01.-FarmacoCinFarmacoGenet

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    1

    FarmacoCineticFarmacoCineticaaII

    FarmacoGeneticaFarmacoGeneticaUSMF NicolaeTESTEMITANUUSMF NicolaeTESTEMITANUCatedra farmacologie &Catedra farmacologie &

    farmacologie clinicfarmacologie clinicLciaLcia !!U"CANU"CAN

    #r$ Med$% conf$ nier'itar#r$ Med$% conf$ nier'itar

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    2

    Contintl Lectiei( #efinitii 'i di'ctii c referire la )arametrii FC( Factorii ce inflentea*a +

    , a-'or-tia, di'tri-tia, meta-oli'ml

    , e.cretia( Cm ace'tea inflentea*a efectl tera)etic$ /Farmacogenetica

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    FARMACOCINETICA(PHARMACON medicament, KINEO a mica)

    este o ramur a !armaco"o#iei care se ocu$ cu studiu"

    $rocese"or ce asi#ur micarea i trans!ormarea

    medicamente"or $rin medii"e %io"o#ice a"e or#anismu"ui&iu i anume, ea caracteri'ea' mecanisme"e de a%sor%ie,

    distri%uie i de$o'itare, %iotrans!ormare i e"iminare a

    medicamete"or din or#anism, studiind de$endena de

    aceste $rocese a e!icacitii i #radu"ui de to"erare a "or

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    Doza medicamentului

    Procesele farmacocinetice schematic pot fi exprimaten felul urmtor:

    Calea de administrare

    Concentraia plasmatica medicamentului

    Concentraia tisulara medicamentului

    Concentraia medicamentuluila locul de aciune

    cile de eliminarea medicamentului

    metabolizarea hepatici tisular

    absorbia

    biotransformarea

    distribuia

    eliminarea

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    6

    Farmacocinetica +termeni

    ( Calea de admini'trare( A-'or)tion /C)( #i'tri-tion/ 0d

    ( Meta-oli'ml/1iotran'formarea( Legarea de 2roteinele )la'matice( E.cretia/Clearance3l

    ( T4/5 67alf3life8( To.icitatea% etc$$$$$

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    7

    *istri%utionMeta%o"ism

    E+cretion

    A%sor$tion

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    Absorbia.

    ( 2entr a inflen9a a')raorgani'mli medicamentele% ca

    regl% tre-ie ' treac )rintr3n :irde mem-rane -iologice+ )ielea%mcoa'ele% )ere9ii ca)ilarelor%

    'trctrile cellare$

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    9

    A%sor$tion

    Route

    Entera"Parentera"

    ITo$ica"

    transderma" in-a"ationora" su%"in#ua"

    *istri%ution

    Systemic circulation

    Absorption Absorption

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    ( drg in ti''e'

    meta-olite' in ti''e'

    Drug at the site of Administration .

    A!"#$P%'(&'P)%*

    Drug in plasma+.

    D&"%$&!)%'

    ,. -%A!#/&"-

    0. /&-&'A%'(#)%P)%*

    Drug 1 metabolites in urine2 feces2 or bile

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    Cile de administrare a medicamentelor

    ( Medicamentele )ot fi introd'e inorgani'm )rin dier'e ci de admini'trare%;n de)enden9 de )ro)riet9ile lor :i 'co)ltea)iei$ Calea de administrare n maremsur determin 3iteza apariieiefectului2 durata i puterea lui2 spectruli gradul de exprimare a efectelorad3erse.i ;n genere de calea deadmini'trare ;n mare m'r de)inde a

    a

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    ( Se deo'e-e'c rmatoarele ci de admini'trare a medicamentelor+

    4r afectarea cutanat:A. prin tubul digesti3 (enterale*

    oral (per os*sublingualrectalintrabucal

    !. topiccutanatocularn ductul auditi3 extern

    C. intraca3itare

    inhalatorieintranazalintrauretralintra3aginal

    Cu afectarea cutanat:A.intra3asculare

    intra3enosintraarterialintracardiac

    !.extra3asculareintramuscularsubcutnatintrasternal

    C.intraca3itareintraperitoneal

    intrapleuralintrapericardiacintraarticularintra3entricularsubarahnoidian

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    Routes of Drug Administration

    3 #etermined)rimaril= -= t>e)ro)ertie' of t>edrg

    + -A5#$ $#)%"#4 D$)6AD-&'&"%$A%'

    .nteral

    +.Parenteral

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    ENTERAL ROUTSA. #$A/

    !. ")!/&'6)A/

    C. $C%A/

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    PARENTERAL routes

    "C 7subcutaneous

    &- 7intramuscular

    &8 7intra3ascular

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    ( Administrarea medicamentelor pe cale oralA&anta

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    /a administrarea sublingual efectulse instaleazrapid2 substanele medicamentoase nimerescdirect n circuitul sistemic e3it9nd primul pasa

    hepatic i influena asupra lor a enzimelor iaciditii gastrice.)n neauns al acestei ci de administrare estenghiirea unei cantiti mici de substanmedicamentoas datprat sali3aiei permanente.

    Pe cale rectal se administreaz substanele ncazurile imposibilitii administrrii lor pe caleperoral (afeciuni gra3e ale tubului digesti32stri de 3om2 con3ulsii2 com*

    Pe cale rectal2 datorit 3ascularizrii specifice a

    aceste regiuni2substanele medicamentoasepreponderent e3it pasaul hepatic nimerinddirect n circuitul sistemic.

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    Routes of DrugAdministration

    ( . '%$A/A.#$A/3 mo't common rote of admini'tration

    3 Mo't aria-le3 mo't com)licated )at>?a=3 C>ea)e't3 Non 3 ina'ie@NTE+ mo't drg' are a-'or-ed in t>e GIT & enconter

    t>e lier -efore t>e= are di'tri-ted into t>e generalcirclationB

    R t f D

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    Routes of DrugAdministration

    ( . nteral!. ")!/&'6)A/

    3 2lacement under the tongue3 Allo?' t>e drg to diff'e into t>e ca)illarie'& t>erefore to enter t>e '='temic circlation

    Adantage+ t>e drg -=)a''e' t>e inte'tine &

    lier & t>' a3oids stpass metabolism

    ou es o rug

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    ou es o rugAdministration

    . nteralc. $ectal3 U'efl if t>e drg indce' omiting if gien

    orall= or if t>e )atient i' alread= omiting3 #rainage of t>e rectal region -=)a''e' t>e)ortal circlation

    3 Similar to t>e '-lingal rote% it )reent' t>e

    de'trction of t>e drg -= inte'tinal en*=me'or -= t>e lo? )7 in t>e 'tomac>@note+ commonl= 'ed to admini'ter anti emetic

    agent'B

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    PARENTERAL routes

    "C 7subcutaneous

    &- 7intramuscular

    &8 7intra3ascular

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    "ote' of #rg Admini'trationD. #thersa.&nhalation3 2roide' a rapid

    deli3er; of a drg

    acro'' a large'rface area of t>emucus membranesof the respirator;and the pulmonar;epithelium

    3 Effect i' a' ra)id a'I0 in

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    "ote' of #rg

    Admini'trationD. #thersb. &ntranasal

    3 T>rog> t>e no'e

    eg$ + de'mo)re''in%

    'almon calcitonin%cocaine

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    "ote' of #rg Admini'tration

    $ #thersc. &ntrathecal2

    intra3entricular

    3 Introdcing drg' directl=into t>e cere-ro')inalflid / CSF

    Eg$% am)>otericin 1

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    "ote' of #rg Admini'tration( D. #thersd. %opical3 I' 'ed ?>en a local

    effect of a drg i'

    reired

    3 Eg$% clotrima*ole%atro)ine

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    "ote' of #rg Admini'trationD$ #therse. %ransdermal

    3 T>i' rote ofadmini'tration ac>iee'

    '='temic effect' -=a))lication of drg' to t>es

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    ( In

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    /a administrarea intra3enoas efectul apare imediat.

    ste posibil administrarea preparatelor n stride urgen i incontien. ste posibiladministrarea a unor cantiti mari de substanmedicamentoas.

    'u se administreaz intra3enos: soluiile uleioase

    (embolie grsoas*2 suspenziile (tromboz*2soluiile hipotonice (hemoliz* -ai des aparreaciile ad3erse.

    &ntramusular = se poate de administrat soluiileuleioase2 suspenziile2 soluile hipotonice. 'u se

    adminitreaz soluiile hipertonice (necrozaesuturilor* i soluiile iritante.

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    Mecani'mele de tran')ort a medicamentelor )rin

    mem-ranele cellare+( Tran')ortl 'im)l 6)a'i&8 are loc fra tili*areamecani'melor de tran')ort :i fr con'm de energie$

    ( Tran')ortl ')eciali*at 6acti&8 care decrge ca

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    ( Filtrarea3 trecerea c a)a% amoleclelor de medicament 6>idro'olo-ilec ma' moleclar mic8% )rin )orii

    mem-ranari% ;n direc9ia gardientli deconcentra9ie% fr tili*area mecani'melorde tran')ort :i fr con'ml de energie$

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    ( #if*inea 'im)l3 trecereamoleclelor de medicament 6li)o'ol-ile%

    neioni*ate8 )rin 'tratl -ili)idicmem-ranar% ;n direc9ia gardientli deconcentra9ie% fr tili*area mecani'melor

    de tran')ort :i fr con'ml de energie$

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    4$ 2a''age of an nc>arged drg t>rog> amem-rane+

    A drg )a''e' t>rog> mem-rane' morereadil= if it i' nc>arged$

    A$#iff'ion of t>e non3

    ioni*ed form of a?ea acid t>rog> ali)id mem-rane$

    1$#iff'ion of t>enonioni*ed form of a

    ?ea -a'e t>rog> a

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    ( #if*inea facilitat3 trecereamoleclelor de medicament )rin

    'tratl -ili)idic mem-ranar% ;n direc9iagardientli de concentra9ie% ctili*area mecani'melor de tran')ort%dar fr con'ml de energie$

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    ( #if*inea de 'c>im-3tran')ortl ;n cell a nei '-'tan9e%iar din cell a altei% folo'ind acela:'i'tem tran')ortor$

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    ( Tran')ortl acti3 trecereamoleclelor de medicament 6ioni*ate8

    )rin 'tratl -ili)idic mem-ranar% ;n 'en'o)' direc9iei gardientli deconcentra9ie% c tili*area mecani'melor

    de tran')ort% :i c con'm de energie$

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    ( 2inocito*a3 nglo-area 6endocito*a8de catre e*icolele mem-ranare a6)icatrilor mari8 de '-'tan9e

    medcamenoa'e c tran')ortarea lorcatre )artea o)' a mem-ranei :ieliminarea 6e.ocito*a8 ;n ')a9il

    cito)la'matic al cellei

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    Factorii ce inflen9ea*

    a-'or-9ia medicamentelor+#e)enden9i de '-'an9a medicamentoa'( 'rctra c>imic( ma'a moleclar( con'tanta )Ja :i gradl de ioni*are( gradl de li)o'ol-ilitate( do*( )ro)riet9ile fi*ico3c>imice$

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    3 )7 medili

    3 tim)l tili*rii alementelor% com)onen9a :icantitatea :i calitatea lor3 'tarea fi*iologic a t-li dige'ti 6'tarea

    'ecretelor :i fermen9ilor dige'tii8

    3 'tarea )eri'talti'mli inte'tinal3 )re*en9a )atologiilor t-li dige'ti :iorgani'mli

    3 'tarea a'clari*rii t-li dige'ti

    3 tili*area a'ciat a medicamentelor c inflen9a')ra fnc9iilor t-li dige'ti3 Hr't$

    #e)enden9ide )acient

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    ( tiind )roriet9ile fi*ico3c>imice ale '-'tan9elor medicamentoa'e:i caracteri'tica )trnderii .eno-ioticli )rin diferite -ariereti'lare% 'e )oate de )re*t% cm nl 'a alt )re)arat 'e aa-'or-i ;n 'Hnge% di'tri-i ;n organe :i 9e'tri :i elimina dinorgani'm$

    ( 2rin cercetri ')eciale a fo't determinat ca niell di'ocierii6ioni*rii8 '-'tan9elor 'e )oate determina c aenderson?>asselbah:

    ( )entr aci*i 'la-i+ lg

    ( -$ )entr -a*e 'la-e+ lg

    #) cm ede9i% :tiind )73l medili :i )Ja '-'tan9elor 6'ntta-ele ')eciale8 )tem d) logaritml calclat ' determinmgradl de ioni*are a medicamentli% iar acea'ta ;n'eamn% gradlli de a-'or-9ie din t-l dige'ti :i eliminarea li )rin rinic>i ladiferite niele a )73li rinei$

    pHpKaionizataforma

    neionizataforma=

    pHpKa

    neionizataforma

    ionizataforma=

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    Distribuia substanelormedicamentose

    ( #) a-'or-9ie '-'tan9elemedicamentoa'e nimere'c% de regl% ;ncircitl 'angin 'i'temic% iar a)oi 'ntdi'tri-ite ;n organe :i 9e'tri$ Caracterldi'tri-9iei '-'tan9elor medicamenta'ee'te determinat de o ml9ime de factori% ;n

    de)enden9 de care medicamentele or fidi'tri-ite niform 'a neniform$

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    41

    *istri%ution

    Factors affecting

    A%sor$tionMeta%o"ism

    .o/ a"%umin Pro%"ems /it-0

    Heart

    Circu"ation*ia%etes

    !ound drugs are pharmacologicall; inacti3e because the drug?protein complex is unable to cross cell membranes.

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    n 'i'teml 'angin ma

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    ( Li)o'ol-ilitatea '-'tan9elor medicamentoa'e determinca)acitatea lor de a )enetra )rin -arierele -iologice$"ubstanele neionizate liposolubile uor penetreaz prinmembranele biologice i sunt distribuite n toate mediilelichide ale organismului.

    ( 2enetrarea mltor '-'tan9e )rin -ariera >ematoencefalice'te de'tl de dificil% din ca*a )articlarit9ilor de'trctr a 'i'temli de ca)ilare de la ace't niel$ Mai

    ;ntHi de toate endotelil e'te li)'it de )ori iar )re*en9aelementelor gliale de )e ')rafa9a e.tern a endotelili

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    ( #eaceea ite*a a)ari9iei :i am)litd efectlide)ind de gradl de legare dintre medicamente :i)roteine :i dritatea ace'tor legtri

    ( e.em)l e'te glico*idl cardiotonic 6digito.ina8%care 'e leag c )roteinele )la'matice la O$

    #) tili*area ace'ti medicament intern el ;:imanife't ac9inea tocmai d) P3 ore$ i iner'%n alt glico*id 6'trofantina8 'la- 'e leag de)roteinele )la'matice :i efectl 'e in'talea*)e'te cHtea minte$

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    Factorii ce inflen9ea*

    di'tri-9ia medicamentelor( gradl de li)o'ol-ilitate a '-'tan9elormedicamentoa'e

    ( )re*en9a -arierelor >i'to>ematice

    ( gradl de legare c )roteinele )la'matice( inten'itatea circitli 'angin regionar( )re*en9a 'trilor )atologice ale organi'mli( )ro)riet9ile fi*ico3c>imice a medicamentelor :i

    afinitatea lor fa9 de 9e'trile ')ecifice

    6de)o*itarea8$( tili*area nor medicamente ;n a'ociere

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    ( Dup distribuie medicamentele pot:( inretac9iona c locrile de ac9ine :i )roocaa)ari9ia com)le.li de efecte farmacologice

    ( )ot fi meta-oli*ate '- ac9inea fermen9ilor

    adeca9i( ' 'e modifice ')ontan% tran'formHnd3'e ;n alte'-'tan9e actie$

    ( )ot ' 'e elimine din organi'm ;n 'tarene'c>im-at$

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    ( n organi'ml man maimice :i-ioc>imice ale '-'tan9elormedicamentoa'e% care a'igrtran'formarea lor ;n com):i mai 'im)li%ioni*a9i% mai )olari :i re')ecti

    >idro'ol-ili% care mai :or 'nt elimina9idin organi'm$

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    ( Se deo'e-e'c 5 ti)ri de reac9ii de-iotran'formare a '-'tan9elormedicamentoa'e ;n organi'm+

    ( nesintetic (transformarea metabolic*a'igrat de reac9iile de o.idare%redcere% >idroli*$

    ( "intetic a'igrat de reac9iile de

    co>

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    Remediumedicamentos

    Transformareametabolic

    cu acidul glucuroniccu acidul sulfuriccu aminoaciziicu glutationul

    metilareacetilare

    Conjugarea

    oxidarereducerehidroliz

    etaboli!i "i conjuga!i

    #xcre!ia

    1.Biotransformarea substanelor medicamentoase

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    ( "eac9iile tran'formrii meta-olice 'nt)re*entate ca I fa* a -iotran'formriia'-'tan9ele medicamentoa'e d) care ele;3:i )ierd radicalii actii :i dein inactie$

    ( n 'tare inacti ele trec ;n a II3a fa* a-iotran'formrii3 con

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    n rma tran'forrii meta-olice :i con

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    ( A fo't o-'erat c% '- ac9inea nor '-'tan9emedicamentoa'e 'e de*olt o inducie6cre:tere8'a o depresie6diminare8 a 'inte*ei )roteineloren*imatice a ficatli$

    ( n calitate de indctori 'ntcno'cte )e'te 5QQde '-'tan9e medicamentoa'e+ barbituricele(fenobarbital2 hexobarbital*2 cofeina2 etanolul2nicotina2 neurolepticele2 difenhidramina2chinina2 ni

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    ( In>i-itori 'nt+ ane'te*icele locale%remediile antiaritmice -eta3-locante6)ro)ranololl% )indolol8% cimetidina%cloramfenicoll% eritromicina% )aracetamol%

    acid acetil'alicilic% metronida*ol%i*onia*ida% clofi-rat% di'lfiram% remediileanticoline'tera*ice% in>i-itorii MA$Ace'te medicamene tili*ate ;n a'ociere

    or )relngi efectele medicamentelor$

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    ( Cile de -a* a e.cre9ieimedicamentelor 'nt+ rinichii2ficatul2 tubul digesti32 plm9nii2pielea2 glandele sali3are2 glandele

    sudoripare2 laptele matern$n )lanclinic mai im)ortant e'te calearenal de eliminare$

    E.cre9ia

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    $$

    E.cre9ia#rg' are primaril;e.creted -= t>e

    idne='( In order for drg' to -e e.cretedt>e= need to -ecome >=dro)>ilic

    ( E.cretion of drg' can -e affected-= t>e rinar= )7( 7o? t>e drg i' e.creted caninflence )re'cri-ing deci'ion'

    R>ic> 1NF a))endi. relate' to )atient' a-ilit= to e.crete

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    A')ra ite*ei de eliminare a '-'tan9elormedicamentoa'e )ot inflen9a n :ir de factori+

    ( )7 rinei( )re*en9a nei )atologii renale 'a )atologiilora'ociate c dereglri >emodinamice 'i'temice :i>idroelectrolitice 6in'ficien9a cardiac% ciro*a>e)atic8%

    ( gradl de c)lare c )roteinele )la'matice%( )ro)riet9ile fi*ico3c>imice ale '-'tan9elormedicamentoa'e 6li)o'ol-ilitatea :i gradl deioni*are a lor8%

    ( Hr'ta )acien9ilor%

    ( tili*area a'ociat a nor '-'tan9emedicamentoa'e 6diretice o'motice% fro'emid8$

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    Parametrii farmacocinetici

    ( !iodisponibilitatea refleccantitatea de '-'tan9 acti

    nemodificat a

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    +. Concentraia plasmatic reflectfrac9ia li-er de medicament a

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    ,. 8olumul aparent de disribuiee'te n olm i)otetic 6imaginar8 de

    lic>id ;n care '-'tan9amedicamentoa' e'te di'tri-itniform aHnd concentra9ie egal ccea )la'matic$

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    0. %impul de numtire e'tetim)l ;n care concentra9ia

    )la'matic a '-'tan9eimedicamentoa'e 'e mic:orea* laPQO din cantitatea de medicamentintrod'$

    T4/5 7 lf Lif f #

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    61

    T4/5 7alf Life of #rg'( #rg e.cretion i' commonl= e.)re''ed in term' of

    >alf life 6t4/58( T>i' i' t>e time reired for t>e concentration oft>e drg in t>e )la'ma to decrea'e -= one3>alf ofit' initial ale

    ( #rg >alf life i' aria-le and can -e long or '>ort( S-'eent do'e' are gien to rai'e t>e

    concentration leel' to a )ea( In t>eor=% t>e o)timal do'age interal -et?een

    drg admini'tration i' eal to t>e >alf3life of t>edrg

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    @. Clearance?ul e.)rim rata de e.cre9ie a '-'tan9elormedicamentoa'e din )la'ma 'angin )e o anmit cale deeliminare ;ntr3n anmit interal de tim)$ Se eiden9ia*clearance3l renal% )la'matic% total$

    ( Temenl de eliminare a '-'tan9elor medicamentoa'e incldeam-ele )roce'e+ -iotran'formarea :i e.cre9ie$ 2entr o ml9imede '-'tan9e medicamentoa'e ite*a de eliminare de)inde deconcentra9ia )la'matic a lor 6c cHt concentra9ia )la'matice'te mai mic c atHt ite*a de eliminare e'te mai mic8$ Un a:ati) de eliminare a medicamentelor core')nde nei cinetici de

    ordinul & (ntr?o unitate de timp se elimin o anumitcantitate de medicament*.Un nmr mai mic de medicamente6etanoll% fenitoina8 'e elimin d) o cinetic de ordinul .0ite*a eliminrii d) o a:a cinetic n de)inde de concentra9ia)la'matic a '-'tan9elor medicamento'e% ;ntr3o nitate de tim)'e elimin o cantitate 'ta-il de medicament 6de e.em)l tim)de 4 or 'e elimin 34Q g de etanol crat8$ Ace't lcr a)are dinca*a 'atrrii organi'mli c fermen9ii ce meta-oli*ea*ace'te '-'tan9e$

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    TEST

    A )atient ?it> renal im)airment%taing a renall= e.creted drg% ?illreire ?>ic> NE of t>e follo?ing

    ( #o'e redction( #o'e increa'e( Same do'e

    6%

    TEST

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    TESTCare din rmtoarele enn9ri

    de'crie -iodi')oni-ilitatea ( C m a

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    ( Farmacogeneticae'te n com)artiment al farmacologiei care 'tdia*

    inflen9a factorilor eriditari a')ra reactiit9iiorgani'mli ca re*ltat la ac9inea '-'tan9elormedicamentoa'e admini'trate$

    C alte cinte e'te n com)artiment al farmacologie care'tdia* ac9inea medicamentelor a')ra organi'mli ;n

    )re*en9a nor dereglri en*imatice congenitale6en*imo)atii8$En*imo)atie e'te o dereglare anomalic congenital 6li)'%

    diminare 'a accelerare8 a actiit9ii nor en*ime aleorgani'mli$

    ( Insuficiena congenital acolinesterazei)la'matice$l d l

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    Ca re*ltat e'te diminat meta-oli*area nei '-'tan9emedicamentoa'e miorela.ante crari*ante 6'.ametoni8$n condi9ii o-i:nite '.ametonil% ca re*ltat al rela.rii

    diafragmei :i m:c>ilor interco'tali% )rooac o a)nee tim)de P3 minte$ n re*ltatl meta-li*rii in'ficiente a lidrata a)neei 'e )relnge:te )Hn la V3W ore :i mai mlt$

    ( Dificitul enzimei glucozo?B?fosfat dehidrogenazei%a)are

    o eritroli* intraa'clar la tili*area remediilorantimalarice 6cloroc>inei% )rimac>inei8% acidliacetil'alicilic% acidli nalidi.ic% cloramfenicolli%fra*olidonei etc$ #ificitl en*imei date )rooac o'cdere a cantit9ii gltationli red' din 'trctramem-ranelor eritrocitare% ca re*ltat ele dein mlt maifragile la ac9inea '-'tan9elor '' nmite$

    ( $

    FG

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    FG( &nsuficiena catalazelordin 9e'trile organi'mlli la

    nele )er'oane% )rooac li)'a efectli ')ecific 6deformare a ')mei )entr cr9irea )lgilor8 la)relcrarea )lgilor c )ero.idl de >idrogen$

    ( &nsuficiena '?acetiltransferazeihepatice ca re*ltate'te diminat meta-oli*area remedili 3 antit-erclo'>idra*idei acidli i'onicotinic 6i'onia*id8$ 2er'oanele ca'tfel de en*imo)atie 'nt nmi9i acetili*atori len9i$ Care*ltat d) o 'ingr admini'trare a i'onia*idei% crina 'e elimin W3O din cantitatea medicamentli

    admini'trat$ La ace:ti )acien9i a)ar+ ame9eli% cefalee%gre9ri% om% dreri retro'ternale% irita-ilitate%in'omnie% ta>icardie% )olinerit

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    0X ml9me'c )entr

    aten9ie :i$$$$$$$S2" LA MUNCX