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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5200_Библиотеки_им_академика_М_И_Перельмана
.pdf
Lungs:Respirations26andshallow;diffuseexpiratorywheezing;peakflow340
Diagnosis:Mildpersistentasthma
Questions
1.Whatistheprescriber’sresponsibilityregardingpotentialdrugtherapyforA.J.?
Answer:Theprescriberisresponsibleforgatheringthedatathatincludesathoroughhistoryand
physicalexam.Itisessentialtoconsiderallpotentialdiagnosesinthedifferentialtomakeasound
decisionaboutprescribing.Knowledgeof anyover-the-counter(OTC) medicationsiscritical to
prescribing.
2.Explainthefactorsthatcancontributetoadverse drugeventsforanymedicationsprescribedfor
A.J.
Answer:Theprescribermustbe knowledgeable abouttheindicationsandappropriatechoice of
medicationsalongwithdosing. Communicationwiththepatientabouthow andwhen totakethe
drugandthepotentialsideeffectsiscritical.
Ascitedabove,knowledgeaboutOTCisvital–patientsoftendonotthinktoincludethemintheir
medicationlist.Interactionsbetweenmedicationscanbethecauseofadversedrugevents.
3.DescribethefactorsthatcouldimprovetheadherenceofA.J.toyourprescribedtherapy.
Answer:TheprescribermusthaveanhonestconversationwithA.J.aboutthemedication.Inthis
case,itappearsthatanAlbuterolInhalerisindicatedbeforeA.J.engagesinexercise.Instructherto
usetheinhaler30-minutesbeforeengaginginsportspracticeorcompetition.Alongwiththetiming,
describehowthismedicationwillhelpherbreathe,soshecansuccessfullyparticipateinhersport.
Being honest about common side effects and what to expect from the drug is also critical to
adherence.
CASESTUDY2
Mrs.S.isa45-year-oldwomanwhopresentstotheofficewiththechiefcomplaintofongoinganxiety
andpalpitations.Thesymptomshavebeenpresentmostofherlifebuthavebecomeworseinthelast
fewmonths.Sheonlysleepsfor4-hoursnightlyanddoesnotfeelresteduponrising.
PMH:Type2DMpoorlycontrolled,Insomnia,Anxiety,andFibromyalgia
Medications:Dulaglutide(Trulicity),Metformin,Zolpidem(Ambien),andFluoxetine(Prozac)
PertinentReviewofsystemsincludesgeneralbodyaches,occasionalpalpitationswithtransientchest
discomfortthatdoesnotradiate,causeshortnessofbreath,ornauseawithvomiting.
Vitalsignsandphysicalexaminationarewithinnormallimits
Questions
1.Whatistheprescriber’sresponsibilityregardingpotentialdrugtherapyforMrs.S?
Answer:Theprescriberisresponsibleforgatheringthedatathatincludesathoroughhistoryand
physicalexam.Inthiscase,thepatienthasotherchronicdiseaseswhichrequireknowledgeabout
medicationinteractions. An additional consideration is that some drugs can cause worseningof
anxiety.Also,knowledgeofanyover-the-counter(OTC)medicationsiscriticaltoprescribing.
2.Explainthefactorsthatcancontributetoadverse drugeventsforanymedicationsprescribedfor
Mrs.S.
Answer:Inthiscase,thepatientisalreadyonfourmedicationsthathavethepotential tointeract
withanyadditionaldrugs.Theprescribermustbeknowledgeableanduseaninteractioncheckerto
understand the ramifications of drug–drug interactions that can create adverse drug reactions
(ADRs).DiscussionwiththepatientaboutpotentialsideeffectsandADRsisimportant;however,
thegoalis to makeaninformed decisionwiththe patient.Communicationwiththepatientabout
howandwhentotakethedrugandthepotentialsideeffectsiscritical.
Ascitedabove,knowledgeofOTCis vital – patientsoftendo notthinktoincludethem intheir
medicationlist.Interactionsbetweenmedicationscanbethecauseofadversedrugevents.
3.DescribethefactorsthatcouldimprovetheadherenceofMrs.Stoyourprescribedtherapy.
Answer:Communicationbetweenthe patientandprovider iscritical to adherence withtherapy.
Whenandifsideeffectsoccur,itisimportanttoexplorehowmanydaysanagentwastakenandthe
typeofsideeffect.Symptomsshouldnotbetreatedwithanothermedication–thisstartsacascade
of polypharmacy. When patients must take too many drugs, adherence often decreases as they
becomewearyofthenumberofpills.
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2
PharmacokineticBasisofTherapeuticsand
PharmacodynamicPrinciples
AndrewM.PetersonandA.MaggieRandazzo
LearningObjective
1.Describethedifferencebetweenpharmacokineticsandpharmacodynamics.
2.Discusstheimpactofeachofthefourpharmacokineticprinciplesonmedicationsadministeredtoa
patient:absorption,distribution,metabolism,andelimination.
3.Describetheconceptofaffinityanddifferentiatebetweenanantagonistandanagonist.
4.Applytheknowledgeofpharmacokineticprinciplestoconsiderationsofapatientcasescenario.
5. Given patient details, calculate renal function utilizing the Cockcroft-Gault formula and the
ModificationofDietinRenalDisease(MDRD)equation.
INTRODUCTION
Theartandscienceofclinicalpracticeisbasedonunderstandingtherelationshipbetweenthepersonand
the disease and determining the most appropriate means for alleviating symptoms, curing disease, or
preventingseveremorbidityorevenmortality.Veryoften,medicationsareprescribedtoaccomplishone
ormoreofthesegoals.
Underpinningthistreatmentprocessistheintricaterelationshipbetweenthebodyandthemedication.
Often,practitionersseektounderstandtheeffectadrughasonthebody(whethertherapeuticorharmful)
butneglecttoconsidertheeffectthebodyhasonthedrug—eventhoughonecannotbeunderstoodwithout
theother.Howthebodyactsonadrugandhowthedrugactsonthebodyarethesubjectsofthischapter.
Pharmacokinetics refers to the movement of the drug through thebody—in essence, how the body
affects the drug. This involves how the drug is absorbed, distributed, metabolized, and eventually
eliminatedorexcretedfromthebody.Pharmacodynamicsreferstohowthedrugaffectsthebody—that
is,howthedruginitiatesitstherapeuticortoxiceffect,bothatthecellularlevelandsystemically.Box2.1
liststermsanddefinitionsusedthroughoutthischapter.
Thepurposeofpharmacokineticprocessesistogetthedrugtothesiteofaction,whereitcanproduce
itspharmacodynamiceffect.Thereisaminimumamountofdrugneededatthesiteofactiontoproducethe
desiredeffect.Althoughtheamountofdrugconcentratedatthesiteofactionisdifficulttomeasure,the
amountofdruginthebloodcanbemeasured.Therelationshipbetweentheconcentrationofdruginthe
bloodandtheconcentrationatthesiteofaction(i.e.,thedrugreceptor)isdifferentforeachdrugandeach
person. Therefore, measuring blood concentrations is only a surrogate marker, an indication of
concentration at the receptor. Figure 2.1 shows the relationship between pharmacokinetics and
pharmacodynamics.
PHARMACOKINETICS
Pharmacokineticsrelatestohowthedrugisabsorbed,distributed,metabolized,andeliminatedfromthe
body. In reality, it is the study of the fate of medications administered to a person. It is sometimes
describedaswhatthebodydoestothedrug.Intheory,pharmacokineticsnotonlydealswithmedications
but also deals with the disposition of all substances administered externally to any living organism.
Pharmacokinetic processesdeterminetheonsetanddurationofa drug’sactionas wellasblood levels
thatwouldproducetherapeuticandtoxiceffects.Assuch,onecandeterminethebloodlevelsnecessary
to produce a desired effect. This target drug concentration is key to monitoring the effects of many
medications.Assumingthatthemagnitudeofthedrugconcentrationatthesiteofactioninfluencesthedrug
effect,whetherdesiredorundesired,itcanbeinferred thatarangeofdruglevelsproducesa rangeof
effects(Figure2.2). Belowaspecificlevel,orthreshold,thedrugexertslittletonotherapeuticeffect.
Abovethisthreshold,theconcentrationofdruginthebloodissufficienttoproduceatherapeuticeffectat
thesiteofaction.However,asthedrugconcentrationincreasesintheblood,sodoestheconcentrationat
thesiteofaction.Aboveaspecificlevel,anincreasedtherapeuticeffectmaynolongeroccur.Instead,an
unacceptabletoxicitymayoccurbecausethedrugconcentrationistoohigh.Betweenthesetwolevels–the
minimallyeffectivelevelandthetoxiclevel–isthetherapeuticwindow.Thetherapeuticwindowis the
rangeofblooddrugconcentrationthatyieldsasufficienttherapeuticresponsewithoutexcessivelytoxic
reactions.Thisrangevariesbasedonindividualdifferencesandthereforeserves onlyasaguidetothe
practitioner.
Box2.1 DefinitionsofTermsRelatedtoPharmacokineticsandPharmacodynamics
Affinity:Theattractionbetweenadrugandareceptor.
Allostericsite:Abindingsiteforsubstratesnotactiveininitiatingaresponse;asubstratethatbindsto
anallostericsitemayinduceaconformationalchangeinthestructureoftheactivesite,renderingit
moreorlesssusceptibletoresponsefromasubstrate.
Bioavailability(F):Thefractionorpercentageofadrugthatreachesthesystemiccirculation.
Biotransformation:Metabolismordegradationofadrugfromanactiveformtoaninactiveform.
Chirality:Specialconfigurationorshapeofadrug;mostdrugsexistintwoshapes.
Clearance:Removalofadrugfromtheplasmaororgans.
Downregulation:Decreasedavailabilityofdrugreceptors.
Enantiomer(alsocalledisomer):Amirror-imagespatialarrangement,orshape,ofadrugthatsuitsit
forbindingwithadrugreceptor.
Enterohepatic recirculation: The process by which a drug excreted in the bile flows into the
gastrointestinaltract,whereitisreabsorbedandreturnedtothegeneralcirculation.
First-passeffect: Thephenomenonbywhicha drugfirstpasses throughthe liver,where it maybe
degradedbeforedistributiontothetissues.
Half-life(t½):Thetimerequiredforhalfofatotaldrugamounttobeeliminatedfromthebody.
Hepaticextractionratio:Acomparisonofthepercentageofdrugextractedandthepercentageofdrug
remainingactiveaftermetabolismintheliver.
Hydrophilic(lipophobic): Molecules that do notreadilycross the plasmamembrane (phospholipid
bilayer)becausetheyarewatersoluble.
Hydrophobic(lipophilic):Molecules thateasilycrosstheplasmamembrane(phospholipidbilayer)
becausetheyarelipidsoluble.
Ligand:Anychemical,endogenousorexogenous,thatinteractswithareceptor.
Pharmacodynamics:Processesthroughwhichdrugsaffectthebody.
Pharmacokinetics:Processesthroughwhichthebodyaffectsdrugs.
Prodrug:Adrugthatistransformedfromaninactiveparentdrugintoanactivemetabolite;ineffect,a
precursortotheactivedrug.
Receptor:Thesiteofdrugaction.
Secondmessenger:Achemicalproducedintracellularlyinresponsetoareceptorsignal;thissecond
messengerinitiatesachangeintheintracellularresponse.
Therapeutic window: The range of drug concentration in the blood between a minimally effective
levelandatoxiclevel.
Threshold:Thelevelbelowwhichadrugexertslittletonotherapeuticeffectandabovewhichadrug
producesatherapeuticeffectatthesiteofaction.
Upregulation:Increasedavailabilityofreceptors.
Volumeofdistribution(Vd):Theextentofdistributionofadruginthebody.
FIGURE 2–1 Relationship between pharmacokinetics and pharmacodynamics. Note the two-way
relationshipbetweentheconcentrationofdrugintheplasmaandtheconcentrationofdrugatthesiteof
action,depictingtheinterrelationshipbetweenpharmacokineticsandpharmacodynamics.
FIGURE2–2Therapeuticwindow:concentrationversusresponse.Theconcentrationofthedruginthe
body produces specific effects. A low concentration is considered subtherapeutic, producing an
insufficientresponse.Astheconcentrationincreases,thedesiredeffectisproducedatagivendruglevel.
Adrugconcentrationthatexceedstheupperlimitofthedesiredresponsemayproduceatoxicreaction.
Theconcentrationrangewithinwhichadesiredresponseoccursisthetherapeuticwindow.
Absorption
Thefirstphaseofpharmacokinetics toconsideris howdrugsareadministered,howtheyareabsorbed
intothebody,andhowtheyeventuallyreachthebloodstream.Merelyintroducingthedrugintothebody
doesnotensurethatthecompoundwillreachalltissuesuniformlyorthatthedrugwillreachthetarget
site at all. Commonly recognized methods of absorption include enteral absorption (after the drug is
administered bytheoralorrectalroute)andparenteralabsorption(associatedwithdrugsadministered
intramuscularly[IM],subcutaneously,ortopically,bypassingthegastrointestinal[GI]tract).Thevarious
administrationroutesarediscussedinthefollowingparagraphsandotherfactorsaffectadrug’sabilityto
enterthebloodstream.
Theextenttowhichthedrugreachesthesystemiccirculationisreferredtoasbioavailability, or F,
which is defined as the fraction or percentage of the drug that reaches the systemic circulation after
administration. Drugs administered intravenously are 100% bioavailable because they are delivered
directlyto thesystemiccirculation.Drugsadministered byother routes (e.g., oral, IM) maybe 100%
bioavailable,butmoreoften,theyarelessthan100%bioavailable.Therefore,bioavailabilitydependson
the route of administration and, equally important, the drug’s ability to pass through membranes or
barriersinthebody.Box2.2discussesthespecificcaseoforalbioavailabilityandthefirst-passeffect.
FactorsAffectingAbsorption
Avarietyoffactorsaffectabsorption,suchasthepresenceorabsenceoffoodinthestomach,bloodflow
totheareaforabsorption,andthedosageformofthedrug.Thefollowingsectionsdiscusssomeofthe
majorfactorsaffectingabsorption.
MovementthroughMembranesandDrugSolubility
Throughoutthebody,biologicmembranesactasbarriers, blockingorpermittingthepassageofvarious
substances.Thesemembranesprotectcertainareasofthebodyfromharmfulchemicalsandallowother
areastobeaccessedasneeded.
Biologic membranes composed of cells serve as barriers primarily because of the structure and
functionofthecellsthatmakeupthemembrane.Cell membranesarecomposedoflipidsandproteins,
creatingaphospholipidbilayer.Thisbilayeractsasabarrierthatisalmostimpermeabletowater,other
hydrophilic (water-loving) substances, and ionizedsubstances. However, thebilayer does allow most
hydrophobic(lipid-soluble) compoundstopass throughreadily.Interspersedthroughoutthis bilayerare
protein molecules and small openings, or pores. The proteins may act as carrier molecules, bringing
moleculesthroughthebarrier(activetransport).Theporesallowhydrophilicmoleculestopassthroughif
they are small enough (passive diffusion). Therefore, drugs and other compounds that pass through
membranebarrierscandosobypassiveoractivemeans.
Passive diffusion. Drugs can pass through membrane barriers by diffusion. In passive diffusion,
moleculesmovefromonesideofabarriertoanotherwithoutexpendingenergy.Inpassing,themolecules
movedownaconcentrationgradient—thatis,theymovefromanareaofhigherconcentrationtoanareaof
lower concentration. The rate of diffusion depends on the differences in concentrations, the relative
strengthof the barrier,the distancethatthemolecules musttravel, andthesizeofthemolecules. This
relationshipisknownasFick’slawofdiffusion.Inessence,Fick’slawstatesthatthegreaterthedistance
totravelandthelargerthemolecule,theslowerthediffusion.
Another majorbarrier to theabsorptionofa drugisitssolubility. Tofacilitatedrugabsorption,the
solubility of the administered drug must match that of the cellular constituents of the absorption site.
Lipid-solubledrugscanpenetratefattycells;water-solubledrugscannot.Forexample,awater-soluble
drugsuchaspenicillincannot easilypass throughthephospholipid bilayer betweenthebloodandthe
brain,whereas a highlylipid-soluble drugsuchasdiazepam(Valium)can.Therelativestrengthofthe
barrierisimportantbecausethebarriermustbepermeabletothediffusingsubstance.Drugsdiffusemore
readilythroughthelipidbilayeriftheyareintheirneutral,nonionizedform.Mostdrugsareweakacids
orweakbases,whichhavethepotentialforbecomingpositivelyornegativelycharged.Thispotentialis
createdthroughthepHofcertainbodyfluids.Intheplasmaandinmostotherfluids,mostdrugsremain
nonionized. However, in the gastric acid of the stomach, weak bases become ionized and are more
difficulttoabsorb.Asthisweakbaseprogressesthroughthealkalineenvironmentofthesmallintestines,
itbecomesnonionizedandthereforemoreeasilyabsorbed.Similarly,weakacidsremainnonionizedin
thestomachandbecomeionizedinthesmallintestines.Theresultisreducedabsorptionbytheintestines.
Box2.2 OralBioavailabilityandtheFirst-PassEffect
Drugsgivenorallymaybesubjecttothefirst-passeffect,bywhichdrugsaremetabolizedbytheliver
before passingintocirculation.After absorptionfromthe alimentarycanal, drugs godirectlytothe
liver throughthe portal vein. In the liver,hepatic enzymes act on the drug, reducingthe amountof
activedrugreachingthebloodstreamanddecreasingtheamountavailabletothebody.Thefraction(or
percentage)ofmedicationreachingsystemiccirculationafterthefirstpassthroughtheliverisreferred
toasthedrug’sbioavailability(F).
Thefirst-passeffectisnottheonlyfactorcontributingtotheoralbioavailabilityofadrug.Poorly
solubledrugsanddrugsadverselyaffectedbygastricpHorotherpresystemicfactorscanalsohavea
lowbioavailability.
Drugs not usually subject to theliver’s first-pass effect are known as drugs with a low hepatic
extractionratiobecausetheliverdoesnotextractalargepercentageofthedrugbeforereleasingitinto
thecirculation.Usually,drugswith a lowextractionratiohavehighoralbioavailability. Incontrast,
drugswithahighextractionratiohaveloworalbioavailability.
Forexample,lidocainehasahepaticextractionratioof0.7;thatis,thelivermetabolizes70%ofthe
drugbeforethedrugreachesthecirculationand,as such,only30%remainsavailablesystemically.
This is one reason lidocaine is administered parenterally. In other words, the first-pass effect for
lidocaineisofsuchmagnitudethatanalternativerouteofadministrationisrequired.Givinglargeoral
doses of a drug to compensate for the high extraction ratio is often an alternative to parenteral
administration. For example, because of the high extraction ratio of propranolol, a 1-mg dose
administeredintravenouslyisapproximatelyequivalenttoa40-mgdoseadministeredorally.
Examplesofdrugswithahighhepaticextractionratio(70%ormore)aremetoprolol(ToprolXL),
lidocaine (Xylocaine), and morphine; drugs with intermediate rankings are codeine, midazolam
(Versed),andnifedipine(ProcardiaXL);andsomedrugswithalowextractionratio(30%orless)are
barbiturates, diazepam (Valium), theophylline (Theo-Dur), indomethacin (Indocin), and warfarin
(Coumadin).
Activetransport.Inactivetransport,membraneproteinsactascarriermoleculestotransportsubstances
acrosscellmembranes.Theroleofactivetransportinmovingdrugsacrosscellmembranesislimited.To
becarriedthroughbyaprotein,theexogenousdrugmustsharemolecularsimilaritieswithanendogenous
substancethetransportsystemroutinelycarries.Cellscanaccomplishthisthroughtheprocessofendocytosis. In this process, the cell forms a vesicle surrounding the molecule, and it is subsequently
invaginatedinthecell.Onceinsidethecell,thevesiclereleasesthemoleculeintothecytoplasmofthe
cell.
PharmaceuticalPreparation
Drugsareformulatedandadministeredinsuchawayastoproduceeitherlocalorsystemiceffects.Local
effects(e.g.,antiseptic,topicalantiinflammatory,andlocalanestheticeffects)areconfinedtooneareaof
thebody.Systemiceffectsoccurwhenthedrugisabsorbedanddeliveredtobodytissuesbywayofthe
circulatorysystem.
Dependingonhowadrugisformulated(e.g.,tabletorliquid),themeansofdrugdeliverycantargeta
site of action. Some drug formulations (dosage forms) deliver the drug into the GI tract quickly
(immediaterelease),whereas others releasethedrugslowly.Thisstrategyforextendingtheactivityof
drugsinthebodydampensthehighpeaksandlowtroughsofdrugconcentrations,therebyyieldingamore
consistentbloodlevel.Manymedicationsareavailableinthesecontrolled-orsustained-releasedosage
forms. The aim of sustained-release dosage forms is to administer them as infrequently as possible,
improvingpatientcomplianceandminimizinghour-to-hour or day-to-dayblood level fluctuations. The
various release systems available are subject to physiologic and pathophysiologic changes in patient
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