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clearance.
Box2.4 RelationshipamongApparentVolumeofDistribution,Clearance,andHalf-Life
ClearanceisusuallyexpressedasL/hour;VdisinL;tyisusuallyinhours.
Clearance of a drug is directly dependent on the apparent volume of distribution and inversely
relatedtotheeliminationhalf-life.ThelargertheVd,thefastertheclearance.Also,thesmallerthety,
thefastertheclearance.
Becausemostdrugsare“cleared”throughthekidney,estimatingtherenaleliminationrateorclearance
can help the practitioner to understand how fast a drug is being eliminated in an individual patient.
Because directly measuring the clearance of the kidney is time intensive and often impractical, the
kidney’sabilitytocleardrugsisestimatedthroughasurrogatesubstrate:creatinine.Creatinine,whichis
produced through the continual breakdown of muscle tissue and eliminated largely by glomerular
filtration,isnotsignificantlysecretedorreabsorbed.Therefore,inestimatingthecreatinineclearance,the
practitioner can also estimate the glomerular filtration rate (GFR). The level of creatinine is usually
measuredthroughabloodtest(serumcreatinine),withnormalvaluesrangingfrom0.8to1.2mg/dL.
InordertoestimatetheGFR,thepractitionergenerallyusesoneofthreeequations(listedinorderof
mostaccurateto leastaccurate): theChronic KidneyDisease Epidemiology Collaboration(CKD-EPI)
equation,theModificationofDietinRenalDisease(MDRD)studyequation,orthe
Cockcroft-Gault(CG)equation.Theseequationsconsiderpatientdemographicssuchasweight,gender,
and race in order to estimate creatinine clearance and evaluate the kidney’s ability to function and
eliminate drugs. However, each equation will produce a different result using the same patient
demographicsandeachhascaveats(seeTable2.3).
TABLE2.3
EstimatingCreatinineClearanceUsingCurrentlyAcceptedFormulas
CG,Cockcroft-Gault;CKD-EPI,ChronicKidneyDiseaseEpidemiologyCollaboration;GFR,glomerularfiltrationrate;MDRD,Modificationof
DietinRenalDisease.
Forexample,a40-year-oldwhitemalewhois70in.tallandweighs70kgandhasaserumcreatinine
of2.0mg/dLhasanestimatedcreatinineclearanceof41mL/min/1.73m2(CKD-EPI),37 mL/min/1.73
m2(MDRD),and49mL/min(CG).
Inanycase, creatinineclearanceorGFRvaluesbelow50mL/minsuggestsignificantimpairmentof
renal functionandthuspossible impairmentofrenal drugelimination.This mayresultinadministered
drugshavinglongerhalf-livesandhighersteady-stateconcentrations,whichmayresultintoxicityifthe
doseisnotdecreasedorthelengthoftimebetweendosesisnotincreased.
Noteverypatientneedstohavecreatinineclearanceestimated.Tworulesofthumbareusefulforthe
practitioner:Patientsolderthanage65orthosewithaserumcreatininevaluegreaterthan1.5mg/dLmay
beatriskforaccumulatingdrug(andthereforetoxicity)becauseofdecreasedrenalfunction.Inpatients
with either of these characteristics, a baseline and routine evaluation of renal function (e.g., serum
creatininedetermination)shouldbeperformed.
PHARMACODYNAMICS
Pharmacodynamics refers to the set of processes by which drugs produce specific biochemical or
physiologicchangesinthebody(howthedrugaffectsthebody). Mostoften,pharmacodynamiceffects
occurbecauseadruginteractswithareceptor.Receptorsmaybecellmembraneproteins,extracellular
enzymes, cytoplasmicenzymes,orintracellular proteins.Areceptoristhecomponentofthecell(oran
enzyme)towhichanendogenoussubstancebinds,or attaches,initiatinga chainofbiochemical events.
Thischainofbiochemicaleventsculminatesinachangeinthephysiologicfunctionofthecelloractivity
of the enzyme. Like endogenous substances, drugs can initiate the biochemical chain of events. For
example,adrugstimulatingareceptoronthesurfaceofanarterymayultimatelycausevasoconstrictionor
vasodilation;or thedrug’s bindingtoa receptormayproducea changeincell wall permeability,thus
allowingothersubstancestoenterorleaveacell,asinnervecells;orthedrugattachedtoareceptormay
initiateanincreaseordecreaseintheproductionofanenzyme,therebychangingtheamountofenzymatic
activityforagivenprocess.
Anychemical,endogenousorexogenous,thatinteractswithareceptoriscalledaligand. Regardless
oftheligand,or theactual interactiontype,a substancecanonlyalterormodifyacellorprocess,not
impartanewfunction.
DrugReceptors
Thecapacityofadrugtobindtoareceptordependsonthesizeandshapeofthedrugandthereceptor.
Thedrugactsasa“key”thatfitsintoonlyacertainreceptororreceptortype(Figure2.7).Oncethedrug
fitsintothereceptor,it mayactto “unlock”theactivityofthereceptor,thus initiatingthebiochemical
chainofevents,muchlikeanignitionkeyinitiatesthechainofeventsthatstartsacar.
Drugreceptors arecommonlyclassifiedbytheeffecttheyproduce.Somedrugsinteractwithseveral
receptors,causingmultipleeffects,whereasothersinteractwithonlyaspecificreceptor,elicitingasingle
response. Epinephrine, for example, interacts with the alpha and beta receptors of the sympathetic
nervous system. As a result, epinephrine produces vasoconstriction (alpha receptor action) and an
increaseinheartrate(betareceptoraction).Variousmoleculesorenzymescanserveasdrugreceptors,
such as ion channels (calcium channels), enzymes (angiotensin-converting enzyme [ACE]), and even
receptors thatgenerateintracellular secondmessengers(substancesthatinteractwithotherintracellular
components).
FIGURE2–7Druganddrug-receptorinteractionandsignaltransduction.Thefiveprimaryreceptorsand
theirmechanismsofsignaltransductionare(1)gatedionchannels;(2and3)transmembranousreceptors–
cytoplasmicenzymeandtyrosinekinaseactivated;(4)Gprotein-coupledreceptors;and(5)intracellular
receptors.
Therearefourknowntypesofreceptors:gatedionchannels,transmembranousreceptors,Gprotein–
coupledreceptors, andintracellular receptors (seeFigure2.7). Understandingthese receptors andthe
signalstheygenerateiscentraltounderstandingtheactionsofmanydrugs.
GatedIonChannels
Thefunctionofgatedionchannel receptorsisto openor close channels toallow certainionstopass
throughthecellmembrane.Bindingofligandstothesereceptorsproducesaconformationalchangethat
widensornarrowsthechannel,therebyregulatingtheaccessofsolubleions(Figure2.7).Thenicotinic
acetylcholinereceptorisagoodexampleofagatedionchannelreceptor.Itsfunctionistotranslatethe
signal from acetylcholine into an electrical signal at the neuromuscular endplate. As such, when
acetylcholinebindstothisreceptor,thechannelopens,allowingsodiumorpotassiumtoenterthecelland
causecellulardepolarization.
Other types of gated ion channel receptors are associated with the neurotransmitters. Gammaaminobutyric acid (GABAA), the primary inhibitory neurotransmitter,opens a chloride channel in the
cell,whichminimizesthedepolarizationpotential.Certaindrugs,suchasthebenzodiazepines,bindtoan
allosteric site andenhance the activityof GABAAby increasing the openingofthe chloride channel.
Thereisnointrinsicactivityattheallostericsite,anditservesonlytoenhancetheprimaryactionofthe
endogenousligand.Other excitatoryneurotransmitters, suchasL-glutamate andL-aspartate,operate by
thismechanism,calledsignaltransduction,whichtransfersthesignalquickly.
TransmembranousReceptors:CytoplasmicEnzymeorTyrosineKinaseActivated
Atransmembranousreceptorhasitsligand-bindingdomain,thespecificregiontowhichligandsbind,on
thecell’ssurface.Theenzymaticportionofthereceptorisinthecellcytoplasm.Whenaligandbindstoa
transmembranous receptor, several things may occur. The receptor–ligand complex produces a
conformationalchangeinthereceptorandtriggersaresponse.Alternatively,theligand–receptorcomplex
can pass through the cell membrane and trigger an intracellular response directly. This intracellular
responseoftenisachangeinenzymaticactivity.Akeyfeatureofthetransmembranousreceptorresponse
isthedownregulationofthereceptorsora decreaseinthenumberofreceptorsavailableforresponse.
Theoppositeofthisisupregulation,whichdoesnotoccurasfrequently.Thenatureofthesignaldepends
on the specific ligand–receptor interaction, but it commonly results in the generation of second
messengers. A second messenger is an intracellular chemical that interacts with other intracellular
components. Ions such as calcium and potassium, along with cyclic adenosine monophosphate, are
common second messengers. Hormones and other endogenous substances, such as growth factors and
insulin,oftenoperatewiththissignalingmechanism.
Thereceptortyrosinekinasesignalingpathwaycanbindwithapolypeptidehormoneorgrowthfactor
atthereceptor’sextracellular domain.Thisresultsinenzymaticallyactivetyrosinekinasedomainsthat
phosphorylate each other, allowing a single receptor to activate multiple biochemical processes. For
example,insulinworksbystimulatingtheuptakeofglucoseaswellasaminoacids,resultinginchanges
inglycogencontentwithinthecell.Alternatively,inhibitionoftyrosinekinaseprocessesthroughblockage
oftheexternalreceptorcanresultinadecreaseinstimulationofgrowthfactorswithinthecell.Thisis
particularly important in cancer treatments, when inhibiting the growth of the cell is key to treatment
success.
Adrawback of this system is the potential for downregulationof thereceptors. Activation of these
receptorsleadstoanendocytosisofthereceptorandsubsequentreceptordegradation.Whenthisactivity
exceedsthe productionofnew receptors, there isa reductioninthenumberofreceptors availablefor
stimulation,thusresultinginadecreaseinthecell’sactivity.
GProtein–CoupledReceptors
G protein–coupled receptors are another family of receptors that generate intracellular second
messengers. These receptors also exist as transmembranous receptors composed of an extracellular
proteinreceptorandanintracellulartypeGprotein.Theinteractionofaligandandthereceptorproduces
aconformationalchangeinthereceptor,bringingitincontactwiththeGprotein.Thiscontactresultsin
activationof an enzyme or opening of an ion channel in the cell and,in turn,increased levels ofthe
secondmessenger.Itisthesecondmessengerthattriggersachangeinthefunctionofthecell.Alpha-and
beta-adrenergicreceptors,alongwithseveralhormonereceptors,useGproteinstoaffectcellfunction.
IntracellularReceptors
Lipid-solubledrugscantraversethelipidbilayerofthecellandenterthecytoplasm.Onceinside,these
drugs attach to intracellular receptors and initiate direct changes in the cell by affecting DNA
transcription.Glucocorticoidsandsexhormonesareknowntoactbythissignalingmechanism.
Drug–ReceptorInteractions
Theabilityofadrugtobindtoanyreceptorisdictatedbyfactorssuchasthesizeandshapeofthedrug
relative totheconfigurationofthebindingsiteonthereceptor.Theelectrostaticattractionbetweenthe
drugandthereceptor may also be importantin determining the extent to whichthedrug binds to the
receptor.
Affinity
Adrugattractedtoareceptordisplaysanaffinityforthatreceptor.Thisaffinity, thedegreetowhicha
drugisattractedtoareceptor,isrelatedtotheconcentrationofdrugrequiredtooccupyareceptorsite.
Drugsdisplayingahighaffinityforagivenreceptorrequireonlyasmallconcentrationinthecirculation
toelicita response, whereas thosewitha lowaffinityrequire highercirculatingconcentrations.There
existsanequilibrium amongtheblood concentrationof a drug,theconcentrationof drugat the site of
action(i.e., near thereceptor),andtheamountofdrugboundtoa receptor.Themagnitudeofadrug’s
effectcanbeexplainedbythereceptor occupancytheory—thatis, a responsefroma cell(orgroupof
cells)dependsonthefractionofreceptorsoccupiedbyadrugorendogenoussubstance.Therefore,one
caninferarelationshipbetweentheminimallyandthemaximallyeffectiveconcentrationsneededatthe
siteofactionandtheminimumandthemaximumbloodconcentrations.
Chirality
Theshapeofadrugcaninfluenceitsinteractionwithareceptor.Mostdrugsdisplaychirality—thatis,
theyexistin two forms, with mirror-image spatial arrangements called enantiomers, orisomers. Each
enantiomerisdistinguishedfromtheotherthroughitsabilitytorotatepolarizedlightinpuresolutionto
the right or left. This results in a dextrorotatory enantiomer, or D-enantiomer, and a levorotatory
enantiomer,orL-companion.
Apair ofenantiomers is likealeftanda righthand.As such,enantiomeric pairsmaynotfitintoa
receptor equally well, just as a right hand does not fit well into a left-hand glove. This is called
stereoselectivity;oneenantiomermayfitbetterintoareceptorthantheotherand,hence,bemoreactive.
Forexample,thedrugdextromethorphan(the“DM”inRobitussinDM)istheD-isomerofacompound.
ThisD-isomerisacommoncoughsuppressantfoundinmostover-the-countermedications.ItsL-isomer
counterpart, levorphanol (Levo-Dromoran), is an extremely potentnarcotic analgesic. Although the Lisomeralsopossessescoughsuppressantactivity,theD-isomerisessentiallydevoidofanalgesicactivity
atcommonlyuseddoses.Thisexampleillustratestheimportanceofisomersinpharmacodynamics.
AgonistsandAntagonists
Notalldrugswithanaffinityforareceptorelicitaresponse.Drugsthatdisplayadegreeofaffinityfora
receptorandstimulatearesponseareconsideredagonists.Othersthatdisplayanaffinityanddonotelicit
a response are called antagonists. Antagonists do not have intrinsic activity; they can only block the
activity of the endogenous agonist. An antagonist may be viewed as a key that fits into the lock but,
becauseofitsdifferentconfiguration,cannotbeturned.Becauseanantagonistcanoccupy, or fitinto,a
receptor,itcompeteswithagonistsforthatreceptor,therebyblockingtheeffectoftheagonist.Antagonists
with a highaffinity for a receptor may be able to “bump”anagonist off the receptor and reverse the
agonistactivity.Antagonistsusuallyareusedtoblocktheactivityofanendogenoussubstance,butthey
also canbeusedtoblocktheactivityofexogenouslyadministered drugs.Forexample,whennaloxone
(Narcan)is giventoapatienttakingopioiddrugs,theanalgesic(andadverse)effectsoftheopioidare
reversedwithin1to2minutes.Inmostcases,naloxonehasahigheraffinityfortheopioidreceptorthan
the opioid itself. This rough explanation of drug–receptor interactions serves only as a basis for
understandingthecomplexityofthisinterplay.
Dose–ResponseRelationships
Formanydrugs,therelationshipbetweenthedoseandtheresponseisobvious:Lowerdosesproduce
smallerresponses,whereashigherdosesincreasetheresponse.Thiscorrelationisbasedontheamount
ofdrugoccupyingspecificreceptors.Astheamountofdrugexceedsthenumberofavailablereceptors,
the response reaches a plateau, so that further increases in dose do not increase response. However,
dose–responserelationshipssuchastheseclearlydependontheaffinityofadrugforareceptor:Adrug
withahighaffinityfora receptor needsa significantlylowerconcentrationtoachieve thesameeffect
comparedtoadrugwithaloweraffinity.
This difference in affinity accounts for the varying “potency” ofdrugs. For example, drugs such as
hydromorphone(Dilaudid)andmorphineproducethesameeffect:analgesia.However,hydromorphoneis
more potent than morphine and therefore requires a smaller concentration to elicit a similar level of
analgesia.Figure2.8demonstratesatypicaldose–responserelationship.
FIGURE2–8 Two drugs with differingreceptor affinities produce similar effects at different dosage
ranges.Thedrugwiththegreateraffinity(solidline)requireslessdrugtoproducethesameeffectasa
drugwithlessaffinity(dottedline).Thisdemonstratestherelationshipbetweenreceptoraffinityanddrug
potency.
FACTORSAFFECTINGPHARMACOKINETICSAND
PHARMACODYNAMICS
Thegoalofpharmacotherapeuticsistoachieveadesiredbeneficialeffectwithminimaladverseeffects.
Once a medication has been selectedfor a patient, the practitioner must determinethedose thatmost
closely achieves this goal. A rational approach to this objective combines the principles of
pharmacokinetics withthose of pharmacodynamics toclarifythedose–response relationship.Knowing
therelationshipbetweendrugconcentrationandresponseallowsthepractitionertotakeintoaccountthe
variouspathologicandphysiologicfeaturesofaparticularpatientthatmakehisorherresponsedifferent
fromtheaverageperson’sresponsetoadrug.
PatientVariables
Ahostofvariablesaffectsthedispositionofadruginthebodyandthereactionthebodyhastothedrug.
Peoplevaryintheirbodytype,weight,diet,ethnicity,andgeneticmakeup.Thesefactors,individuallyand
combined,contributetosignificantvariationintheirresponsetodrugtherapy. Forexample,thegenetic
makeupofthepeopleofJapanisknowntoaffecttheexpressionofcertainhepaticenzymesinvolvedin
the metabolism of drugs. This suggests that, at least pharmacokinetically, some people of Japanese
heritageresponddifferentlytocertaindrugs.Thesamelogicappliestopeoplewhoareoverweightand
underweight,people ofvaryingages,peoplewithvariouspathophysiologicproblems,andevenpeople
withdifferentdietsandnutritionalhabits.
Pathophysiology
Structural or functional damage to an organ or tissue responsible for drug metabolism or excretion
presentsanobviousprobleminpharmacology.Diseasesthatinitiatechangesintissuefunctionorblood
flow to specific organs candramaticallyaffecttheelimination ofvariousdrugs. Certaindiseases may
also impair the absorption and distribution of the drug, complicating the problem of individualized
response.Theroleof diseaseinaffectingthepatient’sresponse is crucial becausetheresponse to the
medication may be affected by the same pathologic process that the drug is being used to treat. For
instance,renal excretionofantibiotics, suchas aminoglycosides, is altered radically inmanytypesof
bacterialinfection,butthesedrugsaretypicallyadministeredtotreatthesameinfectionsthataltertheir
own excretion. Consequently, great care must be taken to adjust the dosage accordingly when
administeringmedicationstopatientswithconditionsinwhichdrugeliminationmaybealtered.
Genetics
Geneticdifferencesareamajorfactorindeterminingthewaythatpeoplemetabolizespecificcompounds.
Geneticvariationsmayresultinabnormalorabsentdrug-metabolizingenzymes, creatingunpredictable
individual responses to medicationtherapy despitetheadministrationof the samedruganddose. The
anomalycanbeharmfulorevenfatalifthedrugcannotbemetabolizedandthereforeexertsatoxiceffect
fromaccumulationorprolongedpharmacologicactivity.Geneticmutationsmayincludemutationssuchas
single nucleotide polymorphisms (SNPs), gene deletions, or gene duplications. Some people, for
example,lacktheenzymethatbreaksdownacetylcholine.Inthesepeople,aneuromuscularblockingdrug
such as succinylcholine (Anectine, an acetylcholine-like drug usually used to induce paralysis for
procedures) isnotdegradedandthereforeaccumulates.Theresultisrespiratoryparalysis becausethe
undegraded,accumulatedsuccinylcholinehas anincreased half-life, causingit toremainactivelonger.
Pharmacogenomics, or the study of responses of individuals to medication based on their genome, is
emergingas thefield ofmedicine dedicated to precisionor personalizedmedicine.See Chapter 7 for
moredetails.
Age
The influence of age on pharmacokinetics and pharmacodynamics is well known. Developmental
differencesintheneonate,toddler,andyoungchild,forinstance,influencehowdrugsarehandledbythe
GItract,liver,andkidneys.Ofequalimportanceis howthesechildrenrespondtodrugsinlightofthe
presence or absence of receptors at different stages of development. For example, drug-metabolizing
enzymes are deficient in the fetus and premature infant. The fetus can metabolize drugs early in its
development,butitsexpressionofdrug-metabolizingenzymesdiffersfromthatintheadultandisusually
lessefficient.
Childrencanmetabolizemanydrugsmore rapidlythanadults,andaschildrenapproachpuberty,the
rateofdrugmetabolismapproachesthatofadults.Similarly, olderadultsundergophysiologic changes
that affect theabsorption,distribution, andelimination ofmanyagents.Thepharmacodynamic changes
imparted by age as well as accompanying diseases pose a greater challenge for the practitioner in
understanding the impact a single agent has ona patient’shealth and well-being. Chapter 4 discusses
pediatricconsiderations,andChapter5discussesgeriatricconsiderationsingreaterdetail.
Sex
Theroleofsexasadistinctpatientvariableisrecognizedbysomebutpoorlyunderstoodbymost.Most
ofthepublishedclinicaldrugstudiesusedmalesubjectsastheprimarystudypopulation,andclinicians
thenextrapolatedthedatatofemales.However,femalesingeneralhaveahigherpercentageofbodyfat,
which could ultimately alter the pharmacokinetic disposition of certain drugs. Similarly, the
pharmacodynamicresponseoffemalesmaybedifferentbecauseofthepresenceorabsenceofhormones
suchasestrogenandtestosterone.Transgender/transsexualpatientspresentanotherchallenge;however,
currentthinkingsuggestsusingtheirbiologicallyassignedgendertoestimateCrCl.
Ethnicity
Ethnicity is a significant factor in both the pharmacokinetic and the pharmacodynamic responses of
patients. The genetic makeup of various ethnic populations governs the levels of hepatic enzymes
expressedinthesegroups.Equallyimportantarethehabitsandtraditionsofcertaingroups,suchasdiet
ortheuseofhomeremedies.
Pharmacodynamically,ethnicallybaseddifferencesexistintheresponsestoagents.Anexampleisthe
minimalresponseofAfricanAmericanpatientstomonotherapywithsomedrugs,suchasACEinhibitors.
AfricanAmericansproducealowlevelofrenin,akeycomponentintherenin–angiotensin–aldosterone
systembywhichtheACEinhibitorswork.Thislowlevelofreninmakesthissystemunaffectedbythe
ACEinhibitor,therebynegatingitseffect.
DietandNutrition
Dietaffectsthemetabolismofandresponsetomanydrugs.Animalandhumanstudiesindicatethattotal
caloricintakeandthepercentageofcaloriesobtainedfromdifferentsources(carbohydrates,proteins,and
fats) influencedrugpharmacokinetics. Specific dietaryconstituents,suchascruciferousvegetables and
charcoal-broiled beef,canalsoalter drugmetabolism.Fortunately,mostfood–druginteractionsarenot
serious and do not alter the clinical effects of the drug. However, a few well-known food and drug
combinations should be avoided because oftheir potentiallyserious interactions. For instance,certain
tyramine-containing foods, such as fermented cheese andwine,should not be ingestedwith drugs that
inhibit the monoamine oxidase enzyme (MAO) inhibitors. Tyraminerich foods stimulate the body to
release catecholamines (norepinephrine, epinephrine). MAO-inhibiting drugs work by suppressing the
destruction of catecholamines, thereby allowing higher levels of norepinephrine and epinephrine to
accumulate. Consequently, when MAO inhibitors are taken with tyramine-containing foods, excessive
catecholamine levels may develop and lead to a dangerous increase in blood pressure (hypertensive
crisis).Practitionersshouldbeawareofthisandshouldbeonthealertforothersuchinteractionsasnew
drugsarriveonthemarket.
CASESTUDY1
J.R.isa90-year-oldJapanesemale.Hehasbeenaonepackperdaysmokerforthepast50years.J.R.
weighs98kgandis67in.tall.Headmitstoeatingadietrichinprocessedfoodsandunhealthyfats.
Hewasrecentlydiagnosedwithrenalinsufficiency(creatinineclearanceof32mL/min).Hecomesto
you because he recently started having some shortness of breath while he is resting and you are
consideringaddingafewnewmedicationstohisregimen.
1.Whichpharmacokineticandpharmacodynamicconsiderationsdoyouneedtotakeintoaccountin
order to prescribe medicine safely to J.R., and what are the possible impacts of each of these
considerations?
Answer:
Administration/Absorption:Smoker,so inhalationroutemaynotbe best;obese,sotransdermal
absorption may be affected; shortness of breath may also impact ability to give inhaled
medications.
Distribution:High-fatdiet,soconsiderthatwhenprescribingoralmedications;patientisobese,
considervolumeofdistribution.
Metabolism: Smoking can alter metabolismof some medications; Japanese ethnicity can alter
metabolismofsomemedications;considerifdrugisaprodrugortheactiveform.
Elimination: Renal insufficiency canaltereliminationofsomemedications-consider ifdrugis
renallyeliminated.
Age:Anolderpatient;thismayaffectmanyoftheprinciplespreviouslymentioned.
CASESTUDY2
M.T., a 75-year-old,60-kg(idealbodyweight[IBW]) whitefemalewithaserumcreatinineof1.8
mg/dL, has atrial fibrillation. A decision has been made to use digoxin for treatment. The target
concentrationofdigoxinforthetreatmentofatrialfibrillationis0.5ng/mLtolessthan1ng/mL,buther
currentlevelishigh,at2ng/mL.
1. Whatis her estimatedcreatinineclearanceusingthe Cockcroft-Gault(CG) method?Glomerular
filtrationrate(GFR)usingtheModificationofDietinRenalDisease(MDRD)method?
Answer:
2.Assuminga4-dayhalf-life,howlongwillittakeforM.T.toachievea1ng/mLlevel?A0.5ng/mL
level?
Answer:
From2ng/mL→1ng/mL=1half-life=4days.
From1ng/mL→0.5ng/mL=1half-life=4moredaysor8daystotal.
Bibliography
Ahmed, S., Zhou, Z., Zhou, J., et al. (2016). Pharmacogenomics of drug metabolizing enzymes and transporters: Relevance to precision
medicine.GenomicsProteonomicsBioinformatics,14(5),298–313.
Bishop, B. M. (2015). Pharmacotherapy considerations in the management of transgender patients: A brief review. Pharmacotherapy,
35(12),1130–1139.
Brunton,L.,Brunton,L.,Knollmann,B.,et al.(2018).Goodman &Gilmans thepharmacologicalbasis oftherapeutics,13th ed. New
York:McGraw-HillMedical.
Chudek,J.,Kolonko,A.,Owczarek,A.,etal.(2018).ClinicalfactorsincreasingdiscrepanciesofrenalfunctionassessmentwithMDRDand
Cockcroft-Gaultequationsinoldindividuals.EuropeanGeriatricMedicine,9,713–720.
DiPiro,J.(2017).Pharmacotherapy:Apathophysiologicapproach,10thed.NewYork:McGraw-HillEducation.
Katzung,B.,&Katzung,B.(2018).Basic&clinicalpharmacology,14thed.NewYork:McGraw-Hill.
Lew,A.,Crass,R.,& Eschenauer,G.(2020).Evolutionofequationsforestimatingrenalfunctionandtheirapplicationtothedosingofnew
antimicrobials.AnnalsofPharmacotherapy,54(5),496–503.
National Kidney Disease Education Program. (2000–2019). Retrieved from https://www.niddk.nih.gov/health-
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.
Ahmed, S., Zhou, Z., Zhou, J., et al. (2016). Pharmacogenomics of drug metabolizing enzymes and transporters: Relevance to precision
medicine.GenomicsProteonomicsBioinformatics,14(5),298-313.
Bishop, B. M. (2015). Pharmacotherapy considerations in the management of transgender patients: A brief review. Pharmacotherapy,
35(12),1130-1139.
Brunton,L.,Brunton,L.,Knollmann,B.,et al.(2018).Goodman &Gilmans thepharmacologicalbasis oftherapeutics,13th ed. New
York:McGraw-HillMedical.
Chudek,J.,Kolonko,A.,Owczarek,A.,etal.(2018).ClinicalfactorsincreasingdiscrepanciesofrenalfunctionassessmentwithMDRDand
Cockcroft-Gaultequationsinoldindividuals.EuropeanGeriatricMedicine,9,713-720.
DiPiro,J.(2017).Pharmacotherapy:Apathophysiologicapproach,10thed.NewYork:McGraw-HillEducation.
Katzung,B.,&Katzung,B.(2018).Basic&clinicalpharmacology,14thed.NewYork:McGraw-Hill.
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