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Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5200_Библиотеки_им_академика_М_И_Перельмана

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conditions.
BloodFlow
Bloodflowensuresthattheconcentrationacrossagradientiscontinuallyinfavorofpassivediffusion— thatis,asbloodflowsthroughanarea,itcontinuallyremovesthedrugfromthearea,therebymaintaining a positive concentration gradient. Many hydrophobic–lipophilic drugs can readily pass through membranesandbeabsorbed.However,ifthebloodflowtothatareaislimited,theextentofabsorptionis limited.Becauseoftheminimalvascularizationinthesubcutaneous(SC)layercomparedwiththegreater vascularityofthemusculature,drugsinjectedsubcutaneouslymayundergolessabsorptioncomparedwith drugsdeliveredbyIMinjection.
GastrointestinalMotility
High-fatmealsandsolid foodsaffectGItransittimebydelayinggastricemptying,whichinturndelays initial drug deliverytointestinal absorptionsurfaces. Theadministrationofagents that delay or slow intestinalmotility(e.g.,anticholinergicagents)prolongsthecontacttime.Thisincreasedintestinalcontact time secondary to prolonged intestinal transit time may increase total drug absorption. Conversely, laxativesor diarrheacanshortenanagent’scontacttimewiththesmallintestine,whichmaydecrease drugabsorption.
EnteralAbsorption
Enteralabsorption,withtheoralrouteofadministrationbeingthemostcommonandprobablythemost preferred,occursanywherethroughouttheGItractbypassiveoractivetransportofthedrugthroughthe cellsoftheGItract.
FollowingFick’slaw,lowmolecularweight,nonionizeddrugsdiffusepassivelydownaconcentration gradientfromthehigherconcentration(intheGItract)tothelowerconcentration(intheblood).Active transportacrosstheGItractoccursmorefrequentlywithlarger,usuallyionized,molecules.Theseactive mechanismsincludebindingofthedrugtocarriermoleculesinthecellmembrane.Themoleculescarry thedrugacrossthelipidbilayerofthecells.However,mostdrugsareabsorbedpassively.
OralAdministration
Theoralrouteofadministrationreferstoanymedicationthatistakenbymouth(perosorPO).Theability toswallowisimplicitinoraladministration;however,manypractitionersconsiderlocalaction,inwhich absorptiondoes notoccur,alsotobe “oral”(e.g.,trochesforfungal infectionsofthemouth).Common dosageformsadministered bymouthincludetablets, capsules, caplets,solutions,suspensions,troches, lozenges,andpowders.
AbsorptionafteroraladministrationusuallyoccursinthelowerGItract(smallorlargeintestine),is slow,anddependsonthepatient’sgastric-emptyingtime,thepresenceorabsenceoffood,andthegastric orintestinalpH.Variationsinoneormoreofthesefactorscanaffectthestabilityofthedrug,thecontact timewiththeintestinalwalls,orthebloodflowtotheGItract.Mostoftheabsorptionoccursinthesmall intestine,wherethelargesurfaceareaenhancesandcontrolsdrugentryintothebody.
DrugsadministeredorallymustberelativelylipidsolubletocrosstheGImucosaintothebloodstream.
Thediffusionrate,afunctionofthelipidsolubilityofadrugacrosstheGImucosa,isamajorfactorin determiningtherateofabsorptionofadrug.TheacidicpHofthestomachandthenearlyneutralpHofthe intestinescandegradesomemedicationsbeforetheyareabsorbed.Inaddition,bacteriainvariousparts oftheintestinessecreteenzymes, whichalsocanbreakdowndrugsbeforeabsorption.Manydrugsare formulatedtopreventthedegradationofthedrugbeforeabsorption.
AlthoughtheGItractisgenerallyresistanttoavarietyofnoxiousagents,considerableirritationand discomfort can arise from certain medications. Nausea, vomiting, diarrhea, and less often mucosal damagearecommonsideeffectsofmedications,andthepractitionershouldmonitorallpatientsforthese effects.
SublingualAdministration
Sublingual(underthetongue,SL)drugadministrationreliesonabsorptionthroughtheoralmucosainto the veins that drain those vascular beds. These veins carry the drug to the superior vena cava and eventually the heart. Drugs administered this way are not subject to thefirst-pass effect because they bypasstheportalvein(seeBox2.2).Thismethodofadministrationislimitedbythesmallamountofdrug that canbeplaced sublinguallyandthe drug’sability to pass through theoralmucosainto the venous system.Buccaladministration,inwhichthedrugisabsorbedthroughthemucousmembranesofthemouth byputtingthedosageforminthebuccal/cheekarea,issimilartoSLadministration.
RectalAdministration
Drugs administered rectally(perrectum, PR) include suppositories andenemas.Primarily usedin the treatmentof local conditions (e.g., hemorrhoids) andinflammatorybowel disease, this methodis less effectivethanotherenteralroutesbecauseoftheerraticabsorptionofmostagents.Bowelirritation,early evacuation,andminimalsurfaceareacontributetoerraticabsorptionandpoortolerabilityofthisroute. Advantages, however, include the ability to administer a medication to an unconscious or nauseated patient.Rectaladministrationofmedicationsbypassessomeofthefirst-passeffect(seeBox2.2).
ParenteralAbsorption
AllroutesofadministrationnotinvolvingtheGItractareconsideredparenteral.Parenteralroutesinclude inhalation,allformsofinjection,andtopicalandtransdermaladministration.
Inhalation
Drugsthataregaseousorsprayableinsmallparticlesmaybedeliveredbyinhalation.Thelungsprovide alargesurfaceareaforabsorptionandquickentryintothebloodstream.Inhaledmedicationsbypassthe first-passeffectandthereforemayhaveahighbioavailability.Examplesofsystemicallyactiveinhalants are anesthetic gases andbeta-adrenergic agonists (e.g.,albuterol) usedin treating asthma. Conversely, agentssuchasinhaledcorticosteroidsareintendedforlocalactioninthelungtissue.Regardlessofthe intentofinhaledmedications,thedisadvantagesincludeirritationtothealveolarspaceandtheneedfor goodcoordinationduringself-administration,suchaswithmetered-doseinhalers.
IntravenousAdministration
Theintravenous(IV)routeprovidesrapidaccesstothecirculatorysystemwithaknownquantityofdrug. Bypassingthefirst-passeffectandanyGImetabolismor degradation,drugabsorptionbythis routeis consideredthegoldstandardwithregardtobioavailability.IVbolusinjectionsallowforlargeamounts ofmedicationtobeadministeredquicklyforahighpeakdruglevelandarapideffect.However,adverse effectsfromthesehighlevelsofmedicationsalsooccurwiththisformofadministration.Repeatedbolus dosesofmedications,atdesignatedintervals,canproducelargefluctuationsinpeakandtrough(lowest concentration before next dose) levels. Although over time these peaks and troughs produce average desiredconcentrations,significantpeakandtroughfluctuationsmaynot be desirableinsome patients. ContinuousadministrationviaanIVinfusioncanminimizeoreliminatethesefluctuationsandproducea consistent,steady-stateconcentration.
Like IV administration, intra-arterial administration produces a rapid effect. However, because the drugis directlyinstilledinanorgan,thisrouteisconsidered more dangerousandinvasive thantheIV route.Therefore,intra-arterialadministrationisusuallyreservedforatimewheninjectionintoaspecific tissueisindicated(e.g.,anticancertreatmentforaspecifictumor).
SubcutaneousAdministration
Subcutaneous(SCorSQ)administrationproducesaslower,moreprolongedreleaseofmedicationinto thebloodstream.Injecteddirectlybeneaththeskin,adrugmustdiffusethroughlayersoffatandmuscleto encounter sufficientblood vessels for entryintothe systemic circulation. This route is limited by the quantityoftheliquidsuitableforadministration(usually2to3mL).Cautionmustalsobetakenbecause dermalirritation,orevennecrosis,mayoccur.Morerecenttechnologicaladvancesallowthepractitioner to implant drug-releasing mechanisms under the skin, providing a reservoir of drug for long-term absorption.Etonogestrel(Nexplanon),ahormonalcontraceptive,isadministeredinthismanner.
IntramuscularAdministration
Injectingmedicationsintothehighlyvascularizedskeletalmuscleisawayofadministeringdrugsquickly butavoidingtherelativelylargechanges inplasmalevelsseenwithIVadministration.Localpainand muscle soreness are drawbacks to this method, as is the wide variability in the rate of absorption resultingfrominjectionsgivenindifferentmusclesandindifferentpatients.Bloodflowtotheareaisthe majorfactorindeterminingtherateofabsorption.Thisisconsideredasafewaytoadministerirritating drugs,althoughnotallIMinjectionsaretrulyIM:Inmorbidlyobesepatients,presumedIMinjectionsmay actuallybeintralipomatous,whichdecreasestherateofabsorptionbecauseofthelowervascularityof fattytissue.
TopicalAdministration
Topicaldrugadministrationinvolvesapplyingdrugs,invariousvehicles(e.g.,liquids,powders),tothe site ofaction,primarilythe skin.Topical ointments, creams,drops,andgels typicallyproducealocal effect. Ointments are occlusive, preventing water absorption or evaporation, and therefore have a hydrating effect and typically produce greater local effects than their cream counterparts. Creams are water soluble and therefore can be washedfrom the skin more readily than ointments.In hairyareas,
creamsarepreferredoverointmentsbecausecreamsarehydrophilicandhenceeasiertoapplyandwash off.Gels,themostwater-solubletopicaldosageform,allowmedicationtobespreadmoreeasilyovera largerarea.
TransdermalAdministration
Transdermal(across the skin) administrationrefers tothe systemicdeliveryof medicationthroughthe skin.Severaltransdermaldrugdeliverysystemsareavailableforawiderangeofmedications,including nicotine(Nicotrol)andfentanyl(Duragesic).Ingeneral,thismethodcontinuouslydeliversmedicationto achieveaconstantbloodlevel.Theconsistentdeliveryofdrugthroughoutthedosingintervalminimizes the peak-to-trough fluctuations seen with other forms of drug administration, thereby minimizing the toxicityassociatedwithhighbloodlevelswhilemaintainingtherapeuticconcentrations.
Distribution
Adiscussionoftheroutesofadministrationofferstheopportunitytoconsiderthefactorsaffectingdrug absorptionandbioavailability;oncethemedicationisinthebody,however,itmustdistributetothesite ofactiontobeeffective.
Distributionofanabsorbeddruginthebodydependsonseveralfactors:bloodflowtoanarea,lipidor watersolubility,andproteinbinding.Foranabsorbeddrugtodistributefromthebloodtoaspecificsite ofaction,theremustbeadequatebloodflowtothatarea.Inpatientswithcompromisedbloodflow(e.g., fromshock),relyingonthebloodtodeliveradrugtoasiteofaction,suchasthekidney,mayberisky.
Inaddition,drugdistributionmaybeaffectedbyobesity,bothimmediatelyafterabsorptionandafter achievinganequilibriumorsteadystateinthebody.Lipid-solubledrugsreadilydistributeintothefatty tissues,wheretheymaybestoredandevenconcentrated.Water-solubledrugs,however,tendtoremainin the highly vascularized spaces of the skeletal muscle. Ideal body weight is usually considered the standardfordeterminingdrugdosage,whichisoftenadjustedforobeseorcachecticpatients.
ProteinBinding
After absorption into the blood (and lymph), a drug maycirculate throughout the body unbound (free drug)orboundtocarrierproteinssuchasalbumin.Theextentofdrugbindingtocarrierproteinsdepends
ontheaffinityofthedrugforthecarrierproteinandtheconcentrationsofboththedrugandtheprotein. Acidicdrugscommonlybindtoalbuminandbasicdrugscommonlybindtoalpha1-acidglycoproteinor
lipoproteins.
FIGURE2–3Relationshipbetweenboundandunbounddrugsandplasmaproteins.
Plasmaprotein bindingis typically a reversible phenomenon, withbindingandunbinding occurring within milliseconds. Therefore, the bound and unbound forms of the drug can be assumed to be at equilibrium at all times. As such, the degree of binding to plasma proteins can be expressed as a percentageofbounddrugtototalconcentration(boundplusunbound).Itisonlytheunboundorfreedrug thatcanexertapharmacologiceffect.Ifthedrugbecomesbound,itbecomesinactivebecauseitcannot leavethebloodstreamorbindtoanenzymeorreceptorandexertitstherapeuticaction(Figure2.3).
Oncethefreedrugiseliminatedfromthebloodstreamthroughmetabolismorexcretion,thebounddrug canbereleasedfromtheproteintobecomeactive.Inessence,thebounddrugmayserveasastoragesite orreservoirofthedrug.Thepercentageofthefreedrugusuallyisconstantforasingledrugbutvaries amongdrugs.Patient-specificfactors,suchasnutritionalstatus,renalfunction,andlevelsofcirculating proteinoralbumin,canchangethepercentageofthefreedrug.
VolumeofDistribution
The amountofdruginthehumanbody cannever be directlymeasured.Observationsaremadeofthe concentrationofdruginplasmaorsometimesinblood.Overtime,theconcentrationofdrugintheplasma depends on the rate and extent of drug distribution to the tissues and on how rapidly the drug is eliminated. For most drugs, distribution occurs more rapidly than elimination. The resultant plasma concentrationafter distributiondependsonthedoseandtheextentofdistributionintothetissues.This extentofdistributioncanbedeterminedbyrelatingtheconcentrationobtainedwitha knownamountof administereddrug.
Forexample,if100mgofanIVdrugisadministeredtoapersonandremainsonlyintheplasmaandif thatperson’stotalplasmavolumemeasures5L,theresultingmeasuredconcentrationofdrugwouldbe20 mg/L(concentration=dose/volume:100mg/5L).However,inreality,fewdrugsdistributesolelyinthe plasma,andmanybindtoplasmaproteins.Drugscommonlybindnotonlytoplasmaproteinsbutalsoto tissue-bindingsitesonfatandmuscle.Inaddition,drugstranslocateintoother“compartments”orspaces throughoutthebody.Thevolume intowhicha drugdistributesinthebodyatequilibrium iscalled the (apparent) volume of distribution (Vd). This volume does not refer to a real volume; rather, it is a
mathematicallycalculatedvolume(Box2.3).Vdisadirectmeasureoftheextentofdistributionofadrug inthebodyandrepresentstheapparentvolumeintowhichadrugmustdistributetocontaintheamountof
drughomogenously.
Drugs that are highly water soluble or highly bound to plasma proteins remain in the blood compartmentanddonotdistributeorbindtofattytissue.ThesedrugshavealowVd,usuallylessthanthe
volumeoftotalbodywater(approximately50L,or0.7L/kg).DrugswithalowVdusuallycirculateat highlevelsintheblood.Incontrast,drugsthatarenothighlyproteinboundandarehighlylipophilichave a high Vd (greater than 150 L, which is greater than the volume of total body water). These drugs distributewidelythroughoutthebodyandmayevencrosstheblood–brainbarrier.
Box2.3 CalculatingtheApparentVolumeofDistribution(Vd)
Vd is usually measured in liters (L);amount in body is usually measured in milligrams (mg); and plasmadrugconcentrationisusuallymeasuredinmilligramsperliter(mg/L).
Theapparentvolumeofdistributionisatheoreticalparametercalculatedbydeterminingtheamount ofdruginthebody(usuallythedoseadministered)dividedbytheconcentrationofdrugintheplasma takenatanappropriatetimeintervalafteradministration.
Elimination
Alldrugsmusteventuallybeeliminatedfromthebodytoterminatetheireffect.Drugscanbeeliminated throughmetabolism(orbiotransformation)ofthedrugfromanactiveformtoaninactiveform.Drugscan alsobeeliminatedbyexcretionfromthebody.Therefore,eliminationisacombinationofthemetabolism andexcretionofdrugsfromthebody.Importantconceptsinunderstandingdrugeliminationarehalf-life, steady state, and clearance. Knowledge of these phenomena in any given patient helps practitioners understandhowlongadrugwilllastinthebodyandhowmuchshouldbegiventomaintaintherapeutic levelsandthereforehelpsindeterminingtheappropriatedoseanddosingintervals.
Metabolism
Metabolism is a functionof thebody designed to change substances into water soluble, more readily excreted forms. The liver primarily performs the body’s metabolic functions because of its high concentrationofmetabolicenzymes.Thisiswhythefirst-passeffectissignificanttothebioavailabilityof adrugadministeredorally.
Otherorgans,suchasthekidneysandintestines,aswellascirculatingenzymesystems,alsocontribute tothemetabolismofdrugs.Metabolicprocessesareusedtodetoxifydrugsandotherforeignsubstances as well as endogenoussubstances. Drugsmaybemetabolizedfromactive componentsintoinactiveor lessactiveones.Somedrugs,however,maybebiologicallytransformedfromaninactiveparentdruginto anactivemetabolite.Thistypeofdrugis calledaprodrugbecauseitisa precursor totheactive drug (Table2.1).Notalldrugsaremetabolizedtothesameextentorbythesamemeans.Infact,somedrugs, suchastheaminoglycosides(e.g.,gentamicin[Garamycin]),arenotmetabolizedatall.
TABLE2.1
SelectedProdrugsandMetabolites
ParentDrug(Prodrug) ActiveMetabolite
Allopurinol oxypurinol Codeine morphine Enalapril enalaprilat Prednisone prednisolone Valacyclovir acyclovir
Enzymeactionsaretheprimarymeansformetabolizingdrugs,andtheseactionsarebroadlyclassified asphase1andphase2enzymaticprocesses.Phase1enzymaticprocessesinvolveoxidationorreduction, bywhichadrugischangedtoformamorepolarorwater-solublecompound.Phase2processesinvolve addingaconjugate(e.g.,a glucuronide) to the parentdrug or thephase 1–metabolized drugtofurther increasewatersolubilityandenhanceexcretion.
The oxidative processofphase 1 metabolism is catalyzedbytheflavin-containingmonooxygenases (FMO),theepoxidehydrolases(EH),andthecytochromeP-450system(CYP).TheFMOsandCYPare composedofsuperfamiliesofmorethan100enzymeseach.Threefamilies(about15totalenzymes)ofthe CYPenzymesareimportantcontributorsto drugmetabolism. Thecommonfeature of these enzymesis their lipidsolubility.Mostlipophilic drugsaresubstratesforoneor moreoftheCYPenzymes(Table
2.2).FMOsarenotconsideredmajorcontributorstodrugmetabolism.
TABLE2.2
KeyCytochromeP-450FamiliesandIsoformsinDrugMetabolism
Family Isoform ExampleofDrugsMetabolized
CYP1 CYP1A2 theophylline CYP2 CYP2C19 omeprazole
CYP2D6 dextromethorphan CYP2E1 acetaminophen
CYP3 CYP3A4 atorvastatin
CYP,cytochromeP-450.
Somedrugscaninduceorstimulatetheproductionofoneormoreisoformsoftheenzymesbyaprocess calledenzymeinduction,whichincreasestheamountofenzymeavailabletometabolizedrugs.Theresult ofenzymeinductionis anincreased metabolism ofother drugs,thereby decreasingtheamountofdrug circulatingthroughoutthebody.
Conversely,somedrugsinhibittheproductionofCYPenzymesandtherebydecreasethemetabolismof drugsandincrease circulatinglevels. This is knownas enzymeinhibition.Bothenzymeinductionand inhibition are the basis of metabolically mediated drug–drug interactions. See Chapter 3 for further discussionofinductionandinhibitionandtheirroleindrug–druginteractions.
Althoughtheliverisregardedastheprimarysiteofdrugmetabolism,othertissuesalsopossessthe enzymes necessary for metabolism. The kidneys, for example, have several enzymes needed for drug metabolismandcanserveasthesiteofdruginactivation.TheGItractisalsoknowntopossessseveralof theCYPisoforms,contributingtotheextrahepaticmetabolismofdrugs.
The nature, function, and amount of any drug-metabolizing enzyme can be different, resulting in differingdrugdispositionamongpatients.Disease-inducedchangescanaffectdrugmetabolismaswell. For example, alterations in liver function induced by long-standing cirrhotic changes can reduce the productionofnecessaryenzymes,resultinginincreasedconcentrationsofdrugstypicallymetabolizedin theliver.Also,decreasedbloodflowtotheliver,asinthecaseofcongestiveheartfailure,candecrease thedeliveryofdrugtometabolicsitesintheliver.Cigarettesmoking,ontheotherhand,canincreasethe levelsofenzymesresponsible fordrugmetabolism,resulting inincreased metabolicratesandtheneed forhigherdosesofdrugs(e.g.,theophylline)insmokersthaninnonsmokers.
DrugExcretion
Metabolismeliminatesadrugfromthebodybychangingthedrugmoleculeintosomethingelse,butdrugs alsocanbeeliminatedfromthebodybyexcretion.Excretoryorgansincludethekidneys,lowerGItract, lungs,andskin.Otherstructures,suchasthesweat,salivary,andmammaryglands,areactiveinexcretion aswell.Drugsmayalsoberemovedforciblybydialysis.
Theprimaryrouteofexcretionisthekidney.Afterthedrugismetabolized,theresultantmetabolitemay befilteredbytheglomerulus.Asthedrugcontinuesthroughtheproximaltubule,loopofHenle,anddistal tubule,severalthingsmayoccur:Thedrugmayexertaction(asinthecaseofdiuretics),bereabsorbed intothebloodstream,or remaininthenephron,eventuallyreachingthecollectingducts,fromwhichit ultimately leaves the body in the patient’s urine. This filtration works well for hydrophilic, ionized compounds andis a commonrouteof elimination. Conversely, active secretion ofdrugs occurs inthe proximaltubule.Twodifferentsystemsexist,onefororganicacids(e.g.,uricacid)andonefororganic bases(e.g.,histamine).OnceionizedbytheacidicpHoftheurine,organicbasesarenotreabsorbedback intothebloodstream.IfthepHoftheurinerises,thenmoreoftheorganicbasebecomesnonionizedand thus more readily reabsorbed into the bloodstream. Similarly, changes in urine pH can alter the reabsorptionoforganicacids,increasingor decreasingthecirculatinglevelsasthepHchanges.Drugs suchaspenicillinareexcretedbytheorganicacidsystem.
FIGURE2–4Enterohepaticrecirculation.Whenadrugisabsorbedfromtheintestineandtravelstothe
liver and gallbladder and into the bile unchanged,it has the potential for being reintroduced intothe intestineandthereforereabsorbed.Thisisknownasenterohepaticrecirculation.
Drugsareexcretedbytheliverintothegallbladder,resultinginbiliaryelimination.Biliaryelimination cansometimesresultindrugreabsorption.Forexample,ifadrugisexcretedinthebile,itgoesintothe
GItract,whereitmaybereabsorbedandreturnedtothegeneralcirculation.Thisiscalledenterohepatic recirculation(Figure2.4).Theresultofsignificantenterohepaticrecirculationisameasurableincrease intheplasmaconcentrationofadrugandadelayinitseliminationfromthebody.
Half-Life
The time required for a drug to be eliminated from the body varies according to the drug and the individual.However,usefulgeneralizationscanbemadethathelppractitionersestimatehowlongadrug willremaininthebody.Thefirstgeneralizationhastodowiththeeliminationhalf-life(t½),whichisthe
timerequiredforhalfofthetotaldrugamounttobeeliminatedfromthebody.Assuming100%ofadrug existsinthebodyattimeX,thenonehalf-lifelater,50%oftheoriginalamountwouldremaininthebody. Anadditionalhalf-lifelater,25%wouldremainandsoon.Forexample,vancomycin(anIVantibiotic) has a half-life of approximately 6 hours in an adult with normal renal function. If the vancomycin concentrationinapatient’sbodyis15mg/L,thenitwouldtake6hourstodeclineto7.5mg/L,another6 hours(12hourstotal)tofallto3.75mg/L,andanother6hours(18hourstotal)tofallto1.875mg/L.The rate of elimination of a drug remains constant, but as can be seen in Figure 2.5, the amount of drug eliminatedisproportionaltotheconcentrationofthedrug—thatis,themoredrugthereis,thefasteritis eliminated.This phenomenon,knownasfirst-orderkinetics, appliestomostdrugs.Rateprocesses can alsobeindependentofconcentration,andfixedamountsofdrugs,ratherthanafractionalproportion,are eliminatedat a constantrate. This phenomenonis called zero-orderkinetics. Alcohol undergoes zero­orderelimination.
Afterfive half-lives, accordingtofirst-orderkinetics,approximately97% (96.875%)ofanydrugis eliminatedfrom thebody.Evenafterthreehalf-lives,nearly90%(87.5%)ofthedrugis eliminated.In most cases, after three to five half-lives, the amount of drug remaining is too low to exert any pharmacologic effect,and the drug is considered essentially eliminated. Understandingthis conceptis usefulforpractitionersinmanysituations.Forexample,ifadrugreachesatoxiclevel,thepractitioner knowsthatitwilltakethreetofivehalf-livesforthedrugtobeessentiallyeliminatedfromthebody.The practitioneralsocanestimatewhenthedruglevelwillapproachaminimallyeffectiveconcentrationand canthencalculatewhentoadministeranotherdoseofmedicationtoreachatherapeuticdruglevel.
FIGURE2–5Drugeliminationbasedonhalf-life(t½).
FIGURE2–6Steadystateachievedwithregulardosing(half-life=8hours).
SteadyState
Inreality,patientstakemedicationsonaconsistentbasis,usuallysomewherebetweenoneandfourtimes daily. Bydoingso, theyareabsorbingandeliminatingthedrugthroughouttheday.Becausetherateof elimination is proportional to the concentration, at some point, equilibrium is reached. Figure 2.6 demonstrateshowdoses ofadrugwitha half-life of8 hours producethisequilibrium. Notethatafter approximatelythree tofive half-lives,thecurvelevels off.This demonstratesequilibrium betweenthe amount ofdrugentering thebody andthe amountleavingthe body.Thispoint, whichiscalled steady state,reflectsaconstantmeanconcentrationofdrug inthebody.Atsteadystate,eventhoughtheblood levelsofadrugfluctuateaboveandbelowthismeanconcentrationandthedrugleveltendstohavepeaks andtroughsduringdosingintervals,thefluctuationsremainwithinaconstantrange.
For some drugs, the timerequired to achieve steadystate may be very long. For example, digoxin (Lanoxin) has a halflife of 39 hours (1.6 days), meaning that between 4.8 and 8 days are needed to achievesteadystate.Clearly,whenitisimperativetogainatherapeuticlevelquickly,waitingthislongis unacceptable. Therefore, an initial loading dose of a drug is needed to reach the desired blood concentrationquickly.Theloadingdoseisbasedonthevolumeofdistributionofthedrug,independentof thehalf-life.Themaintenancedose,however,isbasedonthehalf-lifeofthedrug.Maintenancedosesof thedrugaregivenatscheduledintervalstoreplacetheamountofdrugeliminated.
Clearance
Theconceptofclearance,whichrefers totheremovalofa drugfromtheplasmaor organ,isthefinal elementintheprocessofelimination.Drugswithhighclearancesareremovedrapidly;thosewithlow clearancesareremovedslowly.Drugscanbeclearedbybiliary,hepatic,orrenalmeans.Thefollowing discussionhighlightsrenalclearance.
Clearanceisrelatedtotheapparentvolumeofdistributionandthehalf-life(Box2.4).Clearanceofa drugfromthebodydependsdirectlyontheapparentvolumeofdistributionandisinverselyrelatedtothe elimination half-life:The greaterthevolumeof distributionandthe shorterthehalf-life, the faster the
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