1
Farmacologie en farmacokinetiek
Inhoud
Deel 1 – Inleiding ................................................................................................................................. 9
Absorptie ........................................................................................................................................... 9
Welk traject volgt een tablet? ................................................................................................... 10
Eliminatie (buitenhouden van geneesmiddelen door lichaam): ..................................... 12
(1) Enzymen ‘E’: ...................................................................................................................... 13
(2) Actief transport efflux: .............................................................................................. 13
Toepassing: opname ciprofloxacine (quinolone)............................................................. 15
Toepassing: paracetamol inname ........................................................................................ 15
Distributie........................................................................................................................................ 15
Toepassing distributie: thiopental barbituraat ................................................................. 17
Eliminatie ........................................................................................................................................ 17
Clearance & excretie: .............................................................................................................. 17
lever hepatocyten ..................................................................................................................... 17
Nieren........................................................................................................................................... 21
Kwantificatie ADME ..................................................................................................................... 22
Toepassing: IV toediening heparine ................................................................................... 22
Enkelvoudige toediening intraveneus ................................................................................... 22
Eén-compartimentsmodel .................................................................................................... 22
Twee-compartimentsmodel ................................................................................................. 23
SITUATIE: α >> β ........................................................................................................................ 23
Enkelvoudige toediening extravasculair .............................................................................. 24
ORALE TOEDIENING (extravasculair): ............................................................................... 24
Equivalente toediening............................................................................................................... 24
Research en development .................................................................................................... 24
Slow absorption: flip-flop ..................................................................................................... 25
Herhaaldelijke toediening ......................................................................................................... 25
Therapeutic drug monitoring = TDM....................................................................................26
Toepassing: toediening digoxine ..........................................................................................26
Stereoselectieve farmacokinetiek.......................................................................................26
Chronofarmacokinetiek ..............................................................................................................27
,2
Niet-lineaire farmacokinetiek ..................................................................................................27
Populatie farmacokinetiek .........................................................................................................27
Receptortypes ............................................................................................................................... 28
Orthosterische vs allosterische binding: ......................................................................... 30
Fractionele receptorbinding .................................................................................................. 31
Typen bijwerkingen: ................................................................................................................ 34
Systemische expositie ............................................................................................................... 34
Enteraal ...................................................................................................................................... 34
Parenteraal................................................................................................................................ 36
Deel 2: transmissie systemen in perifere & autonome zenuwstelsel ............................ 37
Geneesmiddelen die inwerken op cholinerge transmissie ............................................ 37
Algemene introductie ............................................................................................................. 37
Receptoren ................................................................................................................................ 38
Activatie van cholinerge transmissie ................................................................................ 39
Inhibitie van cholinerge transmissie ................................................................................. 44
mAchR antagonisten .............................................................................................................. 44
nAchR antagonisten ................................................................................................................ 44
Geneesmiddelen die inwerken op adrenerge transmissie ............................................. 45
Anatomie .................................................................................................................................... 45
Synthese, release, reopname noradrenaline & adrenaline ........................................ 45
Verwijdering & degradatie noradrenaline........................................................................ 46
Receptoren ................................................................................................................................ 47
Activatie adrenerge transmissie: agonisten alfa- en bètareceptoren .................... 48
Neveneffecten ........................................................................................................................... 50
Activatie adrenerge transmissie: indirecte sympatho-mimetica .............................. 51
Inhibitie adrenerge transmissie via alfa en bèta blokkers .......................................... 51
Geneesmiddelen die inwerken op dopaminerge, serotonerge & purinerge
transmissie .................................................................................................................................... 54
Dopaminerge neurotransmissie ......................................................................................... 54
Serotonerge neurotransmissie ........................................................................................... 55
Deel 3: Geneesmiddelen die inwerken op CZS ....................................................................... 58
Gebruik van centrale stimulantia bij narcolepsie & ADHD ............................................. 58
Historisch gebruik amfetaminen ........................................................................................ 58
Therapeutische indicaties ..................................................................................................... 58
,3
Narcolepsie ............................................................................................................................... 58
ADHD ........................................................................................................................................... 58
Medicamenteuze behandeling ziekte van Alzheimer ....................................................... 60
Introductie .................................................................................................................................. 60
Neurobiologische mechanismen AD & potentiële therapeutische targets ........... 60
Farmacologie van pijn ................................................................................................................. 61
Inleiding ....................................................................................................................................... 61
Opioïden .......................................................................................................................................62
Lokale anesthetica .................................................................................................................. 74
Farmacotherapie neuropathische pijn ............................................................................... 76
Atypische analgetica................................................................................................................77
Medicamenteuze behandeling van gemoedsstoornissen ................................................77
Neurobiologische basis van depressie ..............................................................................77
Classificatie antidepressiva ................................................................................................. 78
Farmacokinetische eigenschappen .................................................................................... 81
Behandeling met antidepressiva ........................................................................................ 82
Indicaties en speciale aspecten van behandeling ......................................................... 82
Bijwerkingen ............................................................................................................................. 83
Specifieke aandachtspunten ................................................................................................ 85
Contra-indicaties ..................................................................................................................... 85
Interacties .................................................................................................................................. 85
Farmacotherapie van epilepsie............................................................................................... 87
Introductie .................................................................................................................................. 87
Classificatie ............................................................................................................................... 87
Oorzaken van convulsies ...................................................................................................... 87
Werkingsmechanisme anti-epileptica .............................................................................. 87
Anti-epileptica die Na+ kanalen inhiberen ...................................................................... 88
Anti-epileptica die inwerken op GABA .............................................................................. 90
Anti-epileptica die werken via T-type Ca2+ kanalen..................................................... 91
Levetiracetam ............................................................................................................................92
Lacosamide ................................................................................................................................92
Principes farmacotherapie anti-epileptica .......................................................................92
Bijkomende indicaties .............................................................................................................92
Anxiolytica ..................................................................................................................................... 93
,4
Geneesmiddelen => CZS......................................................................................................... 93
Werkingsmechanisme ............................................................................................................ 93
CZS stoornis => neurotransmissie ..................................................................................... 93
Anxiolytica – Hypnotica ......................................................................................................... 93
Antipsychotica (neuroleptica) ................................................................................................. 102
Dopaminerge banen in CZS ................................................................................................. 102
Dopaminerge receptoren ..................................................................................................... 103
Schizofrenie.............................................................................................................................. 103
Farmacologische effecten ...................................................................................................104
Nevenwerkingen ..................................................................................................................... 105
Farmacokinetiek ..................................................................................................................... 105
Klinische indicaties ................................................................................................................ 105
Parkinson ...................................................................................................................................... 105
Stoornissen in motoriek ....................................................................................................... 105
Ziekte van Parkinson – parkinsonisme ........................................................................... 105
Neurochemische basis ......................................................................................................... 106
Oorzaak ziekte van Parkinson ............................................................................................ 106
Anti-Parkinson middelen ..................................................................................................... 106
Farmacokinetiek ..................................................................................................................... 107
Efficaciteit & indicaties ......................................................................................................... 107
Bijwerkingen ............................................................................................................................ 108
Deel 4: Geneesmiddelen in verband met cardiovasculair stelsel: .................................. 109
Koolzuuranhydrase inhibitoren .............................................................................................. 109
Actie ............................................................................................................................................ 109
Farmacokinetiek ..................................................................................................................... 109
Klinisch gebruik ....................................................................................................................... 110
Toxiciteit ...................................................................................................................................... 110
Thiazides......................................................................................................................................... 110
Mechanismen van acties ....................................................................................................... 110
Farmacokinetiek ...................................................................................................................... 110
Indicaties .....................................................................................................................................111
Ongewenste effecten ...............................................................................................................111
Lisdiuretica .....................................................................................................................................111
Mechanismen van acties ........................................................................................................111
,5
Producten ................................................................................................................................... 112
Farmacokinetiek ...................................................................................................................... 112
Indicaties .................................................................................................................................... 112
Ongewenste effecten .............................................................................................................. 112
K+ sparende diuretica ................................................................................................................ 113
.......................................................................................... 113
Spironolacton............................................................................................................................ 113
Inhibitors van Na+ kanalen in renaal epitheel: amiloride ........................................... 113
Indicaties .................................................................................................................................... 113
Ongewenste effecten & interacties .................................................................................... 113
Diuretica .........................................................................................................................................114
Effecten .......................................................................................................................................114
Bètareceptor blokkers ............................................................................................................... 115
Ongewenste effecten .............................................................................................................. 115
ACE inhibitors ............................................................................................................................... 115
Effecten ....................................................................................................................................... 116
Indicaties .................................................................................................................................... 116
Ongewenste effecten .............................................................................................................. 117
Producten ................................................................................................................................... 117
Angiotensine II receptor antagonisten = ARB ..................................................................... 117
Andere vasodilatoren .................................................................................................................118
Ca2+- kanaal blokkers ...........................................................................................................118
Centraal-werkende antihypertensiva ................................................................................... 119
Clonidine ..................................................................................................................................... 119
Neuronblokkers ....................................................................................................................... 119
Alfa1-blokkers .............................................................................................................................. 119
Positieve inotropica.................................................................................................................... 120
Digitalis glycosiden ................................................................................................................ 120
,6
Geneesmiddelen met bèta-agonist activiteit ................................................................. 122
Diuretica ........................................................................................................................................ 122
ACE-I en alfa2-receptor agonisten & combinatie met neprilysin inhibitor .............. 122
Bètablokkers ................................................................................................................................ 123
SGLT2 inhibitors & impact op HF ........................................................................................... 123
COX inhibitoren en HF ............................................................................................................... 123
Diuretica en HF ............................................................................................................................ 123
Interacties ..................................................................................................................................... 124
Introductie ..................................................................................................................................... 124
Behandeling.................................................................................................................................. 125
Plaatjes-aggregatie inhibitors............................................................................................ 126
Nitraten ...................................................................................................................................... 126
Bètablokkers ............................................................................................................................ 128
CCB .............................................................................................................................................. 128
Transport van vet in circulatie (geel = in ppt) .................................................................... 130
Hyperlipidemie ............................................................................................................................ 132
Therapeutische aanpak............................................................................................................. 132
Hypolipidemica ............................................................................................................................ 133
Fibraten ..................................................................................................................................... 133
Harsen (anion uitwisselaars) ............................................................................................. 134
Statines ...................................................................................................................................... 135
Ezetimibe................................................................................................................................... 137
PCSK9-inhibitors (subcutaan) ............................................................................................ 137
Anticoagulantia............................................................................................................................ 137
Vitamine K antagonisten = VKA .......................................................................................... 137
Orale selectieve stollingsfactoren inhibitoren = DOAC ...............................................140
Injecteerbare anticoagulantia .............................................................................................. 141
Anti-aggregantia ......................................................................................................................... 142
Aspirine...................................................................................................................................... 142
Perorale P2Y12-remmers..................................................................................................... 142
Trombolytica ................................................................................................................................. 142
Contra-indicaties .................................................................................................................... 143
Indicaties ................................................................................................................................... 143
Klinisch gebruik .......................................................................................................................... 143
,7
Arteriële trombose..................................................................................................................... 143
Deel 5: farmacotherapie van inflammatie, allergische reacties, DM, oncologie en GI
..............................................................................................................................................................144
Geneesmiddelen gebruikt bij allergische (typeI) & anafylactische reacties ............144
H1-R antagonisten ..................................................................................................................144
Bijzondere bepalingen i.v.m. behandeling hooikoorts ................................................. 146
Behandeling anafylactische shock .................................................................................... 146
Glucocorticoïden ......................................................................................................................... 146
Bestanddelen: chemie van glucocorticoïden ..................................................................... 147
Werkingsmechanisme ........................................................................................................... 147
Farmacokinetiek ..................................................................................................................... 147
Farmacodynamiek .................................................................................................................. 147
Indicaties ...................................................................................................................................148
Bijwerkingen ............................................................................................................................ 149
Risicopopulaties ....................................................................................................................... 151
Farmacotherapie van astma ................................................................................................... 152
Anti-astmatische geneesmiddelen ................................................................................... 152
Non-steroïdale anti-inflammatoire drugs (NSAID’s) ...................................................... 155
Chemie NSAID’s....................................................................................................................... 155
Chemie NSAID’s....................................................................................................................... 155
Farmacokinetiek NSAID’s..................................................................................................... 156
Farmacodynamiek NSAID’s ................................................................................................. 156
Indicaties ................................................................................................................................... 156
Bijwerkingen ............................................................................................................................ 156
Contra-indicaties & risicopopulaties ................................................................................ 158
Interacties ................................................................................................................................. 158
Praktisch: juiste NSAID kiezen ........................................................................................... 158
Individuele NSAID groepen .................................................................................................. 158
Farmacotherapie GI stelsel ..................................................................................................... 163
H2-receptor antagonisten ....................................................................................................... 164
Eigenschappen, chemie en werkingsmechanisme ...................................................... 164
Farmacodynamiek .................................................................................................................. 164
Farmacokinetiek ..................................................................................................................... 164
Bijwerkingen & interacties .................................................................................................. 164
,8
Klinisch gebruik ...................................................................................................................... 164
Proton pomp inhibitoren (PPI’s) ............................................................................................. 165
Eigenschappen, chemie en werkingsmechanisme ...................................................... 165
Farmacokinetiek & farmacodynamiek ............................................................................. 165
Indicaties ................................................................................................................................... 165
Bijwerkingen ............................................................................................................................ 165
Keuze & gebruik PPI’s ........................................................................................................... 165
Misoprostol ................................................................................................................................... 165
Antacida ......................................................................................................................................... 166
Antibiotica ..................................................................................................................................... 166
Dopamine-2-R antagonisten................................................................................................... 166
Tweede-lijn anti-reumatische middelen ............................................................................. 168
DMARD’s .................................................................................................................................... 168
Andere immunosuppressiva ............................................................................................... 170
Farmacotherapie van diabetes mellitus.............................................................................. 173
Insuline en analogen ............................................................................................................. 173
Orale antidiabetica ................................................................................................................. 174
Farmacotherapie van kanker.................................................................................................. 178
Algemene informatie ............................................................................................................. 178
Strategieën chemotherapie ................................................................................................. 178
Geneesmiddelen ..................................................................................................................... 179
,9
Deel 1 – Inleiding
❖ Geneesmiddel D => wat zijn effecten E?
❖ 2 processen:
o Inname: komt terecht in plasma met concentratie Cp => deze Cp
verandert doorheen de tijd (door opname) => Cp (t)
▪ Gekarakteriseerd door Pk (farmaceutische kinetiek):
Gausscurve
• Farmacokinetiek = Absorptie – Distributie (piek) –
Metabolisme – Excretie => vooral bij orale
geneesmiddelen
o Effecten: farmacodynamiek Pd
▪ Effecten ~ concentratie => pas vanaf bepaalde Cp
• Geneesmiddelen werken meestal niet als ze niet
geabsorbeerd worden in sommige gevallen is dit wel
nuttig, bv. bij een GI infectie moet het geneesmiddel in de
GI tract blijven (bacteriële infectie)
• Grafiek: log concentratie
▪ Conclusie: geneesmiddelen moeten (meestal) in de circulatie
geraken = absorptie nodig
Absorptie
❖ Meestal oraal ingenomen IV of IM kan ook => ook absorptie nodig!
❖ Vb. absorptie van tablet
o Hoe innemen: nuchter + 240 ml water => dit is de IDEALE manier van
inname
▪ Nuchter betekent 4 a 8u niks gegeten
, 10
Welk traject volgt een tablet?
(1) Mond: gewoon inslikken, NIET kauwen
o Waarom niet kauwen?
▪ Weinig stabiele actieve stof kan in mond vrijkomen &
afgebroken worden door enzymen
▪ Actieve stof kan lokaal toxische effecten hebben op mucosa
▪ Er bestaan ook slow release tabletten waarbij er een kleine
dosis tegelijk mag vrijkomen
(2) Maag: waterrijk + zuur milieu (pH = 2)
o Wat is een pH 2: zeer hoge concentratie H+ ionen waarbij pH = - log [H+]
o Fase heeft 2 kenmerken: 1) verbrokkeling waardoor de stof in 2)
oplossing komt (indien genoeg H2O) => 1 + 2 = farmaceutische fase
o Fase in maag duurt ongeveer 1u
(3) Dunne darm: start absorptie
o Tablet bevindt zich in opgeloste vorm in duodenum => moet geabsorbeerd
worden via lumen
o API (actief farmaceutisch bestanddeel = 1 molecule)
o Dit kan op 2 manieren:
▪ Trans cellulair transport: binnen 1 zelfde cel
• Passieve diffusie (PD): hierbij is de drijvende kracht de
concentratiegradiënt => bij de 1e inname ooit van geneesmiddelen is de
Ci = 0 en de Co veel groter dus is er een verschil in concentratie
➢ De flux wordt beschreven door de wet van Fick: v = D * A/d * P * ΔC
=> afgekort als J = K * ΔC
Recht evenredig verband tussen J en ΔC
P = partitie coëfficiënt: om doorheen fosfolipiden dubbellaag te
geraken, hebben geneesmiddelen een bepaalde
vetoplosbaarheid nodig => dit wordt getest in een proefbuisje
met N-octanol en H2O => P = [D]l/[D]H2O => als P = 1 dan even
lipofiel als hydrofiel => als P zeer klein is dan hydrofiel dus
kleine flux (slechtere opname) dus sommige geneesmiddelen
geraken niet eens in circulatie => als P groot is dan lipofiel dus
efficiënte opname maar P moet kleiner zijn dan 5 anders blijft
het molecule vastzitten in de dubbellaag
Farmacologie en farmacokinetiek
Inhoud
Deel 1 – Inleiding ................................................................................................................................. 9
Absorptie ........................................................................................................................................... 9
Welk traject volgt een tablet? ................................................................................................... 10
Eliminatie (buitenhouden van geneesmiddelen door lichaam): ..................................... 12
(1) Enzymen ‘E’: ...................................................................................................................... 13
(2) Actief transport efflux: .............................................................................................. 13
Toepassing: opname ciprofloxacine (quinolone)............................................................. 15
Toepassing: paracetamol inname ........................................................................................ 15
Distributie........................................................................................................................................ 15
Toepassing distributie: thiopental barbituraat ................................................................. 17
Eliminatie ........................................................................................................................................ 17
Clearance & excretie: .............................................................................................................. 17
lever hepatocyten ..................................................................................................................... 17
Nieren........................................................................................................................................... 21
Kwantificatie ADME ..................................................................................................................... 22
Toepassing: IV toediening heparine ................................................................................... 22
Enkelvoudige toediening intraveneus ................................................................................... 22
Eén-compartimentsmodel .................................................................................................... 22
Twee-compartimentsmodel ................................................................................................. 23
SITUATIE: α >> β ........................................................................................................................ 23
Enkelvoudige toediening extravasculair .............................................................................. 24
ORALE TOEDIENING (extravasculair): ............................................................................... 24
Equivalente toediening............................................................................................................... 24
Research en development .................................................................................................... 24
Slow absorption: flip-flop ..................................................................................................... 25
Herhaaldelijke toediening ......................................................................................................... 25
Therapeutic drug monitoring = TDM....................................................................................26
Toepassing: toediening digoxine ..........................................................................................26
Stereoselectieve farmacokinetiek.......................................................................................26
Chronofarmacokinetiek ..............................................................................................................27
,2
Niet-lineaire farmacokinetiek ..................................................................................................27
Populatie farmacokinetiek .........................................................................................................27
Receptortypes ............................................................................................................................... 28
Orthosterische vs allosterische binding: ......................................................................... 30
Fractionele receptorbinding .................................................................................................. 31
Typen bijwerkingen: ................................................................................................................ 34
Systemische expositie ............................................................................................................... 34
Enteraal ...................................................................................................................................... 34
Parenteraal................................................................................................................................ 36
Deel 2: transmissie systemen in perifere & autonome zenuwstelsel ............................ 37
Geneesmiddelen die inwerken op cholinerge transmissie ............................................ 37
Algemene introductie ............................................................................................................. 37
Receptoren ................................................................................................................................ 38
Activatie van cholinerge transmissie ................................................................................ 39
Inhibitie van cholinerge transmissie ................................................................................. 44
mAchR antagonisten .............................................................................................................. 44
nAchR antagonisten ................................................................................................................ 44
Geneesmiddelen die inwerken op adrenerge transmissie ............................................. 45
Anatomie .................................................................................................................................... 45
Synthese, release, reopname noradrenaline & adrenaline ........................................ 45
Verwijdering & degradatie noradrenaline........................................................................ 46
Receptoren ................................................................................................................................ 47
Activatie adrenerge transmissie: agonisten alfa- en bètareceptoren .................... 48
Neveneffecten ........................................................................................................................... 50
Activatie adrenerge transmissie: indirecte sympatho-mimetica .............................. 51
Inhibitie adrenerge transmissie via alfa en bèta blokkers .......................................... 51
Geneesmiddelen die inwerken op dopaminerge, serotonerge & purinerge
transmissie .................................................................................................................................... 54
Dopaminerge neurotransmissie ......................................................................................... 54
Serotonerge neurotransmissie ........................................................................................... 55
Deel 3: Geneesmiddelen die inwerken op CZS ....................................................................... 58
Gebruik van centrale stimulantia bij narcolepsie & ADHD ............................................. 58
Historisch gebruik amfetaminen ........................................................................................ 58
Therapeutische indicaties ..................................................................................................... 58
,3
Narcolepsie ............................................................................................................................... 58
ADHD ........................................................................................................................................... 58
Medicamenteuze behandeling ziekte van Alzheimer ....................................................... 60
Introductie .................................................................................................................................. 60
Neurobiologische mechanismen AD & potentiële therapeutische targets ........... 60
Farmacologie van pijn ................................................................................................................. 61
Inleiding ....................................................................................................................................... 61
Opioïden .......................................................................................................................................62
Lokale anesthetica .................................................................................................................. 74
Farmacotherapie neuropathische pijn ............................................................................... 76
Atypische analgetica................................................................................................................77
Medicamenteuze behandeling van gemoedsstoornissen ................................................77
Neurobiologische basis van depressie ..............................................................................77
Classificatie antidepressiva ................................................................................................. 78
Farmacokinetische eigenschappen .................................................................................... 81
Behandeling met antidepressiva ........................................................................................ 82
Indicaties en speciale aspecten van behandeling ......................................................... 82
Bijwerkingen ............................................................................................................................. 83
Specifieke aandachtspunten ................................................................................................ 85
Contra-indicaties ..................................................................................................................... 85
Interacties .................................................................................................................................. 85
Farmacotherapie van epilepsie............................................................................................... 87
Introductie .................................................................................................................................. 87
Classificatie ............................................................................................................................... 87
Oorzaken van convulsies ...................................................................................................... 87
Werkingsmechanisme anti-epileptica .............................................................................. 87
Anti-epileptica die Na+ kanalen inhiberen ...................................................................... 88
Anti-epileptica die inwerken op GABA .............................................................................. 90
Anti-epileptica die werken via T-type Ca2+ kanalen..................................................... 91
Levetiracetam ............................................................................................................................92
Lacosamide ................................................................................................................................92
Principes farmacotherapie anti-epileptica .......................................................................92
Bijkomende indicaties .............................................................................................................92
Anxiolytica ..................................................................................................................................... 93
,4
Geneesmiddelen => CZS......................................................................................................... 93
Werkingsmechanisme ............................................................................................................ 93
CZS stoornis => neurotransmissie ..................................................................................... 93
Anxiolytica – Hypnotica ......................................................................................................... 93
Antipsychotica (neuroleptica) ................................................................................................. 102
Dopaminerge banen in CZS ................................................................................................. 102
Dopaminerge receptoren ..................................................................................................... 103
Schizofrenie.............................................................................................................................. 103
Farmacologische effecten ...................................................................................................104
Nevenwerkingen ..................................................................................................................... 105
Farmacokinetiek ..................................................................................................................... 105
Klinische indicaties ................................................................................................................ 105
Parkinson ...................................................................................................................................... 105
Stoornissen in motoriek ....................................................................................................... 105
Ziekte van Parkinson – parkinsonisme ........................................................................... 105
Neurochemische basis ......................................................................................................... 106
Oorzaak ziekte van Parkinson ............................................................................................ 106
Anti-Parkinson middelen ..................................................................................................... 106
Farmacokinetiek ..................................................................................................................... 107
Efficaciteit & indicaties ......................................................................................................... 107
Bijwerkingen ............................................................................................................................ 108
Deel 4: Geneesmiddelen in verband met cardiovasculair stelsel: .................................. 109
Koolzuuranhydrase inhibitoren .............................................................................................. 109
Actie ............................................................................................................................................ 109
Farmacokinetiek ..................................................................................................................... 109
Klinisch gebruik ....................................................................................................................... 110
Toxiciteit ...................................................................................................................................... 110
Thiazides......................................................................................................................................... 110
Mechanismen van acties ....................................................................................................... 110
Farmacokinetiek ...................................................................................................................... 110
Indicaties .....................................................................................................................................111
Ongewenste effecten ...............................................................................................................111
Lisdiuretica .....................................................................................................................................111
Mechanismen van acties ........................................................................................................111
,5
Producten ................................................................................................................................... 112
Farmacokinetiek ...................................................................................................................... 112
Indicaties .................................................................................................................................... 112
Ongewenste effecten .............................................................................................................. 112
K+ sparende diuretica ................................................................................................................ 113
.......................................................................................... 113
Spironolacton............................................................................................................................ 113
Inhibitors van Na+ kanalen in renaal epitheel: amiloride ........................................... 113
Indicaties .................................................................................................................................... 113
Ongewenste effecten & interacties .................................................................................... 113
Diuretica .........................................................................................................................................114
Effecten .......................................................................................................................................114
Bètareceptor blokkers ............................................................................................................... 115
Ongewenste effecten .............................................................................................................. 115
ACE inhibitors ............................................................................................................................... 115
Effecten ....................................................................................................................................... 116
Indicaties .................................................................................................................................... 116
Ongewenste effecten .............................................................................................................. 117
Producten ................................................................................................................................... 117
Angiotensine II receptor antagonisten = ARB ..................................................................... 117
Andere vasodilatoren .................................................................................................................118
Ca2+- kanaal blokkers ...........................................................................................................118
Centraal-werkende antihypertensiva ................................................................................... 119
Clonidine ..................................................................................................................................... 119
Neuronblokkers ....................................................................................................................... 119
Alfa1-blokkers .............................................................................................................................. 119
Positieve inotropica.................................................................................................................... 120
Digitalis glycosiden ................................................................................................................ 120
,6
Geneesmiddelen met bèta-agonist activiteit ................................................................. 122
Diuretica ........................................................................................................................................ 122
ACE-I en alfa2-receptor agonisten & combinatie met neprilysin inhibitor .............. 122
Bètablokkers ................................................................................................................................ 123
SGLT2 inhibitors & impact op HF ........................................................................................... 123
COX inhibitoren en HF ............................................................................................................... 123
Diuretica en HF ............................................................................................................................ 123
Interacties ..................................................................................................................................... 124
Introductie ..................................................................................................................................... 124
Behandeling.................................................................................................................................. 125
Plaatjes-aggregatie inhibitors............................................................................................ 126
Nitraten ...................................................................................................................................... 126
Bètablokkers ............................................................................................................................ 128
CCB .............................................................................................................................................. 128
Transport van vet in circulatie (geel = in ppt) .................................................................... 130
Hyperlipidemie ............................................................................................................................ 132
Therapeutische aanpak............................................................................................................. 132
Hypolipidemica ............................................................................................................................ 133
Fibraten ..................................................................................................................................... 133
Harsen (anion uitwisselaars) ............................................................................................. 134
Statines ...................................................................................................................................... 135
Ezetimibe................................................................................................................................... 137
PCSK9-inhibitors (subcutaan) ............................................................................................ 137
Anticoagulantia............................................................................................................................ 137
Vitamine K antagonisten = VKA .......................................................................................... 137
Orale selectieve stollingsfactoren inhibitoren = DOAC ...............................................140
Injecteerbare anticoagulantia .............................................................................................. 141
Anti-aggregantia ......................................................................................................................... 142
Aspirine...................................................................................................................................... 142
Perorale P2Y12-remmers..................................................................................................... 142
Trombolytica ................................................................................................................................. 142
Contra-indicaties .................................................................................................................... 143
Indicaties ................................................................................................................................... 143
Klinisch gebruik .......................................................................................................................... 143
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Arteriële trombose..................................................................................................................... 143
Deel 5: farmacotherapie van inflammatie, allergische reacties, DM, oncologie en GI
..............................................................................................................................................................144
Geneesmiddelen gebruikt bij allergische (typeI) & anafylactische reacties ............144
H1-R antagonisten ..................................................................................................................144
Bijzondere bepalingen i.v.m. behandeling hooikoorts ................................................. 146
Behandeling anafylactische shock .................................................................................... 146
Glucocorticoïden ......................................................................................................................... 146
Bestanddelen: chemie van glucocorticoïden ..................................................................... 147
Werkingsmechanisme ........................................................................................................... 147
Farmacokinetiek ..................................................................................................................... 147
Farmacodynamiek .................................................................................................................. 147
Indicaties ...................................................................................................................................148
Bijwerkingen ............................................................................................................................ 149
Risicopopulaties ....................................................................................................................... 151
Farmacotherapie van astma ................................................................................................... 152
Anti-astmatische geneesmiddelen ................................................................................... 152
Non-steroïdale anti-inflammatoire drugs (NSAID’s) ...................................................... 155
Chemie NSAID’s....................................................................................................................... 155
Chemie NSAID’s....................................................................................................................... 155
Farmacokinetiek NSAID’s..................................................................................................... 156
Farmacodynamiek NSAID’s ................................................................................................. 156
Indicaties ................................................................................................................................... 156
Bijwerkingen ............................................................................................................................ 156
Contra-indicaties & risicopopulaties ................................................................................ 158
Interacties ................................................................................................................................. 158
Praktisch: juiste NSAID kiezen ........................................................................................... 158
Individuele NSAID groepen .................................................................................................. 158
Farmacotherapie GI stelsel ..................................................................................................... 163
H2-receptor antagonisten ....................................................................................................... 164
Eigenschappen, chemie en werkingsmechanisme ...................................................... 164
Farmacodynamiek .................................................................................................................. 164
Farmacokinetiek ..................................................................................................................... 164
Bijwerkingen & interacties .................................................................................................. 164
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Klinisch gebruik ...................................................................................................................... 164
Proton pomp inhibitoren (PPI’s) ............................................................................................. 165
Eigenschappen, chemie en werkingsmechanisme ...................................................... 165
Farmacokinetiek & farmacodynamiek ............................................................................. 165
Indicaties ................................................................................................................................... 165
Bijwerkingen ............................................................................................................................ 165
Keuze & gebruik PPI’s ........................................................................................................... 165
Misoprostol ................................................................................................................................... 165
Antacida ......................................................................................................................................... 166
Antibiotica ..................................................................................................................................... 166
Dopamine-2-R antagonisten................................................................................................... 166
Tweede-lijn anti-reumatische middelen ............................................................................. 168
DMARD’s .................................................................................................................................... 168
Andere immunosuppressiva ............................................................................................... 170
Farmacotherapie van diabetes mellitus.............................................................................. 173
Insuline en analogen ............................................................................................................. 173
Orale antidiabetica ................................................................................................................. 174
Farmacotherapie van kanker.................................................................................................. 178
Algemene informatie ............................................................................................................. 178
Strategieën chemotherapie ................................................................................................. 178
Geneesmiddelen ..................................................................................................................... 179
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Deel 1 – Inleiding
❖ Geneesmiddel D => wat zijn effecten E?
❖ 2 processen:
o Inname: komt terecht in plasma met concentratie Cp => deze Cp
verandert doorheen de tijd (door opname) => Cp (t)
▪ Gekarakteriseerd door Pk (farmaceutische kinetiek):
Gausscurve
• Farmacokinetiek = Absorptie – Distributie (piek) –
Metabolisme – Excretie => vooral bij orale
geneesmiddelen
o Effecten: farmacodynamiek Pd
▪ Effecten ~ concentratie => pas vanaf bepaalde Cp
• Geneesmiddelen werken meestal niet als ze niet
geabsorbeerd worden in sommige gevallen is dit wel
nuttig, bv. bij een GI infectie moet het geneesmiddel in de
GI tract blijven (bacteriële infectie)
• Grafiek: log concentratie
▪ Conclusie: geneesmiddelen moeten (meestal) in de circulatie
geraken = absorptie nodig
Absorptie
❖ Meestal oraal ingenomen IV of IM kan ook => ook absorptie nodig!
❖ Vb. absorptie van tablet
o Hoe innemen: nuchter + 240 ml water => dit is de IDEALE manier van
inname
▪ Nuchter betekent 4 a 8u niks gegeten
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Welk traject volgt een tablet?
(1) Mond: gewoon inslikken, NIET kauwen
o Waarom niet kauwen?
▪ Weinig stabiele actieve stof kan in mond vrijkomen &
afgebroken worden door enzymen
▪ Actieve stof kan lokaal toxische effecten hebben op mucosa
▪ Er bestaan ook slow release tabletten waarbij er een kleine
dosis tegelijk mag vrijkomen
(2) Maag: waterrijk + zuur milieu (pH = 2)
o Wat is een pH 2: zeer hoge concentratie H+ ionen waarbij pH = - log [H+]
o Fase heeft 2 kenmerken: 1) verbrokkeling waardoor de stof in 2)
oplossing komt (indien genoeg H2O) => 1 + 2 = farmaceutische fase
o Fase in maag duurt ongeveer 1u
(3) Dunne darm: start absorptie
o Tablet bevindt zich in opgeloste vorm in duodenum => moet geabsorbeerd
worden via lumen
o API (actief farmaceutisch bestanddeel = 1 molecule)
o Dit kan op 2 manieren:
▪ Trans cellulair transport: binnen 1 zelfde cel
• Passieve diffusie (PD): hierbij is de drijvende kracht de
concentratiegradiënt => bij de 1e inname ooit van geneesmiddelen is de
Ci = 0 en de Co veel groter dus is er een verschil in concentratie
➢ De flux wordt beschreven door de wet van Fick: v = D * A/d * P * ΔC
=> afgekort als J = K * ΔC
Recht evenredig verband tussen J en ΔC
P = partitie coëfficiënt: om doorheen fosfolipiden dubbellaag te
geraken, hebben geneesmiddelen een bepaalde
vetoplosbaarheid nodig => dit wordt getest in een proefbuisje
met N-octanol en H2O => P = [D]l/[D]H2O => als P = 1 dan even
lipofiel als hydrofiel => als P zeer klein is dan hydrofiel dus
kleine flux (slechtere opname) dus sommige geneesmiddelen
geraken niet eens in circulatie => als P groot is dan lipofiel dus
efficiënte opname maar P moet kleiner zijn dan 5 anders blijft
het molecule vastzitten in de dubbellaag
