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chelation avoided
Flaxseed Fibercontentmay
decreaseabsorptionof
oralagents
Oralagents/vitamins/minerals Decreasedabsorption;oralagents
shouldbetaken1hbeforeor2h
afterflaxseed
Psyllium Fibercontentmay
decreaseabsorptionof
oralagents
Carbamazepine,digoxin,
lithium
Decreasedabsorption
Source:AdapteddatafromUlbricht,C.,Chao,W.,Costa,D.,etal.(2008).Clinicalevidenceofherb–druginteractions:Asystematicreview
bytheNaturalStandardResearchCollaboration.CurrentDrugMetabolism,9,1063–1120.
PharmacokineticInteractions
Absorption
Asdiscussedearlierinthechapter,certainagentscaninteractwithothermedicationsintheGItractto
prevent absorption. Likewise, some CAMs can prevent absorption of medications and reduce the
effectivenessofthosemedications.Forexample,acacia,marketedasafibersupplement,hasbeenshown
toimpairtheabsorptionofamoxicillin.Thismaybesecondarytothefibercontentofacacia.Dosesof
acaciaandamoxicillinshouldbeseparatedby4hours.Dandelionhasahighmineralcontentandhasbeen
showntoreducetheeffectivenessofquinolonesinanimals(Ulbrichtetal.,2008).Table3.6summarizes
someofthepotentialCAMinteractionsthatcanoccurintheabsorptiveprocess.
Distribution
Meadowsweet andblack willowcontainsalicylates thathavethepotential todisplace highlyproteinbounddrugs.Toavoidtoxicity,coadministrationoftheseproductswithhighlyprotein-bounddrugswitha
narrowtherapeuticindex,suchaswarfarinandcarbamazepine,shouldbeavoided.
Metabolism
CertainCAMscanbeinducersorinhibitorsofthecytochromeP-450enzymesystem.St.John’swort,an
herbal medication often used to treat depression, has consistently been shown to induce CYP3A4,
CYP2E1,andCYP2C19.Inaddition,St.John’swortinducesintestinalP-gpandhasbeenshowntolower
plasmaconcentrationsofcommonP-gpsubstratessuchas digoxinandfexofenadine.Inductionofthese
enzymes issecondarytohyperforin,aningredientinSt.John’swort.St.John’worthasbeenshownto
clinically interact with a number of drugs, including immunosuppressants, hypoglycemics, antiinflammatoryagents,antimicrobialagents,antimigrainemedications,oralcontraceptives,cardiovascular
agents, andantiretroviral and anticancer drugs as well as drugs affectingthecentral nervous,GI, and
respiratorysystems(Izzo&Ernst,2009).
Incontrast,kava,usedasananxiolytic,andgarlic,usedtotreatdyslipidemia,havebothbeenshownin
pharmacokineticstudies to inhibit thecytochrome P-450enzymesystem, specificallyCYP2E1 (Izzo&
Ernst,2009).Table3.7showssomecommonCAMinteractionsaffectingmetabolism.
PharmacodynamicInteractions
CAMsmaycontainingredientsthatpotentiatethepharmacodynamiceffectsofcertainmedications,which
maylead to adverseeffects.The causative mechanismof these effects may not be well understood in
manycases.
TABLE3.7
ComplementaryAlternativeMedicineMetabolismInteractions
Sources:AdapteddatafromUlbricht,C.,Chao,W.,Costa,D.,etal.(2008).Clinicalevidenceofherb–druginteractions:Asystematicreview
by the NaturalStandardResearch Collaboration.Current DrugMetabolism,9, 1063–1120;Izzo,A. A., & Ernst, E. (2009). Interactions
betweenherbalmedicinesandprescribeddrugs:Anupdatedsystematicreview.Drugs,69,1777–1798.
Box3.4 ComplementaryAlternativeMedicinesThatPotentiallyIncreaseBleeding
WhenTakenwithAntiplatelets/Anticoagulants
Borageseedoil
Clove
Danshen
Devil’sclaw
Dongquai
Feverfew
Garlic
Ginger
Ginkgo
Ginseng
Goji
Omega-3fattyacids
Papaya
Peony
Policosanol
Pycnogenol
Sawpalmetto
Turmeric
Source:AdapteddatafromUlbricht,C.,Chao,W.,Costa,D.,et al.(2008a). Clinicalevidenceofherb-drug interactions:Asystematic
reviewbytheNaturalStandardResearchCollaboration.CurrentDrugMetabolism,9,1063–1120.
Several herbal medications have been shown to inhibit platelet activity and/or have an effect on
increasingtheINR.CasereportsofincreasedbleedinginpatientstakingcertainCAMswithnonsteroidal
anti-inflammatory agents, antiplatelet agents, and anticoagulants have been reported (Ulbricht et al.,
2008).Box3.4showsCAMsthatmayincreasethepotentialforbleedingwhengivenconcomitantlywith
medicationsthatinhibitplateletsoraltercoagulation.
SomeCAMs havebeenshowntopotentiate the central nervoussystem (CNS) depressanteffectsof
somemedications.Kava,lavender,andvalerianmaypotentiatetheeffectsofCNSdepressants,suchas
barbiturates,benzodiazepines,andnarcotics.Inaddition,kavamayinterferewiththeeffectsofdopamine
ordopamineantagonistsanditispotentiallyhepatotoxic(Kuhn,2002;Ulbrichtetal.,2008).
Aloehasbeenassociatedwithhypoglycemiainpatientstakingglibenclamide(glyburide).Bitterorange
containsMAOinhibitorsubstratessuchastyramineandoctopamine,andconcomitantusewithanMAO
inhibitormayincreasethepotentialforhypertensiveeffects(Ulbrichtetal.,2008).
WhilemanypatientsmaybelieveCAMsaresafebecausetheyare“natural”andareavailableoverthe
counter, the potential for interactions still exists. Clinicians must be aware of the potential for these
interactionsandencouragepatientstodiscloseallmedicationstheyaretaking,includingCAMs.
DRUG–DISEASEINTERACTIONS
Certaindrug–disease interactions can change drug pharmacokinetic and pharmacodynamic parameters,
leadingto less-than-optimal drugtherapeutic outcomesandgreater riskoftoxicity. Inaddition,certain
drugscanexacerbateapatient’scoexistingdisease.
EffectofDiseaseonPharmacokineticsofDrugs
Absorption
Asalreadydiscussed,theabsorptionofdrugsmaybeaffectedbythepresenceofotherdrugsandfoodin
theGItract.However,drugabsorptionalsodependsonthephysiologicprocessesthatmaintainnormalGI
function.These processescanincludeenzyme secretion,acidity, gastricemptying,bileproduction,and
transit time. Thus,any disease thatalters thenormal physiologic function oftheGI system potentially
altersdrugabsorption.
VitaminB12deficiencyiscommoninpatientsundergoingstomachsurgery.Stomachacidandintrinsic
factorplayacriticalroleintheabsorptionofvitaminB12.Withoutacid,vitaminB12isnotabletobe
cleaved andreleased fromproteins infood. Vitamin B12 andintrinsic factor form a complexandare
absorbed in the duodenum. Without intrinsic factor, vitaminB12 absorption is impaired (Goldenberg,
2008).
Asanexample,thegastric-emptyingratecanbe reducedinpatientswithduodenalorpyloric ulcers
andhypothyroidism.Inaddition, long-termdiabetes can result in diabetic gastroparesis, whichdelays
gastric emptying. This results in later or fluctuating maximal serum concentrations and has been
documentedwithoralhypoglycemicagents.Thismaybecomeparticularlyimportantwhenarapid-acting
drugisrequired. However, drugs withlonger half-livesmaybe less likely to be affected (Jing et al.,
2009).Anotherexampleincludesboweledemaandintestinalhypoperfusionfromadvancingheartfailure,
whichcan delay theabsorption of diuretics prescribed to control edema(Hunt et al., 2009). Finally,
diarrhea,amanifestationofmanydiseases,canposeaproblemfororalabsorptionofdrugsas wellas
foodandnutrients.
Distribution
The distributionof drugs canbeaffected bycertaindisease states.Of significanceare conditions that
changeplasmaalbuminlevelsandthereforecanincreaseordecreasetheconcentrationofdrugsusually
boundtoalbumin.Examplesofconditionsthatmaydecreaseplasmaalbuminlevelsincludeburns,bone
fractures,acuteinfections,inflammatorydisease,liverdisease,malnutrition,andrenaldisease.Examples
of conditions that may increase plasma albumin levels include benign tumors, gynecologic disorders,
myalgia,andsurgicalprocedures.
Metabolism
Themetabolism ofdrugscanoftenbealtered bydiseases thataffectthefunctions oftheliver,suchas
cirrhosis.Failureoftheliver(theprimaryorganresponsiblefordrugmetabolism)notonlyimpairsdrug
metabolismbutcancauseareductioninalbuminsynthesis.Therefore,theclinicalimpactofliverfailure
includes a strong potential for interactions withdrugs. Heart failure is another disease that can cause
direct reductionintheabilityofthe liver tometabolize drugs.Inpatients withheartfailure, however,
decreasedmetaboliccapacityoftheliverisalsocausedbyadecreaseinbloodflowtotheliverowingto
changesincardiacoutput.
Insomecases,normalliverfunctionis neededtoactivateadrugratherthantoinactivateit.Certain
drugslikeenalaprilarecalledprodrugs,meaningthedrugneedstobeconvertedbythelivertoitsactive
form(enalaprilat)toachievemaximaltherapeuticeffect.Therefore,useofaprodruginpatientswithliver
dysfunctioncanpotentiallyreducetheefficacyofthedrug.
Excretion
Renalfunctioncaninfluenceserumdrugconcentrationsbecausemostdrugsareeliminatedbythekidneys
either as unchangeddrugor as metabolites.Chronic renaldiseasesthatcompromise thefunctionofthe
kidneytocleardrugscanresultindrugaccumulation.Glomerulonephritis,interstitialnephritis,long-term
anduncontrolleddiabetes,andhypertension are primarycauses ofdeclining renal function.Inclinical
practice,oncethepatient’sestimatedcreatinineclearancehasdeclinedto<50mL/min,doseadjustments
usuallyarerequiredfordrugsthatareprimarilyrenallycleared.Forexample,drugssuchasH2receptor
antagonists andfluoroquinolone antibioticscommonlyrequire dose adjustmentsfor patients withrenal
insufficiency. In particular, the drug regimen of older adult patients or those with an elevated serum
creatinine level above 1.5 mg/dL should be evaluated to detect any ADRs from possible drug
accumulationsecondarytodecliningrenalclearance.
EffectsofDrugsonCoexistingDisease
Drugs used to treat one medical condition can sometimes exacerbate the status of another comorbid
disease. Practitioners, therefore, should be aware of potential drug–disease interactions. This is of
particular importance in older individuals who have multiple concomitant diseases and often take
multiplemedications.Detectedratesofdrug–diseaseinteractionsrangefrom6%to30%inolderadults
(Lindbladetal.,2006).Acompletediscussionofthistopicisbeyondthescopeofthischapter.However,
aconsensusstatementhasbeenpublishedfromamultidisciplinarypanelofhealthcareproviderswhose
membersspecializeingeriatricmedicine.Thestatementidentifiesseveraldrug–diseaseinteractionsthat
arecommoninolderindividualsandareconsideredtohaveadeleteriousimpactoncoexistingdiseasein
olderindividuals.Table3.8liststhesecommonandclinicallysignificantdrug–diseaseinteractionsinthe
olderadults(AmericanGeriatricsSociety,2012).
TABLE3.8
Drug–DiseaseInteractionsCommonintheOlderAdults
Disease/Condition Drug/DrugClass
Benignprostatichyperplasia Anticholinergics
Tricyclicantidepressants
Chronicrenalfailure NonaspirinNSAIDs
Heartfailure(systolicdysfunction) First-generationcalciumchannelblockers
Constipation Anticholinergics
Opioidanalgesics
Tricyclicantidepressants
Dementia Anticholinergics
Barbiturates
Benzodiazepines
Tricyclicantidepressants
Diabetes Corticosteroids
Falls Antipsychotics(thioridazine/haloperidol)
Benzodiazepines
Sedativehypnotics
Tricyclicantidepressants
Heartblock Digoxin
Tricyclicantidepressants
Narrow-angleglaucoma Anticholinergics
Parkinson’sdisease Metoclopramide
Pepticulcerdisease Aspirin
NonaspirinNSAIDs
Posturalhypotension Thioridazine
Tricyclicantidepressants
Seizures Bupropion
Syncope Alpha-blockers(e.g.,doxazosin,terazosin,methyldopa)
Source:DatafromLindblad,C.I.,Hanlon,J.T.,Gross,C.R.,etal.(2006).Clinicallyimportantdrug–diseaseinteractionsandtheirprevalence
inolderadults.ClinicalTherapeutics,28,1133–1143.
NSAID,nonsteroidalanti-inflammatorydrug.
PATIENTFACTORSINFLUENCINGDRUGINTERACTIONS
Theoutcomesofdruginteractionsare highlyvariable fromonepersontoanother.Manypatientfactors
caninfluencethepropensityforaninteractiontooccur,suchasgenetics,diseases,environment,smoking,
diet/nutrition,andalcohol.Anunderstandingofthesefactorscanhelptoidentifypotentialsourcesofdrug
interactions.
Heredity
Asdiscussedpreviously, thecytochrome P-450 system candisplaygenetic polymorphism.That is, the
variablemetabolismofdrugsbycytochromeP-450enzymesfromonepersontoanotherinthepopulation
canbe partlyexplainedbygeneticdifferences. For example,approximately8% ofAmericanslackthe
genetoformtheisoenzymeCYP2D6andthereforeareatgreaterriskfortoxicityfrompsychotropicdrugs
and,potentially,otherdrugsthataremetabolizedbytheseisoenzymes.Themetabolismofisoniazidalso
demonstrates variation among different people; some acetylate isoniazid very rapidly, whereas others
acetylateitslowly.
Warfarinisawidelyusedoralanticoagulant.ItsdosedependsonageandCYP2C9genotype.Itworks
bydepletingthesupplyofvitaminK.TheformationofvitaminKdependsonaproteinknownasvitamin
Kepoxidereductasecomplexsubunit1gene.Mutationsofthisparticulargenehavebeenassociatedwith
adecreaseinformationofclottingfactorsandwarfarinresistance(Sconceetal.,2005).
Disease
Another important factor that influences drug interactions is the patient’s existing disease state. Any
diseaseaffectingliveror kidneyfunctioncanpotentiallypredisposethepatienttodruginteractionsand
ADRs because these organs are primary sites of drug metabolism and elimination, respectively.
Significant deterioration in drug metabolism or elimination can lead to increased serum drug
concentrations and therefore increase the likelihood for drugs to interact. Consequently, older adult
patients and those with a history of liver disease or renal insufficiency should be evaluatedfor dose
adjustments ofdrugssignificantlycleared bytheliver andkidneys.For example, enoxaparinisa drug
usedtotreatvariousclottingdisorders. Itisrenallyclearedfromthebody.Poorkidneyfunctioncould
leadtoitsaccumulation.Ifthedoseisnotloweredinthesepatients,theycouldbeexposedtotoomuch
enoxaparinresultinginexcessivebleeding(Nutescuetal.,2009).
Environment
Environmental factors, such as dichlorodiphenyltrichloroethane and other pesticides, can increase the
activity of liver enzymes, potentially causing an increase in drug metabolism. Although the general
significanceoftheeffectofenvironmentalexposureontheclinicaloutcomeofdrugtherapyhasnotbeen
wellstudied,peopleworkinginoccupationswithprolongedexposuretotoxinsandchemicalsshouldbe
morecloselyobserved.
Smoking
Studies show that smoking can increase the liver’s metabolism of certain drugs, including diazepam,
propoxyphene,chlorpromazine,andamitriptyline.Forexample,thepolycyclicaromatichydrocarbonsin
cigarettes can induce CYP1A2 metabolism, resulting in decreased theophylline serum concentrations
(Schein,1995).
Nutrition
The nutritional status anddietary intakeof thepatient can influence the importance of adrug–nutrient
interaction.Drugscandepletevaluablevitaminsandmineralsfromfood;however,theseinteractionsare
oftendifficulttorecognizeandmaygoundetected.Patientswithpoorbaselinenutrition(e.g.,alcoholics)
may experience more pronounced effects mainly because of underlying nutritional deficiency.
Practitioners should be aware of potential drug–nutrientinteractions by identifyingpatients who have
poordietaryintakeandwhoconcurrentlytakemedicationsthatcandepletevitaminsandminerals.
AlcoholIntake
Alcohol can complicate drug therapy onmany differentlevels. Alcohol has a variable effect ondrug
metabolismdependingonacuteorchronicintake.Acutealcoholingestioncaninhibitdrugmetabolism,
thusincreasingserumdrugconcentrations;italsocanenhancethepharmacodynamiceffectofdrugswith
properties of CNS depression. Patients concurrently taking narcotics, antihistamines, antidepressants,
antipsychotics,andmusclerelaxantswithalcoholareatgreatestriskforCNSdepressionandshouldbe
warnedofthisinteraction(Trovatoetal.,1991).Inaddition,acuteingestionofalcoholcanincreasethe
potential for hypoglycemia in diabetic patients taking insulin or insulin secretagogues (e.g.,
sulfonylureas).Metronidazoleisanantibioticusedtotreatintra-abdominalinfections.Whentakenwith
alcohol,itinhibitstheenzyme, aldehydedehydrogenase,whichisresponsibleformetabolizingalcohol.
This results in anaccumulationof the intermediate metabolite, acetaldehyde, causinga disulfiram-like
reaction such as facial flushing, headache, nausea and vomiting, weakness, dizziness, blurred vision,
confusion,andhypotension.
Incontrast,chronicalcoholintaketendstoincreasethesynthesisofdrug-metabolizingenzymes,leading
toinduction.Enzymeinductioncauses decreases inserum druglevels. Enzymeinductionsecondaryto
chronic alcohol useincreases conversionof acetaminophentohepatotoxicmetabolites. Chronic useof
alcohol in combination with high doses of acetaminophen (often from several sources) above that
recommendedinthelabelingmayresultinliverdamage(Jang&Harris,2007).Inaddition,chronicuse
ofalcoholincombinationwithNSAIDsoraspirinincreasestheriskofGIbleeding.Long-termabuseof
alcoholleads to livercirrhosis, whichultimatelyimpairs drugmetabolismbydestructionoffunctional
hepatocytes.
ADVERSEDRUGREACTIONS
AnADRcanbedefinedasanundesirableclinicalmanifestationthatisconsequenttoandcausedbythe
administrationofaparticulardrug.ADRsarebasicallydrug-inducedtoxicreactions.TheWorldHealth
OrganizationdefinesanADRas“aresponsetoamedicinewhichisnoxiousandunintended,andwhich
occursatdosesnormallyusedinman”(Nebekeretal.,2004).
There are two generaltypes to consider.The first type of ADRis anexaggerationof theprincipal
pharmacologic actionof the drug.The ADRissimply a morepronounced drugresponse than normal.
These reactions usually are dose dependent and predictable. These are often referred to as type A
reactions.
Inthesecondtype,typeBreactions,theADRisunrelatedtotheprincipalpharmacologicactionofthe
drugitself.Thesereactionsareprecipitatedbythesecondarypharmacologicactionsofthedrug,maybe
unpredictable,andmayormaynotbedosedependent.Ineithertype,theADRcanresultfromoverdosage
ofdrug or administration of therapeutic doses to a patient hyperreactive tothe drug or as anindirect
consequenceoftheprimaryaction.
ADRs are sometimesreferredto as side effects.Aside effectis alsorecognizedas anundesirable
pharmacologiceffectthataccompaniestheprimarydrugactionandusuallyoccurswithinthetherapeutic
dosingrange.ADRsorsideeffectscanhavevaryinglevelsofintensity.Forexample,thedrymouthand
blurredvisionthatoccurfromdrugswithanticholinergicpropertiesareconsideredroutinesideeffectsof
thatclassofmedication.Incontrast,drug-inducedliverdamagewouldbeanuncommonandsevereADR
orsideeffectnotroutinelyassociatedwiththatclassofmedication.PatientsexperiencingADRsorside
effectsfromdrugsdonotnecessarilyrequirediscontinuationoftherapy;however,properdrugselection
emphasizing agents with minimal side effect profiles may help improve patient acceptance of and
compliancewiththedrug.
MedicationErrors
MedicationerrorsarealsoapotentialcauseofADRs.Theseerrorscouldrangefromswitchingfromone
dosageformtoanothertousingforeigndrugs.Table3.9listssomepotentialcausesofADRs.Somedrugs
maylookalikeand soundalike.The Institute for SafeMedicationPractices (2015) provides a list of
drugs withconfuseddrugnames. For example, Figure 3.3 shows two look-alike vials of drugs were
mixedupandapatientinadvertentlyreceivedphenylephrineinsteadofmetoclopramide.Phenylephrineis
apotentbloodvesselvasoconstrictoroftenusedtomanagehypotension.Metoclopramideisadrugoften
usedtotreatnauseaandvomiting.Theeventcanleadtopulmonaryedemaandcardiacarrest.
TrackingDrugInteractionsandAdverseDrugReactions
TheinitialsourceofdocumentedADRscomesprimarilyfromtheexperiencegainedwhileusingadrug
during clinical trials. Usually, the number of people taking the drug in clinical trials, on the order of
hundreds to several thousands, is too few to detect all the possible adverse reactions from the drug.
However,afteradrugisapprovedbytheFDA,itbecomesreadilyavailableforpublicuseinhundredsof
thousandstomillionsofpeople.ThepotentialfordruginteractionsandADRsthenbecomesmuchgreater
thanduringclinicaltrials.
TABLE3.9
PotentialCausesofMedicationErrors
PotentialCausesof
MedicationErrors
Example
Dosageconversion WhenconvertingfromoraltoIVmedicationsandviceversa,itisoftennota1to1
conversion.Levothyroxine100mcgoraldoseisequalto~50mcgIVdose.
Foreigndrugs Dilacoristhebrand-namedrugfordiltiazemintheUnitedStates.InSerbia,itisthebrand-
namedrugfordigoxin.
Illegiblehandwriting IsordilwasmistakenlyfilledwithPlendil.
Lookalikeandsound
alike
Phenylephrinevialmistakenformetoclopramidevial.
Unacceptable
abbreviations
Insulin5.0unitswasmistakenfor50units.
IV,intravenous.
FIGURE3–3Look-alikedrugs:Phenylephrinevialwasmistakenforametoclopramidevial.
Therefore, practitioners should have a basic understandingof drug interactions and ADRs and report
theseeventstotheFDAwhentheyoccur.
MedWatchisamedicalproductreportingprogramconductedbytheFDA(Figure3.4).Thethreeways
tosubmitaMedWatchreportare byphone(1-800-FDA-1088),byfax(1-800-FDA-0178),oronlineat
www.fda.gov/medwatch/report.htm. The purpose of the MedWatch program is to enhance the
effectivenessofsurveillanceofdrugsandmedicalproductsaftertheyaremarketedandastheyareused
inclinicalpractice.ThebenefittohealthcareprovidersforreportingdruginteractionsandADRsisto
ensurethatdrugsafetyinformationisrapidlycommunicatedtohealthcareprofessionals,thusimproving
patientcare.Healthcareprovidersshouldalsobeawareofprogramsintheirowninstitutionsthatcollect
andreportADRsordruginteractions.
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