TOEGEPASTE
FARMACOLOGIE
,Inhoudsopgave
Inleiding.......................................................................................................................................................... 1
Terminologie ................................................................................................................................................... 1
Toepassingen .................................................................................................................................................. 2
Geneesmiddelen: Indeling volgens werkingsmechanisme .................................................................................. 2
Naamgeving .................................................................................................................................................... 2
Algemene aspecten......................................................................................................................................... 3
Farmacokine8ek ................................................................................................................................................. 3
Defini8e .............................................................................................................................................................. 4
Absorp:e ........................................................................................................................................................ 4
Mechanismen en terminologie ........................................................................................................................... 7
First-pass-effect.............................................................................................................................................. 8
Biologische beschikbaarheid ......................................................................................................................... 9
Mechanismen bij absorp8e .............................................................................................................................. 10
Mechanismen bij de opname van stoffen over biologische membranen .................................................... 10
Mechanismen die de opname van stoffen over membranen tegenwerken ................................................ 14
Interferende factoren bij opname vanuit het gastro-intes8naal stelsel............................................................ 15
Distribu:e..................................................................................................................................................... 20
Bijzondere weefsels (distribuEe) ................................................................................................................. 24
Elimina8e .......................................................................................................................................................... 26
EliminaEe mechanismen.............................................................................................................................. 26
Metabolisa:e................................................................................................................................................ 27
Lever ................................................................................................................................................................. 28
Metabolisa8e: enzyma8sche reac8es .............................................................................................................. 29
Fase I en fase II reacEes ............................................................................................................................... 29
Fase I reacEes .............................................................................................................................................. 29
Fase II reacEes ............................................................................................................................................. 32
Gevolgen metabolisaEe ............................................................................................................................... 33
Beïnvloedende factoren van het metabolisaEe proces ............................................................................... 33
InteracEe tussen GM ................................................................................................................................... 34
Beïnvloedende factoren samenvaNng ........................................................................................................ 37
Excre:e ......................................................................................................................................................... 41
Glomerulaire filtra8e ........................................................................................................................................ 43
Passieve terugdiffusie ....................................................................................................................................... 43
Tubulaire secre8e ............................................................................................................................................. 44
Tubulaire (ac8eve) reabsorp8e ......................................................................................................................... 44
Andere excre8ewegen ...................................................................................................................................... 45
EnterohepaEsche circulaEe ......................................................................................................................... 45
Farmacokine:ek ........................................................................................................................................... 47
, Defini8e ............................................................................................................................................................ 47
Plasmaconcentra8e – 8jdscurve na éénmalige toediening .............................................................................. 50
Mul8pele toedieningen..................................................................................................................................... 51
Evenwichtsconcentra8e / Steady state ............................................................................................................. 52
Varia8e van dosis bij meervoudige toediening ................................................................................................. 53
Algemene PK begrippen ................................................................................................................................... 55
Area under the curve (AUC) ......................................................................................................................... 55
AbsorpEe: Cmax en Tmax ................................................................................................................................. 56
AbsorpEe: latenEeEjd .................................................................................................................................. 56
Herhaalde orale toedieningen: Tmax,ss en Cmax,ss bij steady state ................................................................... 57
DistribuEe .................................................................................................................................................... 57
Farmacokine8sche modellen ............................................................................................................................ 58
ComparEmenten ......................................................................................................................................... 58
Distribu8evolume (Vd) ...................................................................................................................................... 60
EliminaEe fase.............................................................................................................................................. 62
Halfwaarde8jd (t1/2) ......................................................................................................................................... 63
PlasmahalfwaardeEjd .................................................................................................................................. 64
Lineaire kineEek........................................................................................................................................... 64
Klaring: een primaire PK parameter............................................................................................................. 65
Tijd nodig voor volledige eliminaEe ............................................................................................................. 66
Herhaalde toediening .................................................................................................................................. 67
Terminologie: MEC, MTD en therapeu8sch venster .......................................................................................... 68
Minimale effecEeve concentraEe (MEC) ..................................................................................................... 68
Maximaal getolereerde dosis (MTD) ........................................................................................................... 68
Oplaaddosis ...................................................................................................................................................... 69
Aanpassing van het doseringsschema ......................................................................................................... 70
Therapeu:sche drug monitoring (TDM) ........................................................................................................ 71
Farmacodynamiek ........................................................................................................................................ 72
Geneesmiddeleffect op moleculair niveau ........................................................................................................ 72
Receptor affiniteit ............................................................................................................................................. 76
Geneesmiddeleffect op orgaan niveau ............................................................................................................. 76
Types van effecten ............................................................................................................................................ 79
Agonist VS antagonist .................................................................................................................................. 79
Geneesmiddeleffecten op organisme of popula8e niveau................................................................................ 82
Bijwerkingen van geneesmiddelen ................................................................................................................ 82
Toedieningsvormen en toedieningswijzen ........................................................................................................ 85
Orale toediening .......................................................................................................................................... 86
Rectale toediening ....................................................................................................................................... 87
Parenterale toediening ................................................................................................................................ 87
De pediatrische pa:ënt ................................................................................................................................. 88
Historisch perspec8ef ....................................................................................................................................... 88
Groeisnelheid .................................................................................................................................................... 89
Leecijdsspecifieke veranderingen in absorp8e ................................................................................................. 89
, Leecijdsspecifieke veranderingen in distribu8e ................................................................................................ 89
Veranderingen in lichaamssamenstelling ......................................................................................................... 90
Farmacokine8ek van hydrofiele geneesmiddelen............................................................................................. 90
Farmacokine8ek van lypofiele geneesmiddelen ............................................................................................... 91
Distribu8e van geneesmiddelen: eiwitbinding ................................................................................................. 91
Impact van ontwikkeling op metabolisa8e ....................................................................................................... 91
Covariabelen van geneesmiddelen metabolisme ........................................................................................ 93
Propofol klaring bij neonaten ........................................................................................................................... 93
Matura8e van de nierfunc8e ............................................................................................................................ 94
Toediening van geneesmiddelen aan kinderen ................................................................................................. 96
De geriatrische pa:ënt .................................................................................................................................. 96
Farmacotherapie bij de geriatrische pa8ënt .................................................................................................... 96
Geneesmiddelen absorp8e op hoge leecijd ..................................................................................................... 97
Farmacodynamiek: variabiliteit in respons ....................................................................................................... 98
Samenvaeng.................................................................................................................................................... 98
Aanbevelingen .................................................................................................................................................. 98
Farmacotherapie :jdens concep:e, zwangerschap en borstvoeding.............................................................. 99
Zwangerschap .................................................................................................................................................. 99
Transfer van endogene stoffen en medica8e naar moedermelk .................................................................... 100
Absorp8e van moedermelk in de baby ........................................................................................................... 101
Kwan8ficeren van de transfer ......................................................................................................................... 101
M/P raEo.................................................................................................................................................... 101
RID relaEve infant dose.............................................................................................................................. 101
Lacta8on risk categories ................................................................................................................................. 101
Lacta8e ........................................................................................................................................................... 102
Neonataal abs8nen8e syndroom (NAS).......................................................................................................... 102
De pa:ënt met nierinsufficiën:e ................................................................................................................. 103
De kri8ek zieke pa8ënt: belangrijkste PK veranderingen................................................................................ 103
De pa:ënt met leverlijden .......................................................................................................................... 104
Verhoogde biologische beschikbaarheid ........................................................................................................ 104
Dosisaanpassing bij leverinsufficiën8e ........................................................................................................... 104
Farmacotherapie van pijn ........................................................................................................................... 105
Defini8e en pathofysiologie ............................................................................................................................ 105
Klinisch beeld (inflamma8e) ........................................................................................................................... 107
Pijnbehandeling .............................................................................................................................................. 107
Lokale anesthe8ca .......................................................................................................................................... 108
Mineure / perifeer werkende analge8ca ........................................................................................................ 109
NSAID’s ........................................................................................................................................................... 109
FARMACOLOGIE
,Inhoudsopgave
Inleiding.......................................................................................................................................................... 1
Terminologie ................................................................................................................................................... 1
Toepassingen .................................................................................................................................................. 2
Geneesmiddelen: Indeling volgens werkingsmechanisme .................................................................................. 2
Naamgeving .................................................................................................................................................... 2
Algemene aspecten......................................................................................................................................... 3
Farmacokine8ek ................................................................................................................................................. 3
Defini8e .............................................................................................................................................................. 4
Absorp:e ........................................................................................................................................................ 4
Mechanismen en terminologie ........................................................................................................................... 7
First-pass-effect.............................................................................................................................................. 8
Biologische beschikbaarheid ......................................................................................................................... 9
Mechanismen bij absorp8e .............................................................................................................................. 10
Mechanismen bij de opname van stoffen over biologische membranen .................................................... 10
Mechanismen die de opname van stoffen over membranen tegenwerken ................................................ 14
Interferende factoren bij opname vanuit het gastro-intes8naal stelsel............................................................ 15
Distribu:e..................................................................................................................................................... 20
Bijzondere weefsels (distribuEe) ................................................................................................................. 24
Elimina8e .......................................................................................................................................................... 26
EliminaEe mechanismen.............................................................................................................................. 26
Metabolisa:e................................................................................................................................................ 27
Lever ................................................................................................................................................................. 28
Metabolisa8e: enzyma8sche reac8es .............................................................................................................. 29
Fase I en fase II reacEes ............................................................................................................................... 29
Fase I reacEes .............................................................................................................................................. 29
Fase II reacEes ............................................................................................................................................. 32
Gevolgen metabolisaEe ............................................................................................................................... 33
Beïnvloedende factoren van het metabolisaEe proces ............................................................................... 33
InteracEe tussen GM ................................................................................................................................... 34
Beïnvloedende factoren samenvaNng ........................................................................................................ 37
Excre:e ......................................................................................................................................................... 41
Glomerulaire filtra8e ........................................................................................................................................ 43
Passieve terugdiffusie ....................................................................................................................................... 43
Tubulaire secre8e ............................................................................................................................................. 44
Tubulaire (ac8eve) reabsorp8e ......................................................................................................................... 44
Andere excre8ewegen ...................................................................................................................................... 45
EnterohepaEsche circulaEe ......................................................................................................................... 45
Farmacokine:ek ........................................................................................................................................... 47
, Defini8e ............................................................................................................................................................ 47
Plasmaconcentra8e – 8jdscurve na éénmalige toediening .............................................................................. 50
Mul8pele toedieningen..................................................................................................................................... 51
Evenwichtsconcentra8e / Steady state ............................................................................................................. 52
Varia8e van dosis bij meervoudige toediening ................................................................................................. 53
Algemene PK begrippen ................................................................................................................................... 55
Area under the curve (AUC) ......................................................................................................................... 55
AbsorpEe: Cmax en Tmax ................................................................................................................................. 56
AbsorpEe: latenEeEjd .................................................................................................................................. 56
Herhaalde orale toedieningen: Tmax,ss en Cmax,ss bij steady state ................................................................... 57
DistribuEe .................................................................................................................................................... 57
Farmacokine8sche modellen ............................................................................................................................ 58
ComparEmenten ......................................................................................................................................... 58
Distribu8evolume (Vd) ...................................................................................................................................... 60
EliminaEe fase.............................................................................................................................................. 62
Halfwaarde8jd (t1/2) ......................................................................................................................................... 63
PlasmahalfwaardeEjd .................................................................................................................................. 64
Lineaire kineEek........................................................................................................................................... 64
Klaring: een primaire PK parameter............................................................................................................. 65
Tijd nodig voor volledige eliminaEe ............................................................................................................. 66
Herhaalde toediening .................................................................................................................................. 67
Terminologie: MEC, MTD en therapeu8sch venster .......................................................................................... 68
Minimale effecEeve concentraEe (MEC) ..................................................................................................... 68
Maximaal getolereerde dosis (MTD) ........................................................................................................... 68
Oplaaddosis ...................................................................................................................................................... 69
Aanpassing van het doseringsschema ......................................................................................................... 70
Therapeu:sche drug monitoring (TDM) ........................................................................................................ 71
Farmacodynamiek ........................................................................................................................................ 72
Geneesmiddeleffect op moleculair niveau ........................................................................................................ 72
Receptor affiniteit ............................................................................................................................................. 76
Geneesmiddeleffect op orgaan niveau ............................................................................................................. 76
Types van effecten ............................................................................................................................................ 79
Agonist VS antagonist .................................................................................................................................. 79
Geneesmiddeleffecten op organisme of popula8e niveau................................................................................ 82
Bijwerkingen van geneesmiddelen ................................................................................................................ 82
Toedieningsvormen en toedieningswijzen ........................................................................................................ 85
Orale toediening .......................................................................................................................................... 86
Rectale toediening ....................................................................................................................................... 87
Parenterale toediening ................................................................................................................................ 87
De pediatrische pa:ënt ................................................................................................................................. 88
Historisch perspec8ef ....................................................................................................................................... 88
Groeisnelheid .................................................................................................................................................... 89
Leecijdsspecifieke veranderingen in absorp8e ................................................................................................. 89
, Leecijdsspecifieke veranderingen in distribu8e ................................................................................................ 89
Veranderingen in lichaamssamenstelling ......................................................................................................... 90
Farmacokine8ek van hydrofiele geneesmiddelen............................................................................................. 90
Farmacokine8ek van lypofiele geneesmiddelen ............................................................................................... 91
Distribu8e van geneesmiddelen: eiwitbinding ................................................................................................. 91
Impact van ontwikkeling op metabolisa8e ....................................................................................................... 91
Covariabelen van geneesmiddelen metabolisme ........................................................................................ 93
Propofol klaring bij neonaten ........................................................................................................................... 93
Matura8e van de nierfunc8e ............................................................................................................................ 94
Toediening van geneesmiddelen aan kinderen ................................................................................................. 96
De geriatrische pa:ënt .................................................................................................................................. 96
Farmacotherapie bij de geriatrische pa8ënt .................................................................................................... 96
Geneesmiddelen absorp8e op hoge leecijd ..................................................................................................... 97
Farmacodynamiek: variabiliteit in respons ....................................................................................................... 98
Samenvaeng.................................................................................................................................................... 98
Aanbevelingen .................................................................................................................................................. 98
Farmacotherapie :jdens concep:e, zwangerschap en borstvoeding.............................................................. 99
Zwangerschap .................................................................................................................................................. 99
Transfer van endogene stoffen en medica8e naar moedermelk .................................................................... 100
Absorp8e van moedermelk in de baby ........................................................................................................... 101
Kwan8ficeren van de transfer ......................................................................................................................... 101
M/P raEo.................................................................................................................................................... 101
RID relaEve infant dose.............................................................................................................................. 101
Lacta8on risk categories ................................................................................................................................. 101
Lacta8e ........................................................................................................................................................... 102
Neonataal abs8nen8e syndroom (NAS).......................................................................................................... 102
De pa:ënt met nierinsufficiën:e ................................................................................................................. 103
De kri8ek zieke pa8ënt: belangrijkste PK veranderingen................................................................................ 103
De pa:ënt met leverlijden .......................................................................................................................... 104
Verhoogde biologische beschikbaarheid ........................................................................................................ 104
Dosisaanpassing bij leverinsufficiën8e ........................................................................................................... 104
Farmacotherapie van pijn ........................................................................................................................... 105
Defini8e en pathofysiologie ............................................................................................................................ 105
Klinisch beeld (inflamma8e) ........................................................................................................................... 107
Pijnbehandeling .............................................................................................................................................. 107
Lokale anesthe8ca .......................................................................................................................................... 108
Mineure / perifeer werkende analge8ca ........................................................................................................ 109
NSAID’s ........................................................................................................................................................... 109
