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Lew,A.,Crass,R.,& Eschenauer,G.(2020).Evolutionofequationsforestimatingrenalfunctionandtheirapplicationtothedosingofnew
antimicrobials.AnnalsofPharmacotherapy,54(5),496–503.
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information/professionals/clinical-tools-patient-management/kidney-disease/laboratory-evaluation/glomerular-filtration-rate-calculators.
AccessedJanuary13,2020.
Spruill,W., Wade, W.,DiPiro,J. T., etal. (2014). Concepts in clinical pharmacokinetics, 6th ed. Bethesda, MD:American Society of
Health-SystemPharmacists.
3
ImpactofDrugInteractionsandAdverseEventson
Therapeutics
TepM.Kang
LearningObjective
1. Able toidentifyfactorsknowntocausedrug–druginteractions,drug–foodinteractions,anddrug–
herbinteractions.
2.Describeselecteddrug–druginteractions,drug–foodinteractions,anddrug–herbinteractions.
3.Recognizeriskfactorsassociatedwithadversedrugreactions.
INTRODUCTION
Asthequantityandtypesofpharmacologicagentscontinuetoexpand,thelikelihoodofdruginteractions
and adverse reactions increases. Currently, more than 8,000 drugs are available to treat various
conditions. Each agent is designed to alter the homeostasis of the human body to some degree, and
individualresponsestotheseagentscanbeunpredictable.
In a prospective study, Benard-Laribiere et al. (2014) found that 3.6% (97/2,692) of hospital
admissions were due to serious adverse drug reactions (ADRs). Thirty percent of which were
preventableand16.5%ofwhichwerepotentiallypreventable.Druginteractionscaused29.9%ofADRrelatedhospitaladmissions.AccordingtotheInstituteforSafeMedicinePractices(QuarterWatch,2014),
psychiatricadversedrugevents,notablysuicidalbehaviors,representthemajoradverseeffectsreported
inchildrenunder age18. Inameta-analysis ofobservational studies, Martinsetal. (2014)reporteda
21.3% incidence of adverse drug events among adult inpatients. These data were captured during
prospective monitoring whereby the events are detected during the hospital stay and can include
interviewsofthepatientand/orcareteamandreviewsofclinicalandlaboratoryrecords.
ADRspresentanalarmingproblemthatwarrants significantattentionfromhealthcarepractitioners.
ADRs notonly affect morbidityandmortality butalso dramatically increase health care costs. In the
UnitedStates,theimpactofADRsmaycostupto$30.1billionperyear.Mostofthecostisattributedto
increased hospitalization, increased length of stay, and increased cost of performing additional tests
(Sultanaetal.,2013).
Similarly,druginteractionsarepotentiallypreventableADRsposingasignificantproblemtothehealth
care community. Ithas beenreportedthatapproximately10%to 20% ofhospital admissions are drug
related and about 1% of these are secondary to drug interactions. Others have reported that drug
interactionsareresponsibleforupto3%ofhospitaladmissions(Bjerrumetal.,2008).Inaddition,the
prevalenceofafirstdispensingofdrug–druginteractionsinpeopleolderthanage70hasbeenreportedto
have increased from 10.5% in 1992 to 19.2% in 2005 (Becker et al., 2008). Therefore, a thorough
understandingofhowdrug–druginteractionsoccurandhowtheyrelatetoADRsshouldhelpdecreasethe
rateofoccurrenceandtheassociatedmorbidity/mortality.Thischapterdiscussesthemechanismsofdrug
interactions and their potential consequences. For the purpose of this chapter, these interactions are
brokendownintofourmajorcategories:drug–druginteractions,drug–foodinteractions,complementary
alternative medicine (CAM) interactions, and drug–disease interactions. Each of the interaction
categories can affect the drug’s pharmacokinetic or pharmacodynamic profile. The definition,
identification,andmanagementofADRsarediscussedattheendofthechapter.
DRUG–DRUGINTERACTIONS
Whenapersontakestwoormoremedicationsconcomitantly,thepotentialexistsforoneormoredrugsto
changetheeffectofotherdrugs.Thedrugwhoseeffectisalteredbyanotherdrugistermedtheobjector
targetdrug.Althoughminorinteractionsbetweendrugsprobablyoccurfrequently,theseinteractionsmay
notbesignificantenoughtoaltertheeffectofeitherdrug.However,itisimportantforthepractitionerto
understand the mechanisms behind these interactions to predict more accurately when clinically
significant(andpotentiallyfatal)druginteractionsmayoccur.
PharmacokineticInteractions
Absorption
Becausemostmedicationsintheambulatorycaresettingareadministeredorally,thisrouteisthefocusof
discussion.Foradrugtoexertitseffect,itmustreachitssiteofaction.Normally,thisrequiresaccessto
thebloodstream.AsdiscussedinChapter2,drugsadministeredorallymustbeabsorbedintotheportal
vein,throughtheintestinalwall, toreachthesystemiccirculation.Theoraltabletmustdissolve inthe
gastrointestinal(GI)tractbeforeitcanpenetratetheintestinalwall.
Acidity(pH)
Forsomedrugs,thisprocessdependsontheacidityintheGItract.Therefore,ifadrugthatalters the
gastricpHisadministeredconcomitantlywithadrugthatdependsonanormalgastricpHfordissolution,
theabsorptionofthetargetdrugwillbeaffected.Anexampleofthistypeofinteractionistheconcurrent
administrationofahistamine-2(H2)receptorantagonist(e.g.,famotidine)andketoconazole,animidazole
antifungal agent. Ketoconazole is the target drug that requires an acidic pH for absorption. When
famotidineisadministeredalongwithketoconazole,theincreaseingastricpHhindersthedissolutionof
ketoconazole and therefore decreases its absorption. Similarly, this change in pH can increase the
absorptionofotherdrugsthatrequireamorealkalineenvironmentforabsorption.
Adsorption
Anothermechanismofdrug–druginteractionsisadsorption.Adsorptionoccurswhenoneagentbindsthe
othertoitssurfacetoformacomplex.Themostcommonagentsassociatedwiththistypeofinteraction
aredivalentandtrivalentcations(Mg2+,Ca2+,Al3+,foundinantacidsandsomevitaminpreparations)
andanionic-bindingresins(colestipolandcholestyramine).Thistypeofinteractionoccurswhencertain
medications such as tetracyclines or fluoroquinolones are given with antacids. The metal ions in the
antacid chelateforma complexwiththeantibiotic, preventingabsorptionofbothcomponents(ionand
antibiotic). Adsorbents can interact with a variety of drugs; therefore, appropriate intervals between
doses of the interacting medications are warranted. In general, with agents known to interact in this
manner,thetargetdrugshouldbeadministeredatleast2hoursbeforeor4to6hoursaftertheinteracting
agent.
GastrointestinalMotilityandRateofAbsorption
DrugsthataffectthemotilityoftheGItractproducealesscommonabsorption-alteringmechanism.These
agentstendtoaffecttherateofabsorptionandnottheamountofdrugabsorbed.Anyagent—forexample,
metoclopramide—that stimulates peristalsis and increases gastric-emptying time can affect the rate of
absorptionofothermedications.Inmostcases,anincreaseintherateofabsorptionoccursbecausethe
targetdrugreachestheduodenumfaster,allowingabsorptiontooccursooner.However,insomecases
suchaswith metoclopramide and digoxin,a decrease indigoxin concentrations may occur (American
SocietyofHealth-SystemPharmacists,2008).
Conversely,anticholinergicagentsandopiatesdecreasegastricmotility,therebydecreasingtherateof
absorption of target drugs. However, this interaction is usually clinically insignificant since the total
amountofdrugabsorbedisnotaffected.
GastrointestinalFloraandAbsorption
ThebacteriapresentintheGItractarealsoresponsibleforaportionofthemetabolismofsomeagents.
An example of this is digoxin; concomitant administration with antibiotics (such as erythromycin or
tetracycline) may alter the normal bacterial flora and reduce digoxin metabolism, thereby increasing
bioavailability and serum concentrations in some patients (Susla, 2005). To the contrary, GI bacteria
produce enzymes that de-conjugate inactive unabsorbable ethinyl estradiol metabolites of oral
contraceptivesthathavebeenexcretedintotheGItractviathebile.De-conjugationallowsreabsorption
of active ethinyl estradiol back into the bloodstream. By disrupting the GI flora, anti-infectives may
decreaseoreliminatereabsorptionofactiveethinylestradiol,therebydecreasingplasmaconcentrations
andthe effectivenessoforal contraceptives (Weaver& Glasier,1999). However,in a case-crossover
studyof1,330failurecases,Tohetal.(2011)didnotfindanassociationbetweenconcomitantantibiotic
useandtheriskofbreakthroughpregnancyamongcombinedoralcontraceptiveusers.
Table3.1summarizessomeofthemajordruginteractionsthatoccurintheabsorptiveprocess.
Distribution
Afterdrugsareabsorbedintothebloodstream,mostofthem,tosomedegree,areboundtoplasmaprotein
suchasalbuminorα1-acidglycoprotein.Acompilationof222drugsforvariousindicationsshowedthat
about50%ofthemare90%ormoreproteinbound.AsdescribedinChapter2,onlyanunbounddrugis
freetointeractwithitstargetreceptorsiteandisthereforeactive.Thepercentageofdrugthatbindsto
plasmaproteinsdependsontheaffinityofthatdrugfortheprotein-bindingsite.Iftwodrugswithhigh
affinityforcirculatingproteinsareadministeredtogether,theymaycompeteforasinglebindingsiteon
theprotein.Infact,onedrugmaydisplacetheotherfromthebindingsitewiththeresultbeinganincrease
intheunbound(free)fractionofthedisplaceddrug.Thisincreaseinfreedrugmaytriggeranexaggerated
pharmacodynamicresponseortoxicreaction.However,becausetheexcessunbounddrugisnowsubject
toeliminationprocesses, theincreases inbothfree drugfraction andtheeffectsproduced are usually
transient.
TABLE3.1
DrugAbsorptionInteractions
GI,gastrointestinal.
TABLE3.2
Protein-BoundDrugInteractions
DisplacingDrug TargetDrug
Aspirin Meclofenamate,tolmetin
Salicylates Methotrexate
TMP-SMZ
Sulfaphenazole Phenytoin
Tolbutamide
Valproicacid
Halofenate Sulfonylureas
Quinidine Digoxin
Aspirin Warfarin
Chloralhydrate
Diazoxide
Etodolac
Fenoprofen
Lovastatin
Nalidixicacid
Phenylbutazone
Phenytoin
Sulfinpyrazone
TMP-SMZ,trimethoprim-sulfamethoxazole.
Clinicallysignificantdrugdisplacement interactions normallyoccur only whendrugsare more than
90%proteinboundandhaveanarrowtherapeuticindex.Forexample,warfarinis 99%proteinbound,
andtherefore, only1% ofthe druginthebloodstreamis free to induce a pharmacodynamic response
(inhibitionofclottingfactors).Ifaseconddrugis administeredthatdisplaceseven1% ofthewarfarin
bound toalbumin, theamount offree warfarinis doubled, to2%free. This can resultin a significant
increase in its pharmacodynamic action, leading to excessive bleeding. Table 3.2 lists examples of
severaldisplacementinteractions.
Metabolism
Lipophilicity (fat solubility) enables drug molecules to be absorbed and reach their site of action.
However,lipophilicdrugsaredifficultforthebodytoexcrete.Therefore,theymustbetransformedbythe
bodytomorehydrophilic(water-soluble)molecules.ThisisaccomplishedprimarilythroughphaseI,or
oxidation, reactions. The main sites of metabolism in the body are the liver (hepatocytes) and small
intestine (enterocytes). Other tissues, such as the kidneys, lungs, and brain, play a minor role in the
metabolism of drug molecules (Michalets, 1998). These sites of metabolism contain enzymes called
cytochrome P-450 isoenzymes. This group of isoenzymes has been identified as the major catalyst of
phaseImetabolicreactionsinhumans.
The nomenclature of the cytochrome P-450 system classifies the isoenzymes (designated CYP)
according to family (>36% homology in amino acid sequence), subfamily (77% homology), and
individual gene (Brosen, 1990; Guengerich, 1994; Nebert et al., 1987). For example, the isoenzyme
CYP3A4belongs tofamily3, subfamilyA, andgene4. Asonemovesdowntheclassificationsystem
fromfamilytogene,thestructuresoftheisoenzymesbecomemoresimilar.
Thisenzymesystemhasevolvedtoformnewisoenzymesthatmetabolizeforeignsubstrates(i.e.,drugs)
thatarepresentedtothebody.Theseenzymesarestructuredtorecognizeandbindtomolecularentitieson
substrates.Manydifferentsubstratesmayhavemolecularstructuresthatdifferonlyslightly;therefore,an
isoenzymecanbindtoanyoneofthesesubstrates.Althoughseveraldifferentsubstratesmaycompetefor
thesameenzymereceptor,thesubstratewiththehighestaffinitybindsmostoften.Theconverseofthisis
alsotrue.Twoisoenzymescanbindtothesamesubstrate(Figure3.1),butthesubstratebindsmoreoften
totheisoenzymetowhichithasthemostaffinity.However,noteverydrugmolecule(“substrate”)canbe
metabolizedbyeveryenzymewithwhichitbinds;therefore,itisnotatruesubstrate.Theseconceptsform
thebackboneforthedruginteractionsthatareexpandedonlater.
Five isoenzymes have been determined to be responsible for most metabolism-related drug
interactions.TheyaretheisoformsCYP1A2,CYP2C9,CYP2C19,CYP2D6,andCYP3A4.TheCYP3A4
isoform is responsible for 40% to 45% of drug metabolism, the CYP2D6 for the next 20% to 30%,
CYP2C9about10%,andCYP1A2responsibleforabout5%(Ingelman-Sundberg,2004).Theremaining
5%to20%isaccountedforbyseverallesserimportantisoforms.Becausetherearesofewenzymesthat
transformamultitudeofsubstrates,itiseasytoseehowtherewouldbeagreatpotentialforinteractions.
FIGURE 3–1 Substrate binding. A, Different substrates. Although Enzyme X (Ex) can bind to both
Substrate1(S1)andSubstrate2(S2),S2hasgreateraffinityforExthanS1.Therefore,Exwillbindto
S2 most often.B, Different enzymes. Although Substrate X (Sx) can bind to both Enzyme 1 (E1) and
Enzyme2(E2),E1hasagreateraffinityforSxthanE2.Therefore,SxwillbindtoE1mostoften.
Therearesomegeneticvariationswithrespecttothedistributionoftheenzymes.Forexample,about
10% ofEuropeanslacktheCYP2D6enzymeandarethereforeconsidered poor metabolizers ofdrugs
usingthispathwayforbiotransformation.TheseindividualsareatgreaterriskforADRsrelatedtodrugs
metabolized by CYP2D6. In addition, prodrugs requiring this enzyme for activation (e.g., codeine,
tamoxifen)maybelesseffectiveorhavenoeffect.Incontrast,about5%ofthispopulationareconsidered
ultrametabolizers, have too rapid metabolism, and may show little to no response related to drugs
metabolizedbytheCYP2D6pathway(Ingelman-Sundberg,2004).Similarly, thereis variabilitywithin
the CYP2C19 isoform, with about 14% of Chinese, 2% of Whites, and 4% of Blacks being poor
metabolizers (Scottet al., 2011).Theeffectivenessofcertain prodrugs (e.g., clopidogrel)that require
metabolicactivationbythisenzymesystemmaybereduced(Holmesetal.,2010).Formoreinformation
onthecytochromeP-450enzymes,refertoChapter7onPharmacogenomics.
TherehasbeenincreasinginterestingenetictestingtoidentifystrategiestoreducetheriskofADRs
andtooptimizetherapyforindividuals.Pharmacogenomicinformationhasbeenincorporatedintoabout
10% of labels for drugs approved by the U.S. Food and Drug Administration (FDA) in an effort to
identify responders and nonresponders, avoid toxicity, and adjust doses of medications to optimize
efficacyandensuresafety(FDA,2015).Inaddition,regulatoryauthoritieshaverecentlyrecommended
genetictestingtoaidtheclinicianindeterminingifanagentissafeandeffectiveincertainindividuals
(e.g., abacavir) (Highlights of Prescribing Information: Ziagen [abacavir sulfate] Tablets and Oral
SolutionaccessedJuly16, 2015). While commercial assaysareavailable forgenetictesting,thereare
somelimitations.Thesearevariableturnaroundtimefortheresults,andhighcostandthereliabilityand
reproducibility of data on the validation of techniques used are limited. Currently, there is limited
evidence-based datatodevelopspecific recommendationsontherole ofgenetictestinginroutinecare
(Holmesetal.,2010).
There aretwo types ofmetabolicdruginteractions: drugs thatinhibit theactivity ofanenzymeand
thosethatinducetheactivityoftheenzyme.
Inhibition
Inhibitionofdrugmetabolismoccursthroughcompetitiveandnoncompetitiveinhibition.Whentwodrugs,
administered concurrently, are metabolized by the same isoenzyme, they are defined as competitive
inhibitors of each other. In essence, they compete for the same binding site on an enzyme to be
metabolized.
Noncompetitiveinhibitionalsooccurswhenbothdrugscompeteforthesamebindingsite,butonedrug
ismetabolizedbythatisoenzymeandtheotherdrugisnot.Thebestknownexampleofanoncompetitive
inhibitor is quinidine. Quinidine is metabolized by the CYP3A4 isoenzyme but can also bind to the
CYP2D6 enzyme. Therefore, although quinidine does not compete for metabolism by the CYP2D6
isoenzyme,itdoescompetefortheCYP2D6isoenzyme–bindingsite.
Inbothcompetitiveandnoncompetitiveinhibition,thedrugwiththegreatestaffinityfortheisoenzyme
receptorisusuallytheinhibitingdrugbecauseitbindsinthereceptorsite,preventingtheotherdrugfrom
beingboundandmetabolized(Figure 3.2). Thesignificanceofthedruginteractiondependsonseveral
characteristicsoftheinhibitingdrug.
FIGURE3–2Inhibition.A,Competitiveinhibition.DrugX(DXandDrugY(DY)arebothmetabolized
byEnzyme2(E2).B,Noncompetitiveinhibition.AlthoughDxandDYcompeteforthebindingsiteonE2,
onlyDYismetabolizedbyE2.Therefore,DxnoncompetitivelyinhibitsDY.
Affinity.Manydrugsmayinhibitthesameisoenzymebutnottothesameextent.Thegreatertheaffinityof
aninhibitingdrugforanenzyme,themoreitblocksbindingofotherdrugmolecules.
Half-Life. Along with affinity, the half-life (t½) of the inhibiting drug determines the duration of the
interaction. The longer the half-life of the inhibiting drug, the longer the drug interaction lasts. For
example,afteraregimenofketoconazole(t½=8hours)isdiscontinued,itsabilitytoinhibittheCYP3A4
enzyme lasts until it is eliminated, in three to five half-lives or approximately 1 day. However, the
inhibitingeffectofamiodarone,withat½ofapproximately53days,lastsforweekstomonthsafterits
discontinuation.
Concentration.Thethirdmajor factorcontributingtoa drug’sabilitytoinhibithepaticenzymesis the
concentrationoftheinhibitingdrug.Athresholdconcentrationmustbereachedorexceededtoinhibitan
enzyme. This is similar to the threshold concentration discussed in Chapter 2 regarding minimally
effectiveconcentrationsandtherapeutic responses.Thisminimallyeffectivethresholdconcentration,or
concentration-dependent inhibition, is exhibited by a variety of drugs. The dose yielding this
concentration-dependentinhibitionvariesbasedonvolumeofdistribution,drugandreceptoraffinity,and
characteristics oftheindividualpatient.Anexampleofa dose-or concentration-dependentinhibitor is
cimetidine.Inmostpatients, a doseof 400 mg/d results inonlyweakenzymeinhibition. However, at
higherdoses,itinteractssignificantlywithboththeCYP2D6andCYP1A2isoenzymes(Shinn,1992).
Someenzymeinhibitorsmayaffectoneenzymeatasmallerconcentrationandmorethanoneisoenzyme
at higher concentrations. These enzyme inhibitors demonstrate that some isoenzymes have differing
thresholds. For example, fluconazole at a dose of 200 mg/d significantly inhibits only the CYP2C9
isoenzyme,butasthedoseincreasesabove400mg/d,italsoinhibitstheCYP3A4isoenzyme(Hansten&
Horn,2015).
ToxicPotential.Anotherconsiderationwithregardtoinhibitioninteractionsisthetoxicpotentialofthe
targetdrug.Forexample,statinslikesimvastatinaremetabolizedbytheCYP3A4isoenzyme.Ifapotent
CYP3A4 inhibitor (e.g., ketoconazole) is administered concurrently with simvastatin, simvastatin
accumulates in the body. This interaction could cause myopathy (muscle pain) as well as rare
rhabdomyolysis(breakdownofskeletalmuscles)leadingtokidneydamage.Itisimportanttomonitorfor
anysignsofnewonsetmusclepainwhenpatientsareinitiatedonstatins(Watkinsetal.,2011).
AnotherexampleoftoxicpotentialofCYPinhibitionistheinteractionbetweenwarfarin(Coumadin)
andtrimethoprim-sulfamethoxazole(TMP-SMZ).Warfarinlevelsaremeasuredusingasurrogatemarker
calledinternationalnormalizedratio(INR)fortherapeuticdruglevelmonitoringonaregularbias.The
CYP2C9enzymemetabolizeswarfarinbutis inhibitedbyTMP-SMZ.Thisinhibitionwill increasethe
concentrationofwarfarinandputpatientsatanincreasedriskofbleedingduetoasupratherapeuticINR
(Hale&Lesar,2014).
Efficacy.Anadditionalconsiderationrelatedtoinhibitioninteractionsistheeffectivenessofthetarget
drug.ThisisparticularlyimportantforprodrugsthatrequirecytochromeP-450metabolismtotheactive
metaboliteinorderforthedrugtobeeffective.Anexampleofthisisclopidogrel,anantiplateletagent,
which requires CYP2C19 enzymes to be metabolized to the active form. When administered with
omeprazole, a CYP2C19 inhibitor, a reduction in plasma concentrations of the active metabolite of
clopidogrel as well as reducedplatelet functionoccurs (Clopidogrel [Plavix]prescribing information,
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