Lecture 02 BBDA 2 Kinetics

7/31/2019 Lecture 02 BBDA 2 Kinetics

1/24

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


2/24

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


3/24

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


4/24

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


5/24

Otherimplica,onsofpermea,on

DrugsthatenterthebloodstreammaybecarriedANYWHEREinthebody

Thedesiredtargetsiteisjustonepossibleloca;onfordelivery

Basedontheirpermeability,ioniza;on,pH,andothercharacteris;cs,drugsmay:

CrosstheplacentaEnterbreastmilkCrosstheblood-brainbarrierConcentrateinthetheurine

Pharmacokine,cs&

Pharmacodynamics


6/24


7/24

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


8/24

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


9/24

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


10/24


11/24


12/24

Bioavailability

Definedasthefrac,onofunchangeddrugreachingsystemiccircula;onfollowingadministra;on RepresentedasFin

calcula;ons

FordrugsadministeredIV,F=100%

OrallyadministereddrugshaveF


13/24

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


14/24

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


15/24

PhasesofMetabolism

Mostbiotransforma;onoccursintheliver,butmetabolismmayalsotakeplaceinthegut

PhaseIreac;onsaddorunmaskfunc;onalgroupslike(OH)or(NH2)

Usuallyreadilyexcreted PhaseIIreac;onsarealsoalsoreferredtoasconjuga;on

Glucuronicacidoranaminoacidisadded

MetabolismIllustra,on


16/24

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


17/24

CYP450IsoformsandSubstrates

CYP450Inducers&Inhibitors

Somedrugscauseaninduc;onofcertainCYP450isoformsandresultinacceleratedsubstratemetabolismRifampininducesCYP3A4(andothers),resul;ngin

increasedmetabolism(anddecreasedbloodlevels)ofsubstrateslikewarfarinandoralcontracep;ves

Somedrugscauseaninhibi;onofCYP450subtypesandresultindecreasedsubstrate

metabolismErythromycininhibitsCYP3A4(andothers),resul;ng

indecreasedmetabolism(andincreasedbloodlevels)ofsubstrateslikelovasta;n


18/24

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


19/24

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


20/24

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


21/24

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


22/24

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


23/24

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


24/24

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?

Lecture 02 BBDA 2 Kinetics

Documents

Transcript of Lecture 02 BBDA 2 Kinetics