Psychofarmaca bij probleemgedrag
Rob van Marum
Klinisch geriater, klinisch farmacoloog
Hoogleraar Farmacotherapie bij ouderen
Neuropsychiatrische symptomen
Cognitieve
symptomen
Functionele
symptomen
Neuropsychiatrische
symptomen
probleemgedrag
- Roepen
- Agressie
- Dwalen
- Ontremming
- Apathie
psychiatrische stoornissen
- Hallucinaties
- Wanen
- Depressie
- Angststoornissen
aantal gebruikers van
antipsychotica per 1000 inwoners
in de betreffende leeftijdsgroep
17 september 2010, Pharmaceutisch Weekblad, Jaargang 145
Nr 37
Aantal voorschriften antipsychotica
Antipsychoticum
21-64 jaar
≥ 65 jaar
Haloperidol
6%
26%
Risperidon
16%
21%
Olanzapine
20%
17%
Quetiapine
23%
13%
Pipamperon
6%
7%
Clozapine
8%
4%
1.041.000
voorschriften
380.000
voorschriften
17 september 2010, Pharmaceutisch Weekblad, Jaargang 145 Nr 37
Het eerste AP: chloorpromazine (1950)
When Thorazine is administred to the
agitated senile, there is a marked decrease in
his nerve racking outbursts of hostility,
irritability, abusiveness and ‘day-and-night’
pacing.
.. more regular eating and sleeping habits
and improves in his personal hygiene.
Dopamine pathways
a: nigrostriataal
b: mesolimbisch
c: mesocorticaal
d: tuberoinfundibulair
e: 5e
Dopamine-blokkade
• Mesolimbisch systeem
- Reductie positieve symptomen (hallucinaties, wanen)
- Versterking negatieve symptomen (minder motivatie, apathie,
anhedonie, minder reward)
• Nigrostriatale systeem
- Extrapyramidale bewegingsstoornissen
• Mesocorticale systeem naar prefrontaal (DLPFC/VMPFC)
- Cognitieve en emotionele achteruitgang
Klassiek AP
• D2 antagonisme
- Vermindering psychose
- EPS: parkinsonisme, tardieve dyskinesie
- Verhoging prolactine (galactorrhoe, amenorroe, impotentie, osteoporose)
- Neurolepsie
• >60-70% bezetting D2 receptor. Bij >80% bijwerkingen
Conventioneel AP
Anticholinergicum bij EPS?
Wat is atypisch?
minder D2 blokkade!
Hoe doe je dat?
• 5HT2a-antagonisme
- Clozapine, risperidon, olanzapine, ziprasidone (quetiapine? )
• 5HT1a-agonisme (partieel)
- Ziprasidone, quetiapine, clozapine, aripiprazole
• D2 antagonisme met snelle dissociatie (hit and run)
- Clozapine, quetiapine
• D2 partieel agonisme
- Aripiprazole, sulpiride
Atypisch AP:
de rol van serotonine
5HT2a receptor
• M.n. nigrostriatale en
5HT1a receptor tuburo infundibulaire
systeem
Atypisch AP
Receptor en bijwerkingen: overig
• Anticholinerg
- Cognitie ⇓
- Urineretentie
- Obstipatie
- Wazige visus
- Droge mond
- Sufheid, slaperigheid
• Anti-5HT2
- Minder agitatie, agressie
- Verlengen diepe slaap
• α-Adrenerg
- Orthostase
- Vallen
- hypnosedatie
• Histaminerg
- Sedatie
- gewichtstoename
AP
generiek
D2
5HT2a
ACh
Alfa1
Hist
Haloperidol
++++
+
nvt
+
-
risperidon
+++
+++++
nvt
++
+
olanzapine
++
+++
++
+
+++
quetiapine
+
++
+
+
+++
clozapine
+
++
++
++
++++
aripiprazole
+++
+++
?
++
++
pipamperon
++
+++
nvt
++
-
Sedatie?
• Demping: remming psychomotoriek, angst. agitatie
• Onverschillig makend: minder agressie, vijandigheid
• Hypnosedatie: suf en slaperig
Kinetiek
T1/2 (uren)
Tmax (uren)
Metabolisme
Haloperidol
20
2-6
3A4, 2D6
Pipamperon
11-35
2
-
Risperidon
3 (24)
1-2
2D6
Clozapine
12 (6-26)
1-3
1A2, 3A4, 2D6
Olanzapine
30 (50)
5-8
1A2, 2D6
Quetiapine
9-11
1-2
3A4
Levomepromazine
15-78
1-4
Eliminatie
Concentratie
x
100%
50%
x
25%
x
1
2
12.5%
x
3
6.25%
x
4
3.125%
x
5
Halfwaardetijd
Zwart: dosering T1/2
Concentratie
Rood: ½ dosering 2x/T1/2
Blauw: continue infusie
2
1
T 1/2
Tijd
Zwart: dosering T1/2
Concentratie
Rood: 2x dosering bolus +
dosering T 1/2
Blauw: continue infusie
2
1
T 1/2
Tijd
Antidepressiva
Serotonine reuptake inhibition
NE reuptake inhibition
Histamine blokkade
Alfa-1 blokkade
Muscarine blokkade
SSRI’s en remming CYP450
CYP
isoform
Citalopram
Fluoxetine
CYP1A2
NA
NA
CYP2C9
CYP2D6
-/+
CYP3A4
NA
+
+++
+
CYP2C19
Fluvoxamine
+++
+/++
++/+++
+
+
Paroxetine Sertraline
NA
+++
-
-/+
-/+
+
-
NA: niet beschikbaar, - geen effect, + >50% verandering
++ 50-150% verandering,
+++ >150% verandering
Benzodiazepines en vallen
• Alle benzo’s geven een verhoogd valrisico,
• Vallen meestal ‘s nachts
• Exponentieel risico
2002 (revisie 2008)
Effectiveness of Atypical Antipsychotic Drugs in Patients with
Alzheimer's Disease
N Engl J Med. 2006 Oct 12;355(15):1604-6.
Memantine en agitatie
Psychofarmaca zijn niet onschuldig!!
FDA 2008
•
FDA ALERT [6/16/2008]: FDA is notifying healthcare professionals that both
conventional and atypical antipsychotics are associated with an increased risk of
mortality in elderly patients treated for dementia-related psychosis.
Considerations for Healthcare Professionals
• Elderly patients with dementia-related psychosis treated with conventional or
atypical antipsychotic drugs are at an increased risk of death.
• Antipsychotic drugs are not approved for the treatment of dementia-related
psychosis. Furthermore, there is no approved drug for the treatment of dementiarelated psychosis. Healthcare professionals should consider other management
options.
• Physicians who prescribe antipsychotics to elderly patients with dementia-related
psychosis should discuss this risk of increased mortality with their patients, patients’
families, and caregivers.
• Fifteen trials (9 unpublished), generally 10 to 12 weeks in
duration, including 16 contrasts of atypical antipsychotic drugs
with placebo
• Death occurred more often among patients randomized to drugs
(118 [3.5%] vs 40 [2.3%]. The OR by meta-analysis was 1.54;
95% confidence interval [CI], 1.06-2.23; P=.02;
• Considering that many of these trials demonstrated that these
medications are only modestly effective with numbers needing to
treat ranging from 4 to 12 in specific metaanalyses, the likelihood
for helping vs harming may be rather modest as well, such that for
every 9 to 25 persons helped in these trials there possibly will be
1 death.
Behandelen van 1000 patienten met BPSD met een
ap gedurende 3 maanden leidt tot:
• Klinische verbetering bij 91-200 pten
• Overlijden 10 patienten
- Bij langer behandelen toename sterfte
• Beroerte 18 patienten
http://www.dh.gov.uk/prod_consum_
dh/groups/dh_digitalassets/document
s/digitalasset/dh_108302.pdf
Antipsychotica en CVA
Kleijer BC, van Marum RJ, Egberts AC, Jansen PA, Knol W, Heerdink ER.
All cause mortality
TCA
SSRI
other
Myocard infarct
TCA
SSRI
other
Beroerte/TIA
TCA
SSRI
other
Vallen
TCA
SSRI
other
Fractuur
TCA
SSRI
other
Adj. OR (95% CI)
1.16 (1.10 – 1.22)
1.54 (1.48 – 1.59)
1.66 (1.56 – 1.77)
1.09 (0.96 – 1.23)
1.15 (1.04 – 1.27)
5.16 (3.90 – 6.83)
1.02 ( 0.93 – 1.11)
1.17 (1.10 – 1.26)
1.37 (1.22 – 1.55)
1.30 ( 1.23 – 1.38)
1.66 (1.58 – 1.73)
1.39 (1.28 – 1.52)
1.26 (1.16 – 1.37)
1.58 (1.48 – 1.68)
1.64 (1.46 – 1.84)
Hoge tr. Digest.
bloeding
TCA
SSRI
other
Insulten
TCA
SSRI
other
Bijwerkingen
TCA
SSRI
other
Hyponatriemie
TCA
SSRI
other
Adj. OR (95% CI)
1.29 (1.10 – 1.51)
1.22 (1.07 – 1.40)
1.37 (1.08 – 1.74)
1.02 (0.76 – 1.38)
1.83 (1.49 – 2.26)
2.24 (1.60 – 3.15)
1.06 ( 0.86 – 1.29)
1.16 (0.98 – 1.37)
0.95(0.68– 1.34)
1.05 ( 0.87 – 1.27)
1.52 (1.33 – 1.75)
1.28 (0.98 – 1.672)