lecture 02 bbda 2 kinetics
TRANSCRIPT
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Pharmacokine,cs
ChristopherOwens,PharmD,BCPS
BiologicalBasisofDrugAc;on2
Spring2011
LearningObjec,ves
Becomefamiliarwithbasicpharmacokine;cparameters,includingbioavailability,proteinbinding,volumeofdistribu;on,andhalf-life
Understandtheprocessesofabsorp;on,distribu;on,metabolism,andelimina;on
Understandthedifferentroutesofadministra;on,theirbenefitsandlimita;ons
BecomefamiliarwiththeCYP450systemandthetermssubstrate,inducer,andinhibitor Describethefactorsthatmayeffectmetabolismandtheirclinicalrelevance
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RecommendedReading
KatzungBG,etal.(eds)BasicandClinicalPharmacology,11thedi;on.
Chapter3:Pharmacokine;csandpharmacodynamics:Ra;onaldosingandthe;mecourseofdrugac;on
Chapter4:DrugBiotransforma;on LehneRA.PharmacologyforNursingCare,7thedi;on
Chapters4-8
Introduc,on
Toachieveapharmacodynamicgoal,adrugmustreachitssiteofac;on
Convenienceimportant Some;mes,drugsmaybe
applieddirectlytotarget;ssue
Topicals,drops,sprays Moreoen,drugsmustbe
administeredtoonebodycompartmentandthenbeabletomovetoanother
Dr. Mario
Available at: www.joystiq.com
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Pharmacokine,cs
Pharmacokine;csistheprocessbywhichadruggetsintoandoutofthebodymaybesimplydefinedas:theeffectsofthebodyonthedrug Importantfact:becausedrugsareforeignchemicals
(xenobio'cs),onceingestedthebodyac;velytriestoremovethem
Mainpharmacokine;cprocesses:Absorp;onDistribu;onMetabolismElimina;on
Pharmacokine,cParameters
Importantterms: Oralbioavailability Urinaryexcre;on BoundinPlasma Clearance VolumeofDistribu;on Half-life Targetconcentra;on Toxicconcentra;on
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Permea,onAsadrugmovesfromonebodycompartmenttoanother(togetinandgetout),itmustpassthroughvariousbarriers
alongtheway
Theseprocessesaretakenintoaccountwhendrugsareformulated,sothatdrugsareabletoreachtheirtargetsandbe
safelyeliminated
Permea,oncon,nued Aqueousdiffusion
Drivenbyconcentra;ongradientofthedrug Down-hillmovementisdescribedbyFicksLaw
Lipiddiffusion Veryimportantprocess,astherearemanylipidbarrierssepara;ng
bodycompartments
Lipid:aqueouspar;;oncoefficientisimportant Specialcarriers
Necessaryforsubstancestoolargeortooinsolublefordiffusion(e.g.pep;des,aminoacids,glucose)
Manydrugsresemblethesesubstancesandusetheseac;vetransporterstogetinandoutofcells
Endocytosisandexocytosis Somesubstancesaresolargetheycanonlyentercellsviathisprocess ExamplesincludevitaminB12complexandiron
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Otherimplica,onsofpermea,on
DrugsthatenterthebloodstreammaybecarriedANYWHEREinthebody
Thedesiredtargetsiteisjustonepossibleloca;onfordelivery
Basedontheirpermeability,ioniza;on,pH,andothercharacteris;cs,drugsmay:
CrosstheplacentaEnterbreastmilkCrosstheblood-brainbarrierConcentrateinthetheurine
Pharmacokine,cs&
Pharmacodynamics
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EnteralParenteral&Topical
IfadrugsdesiredeffectisLOCAL,themostcommonroutesofadministra;oninclude: Topical(skin,nasal,rectal,vaginal) Inhala;on(lungs) Ins;lla;on(eyes,ears)
IfthedrugsdesiredeffectisSYSTEMIC,commonroutesinclude:
Enteral(usingtheGItract) Oral,sublingual,rectal
Parenteral(notusingtheGItract) Intravenous,intramuscular,subcutaneous,transdermal,insuffla;on(snor;ng)
Pharmacokine,cProcesses
Absorp;on
Distribu;on
Metabolism
Elimina;on
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ABSORPTION
Processofadrugenteringthebody Absorp;onintothe
bloodstreamisthegoalofdrugswithsystemiceffects
Howwellitaccomplishesthis(orifitdoesatall)dependsupontheroute
Importantterm:Bioavailability
ORAL(P.O.)
Advantages: Easiestforself-administra;on Rela;velysafe(nodrama;cincreasesinplasma
concentra;ons)
Disadvantages: Adequateabsorp;on? Gastricirrita;on(N&V) Acidicenvironmentanddrugstability First-passeffect
Examples: Mostcommonlyusedmedica;ons
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SUBLINGUAL
Drugisplacedunderthetongue Advantages:
Absorbedthroughoralmucosaintothevenoussystem Avoidsfirst-passeffect Goodforpa;entswhohavedifficultyswallowing
Disadvantages: Smallamountsofdrugonly
Example: Nitroglycerin
BUCCAL
Placingthedrugbetweenthecheekandgums Advantages:
Similartosublingual Disadvantages:
Similartosublingual Examples:
Nicoreegum Oraldisintegra;ngtablets(ODT)formula;onsofZyprexa
andZofranmayalsofitthiscategory
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Bioavailability
Definedasthefrac,onofunchangeddrugreachingsystemiccircula;onfollowingadministra;on RepresentedasFin
calcula;ons
FordrugsadministeredIV,F=100%
OrallyadministereddrugshaveF
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DISTRIBUTION
Followingabsorp;onintothesystemiccircula;on,adrugisdistributedthroughoutthebody
Factorsthataffectdistribu;on: Tissuepermeability
Justasduringtheabsorp;onphase Bloodflow
Highlyperfused;ssuesvslowperfusion(an;bio;csinpa;entswithdiabetes)
Plasmaproteins Importantterms:
Volumeofdistribu,on(Vd)Proteinbinding
VolumeofDistribu,on
Themeasureofapparentspaceinthebodyavailabletocontainadrug Reflectsthebalancebetween
bloodinplasmaanditsbindingto;ssue
Mayvarywithage,weight,otherfactors
Importantconsidera;onfordosingandmonitoring
certaindrugs: IVan;bio;cs Digoxin Theophylline
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ProteinBinding
Drugsarehighlyvariableintheextendtowhichtheybindtoplasmaproteins(albumin) Onlyfree(unbound)drugis
abletointeractwithreceptors
Clinicallyimportanteffectsmayoccurwhenhigher-than-expectedlevelsofdrugaredisplaced Pregnancyincreasesplasma
proteinlevels(morebound
drug) Malnutri;onmaydecrease
plasmaproteinlevels
Drugname %Proteinbound
Aspirin 49
Acyclovir 15
Amoxicillin 18
Digoxin 25
Lithium 0
Propranolol 87
Tetracyline 65
Verapamil 90
Warfarin 99
METABOLISM
Alsoknownasbiotransforma;onBodysaempttoprepareaningestedsubstancefor
elimina;onfromthebody(oenviathekidneys)
Transformlipophilictohydrophilic Forma;onofpharmacologicallyac;veand/orinac;vemetabolites
Pro-drugs PhaseIandPhaseIIreac;ons
Chemicalreac;onsintheliver(orelsewhere)toconvertthedrugtomoreeasilyexcretedcompound
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PhasesofMetabolism
Mostbiotransforma;onoccursintheliver,butmetabolismmayalsotakeplaceinthegut
PhaseIreac;onsaddorunmaskfunc;onalgroupslike(OH)or(NH2)
Usuallyreadilyexcreted PhaseIIreac;onsarealsoalsoreferredtoasconjuga;on
Glucuronicacidoranaminoacidisadded
MetabolismIllustra,on
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First-PassMetabolism
Aeroraladministra;on,drugsareabsorbedintotheportalvenoussystem
Beforeenteringthegeneralcircula;on,drugsmayundergosignificantfirst-passmetabolism
Forsomedrugs,thiseffectissogreatthattheirbioavailabilityisclosetozero Lidocaine Nitroglycerin
CytochromeP-450
Thelivercontainsanextensivesystemofmicrosomalenzymesformetabolizingxenobio;cs
Thissystemrequiresenzymes,reducingagents,andmolecularoxygen
ManyP450isoformsexist:CYP1A2,CYP2A6,CYP2C9,CYP3A4
The3A4isoformaloneisresponsiblefor>50%oftheprescrip;ondrugsmetabolizedbytheliver
Somedrugsaremetabolizedbymorethanoneisoform
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CYP450IsoformsandSubstrates
CYP450Inducers&Inhibitors
Somedrugscauseaninduc;onofcertainCYP450isoformsandresultinacceleratedsubstratemetabolismRifampininducesCYP3A4(andothers),resul;ngin
increasedmetabolism(anddecreasedbloodlevels)ofsubstrateslikewarfarinandoralcontracep;ves
Somedrugscauseaninhibi;onofCYP450subtypesandresultindecreasedsubstrate
metabolismErythromycininhibitsCYP3A4(andothers),resul;ng
indecreasedmetabolism(andincreasedbloodlevels)ofsubstrateslikelovasta;n
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CommonInducers&Inhibitors
CYPInducers
Smoking Charcoal-broiledfoods Tuberculosisan;bio;cs
Rifampin Isoniazid
Barbiturates Phenobarbital
An;-convulsants Carbamazepine Phenytoin
St.JohnsWort
CYPInhibitors
Grapefruitjuice Cime;dine Fluvoxamine Macrolidean;bio;cs
Erythromycin Clarithromycin
Azolean;fungals Fluconazole Itraconazole Ketoconazole
Dil;azem
MetabolismtoToxicProducts
Biotransforma;onmayresultin:
Inac;vemetabolites(readyforexcre;on)
Ac;vemetabolites(con;nuetohavepharmacologicac;vity)
Ac;vemetabolites(aswithpro-drugs)
However,toxicmetabolitesarealsopossible
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FactorsAffec,ngMetabolism
Metabolismmaybeinfluencedbyseveralfactors,including:
Individualdifferences(gene;cs)Liversize&func;onalcapacityDiet&environmentalfactorsAge&sexDrug-druginterac;onsDrug-diseaseinterac;ons
Pharmacogenomics Gene;cpolymorphisms
influencetheexpressionofphaseIandphaseIIenzymes Neteffectdependsuponthe
typeofenzyme
Possibleconsequences: Slowacetylators Ultrarapidorextensive
metabolizers
Poormetabolizers Higherincidenceofdrug-
inducedautoimmunedisease
Abilitytopredicttheseeffectsbasedongene;csisagrowingfieldofstudy
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Diet&Environment
Individualvaria;onsindrugmetabolismmaybeaffectedby:Consumingcharcoal-broiledfoodsandcruciferous
vegetables(cabbage,brusselssprouts,broccoli)--induceCYP1A
Grapefruitjuice--inhibitsCYP3A4CigareesmokinginducescertainCYPenzymesWorkersexposedtopes;cidesmaymetabolizedrugs
morequickly
Canaffectappropriatedosing,especiallyofnarrowtherapeu;cindexdrugs
Age&Sex
Children,youngadults,adults,andtheelderlydonotmetabolizedrugsinthesameway Differencesinabsorp;on,
distribu;on,andelimina;onalsoimportant
Salicylates&ReyesSyndrome Pregnantwomenalsohave
physiologicchangesthat
affecttheseprocesses Importantdrugsto
remember: Ethanol,benzodiazepines,
propranolol,salicylates
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Drug-drugInterac,ons
Fact:drugsthatshareacommonmetabolicpathwayinthebodywillinteractiftakenatthesame;mebythesamepa;ent!!
Severityoftheinterac;onmayrangefrominsignificanttofatal
Prac;cally,somepa;entsmayrequire2ormoreinterac;ngdrugs
Dosagesareadjustedandmonitoredcarefully Examples:sulfaan;bio;candwarfarinmacrolideandlovasta;n
Drug-diseaseInterac,ons
Chronicliverdiseasemayaffectthehepa;cmetabolismofdrugs
Alcoholichepa;;s,cirrhosis Hypo-orhyperthryoidismcanhaveeffectsonthemetabolismwarfarin,digoxin,andinsulin
Pa;entswhoarehypothyroidmayneedhigherthanexpecteddosagesdigoxinandinsulinlower
thanexpecteddosagesofwarfarin
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ELIMINATION
Theintrinsicabilityofthebodytoremoveadrugfromcircula;on(alsocalledexcre;on)
Severalroutes: Sweat Tears Exhaledairviathelungs Bileviatheliver Urineviathekidneys
Importantandrelatedterms: Clearance Elimina,onhalf-life
Clearance
Themeasureofthebodysabilitytoeliminateadrug Formostdrugs,thisis
closelyrelatedtoprinciplesofrenalphysiology
Crea;nineclearanceiscalculatedtohelpindosingdrugsand
monitoringtoxicity Somedrugsrequire
dosageadjustmentsdependinguponkidneyfunc;on
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Elimina,onhalf-life(t1/2)
Definedasthe;merequiredtodecreaseconcentra;onofthedrugbyone-half
Rela;onshiptoVdandCL:T1/2=0.7xVd/CL
Somedrugsfollowmul;-compartmentkine;cs,sohalf-lifemaybedifferentfromthestandardequa;onshownabove
Forbasiccalcula;ons,takethet1/2X5tohaveeffec;velyclearedthedrugfromthebody
Accumula,on&half-life
Simpleexample: Acetaminophenhasat1/2
listedas2hours
Aer4half-lives(8hours),theconcentra;onisdecreasedby>90%
Acetaminophenisdosedclinicallyevery6hours
Sincemanyfactorsinfluenceclearanceanddosing,oenneedtoconsidermorethant1/2
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SUMMARY
Pharmacokine;csreferstoac;onsofthebodyonadrugandincludestheprocessesofabsorp;on,distribu;on,metabolism,andelimina;on
Differentroutesareusedtoadministerdrugs,dependinguponthedrugscharacteris;csandindica;on
Properdosingofadrugtakesintoaccountpa;ent-specificparametersthatmayaffectitsefficacyandtoxicpoten;al
Drug-druganddrug-diseaseinterac;onsareoenrelatedtometabolicprinciples
Thereareanumberofindividualvaria;onsthatmayaffectthewayadrugworksanditsadverseeffects
QUESTIONS?