1. Drug interactions in dementia Stephen Bleakley Locality Lead Pharmacist November 2010 stephen.bleakley@nhs.net

2. Aims of talk Refresher on some pharmacology ADME ADME Absorption, distribution, metabolism and excretion Focus on P450 enzyme system Focus on P450 enzyme system Overview of interactions relating to Acetylcholinergics Acetylcholinergics Antipsychotics Antipsychotics Antidepressants Antidepressants Few others Few others

3. 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

4. Classifying drug interactions Pharmacodynamic – the effects of the drug on the body Pharmacokinetics – the way the body effects the drug over time (ADME)

6. Drug administration

7. 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)

8. Drug metabolism 2 Cytochrome P-450 enzymes Over 40 different enzymes Over 40 different enzymes 1A2, 2D6, 2C9 and 3A4 especially important in psychiatry 1A2, 2D6, 2C9 and 3A4 especially important in psychiatry Genetic polymorphism can occur

9. An enzyme induction interaction Transplant Proc 1984, 16: 1642-5

10. At a glace guide to the P450 enzyme system IsoenzymeInhibitorInducerSubstrate CYP 1A2 CiprofloxacinFluvoxamine Grapefruit juice ClarithromycinErythromycin Tobacco Smoke ClozapineDuloxetineOlanzapine Tricyclic antidepressants CYP 2C9 FluconazoleFluoxetineFluvoxamine Cranberry Juice DiclofenacGliclazideNSAIDsTrimethoprimWarfarin CYP2D6 (genetic polymorphism) BupropionDuloxetineFluoxetineParoxetine Sertraline (dose dependent) CiprofloxacinDonepezilGalantamineClozapineRisperidone Tricyclic antidepressants Venlafaxine CYP3A4Amiodarone Grapefruit juice ErythromycinClarithromycinFluconazoleCarbamazepine St John’s Wort AripiprazoleBuspirone Calcium Channel Blockers DigoxinHaloperidolDonepezilGalantamineBenzodiazepinesCarbamazepineMethadoneFentanylQuetiapineSimvastatinZopiclone

11. Comparison interactions of the acetylcholinesterases Compiled from SPCs; Grossberg GT et al., Int. J. Geriat. Psychiatry 2000; 15, 242-247 Donepezil and Galantamine CYP3A4 and CYP2D6 inhibitors, - erythromycin - fluoxetine CYP3A4 and CYP2D6 inducers, - carbamazepine -St John’s Wort Rivastigmine No significant CYP interactions

12. 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

13. Anticholinergic effects Anticholinergic drugs can oppose the effects of Acetylcholinesterase inhibitors ClassExamples Anticholinergics Procyclidine, orphenadrine, trihexyphenidyl Tricyclic antidepressants Amitriptyline, nortriptyline, imipramine, clomipramine Antipsychotics (not all) Chlorpromazine, clozapine, flupentixol, zuclopentixol Antimuscarinics for incontinence Oxybuyynin, tolterodine

14. Pharmacodynamic interactions Co-prescribed drugs have similar side effects. Consider the potential pharmacodynamic interactions: Donepezil + Procyclidine Donepezil + Procyclidine Rivastigmine + fluoxetine Rivastigmine + fluoxetine Donepezil + atenolol Donepezil + atenolol Donepezil + NSAIDs Donepezil + NSAIDs

15. 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

16. Clinical relevance Baxter K (ed), Stockley’s Drug Interactions. [online] London: Pharmaceutical Press (assessed January 2010) Clinical significance often unknown due to limited data Clinical significance often unknown due to limited data Erythromycin + galantamine 10% increase in levels Erythromycin + galantamine 10% increase in levels Ketoconazole + donepezil 30% increase in levels Paroxetine increases galantamine by 40%

17. Memantine No P450 metabolism detected in vitro Isolated reports of increased INR with warfarin No kinetic interaction on acetylchinesterase inhibitors

18. Adverse effects AntipsychoticEPSERaised prolactin Weight gain DiabetesRaised lipids QT prolongati on Haloperidol+++ ++- Zuclopenthixol+++ ++ +? Flupenthixol+++++++ ++ Chlorpromazine+++++++ + Sulpiride+++++-? + Amisulpiride+++++--?+ Risperidone++++++ ++ Paliperidone++++++++?++? Olanzapine-++++ - Quetiapine--++ Aripiprazole--+--- Clozapine--+++ +

19. Antidepressant interactions Fluoxetine, paroxetine, sertraline and duloxetine Inhibitors at CYP2D6 Inhibitors at CYP2D6 Increases levels of TCAs Increases levels of TCAs Some antipsychotics Some antipsychotics Serotonin syndrome MAOIs Tyramine interactions Tyramine interactions

20. 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

21. Carbamazepine Major inducer of 3A4 isoenzyme Increases the clearance of: many antidepressants, some antipsychotics, benzodiazepines, oestrogens, erythromycin, SSRIs and methadone Causes enzyme auto-induction

22. Drug – disease interactions Liver disease Renal disease Cardiac disease Epilepsy Type of dementia

23. 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

24. Thank you Any questions?