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Presented by:Vanessa Pomarico-Denino,
EdD, FNP-BC, FAANPFaculty
Fitzgerald Health Education Associates,North Andover, MA
Northeast Medical Group (NEMG) APRNAdjunct faculty for Southern
CT State University
and Quinnipiac University
Developed by:Margaret A. Fitzgerald,
DNP, FNP-BC, NP-C, FAANP, CSP, FAAN, DCC, FNAPPresident,
Fitzgerald Health Education Associates, North Andover, MA
Dangerous Liaisons: Drug-drug, drug-nutrient interactions
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 2
• Having completed the learning activities, the participant will
be able to:– Identify mechanisms of common drug-
drug, drug-nutrient interactions. – Describe commonly
encountered and
potentially hazardous drug-drug, drug-nutrient interactions.
– Develop strategies to avoid the above-mentioned
interactions.
Fitzgerald Health Education Associates 3
Objectives
ReferencesAdditional References Listed
at End of Presentation
Fitzgerald Health Education Associates 4
• …think about when considering drug interactions?
Fitzgerald Health Education Associates 5
Is this what you…
• Drug-drug• Drug-food• Drug-herb• Drug-disease
Fitzgerald Health Education Associates 6
How do drug interactions occur?
Dangerous Liaisons: Drug-drug, drug-nutrient interactions
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Reproduction is prohibited. Prior permission required for use of
questions or course content.
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• Study of biochemical and physiological effects of drugs– What
the drug
does to the body and/or disease
Fitzgerald Health Education Associates 7
Pharmacodynamics (PD)
• The pharmacodynamic profile of a medication is unchanged over
the lifespan.
Fitzgerald Health Education Associates 8
Pharmacodynamics True or false?
• What the body does to the drug• Includes
– Absorption– Distribution– Biotransformation (metabolism)–
Excretion of drugs
Fitzgerald Health Education Associates 9
Pharmacokinetics (PK)
• Age and gender significantly impact a medication’s
pharmacokinetics.
Fitzgerald Health Education Associates 10
PharmacokineticsTrue or false?
• 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 11
Case Example ofPD Drug Interaction
What is the etiology of the problem?
Receptor site blockage (propranalol, β2 blocker) prevents
receptor site activation (albuterol, β2 agonist).
Fitzgerald Health Education Associates 12
Dangerous Liaisons: Drug-drug, drug-nutrient interactions
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• Ipratropium bromide (Atrovent®)• Short-acting muscarinic
antagonists (SAMA)
– Acts at cholinergic receptor sites– Onset of action=1 h–
Duration of action=4−6 h
Fitzgerald Health Education Associates 13
Bronchodilator in β2-blockade: Use different receptor sites
True or false?
When propranolol is discontinued, within 3−5 drug half-lives,
albuterol use will once again
provide bronchodilator effect.
Fitzgerald Health Education Associates 14
• 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 15
Chemical/Pharmacokinetic DIIron Ingestion and
Levothyroxine Therapy
Source: Campbell NR, et al. Ann Intern Med.
1992;117:1010-1013.
Ferrous sulfate effect on TSH levels in patients with
hypothyroidism
P
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• 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 19
Chemical/Pharmacokinetic DI
Fitzgerald Health Education Associates 20
• 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: https://www.drugs.com/pro/cipro.html
Inactivation of AntimicrobialEffect via Chelation
True or false?
The warning about drug interaction potential when taken with
metals and
cations extends to all antimicrobials with the -floxacin
suffix.
Fitzgerald Health Education Associates 21
• 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:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/050795s005lbl.pdf
Fitzgerald Health Education Associates 22
Are other antimicrobials similarly impacted?
Taking Medications with Food: Is this simply to avoid stomach
upset?
Fitzgerald Health Education Associates 23 Fitzgerald Health
Education Associates 24
• 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
Examples Medications Labeled to Take with Food
Dangerous Liaisons: Drug-drug, drug-nutrient interactions
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Examples Medications Labeled to Take with Food
(continued)
• 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:
https://globalrph.com/drugs/drug-food-interactions/
Fitzgerald Health Education Associates 25
• 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:
https://globalrph.com/drugs/drug-food-interactions/
Examples Medications Labeled to Take with Food
(continued)
Fitzgerald Health Education Associates 26
Fitzgerald Health Education Associates 27
• 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
Drug-food Interactions Potential for Decreased Drug
Absorption
• 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 28
Medications Given with Enteral Feedings
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 29
Drug-disease Interaction
Fitzgerald Health Education Associates 30
Dangerous Liaisons: Drug-drug, drug-nutrient interactions
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• Altered (decreased) liver function – Varied impact on drug
biotransformation
• Increased levels– If drug needs to be hepatically
biotransformed in
order to be renally eliminated– Examples– Opiates, opioids,
benzodiazepines,
NSAIDs, diuretics– No particular hepatic marker to advise on
this
issue as there is in renal disease (GFR)
Fitzgerald Health Education Associates 31
Drug-disease Interaction Drug-disease Interaction
(continued)
• Altered (decreased) liver function (cont.) – Varied impact on
drug biotransformation
(cont.)• Suppressed levels
– If drug is taken in as inactive prodrug and cannot be
biotransformed to active medication
– Examples– Codeine, enalapril» Source:
https://www.ncbi.nlm.nih.gov/pubmed/15924505
Fitzgerald Health Education Associates 32
• Renal disease– Renally eliminated
medications impacted with elevated level• Example–
Ciprofloxacin, levofloxacin but not moxifloxacin
– Depends on whether renal or fecal route of elimination
» Source: https://globalrph.com/drugs/renal-dosing-database/
Fitzgerald Health Education Associates 33
Drug-disease Interaction (continued)
Fitzgerald Health Education Associates 34
• Narrow therapeutic index (NTI) vs. wide therapeutic index
(WTI) medications
– Source:
http://www.ncbop.org/faqs/Pharmacist/faq_NTIDrugs.htm
With drug-drug interactions, what drugs are most worrisome?
What is a drug’s therapeutic index?
Fitzgerald Health Education Associates 35
• 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
Narrow Therapeutic Index(NTI) Medications
Defined: Any pharmaceutical which has a
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Fitzgerald Health Education Associates 37
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 38
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
• Hang on to these foreign substances?
• Get rid of the “invader” as quickly as possible?
Fitzgerald Health Education Associates 39
What does the body want to do to drugs?
Fitzgerald Health Education Associates 40
• 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.
Biotransformation
• 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 41
Lipophilic vs. Hydrophilic
• 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 42
CYP450 Drug Metabolism
Dangerous Liaisons: Drug-drug, drug-nutrient interactions
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• Liver• Kidney• Placenta• Lung• Plasma• Intestinal mucosa
Fitzgerald Health Education Associates 43
Biotransformation Sites via CYP450
• Important to drug metabolism– CYP1A2– CYP2C9– CYP2C19– CYP2D6–
CYP2E1– CYP3A4
• A source of pharmacokinetic DI
Fitzgerald Health Education Associates 44
Cytochromes P450 (CYP)
Source: Michalets EL. Pharmacotherapy. 1998;18:84-112. Katzung,
2014.
CYP3A4
CYP2D6
CYP1A2
CYP2C9/19 47%
25%
15%
13%
Fitzgerald Health Education Associates 45
Proportion of Medications Metabolized by Select CYP450
Isoenzymes
CYP450 Drug-metabolizing Isoenzymes: A potential source of
drug-drug interactions
Fitzgerald Health Education Associates 46
MedicationsParent Drug to Metabolite
• Amitriptyline ---> nortriptyline • Codeine ---> morphine
• Primidone ---> phenobarbital• Valacyclovir --->
acyclovir
Fitzgerald Health Education Associates 48
Dangerous Liaisons: Drug-drug, drug-nutrient interactions
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Clopidogrel Activation
Fitzgerald Health Education Associates 49
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
CYP450 3A4 substrates: Sildenafil (Viagra®), atorvastatin,
simvastatin, venlafaxine (Effexor®), alprazolam (Xanax®), many
others About 50% of all prescription medications are CYP450 3A4
substrates
Fitzgerald Health Education Associates 50
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
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
Fitzgerald Health Education Associates 52
Caution DI of Select Statins and Clarithromycin
• “Clarithromycin significantly (p
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What about statin choices if one of aforementioned meds is
needed?
Fitzgerald Health Education Associates 55
CYP450 Substrates
• CYP450 3A4– Atorvastatin– Lovastatin– Simvastatin
• CYP450 2C9– Pitavastatin– Rosuvastatin
• Not metabolized by CYP450 – Pravastatin
Fitzgerald Health Education Associates 56
Other than typical clinical indications, where might
rosuvastatin, pravastatin fit?
A person in need of statin therapy who is also on diltiazem (3A4
inhibitor)
A person who is a “heavy chronic” grapefruit juice drinker (3A4
inhibitor)
Fitzgerald Health Education Associates 57
• 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 58
CYP1A2
Alternate Antibiotics for UTI?
Per 2019 Sanford Guide Nitrofurantoin
CefdinirSee information later in program on
use of TMP-SMX in older adults.
Fitzgerald Health Education Associates 59
Dangerous Liaisons: Drug-drug, drug-nutrient interactions
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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
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
Fitzgerald Health Education Associates 61
• 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
https://drug-interactions.medicine.iu.edu/Main-Table.aspx
Fitzgerald Health Education Associates 62
CYP450 3A4 Inducer
Fitzgerald Health Education Associates 63
• ...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.
“But that St. John’s wort really works…”
Fitzgerald Health Education Associates 64
“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 66
• A cigarette smoker – Tobacco as a CYP450 1A2 inducer
• Takes theophylline– CYP450 1A2 substrate
• Cuts down on smoking due to a “bad cold”
• Feels jittery and nauseated
CYP450 1A2
Warfarin- Antibiotic Interaction
Fitzgerald Health Education Associates 67
Dangerous Liaisons: Drug-drug, drug-nutrient interactions
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True or False?
The primary mechanisms by which antibiotic medications interact
with warfarin to increase
the risk of major bleeding is through disruption of intestinal
flora that synthesize vitamin K.
Fitzgerald Health Education Associates 68
Place in rank order from highest to lowest impact on INR for PO
antibiotic
use with warfarin.
____ Itraconazole____ Cefpodoxime____ TMP-SMX____
Amoxicillin____ Levofloxacin ____ Azithromycin
Fitzgerald Health Education Associates 69
Concurrent Use of Warfarin and Antibiotics and the Risk of
Bleeding in Older Adults
Am J Med. 2012 Feb;125(2):183–9. doi:
10.1016/j.amjmed.2011.08.014
• Exposure to any antibiotic agent within 15 days of the
event/index date was associated with an increased risk of bleeding
(aOR 2.01; 95% CI, 1.62–2.50).
Fitzgerald Health Education Associates 70
Concurrent Use of Warfarin and Antibiotics and the Risk of
Bleeding in Older Adults
Am J Med. 2012 Feb;125(2):183–9. doi:
10.1016/j.amjmed.2011.08.014
(continued)
Fitzgerald Health Education Associates 71
• Azole antifungals [aOR, 4.57; 95% CI, 1.90–11.03]
•TMP-SMX [aOR, 2.70; 95% CI, 1.46–5.05]
•Cephalosporins [aOR, 2.45; 95% CI, 1.52–3.95]
Concurrent Use of Warfarin and Antibiotics and the Risk of
Bleeding in Older Adults
Am J Med. 2012 Feb;125(2):183–9. doi:
10.1016/j.amjmed.2011.08.014
(continued)
Fitzgerald Health Education Associates 72
• Penicillins [aOR, 1.92; 95% CI, 1.21–2.07]
•Macrolides [aOR, 1.86; 95% CI, 1.08–3.21]
•Quinolones [aOR, 1.69; 95% CI, 1.09–2.62]
Fitzgerald Health Education Associates 73
• Avoid concomitant use of a sulfa drug with warfarin,
particularly trimethoprim-sulfamethoxazole.
• If use of a sulfa-containing antibiotic is imperative, then
reduce warfarin dose by 50% during antibiotic administration and
for one week following completion of the antibiotic.
Warfarin-TMP-SMX InteractionPrevention and Intervention
Dangerous Liaisons: Drug-drug, drug-nutrient interactions
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• If trimethoprim-sulfamethoxazole therapy is required, then
monitor INR every other day for elevating trends.
– Source: http://www.medscape.com/viewarticle/567679_3
Fitzgerald Health Education Associates 74
Warfarin-TMP-SMX InteractionPrevention and Intervention
(continued)
Fitzgerald Health Education Associates 75
• TMP-SMX or metronidazole• If use cannot be avoided
– Consider empirically lowering the warfarin dose 25% to 40% for
duration of antimicrobial therapy in patients at high risk for
bleeding.
– Monitor INR every or every other day.– Source: PL
Detail-Document, Antimicrobial Drug Interactions and
Warfarin. Pharmacist’s Letter/Prescriber’s Letter. August
2012.
Advise on INR Monitoring During Warfarin Therapy
Fitzgerald Health Education Associates 76
●For other antimicrobials–Consider baseline INR when
starting,
particularly when history of INR instability–Recheck at 5 days,
earlier if
clinically indicated. ̶ Source: PL Detail-Document,
Antimicrobial Drug Interactions and
Warfarin. Pharmacist’s Letter/Prescriber’s Letter. August
2012.
Advise on INR Monitoring During Warfarin Therapy
(continued)
Avoid used w/ ACEI or ARB due to hyperkalemia risk.Vulnerable to
destruction by beta-lactamase
QT-prolongation risk
Use associated with tendon rupture risk, especially when used
with systemic corticosteroidLess than 1% cross-risk in PCN
allergy
Match the following antimicrobialswith listed
characteristics.
A. AmoxicillinB. TMP-SMX C. Azithromycin
D. CefpodoximeE. Moxifloxacin
Fitzgerald Health Education Associates 77
Fitzgerald Health Education Associates 78
• Polypharmacy is a reality. • Avoid drug interactions and
you
will avoid problems for you and your patients.
Conclusions
End of PresentationThank you for your time and attention.
Vanessa Pomarico-Denino, EdD, FNP-BC, FAANP
www.fhea.com [email protected]
Fitzgerald Health Education Associates 79
Dangerous Liaisons: Drug-drug, drug-nutrient interactions
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References
• Fitzgerald, M. Nurse Practitioner Examination and Practice
Preparation. 5th edition, Philadelphia: F. A. Davis, available at
fhea.com
• Stringer, J. (2017) Basic Concepts in Pharmacology: All you
need to know for each drug class. 5th edition, New York, NY:
McGraw-Hill.
Fitzgerald Health Education Associates 80
Resources
• Fitzgerald, M., et al., Adult-Gerontology Nurse Practitioner
Pharmacology Package, available at fhea.com
• Fitzgerald, M., Miller, S. Comprehensive Clinical Pharmacology
Course, available at fhea.com
Fitzgerald Health Education Associates 81
Resources(continued)
• Fitzgerald, M., et al., Family Nurse Practitioner Pharmacology
Package, available at fhea.com
• Fitzgerald, M., Laboratory Data Interpretation: A Case Study
Approach, available at fhea.com
Fitzgerald Health Education Associates 82
Resources(continued)
• Fitzgerald, M., Miller, S., Pathophysiology for Advanced
Practice Course, available at fhea.com
Fitzgerald Health Education Associates 83
• 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 84
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system, without permission
from Fitzgerald Health Education Associates
Requests for permission to make copies of any part of the work
should be mailed to:
Fitzgerald Health Education Associates85 Flagship Drive
North Andover, MA 01845-6184
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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 disclaims any
liability, loss, injury or damage incurred as a consequence,
directly or indirectly, of the use and application of any of the
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Learning & Testing Center: fhea.com/npexpert
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