Download IOW Dementia MUR Steve Bleakley Nov 2010

Drug interactions in dementia
Stephen Bleakley
Locality Lead Pharmacist
November 2010
[email protected]
Aims of talk
Refresher on some pharmacology

ADME
Absorption, distribution, metabolism and excretion

Focus on P450 enzyme system
Overview of interactions relating to




Acetylcholinergics
Antipsychotics
Antidepressants
Few others
Why worry?
BMJ 2004: 329; 15-19
6-7% of hospital admissions related to
adverse drug reactions
Drug interactions account for 1-2%
0.13% are fatal (US data)
Around 70% considered avoidable
Estimated NHS costs £500million
Classifying drug interactions
Pharmacodynamic – the effects of the
drug on the body
Pharmacokinetics – the way the body
effects the drug over time (ADME)
Drug administration
Drug metabolism 1
Substrate – a drug which is metabolised
by that enzyme
Enzyme induction – some drugs increase
the activity of the liver enzymes (1-2
weeks)
Enzyme inhibition – some drugs reduce
the activity of the liver enzymes (usually
occurs over 1-2 days)
Drug metabolism 2
Cytochrome P-450 enzymes


Over 40 different enzymes
1A2, 2D6, 2C9 and 3A4 especially important
in psychiatry
Genetic polymorphism can occur
An enzyme induction interaction
Transplant Proc 1984, 16: 1642-5
At a glace guide to the P450 enzyme system
Isoenzyme
Inhibitor
Inducer
Substrate
CYP 1A2
Ciprofloxacin
Fluvoxamine
Grapefruit juice
Clarithromycin
Erythromycin
Tobacco Smoke
Clozapine
Duloxetine
Olanzapine
Tricyclic antidepressants
CYP 2C9
Fluconazole
Fluoxetine
Fluvoxamine
Cranberry Juice
Diclofenac
Gliclazide
NSAIDs
Trimethoprim
Warfarin
CYP2D6
(genetic polymorphism)
Bupropion
Duloxetine
Fluoxetine
Paroxetine
Sertraline (dose dependent)
Ciprofloxacin
Donepezil
Galantamine
Clozapine
Risperidone
Tricyclic antidepressants
Venlafaxine
CYP3A4
Amiodarone
Grapefruit juice
Erythromycin
Clarithromycin
Fluconazole
Carbamazepine
St John’s Wort
Aripiprazole
Buspirone
Calcium Channel Blockers
Digoxin
Haloperidol
Donepezil
Galantamine
Benzodiazepines
Carbamazepine
Methadone
Fentanyl
Quetiapine
Simvastatin
Zopiclone
Comparison interactions of the
acetylcholinesterases
Rivastigmine
No
significant
CYP
interactions
Donepezil and Galantamine
CYP3A4 and CYP2D6 inhibitors,
- erythromycin
- fluoxetine
CYP3A4 and CYP2D6 inducers,
- carbamazepine
- St John’s Wort
Compiled from SPCs; Grossberg GT et al., Int. J. Geriat. Psychiatry 2000; 15, 242-247
Pharmacodynamic interactions
Think how the drug works
What may oppose its actions
What side effects are known
Do co-prescribed drugs have similar side
effects
Anticholinergic effects
Anticholinergic drugs can oppose the effects of
Acetylcholinesterase inhibitors
Class
Anticholinergics
Tricyclic
antidepressants
Examples
Procyclidine, orphenadrine,
trihexyphenidyl
Amitriptyline, nortriptyline, imipramine,
clomipramine
Antipsychotics
(not all)
Chlorpromazine, clozapine, flupentixol,
zuclopentixol
Antimuscarinics
for incontinence
Oxybuyynin, tolterodine
Pharmacodynamic interactions
Co-prescribed drugs have similar side
effects.
Consider the potential pharmacodynamic
interactions:




Donepezil + Procyclidine
Rivastigmine + fluoxetine
Donepezil + atenolol
Donepezil + NSAIDs
Rivastigmine patches
Windbland B et al. Int J of Geriatr Psychiatry 2007; 22: 456-467
Improved tolerability compared against
rivastigmine oral capsules
No comparative data against donepezil or
galantamine yet
Probably reduced risk of additive adverse
reactions
Clinical relevance
Baxter K (ed), Stockley’s Drug Interactions. [online] London: Pharmaceutical Press
<http://www.medicinescomplete.com/> (assessed January 2010)
Clinical significance often unknown due to
limited data
Erythromycin + galantamine 10%
increase in levels
Ketoconazole + donepezil 30% increase in
levels
Paroxetine increases galantamine by 40%
Memantine
No P450 metabolism detected in
vitro
Isolated reports of increased INR
with warfarin
No kinetic interaction on
acetylchinesterase inhibitors
Adverse effects
Antipsychotic
EPSE
Raised
prolactin
Weight Diabetes
gain
Raised
lipids
QT
prolongati
on
Haloperidol
+++
+++
+
+
-
+++
Zuclopenthixol
+++
+++
++
++
+
?
Flupenthixol
++
+++
++
++
+
+
Chlorpromazine
++
+++
++
++
+
++
Sulpiride
+
+++
+
-?
-?
+
Amisulpiride
+
+++
+
-
-?
+
Risperidone
+
+++
++
++
+
+
Paliperidone
+
+++
++
++?
+
+?
Olanzapine
-
+
+++
+++
+++
-
Quetiapine
-
-
++
++
++
++
Aripiprazole
-
-
+
-
-
-
Clozapine
-
-
+++
+++
+++
+
Antidepressant interactions
Fluoxetine, paroxetine, sertraline and
duloxetine



Inhibitors at CYP2D6
Increases levels of TCAs
Some antipsychotics
Serotonin syndrome
MAOIs

Tyramine interactions
Lithium interactions
Thiazides increase lithium levels
NSAIDs increase lithium levels
Do not use p.r.n NSAIDs
ACE inhibitors increase lithium levels
Dehydration and salt free diet increase
lithium levels
Carbamazepine
Major inducer of 3A4 isoenzyme
Increases the clearance of: many
antidepressants, some antipsychotics,
benzodiazepines, oestrogens,
erythromycin, SSRIs and methadone
Causes enzyme auto-induction
Drug – disease interactions
Liver disease
Renal disease
Cardiac disease
Epilepsy
Type of dementia
Conclusions
Interactions to look out for
Anticholinergics with acetylchonesterase
inhibitors
2D6 and 3A4 inhibitors and inducers with
donepezil and galantamine
St Johns wort and carbamazepine with anything
Drugs which worsen or exacerbate side effects
Lithium with any drug which alters renal or
electrolyte balance
Thank you
Any questions?