.iupui.edu/clinpharm/ddis/clinic
al-table/● AZCert’s website on drugs that potentially
prolong the QT interval – http://crediblemeds.org/everyone/composite-
list-all-qtdrugs/?rf=US
Fitzgerald Health Education Associates, LLC 72
Conclusions
• Polypharmacy is a reality. • Avoid drug interactions and you
will avoid problems for you and your patients.
Fitzgerald Health Education Associates, LLC 73 Fitzgerald Health Education Associates, LLC 74
End of Presentation
Thank you for your time and attention.
fhea.com [email protected]
Fitzgerald Health Education Associates, LLC 75
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 76
Copyright Notice
Copyright by Fitzgerald Health Education Associates, LLCAll 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, LLC85 Flagship Drive
North Andover, MA 01845-6184
Fitzgerald Health Education Associates, LLC 77
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 78
Fitzgerald Health Education Associates, LLC
85 Flagship Drive
North Andover, MA 01845-6154978.794.8366 Fax-978.794.2455
Website: fhea.com
Learning & Testing Center: fhea.com/npexpert
www.facebook.com/fitzgeraldhealth
@npcert
Fitzgerald Health Education Associates, LLC 79