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1997). Inaddition,tamoxifen,anagentusedfor breastcancer,is convertedtoitsactive metabolite by
CYP2D6. Women may have a higher risk of breast cancer recurrence if they take tamoxifen in
combinationwithCYP2D6inhibitorssuchastheserotoninreuptakeinhibitorsparoxetine,fluoxetine,or
sertraline(TheMedicalLetter,2009).
Not all inhibition reactions result in harmful effects; however, some interactions may be
inconsequential or even beneficial. For example, ketoconazole (a potent inhibitor of the CYP3A4
isoenzyme)canbegivenwithcyclosporine.Theconsequentinteractionenablespractitionerstogiveless
cyclosporinetoachievethesameimmunosuppressiveresponse(Hansten&Horn,2015).
The cytochromeP-450 system is complex,but an understanding of the basic conceptsof inhibitory
interactionsleadstotheabilitytoanticipatewhichagentsarelikelytointeract.Theaffinity,half-life,and
drugconcentrationdeterminethepotencyoftheinhibitingdrug.Apotentenzymeinhibitorinhibitsmost
drugs metabolized by that enzyme. A clinically significant drug interaction also depends on the toxic
potentialofthedrugbeinginhibited.Table3.3listsseveralenzymesandtheirinhibitors, inducers, and
substrates.
Induction
Drug–druginteractionscanalsoresultfromtheactionofonedrug(inducer)stimulatingthemetabolismof
atargetdrug(substrate).Thisenhancedmetabolism isthoughttobeproducedbyanincreaseinhepatic
bloodfloworanincreaseintheformationofhepaticenzymes.Thisprocess,knownasenzymeinduction,
increases the amount of enzymes available to metabolize drug molecules, thereby decreasing the
concentrationandpharmacodynamiceffectofthetargetdrug.
TABLE3.3
KeyDrug–DrugInteractionswithCytochromeP-450Enzymes
*Thesewillslowdownsubstratedrugmetabolismandincreasedrugeffect.
*Thesewillspeedupsubstratedrugmetabolismanddecreasedrugeffect.
Some common CYP enzyme inducers are rifampin, phenobarbital, phenytoin, and carbamazepine.
Enzyme induction, like enzymeinhibition, is substrate dependent. Therefore, any drug that is a potent
inducer of a cytochrome P-450 system increases the metabolism of most drugs metabolized by that
enzyme. Also, in a manner similar to that of enzyme inhibitors, inducers may affect more than one
cytochrome P-450 isoform; for example, rifampin is a potent inducer of the CYP3A4, CYP1A2, and
CYP2Cisoforms.
Some enzyme inducers, such as carbamazepine, also increase their own metabolism. Over time,
carbamazepinestimulatesitsownmetabolism,therebydecreasingitshalflifeandfrequentlyresultingin
an increased dose requirement to maintain the same therapeutic drug level. This process is termed
autoinduction.
Theonsetandduration/cessationofenzymeinductiondependonboththehalf-lifeoftheinducerandthe
halflife of the isoenzyme that is being stimulated. For example, rifampin (t½ = 3–4 hours) results in
enzymeinductionwithin24hours,whereastheenzymeinductioncapacityofphenobarbital(t½=53–140
hours) is notevidentforapproximately7days.Thelevelofinductionremainsconstantwhilethedrugs
are beingadministered. However, ondiscontinuationoftherespectiveinducers, theinducingactionof
rifampinendsmorerapidlybecauseofitsshorterhalf-life.Thisoccursbecauserifampinisremovedfrom
thebodyatafasterratethanphenobarbitalandthereforeisnotavailabletoinhibithepaticenzymesforas
long.
Theinitiationanddurationofenzymeinductionalsodependonthehalf-lifeoftheinducedisoenzyme.It
takesanywherefrom1to6daysforacytochromeP-450enzymetobedegradedorproduced.Therefore,
evenifadrugachievesahighenoughconcentrationtoproduceinductionofliverenzymes,theincreasein
metabolismof a target drug may not be evidentuntil more liver enzymes have formed. The effect of
rifampinonwarfarinmetabolismisagoodexampleofthis.Althoughinductionbeginswithin24hoursof
rifampinadministration,its effectonwarfarinmetabolismis notevidentforapproximately4 days.On
discontinuationofrifampin,theremainingdrugis metabolizedtonegligible levels beforetheeffecton
warfarinmetabolismdissipates.Thisoccursbecausethehalflifeoftheliverenzymesisgreaterthanthe
half-life of rifampin, and therefore, the enzymes remain to metabolize warfarin after rifampin is
eliminatedfromthebody.
These concepts are important to remember when monitoring laboratory values that demonstrate the
effectiveness of the targetmedication.For example, theINR,whichis a surrogate markerofwarfarin
levels, fluctuates significantly within a couple of days of the initiation or discontinuation of rifampin.
Accordingtoasystematic reviewbySimmonsetal., rifampin’sabilitytoinduceCYP3A4reducesthe
systemicexposureofcombinedhormonal oralcontraceptives.Intheory,this couldcausecontraceptive
failureleadingtounwantedpregnancies.However,nostudieshaveevaluatedtheriskofpregnancy,but
the interaction is clinically relevant andwarrants attention fromtheprovider (Simmons et al., 2018).
Table3.3listsseveralenzymeinducers/inhibitorsandthedrugstheyaffect.
Excretion
Althoughmostdrugsare metabolizedbytheliver,theprimarymodes ofeliminationfromthebodyare
biliaryandrenalexcretion.Drugsareremovedfromthebloodstreambythekidneysbyfiltrationorby
urinarysecretion.However,reabsorptionfromtheurineintothebloodstreammayalsooccur.
Changesintheseprocessesbecomeimportantwhentheyaffectdrugsthatareunchangedorstillactive.
Excretionofdrugmoleculescanbeaffectedinanumberofways;theseinclude,butarenotlimitedto,
acidificationor alkalinizationoftheurineandalterationofsecretoryor activetransportpathways.For
example, amphetamine is excreted predominantly via the urine. Thirty percent of the drug can be
recoveredfrom theurine after24 hours of administration.Acidic urineincreaseswhile alkalineurine
slows down the renal excretion of amphetamine (Jones & Karlsson, 2005). Although they are not
discussed here for various reasons, there are a select number of other mechanisms of renal drug
interactions.
The ionization state of drug molecules plays a key role in the excretion process. The urine pH
determines the ionization state of the excreted molecule. Because lipophilic membranes are less
permeabletoionizedmolecules(hydrophilic),ionizedmoleculesbecome“trapped”intheurineandare
subsequentlyexcreted.Drugsthatarenonionizedintheurinemaybereabsorbedandthenrecirculated,
effectivelydecreasingtheireliminationandincreasingtheirhalf-lives.
Acidic drugs remain in their nonionized state in anacidic urineand become ionizedin analkaline
urine.Theoppositeistrueforbasicdrugmolecules,whichremainnonionizedinanalkalineurineandare
ionized in an acidic urine. When a drug is administered that alters the urine pH, it may promote an
increasedreabsorptionorexcretionofanotherdrug.Forexample,theadministrationofbicarbonatecan
potentiallyincreasetheurinepH.Thisleadstotheincreasedexcretionofacidicdrugs(e.g.,aspirin)and
theincreasedreabsorptionofbasicdrugs(e.g.,pseudoephedrine).
Althoughmostdrugscrossthemembraneoftherenaltubulebysimplediffusion,somedrugsarealso
secreted into the urine through active transport pathways. These pathways, however, have a limited
capacityandcanaccommodate only a set amountof drugmolecules. Therefore, if two differentdrugs
usingthesamepathwayarecoadministered,thetransportpathwaymaybecomesaturated.Thiscausesa
“trafficjam”andtheexcretionofoneorbothofthedrugsisinhibited.
Theseinteractionscanbebeneficialordetrimental,dependingontheagentsthatareadministered.For
example, when probenecid and penicillin are given together, they compete for secretion through an
organicacidpathwayintherenaltubule.Theprobenecidblocksthesecretionofthepenicillin,thereby
increasingthetherapeuticconcentrationofpenicillininthebloodstream.Thisisaprimeexampleofdrug
interactions benefitingthe patient. In contrast, digoxinand verapamil also share an active transport
pathway. When they are administered concomitantly, their interaction leads to an increase in digoxin
levels resulting in potential cardiotoxicity (e.g., arrhythmia). Table 3.4 lists some other clinically
importantexcretioninteractions.
TABLE3.4
DrugsAffectingExcretion
Renal
Elimination
Mechanism TargetDrug Results
Acetazolamide IncreasesurinepH Salicylates Increasedelimination
Losartan Unknown Lithium Decreasedelimination
Salicylates Unknown Acetazolamide Decreasedelimination
Cetazolamide IncreasesurinepH Quinidine Decreasedelimination
Triamterene Unknown Amantadine Decreasedelimination
Amiodarone Unknown Digoxin Decreasedelimination
Unknown Procainamide Decreasedrenaland
hepaticelimination
Antacids IncreaseurinepH Dextroamphetamine,
quinidine,pseudoephedrine
Decreasedelimination
Diuretics Inhibitsodiumreabsorptionwithsubsequent
renaltubularreabsorptionoflithium
Lithium Decreasedelimination
Salicylates Inhibitrenaltubularsecretionofmethotrexate Methotrexate Decreasedelimination
Theothercommonpathwayofexcretion,thebiliarytract,allowsfortheeliminationofdrugsandtheir
metabolites into the feces. This route of excretion is involved in interactions with drugs that undergo
enterohepaticrecirculation.DrugssubjecttothisprocessareexcretedintotheGItractthroughthebiliary
ductsandhavethepotentialtobe reabsorbedthroughtheintestinalwall intothebloodstream.Someof
thesedrugsdependonenterohepaticrecirculationtoachievetherapeuticconcentrations.Anexampleofa
drugclassthatundergoesenterohepaticrecirculationistheoralcontraceptive.Aspreviouslydescribed,
antibiotics can adversely affect reabsorption of the estrogen components of oral contraceptives,
potentiallyrenderingthemineffective.Inaddition,drugsthatundergoenterohepaticrecirculationmayalso
be affected by binding agents. An example of this is warfarin in combination with the bile acid
sequestrants colestipol and cholestyramine. Warfarin undergoes enterohepatic recirculation. Once
warfarin has been excreted in the bile, the bile acid sequestrant binds with warfarin, preventing its
reabsorptionandincreasingits clearance, decreasingitsefficacy. This has been shownto occur even
whenwarfarinisadministeredintravenously(Jahnchenetal.,1978).Therefore,itisnotonlyimportantto
administerwarfarin2hoursbeforeor6hoursaftercholestyramine,butconsistencyintheadministration
timeoftheseagentsisimportantaswell(Mancano,2005).
Pharmacokinetic interactionsmakeupa largepart ofthe interactionsthatpractitioners mustcontend
witheveryday.
Theseinteractionsarethemoststudiedbecausetheyhaveanobjectivemeasurableoutcome(e.g.,drug
concentrations, enzyme concentrations). However, a drug’s pharmacodynamic profile must also be
consideredwhenitisadministeredwithotheragents.
P-GlycoproteinInteractions
Inhibition or induction of P-glycoprotein (P-gp), an energy-dependent efflux transporter, can result in
interactionsinvolvingabsorptionorexcretion(biliaryorrenal).P-gppumpsdrugmoleculesoutofcells
andis found in the epithelial cells of the intestine (enterocytes), liver, and kidney. As a drug passes
throughtheenterocyteintheintestinetobeabsorbedintothesystemiccirculation,P-gpcanpickupthe
moleculeandcarryitbacktotheintestinallumen,preventingabsorption.P-gpintheliverandkidneyacts
to increase the excretion of drugs by transporting the molecules into the bile and urine, respectively
(Hansten&Horn,2015).
If P-gp is inhibited, more drugs will be absorbed through the enterocytes. This will result in an
increaseinplasmaconcentrationsofthetargetdrug.Anexampleofthisinteractioniswhenquinidineis
administered withdigoxin.Quinidineinhibits intestinalP-gp,whichresults inincreased absorption of
digoxin.Inaddition,quinidineinhibitionofrenalP-gpresultsinreducedeliminationofdigoxinbythe
kidney.Theendresultisincreasedconcentrationsofserumdigoxin(Horn&Hansten,2004).
IfP-gpisinduced,lessdrugwillbeabsorbed throughthe enterocytes.Anexample ofan induction
interactionofP-gpiswhenrifampinisgivenwithdigoxin.RifampininducesintestinalP-gp,resultingin
reducedabsorptionandreducedserumdigoxinconcentrations(Hansten&Horn,2015).
TABLE3.5
ExamplesofSubstrates,Inhibitors,andInducersofP-Glycoprotein
Substrates Inhibitors Inducers
Aldosterone Amiodarone Indinavir
Cimetidine Atorvastatin Morphine
Colchicine Clarithromycin Nelfinavir
Cyclosporine Cyclosporine Phenothiazine
Digoxin Diltiazem Rifampin
Diltiazem Erythromycin Ritonavir
Erythromycin Felodipine Saquinavir
Fexofenadine Indinavir St.John’swort
Indinavir Itraconazole
Itraconazole Ketoconazole
Morphine Methadone
Nelfinavir Nelfinavir
Quinidine Nicardipine
Ranitidine Quinidine
Saquinavir Ritonavir
Tetracycline Sirolimus
Verapamil Tacrolimus
Verapamil
Sources: Data from Horn, J. R., & Hansten,P. D. (2004). Drug interactionswith digoxin: The role of P-glycoprotein. Pharmacy Times
(October). Retrieved from http://www.hanstenandhorn.com/hh-article10-04.pdf; Kim, R. B. (2002). Drugs as P-glycoprotein substrates,
inhibitors,andinducers.DrugMetabolismReviews,34,47–54.
Table3.5providesexamplesofcommonsubstrates,inhibitors,andinducersofP-gp(Hansten&Horn,
2015;Kim,2002).
PharmacodynamicInteractions
Theresponses or effectsproducedbya drug’sactionsare referredto as thedrug’spharmacodynamic
profile. Althoughdrugs are administered to elicita specificresponseorchange indynamics, anagent
usually causes several changes in the body. When one or more drugs are coadministered, the entire
pharmacodynamicprofileofeachdrugmustbeconsidered becauseofthepotentialforeachtointeract.
Drugsthathave a similar characteristic intheir pharmacodynamicprofile mayproduceanexaggerated
response.Forexample,whenabenzodiazepine(e.g.,alprazolam)isadministeredwithamusclerelaxant
(e.g.,cyclobenzaprine),thesedativeeffectsofbothdrugscombinetoproduceexcessive drowsiness.A
less obvious pharmacodynamic interaction occurs with the coadministration of angiotensin-converting
enzyme (ACE) inhibitors (e.g., enalapril) and potassium-sparing diuretics (e.g., triamterene). These
agentsindividuallycanbothproduceanincrease inthepotassium (K+)level. Unlesstheprescriberis
aware of the pharmacodynamic profile of both drugs, the potential for an excessive increase in the
potassiumlevelmaygounnoticedandarrhythmiamayensue.
Incontrast,drugsmayalso produceopposingpharmacodynamiceffects.Thistypeofinteractionmay
causetheexpecteddrugresponsetobediminishedorevenabolished.Unfortunately,theseinteractionsare
often overlooked. Instead of the lack of response being interpreted as a pharmacodynamic drug
interaction,itissuspectedtobeduetoanineffectivedoseordrug.Thisoftenleadstoanincreaseinthe
amountofdrugadministeredandconsequentunwantedsideeffectsorinteractions.Thistypeofinteraction
is illustrated by the concomitant administration of an antihypertensive agent (e.g., a diuretic) and a
nonsteroidal anti-inflammatorydrug (NSAID). Thiazide diuretics produce their hypotensive effects by
blocking sodiumreabsorptionin the distal tubule ofthekidney, which leads to increased sodiumand
waterexcretion.IfNSAIDsareadministeredconcomitantly,thesodiumandwaterretentioneffectsofthe
NSAIDsmayreduceornullifythehypotensiveactionofthediuretic.
DRUG–FOODINTERACTIONS
The interaction between food and drugs can affect both pharmacokinetic and pharmacodynamic
parameters. The mechanism of these pharmacokinetic interactions is mediated by alteration of drug
bioavailability,distribution,metabolism,orexcretion,asseenwithdrug–druginteractions.Thepotential
forpharmacodynamicdrug–foodinteractionswarrantsconcernaboutproper dietforpatientsoncertain
drugs. Although practicing clinicians often overlook drug–food interactions, these interactions can
significantlyaffectefficacyofdrugtherapy.Awarenessofsignificantdrug–foodinteractionscanreduce
theincidenceoftheseeffectsandoptimizedrugtherapy.
EffectofFoodonDrugPharmacokinetics
Absorption
Foodcanaffecttheabsorptionofdrugsintwoways:first,byalteringtheextentofdrugabsorptionand
second,bychangingtherateofdrugabsorption.Usually,changesintherateofdrugabsorptionhaveless
significanceif only the rateofabsorption is delayed without affecting bioavailability. The underlying
mechanismsthatmediatetheseinteractionsarehighlyvariableanddependonboththecontentoffoodand
thepropertiesofthedruginvolved.
Foodcaneitherincrease ordecrease theamount(extent)ofdrugabsorption,potentiallyalteringthe
bioavailabilityofadrug.Onemechanism,similartodrug–druginteractions,isadsorption.Forexample,
tetracycline and fluoroquinolone antibiotics (e.g., ciprofloxacin, ofloxacin) can chelate with calcium
cationsfoundinmilkormilkproducts,thussignificantlylimitingthedrug’sbioavailability.
Asecondtypeofdrug–foodinteractionoccurswhenfoodservesasaphysicalbarrierandpreventsthe
absorptionoforallyadministereddrugs.Theabsorptivecapacityofthesmallintestineis relatedtothe
accessibilityofadrugtotheGImucosalsurfaces,thesitewhereabsorptionoccurs.Whenfoodiscoadministered with a drug, access to the mucosa is reduced, resulting in delayed or decreased drug
absorption.Forexample,thebioavailabilityofazithromycinisreducedby43%whenthedrugis taken
with food(Zithromax[Pfizer Pharmaceuticals], 2013). Similartypesof interactionscanbe seen when
erythromycin,isoniazid,penicillins,andzidovudinearegivenorally.Toavoid suchinteractions,these
drugscanbeadministered2 hoursapartfrommealtime.Box3.1 identifies somecommonlyprescribed
drugs that should be taken on an empty stomach. Note, however, if patients cannot tolerate these
medicationsonanemptystomach(becauseofGIsideeffectslikediarrhea),coadministrationwithfood
maybeadvisable.
Box3.1 DrugstoBeTakenonanEmptyStomach
Azithromycin
Captopril
Erythromycin
Fluoroquinolones(e.g.,ciprofloxacin,ofloxacin)
Griseofulvin
Isoniazid
Oralpenicillins
Sucralfate
Tetracycline
Theophylline,timedrelease(e.g.,Theo-DurSprinkle,Theo-24,Uniphyl)Zidovudine
Incontrast,foodcanalsodecreasetheabsorptionofsomedrugs.Forexample,phenytoinisknownto
bindto protein source, heavy metals suchas calcium carbonate,and enteral feedingformulas (Sacks,
2004).Dosesofphenytoinmayhavetobeincreasedupto1,000mg/dcomparedto300mg/dwhenitis
givenwithoutfood.Toavoidthedrug–foodinteraction,phenytoindosescanbegiven1hourbeforeor2
hoursaftereating.
Metabolism
Foodcanalsoaffectdrugmetabolism.Grapefruitjuice,forexample,canaffectthemetabolismofmany
drugs.Grapefruitjuicespecificallyinhibitsthe3A4subsetofintestinalcytochromeP-450enzymesand
thusincreases theserumconcentrationofdrugsdependentontheseenzymesfor metabolism(Ameer&
Weintraub,1997;Huangetal.,2004).
Theextrahepaticcytochromeenzymesarefoundinhighestconcentrationsintheproximaltwothirdsof
thesmallintestine.Theseenzymesarelocatedatthedistalportionofthevillithatlinethesmallintestine
andareresponsible fortheextrahepaticmetabolism ofmorethan20drugs(Ameer&Weintraub,1997;
Huang et al., 2004). The componentin grapefruitjuice that isresponsible for this interactionremains
undetermined; however, the flavonoid naringin, found in high concentrations in grapefruit juice, is
suspected.Increasesinthebioavailabilityofverapamil anddihydropyridinecalcium channelblockers
suchasfelodipine,nisoldipine,nitrendipine,nifedipine,andamlodipinehavebeendocumentedwiththe
coadministration of grapefruit juice (Bailey et al., 1991, 1992, 1993; Rashid et al., 1993). The
bioavailabilityofcarbamazepineandmidazolamismarkedlyincreasedwhentakenwithgrapefruitjuice
(Sacks,2004).However,unlikeverapamilanddihydropyridinecalciumchannelblockers,diltiazemdoes
notdemonstrateanincreaseinbioavailabilitywithgrapefruitjuice.
Theamountofgrapefruitjuicerequiredtoincreaseplasmaconcentrationscanvarybetweenagents.A
singleglassofgrapefruitjuicecanincreasetheareaunderthecurveandmaximumconcentration(C
max
)
offelodipinebyseveralfold(Baileyetal.,1998)while thewarningsintheproductlabelingforsome
hydroxy-methylglutaryl-coenzymeAreductaseinhibitorsmetabolizedbyCYP3A4saytoavoidquantities
>1quart/day(Zocor,2015). Theextentoftheincrease infelodipineplasmaconcentrationsismaximal
between simultaneous and 4 hours before administration of grapefruit juice. However, higher C
max
concentrations were evident even when grapefruit juice is consumed 24 hours before felodipine.
Therefore,separatingdosesmayreducebutdoesnoteliminatethepotentialfortheinteraction(Baileyet
al.,1998).BecausegrapefruitjuiceappearstoinhibitmostlyintestinalCYP3A4andnothepaticCYP3A4
enzymes, themetabolismofdrugsadministered intravenouslyisunlikelytobealtered.Further,thedata
suggest that only those agents given at doses higher than usual or if the patients’ livers are severely
damagedresultintheintestinalCYP3A4astheprimarymetabolicpathway(Huangetal.,2004).Box3.2
identifiessomedrugsthatmayinteractwithgrapefruitjuice.
Box3.2 DrugConcentrationsThatIncreaseWhenTakenwithGrapefruitJuice
17-beta-estradiol
Amlodipine
Benzodiazepines
Cyclosporine
Dihydropyridinecalciumchannelblockers
Felodipine
Lovastatin
Midazolam
Nifedipine
Nisoldipine
Nitrendipine
Simvastatin
Triazolam
verapamil
Incontrasttotheabilityofgrapefruitjuicetoinhibitdrugmetabolism,othercomponentsoffoodmay
inducedrugmetabolismandthereforedecreasedrugefficacy.Forexample,inthetreatmentofParkinson’s
disease,dopamineinthebrainneedstobereplenished.However,exogenousdopaminedoesnotcrossthe
blood–brain barrier, but its precursor, levodopa, does. Unfortunately,muchof the levodopa is lost to
metabolismwhengivenorallyandonlyapproximately1%oftheadministeredamountentersthebrainto
be converted to dopamine (Trovato et al., 1991). Concomitant administration with food containing
pyridoxine(orvitaminB6)canpotentiallyfurtherenhancetheperipheralmetabolismoflevodopa,thus
decreasing drugefficacy(Trovatoetal., 1991).Patientstakinglevodopashould therefore be educated
aboutmoderateintakeofpyridoxinerichfoods,suchasavocados,beans,bacon,beef,liver,peas,pork,
sweet potatoes, and tuna. Similarly, charcoal-broiled meats can induce the activity of the CYP1A2
isoenzymes,thusincreasingthemetabolismofdrugssuchastheophylline.
Excretion
Ingestionof certainfruitjuices canaltertheurinary pHandaffecttheeliminationandreabsorptionof
drugssuchas quinidineandamphetamine.Orange,tomato, andgrapefruitjuices aremetabolizedto an
alkalineresidue,whichcanincreasetheurinarypH.Fordrugsthatareweakbases,makingtheurinemore
alkalinebyraisingthepHincreasestheproportionofnonionizeddrugandenhancesthereabsorptionof
thedrugsystemically.(Recallthattheionizationofdrugshelpspromotewatersolubilityandultimately
enhancesdrugeliminationintotheurine.)
EffectofFoodonPharmacodynamics
Foodaffectsthepharmacodynamicsofdrugseitherbyopposingorpotentiatingadrug’spharmacologic
action. For example, warfarin exerts its anticoagulant effects by inhibiting synthesis of vitamin K–
dependentclottingfactors.VitaminKisrequiredforactivationbyseveralproteinfactorsoftheclotting
cascade, namely, factors II, VII, IX, and X. When foods rich in vitamin K are ingested, they can
significantly oppose the anticoagulatory efficacy of warfarin. Leafy green vegetables, such as collard
greens, kale, lettuce, spinach, mustard greens, and broccoli, are generally recognized to contain large
quantitiesofvitaminK.Healthcareprovidersshouldeducatepatientswhoaretakingwarfarinaboutthis
interaction.Moreimportantly, however,practitionersshouldstressmaintaininga balanceddietwithout
abruptlychangingtheintakeoffoodsrichinvitaminK.
Another significantdrug–foodinteractionoccurs betweenmonoamineoxidase (MAO)inhibitors and
foodscontainingtyramine,anaminoacidthatiscontainedinmanytypesoffood.Tyraminecanprecipitate
a hypertensive reaction in patients taking MAO inhibitors, such as phenelzine, tranylcypromine, or
isocarboxazid.MAOsareenzymeslocatedintheGItractthatinactivatetyramineinfood.Whenpatients
are taking MAO inhibitors, the breakdown of tyramine is prevented and therefore allows for more
tyraminetobeabsorbedsystemically.Becauseoftheindirectsympathomimeticpropertyoftyramine,this
aminoacidprovokesthereleaseofnorepinephrinefromsympatheticnerveendingsandepinephrinefrom
the adrenal glands, resulting in an excessive pressor effect. Clinically, patients may complain of
diaphoresis,mydriasis,occipitalortemporalheadache,nuchalrigidity,palpitations,andelevatedblood
pressure.ExamplesoffoodsthatcontaintyraminearelistedinBox3.3.
Box3.3 FoodsHighinTyramine
Beanpods
Beer(draft)
Cheese(aged)
Curedmeats(i.e.,salami,pepperoni,sausage)
Fruits(overripe,suchasfigs,avocados,prunes,andraisins)
Herring(pickled)
Liver
Sauerkraut
Soysauce
Wine
EffectofDrugsonFoodandNutrients
Manyoftheaforementionedexamplesindicatethatfoodcanprecipitateaninteractionwithadrug,butin
somecases,areciprocalrelationshipalsoholdstrue.First,somedrugscancauseadepletionofnutrients
ormineralsfoundinfoodthroughvariousmechanisms.Forexample,drugssuchas cholestyramineand
colestipol,whichweredesignedtobindbileacidintheGItract,couldalsopotentiallybindtofat-soluble
vitamins(i.e.,vitaminsA,D,E,andK)andfolicacidwhentakenwithfood,resultinginthedecreased
absorptionofthese vitamins.Orlistat,anover-the-counterandprescriptionmedicationused forweight
loss,reducesfatabsorption.Inadditiontoreducingfatabsorption,itcanalsodecreasetheabsorptionof
fat-solublevitaminsandbeta-carotene.Similarly,thechronicuseofmineraloilasalaxativereducesthe
absorptionoffat-solublevitamins.CarefulmonitoringoftheINRinpatientstakingwarfarinanddrugs
thataffectvitaminKabsorptioniswarrantedtoavoidchangesinbleedingtimes.
Second,drug-inducedmalabsorptioncanoccurinpatientswithpreexistingpoornutritionalstatus.For
example, long-term use of isoniazid can cause pyridoxine (vitamin B6) deficiency. Pyridoxine
supplementationisrecommendedforpatientswhoaremalnourishedorpredisposedtoneuropathy(e.g.,
patientswithdiabetesoralcoholism)whentreatedwithisoniazid.Metforminisassociatedwithvitamin
B12deficiencyinabout7%ofpatients,whichmayleadtoanemia.Ingeneral,theclinicalsignificanceof
theseinteractionsmaydependonthebaselinenutritionalstatusofthepatient.Patientswithpoornutrition
or inadequate dietary intake(e.g., older adultor alcoholic patients) are potentially at greater risk for
drug-inducedvitaminandmineraldepletion.
Third, drugscanchangenutrientexcretionaswell. Boththiazideandloop diureticscanenhancethe
excretion of potassium, possiblyleadingto hypokalemia. Digoxin, in the presence of diuretic-induced
hypokalemia, can lead to digoxin-induced arrhythmias. Spironolactone, an aldosterone antagonist and
potassium-sparingdiuretic,canincreasepotassiumlevels,especiallyinthepresenceofanACEinhibitor
or angiotensin receptor blocker. Loop diuretics can increase urinary excretion of calcium, whereas
thiazidediureticscandecreaseit.Inaddition,ascorbicacidandpotassiumdepletioncanoccurwithhigh
dosesoflong-termaspirintherapy(Trovatoetal.,1991).Lithium,adrugusedinthetreatmentofbipolar
disorder,dependsonrenaltubulartransportforclearance.Sodiumcancompetewiththisprocess.Adiet
lowinsodiumcanenhancetherenaltubularreabsorptionoflithium,whichcouldleadtolithiumtoxicity
(Chan,2013).
Continuous enteral feedingimpairs the dissolution of levothyroxine tablets. The drug could also be
boundtotheenteralfeedingtubes.Allofwhichcouldlead tofurtherhypothyroidismduetoinadequate
levothyroxinereachingthesystemiccirculation.
COMPLEMENTARYALTERNATIVEMEDICINEINTERACTIONS
Intoday’ssociety,thesearchfora“naturalway”totreatandpreventdiseaseshasbecomecommonplace.
Thispotentiallystemsfrom themisconceptionthat“natural” means“safer.”AmongU.S. adultsaged18
yearsandolder,33.2%ofthepopulationhasusedsomeformofherbalproductsin2012(Clarkeetal.,
2015).Forthemostpart,theseCAMsare notregulatedbytheFDA.Inmanycases,littleresearchhas
beenconductedtoassess theefficacyandsafetyoftheseagentsorthepotential forpharmacokineticor
pharmacodynamic interactions. Some clinical trials have been conducted to evaluate the safety and
efficacyofcertainherbalmedications;however,muchofavailabledataarebasedonanimalstudies,case
reports,andthepotentialforinteractionsderivedfromwhatisknownaboutthechemicalcharacteristics
andpharmacokineticparametersoftheherbs.
TABLE3.6
ComplementaryAlternativeMedicineInteractionsAffectingAbsorption
Complementary
Alternative
Medication
MechanismofAction TargetDrug Results
Acacia Fibercontentmayslowor
reduceabsorptionof
medications
Amoxicillin Decreasedabsorption(separate
dosesbyatleast4h)
Carob Decreasedboweltransit
time
Oralmedications Decreasedabsorption(separate
dosesbyseveralhours)
Citruspectin Fibercontentmayslowor
reduceabsorptionof
medications
Oralmedications Take1hbeforeor2hafterintakeof
otheroralmedications
Dandelion Highmineralcontent
(chelation)
Ciprofloxacinandpotentially
othermedicationsaffectedby
Decreasedabsorption;dandelionand
quinolonecoadministrationshouldbe
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