AFPC Conference InterMed-Rx : Harmony and optimal therapy in the use of medication. June
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1 AFPC Conference 2009 InterMed-Rx : Harmony and optimal therapy in the use of medication June Jacques Turgeon, B.Pharm., Ph.D. Full professor, Faculty of pharmacy Research Director, CHUM Université de Montréal
2 Conflict of interests Expert consultant: Solvay Abbott Janssen Ortho PharmaSciences Bayer President et stock holder: Intermed-Rx
3 Objectives To understand basic principles of drug-drug interactions in order to avoid misuse of drugs in multiple drug prescriptions especially, with regards to CYP450 substrates. To explain and predict the clinical relevance and consequences of drug-drug interactions. To present clinical tools that allow identification of relevant drug-drug interactions.
4 Most frequent drug-drug interactions
5 Most frequent drug-drug interactions Warfarin aspirin acetaminophen Resins and acidic products NSAIDs, diuretics, warfarin, hypoglycemic agents Antiacids and antibiotics MAO inhibitors and SSRI Nitrates and...afil (Viagra,, Levitra,, Cialis ) Thyroxin and antiacids and resins Potassium and ACE inhibitors Calcium et tetracyclines/quinolones β-blockers and hypoglycemic agents β-blockers and stimulants (ephedrine) Digoxin and Ca channel blockers and β-blockers Cytochromes P450
6 Basic concepts in drug-drug interactions Three concepts to master Isoenzyme concepts Affinity concepts Oral clearance concepts
7 Basic concepts in drug-drug interactions Three concepts to master Isoenzyme concepts Affinity concepts Oral clearance concepts
8 Intersubject variability in drug response Cytochromes P450 O 2 H 2 O SH NADPH/H + SOH NADP +
9 Intersubject variability in drug response CYP2 CYP1 CYP3
10 Basic concepts in drug-drug interactions CYP Substrates Inhibitors Inducers 1A2 Theophylline, caffein, imipramine, mexiletine Quinolones Cigarette smoking 2A6 Coumarin, nicotine Diethyldithiocar- bamate 2C9 NSAID, losartan, irbesartan, S-warfarin, S celecoxib Sulfaphenazole Rifampin 2C19 Omeprazole, R-warfarinR 2D6 Codein, antiarrhythmics, β-blockers, anti-h1, SSRI Quinidine 2E1 Alcohol, chlorzoxazone Alcohol 3A4 CCB, anti-h1 2 nd, BZD, cyclosporin, HMG CoA Macrolides, imidazoles Rifampin, phenytoin
11 Basic concepts in drug-drug interactions Three concepts to master Isoenzyme concepts Affinity concepts Oral clearance concepts
12 CYP2C9 Inhibitors Substrates Inducers Fluconazole Fluvastatin Ibuprofene Glyburide Rifampin Sulfaphenazole S-warfarin Diclofenac Irbesartan Sulfinpyrazone Celecoxib Flurbiprofene Losartan Naproxene Candesartan Phenytoin Tolbutamide
13 Basic concepts in drug-drug interactions Three concepts to master Isozenzyme concepts Affinity concepts Oral clearance concepts
14 Intersubject variability in drug response
15 Basic concepts in drug-drug interactions Simvastatin has an oral bioavailability of 5%. By how much would its plasma concentrations raise during the co-administration of clarithromycine? 20 fois
16 Basic concepts in drug-drug interactions Interactions between inhibitors and substrates of CYP3A4 The coadministration of erythromycin, clarithromycin, ketoconazole, itraconazole Simvastatine/lovastatine : Cmax increases 5-5 à 20-fold Rhabdomyolysis Pravastatin, Cerivastatin, Fluvastatin, Atorvastatin < 2-change increase in PK parameters Rhabdomyolysis Clin Pharmacol Ther 1998;64: Clin Pharmacol Ther 1996;60:54-61 Eur J Clin Pharmacol 1999;54: J Clin Pharmacol 1999;39: Transplantation 1996;15:
17 Drug-drug interactions Case #1 A 56 years old man has symptoms of depression and fatigue. He has known hypertension treated with hydrochlorothiazide 12,5 mg ID and metoprolol 100 mg BID. He has been started 5 days ago on paroxetine (Paxil ) 10 mg ID to improve its depression related symptoms. The patient complains that he is really tired, with no energy. His pulse rate is at 44 beats/min.
18 Drug-drug interactions Drug-drug interaction softwares 1) Based on data bank and case reports a) Epocrates b) First Data Bank c) Vigilance Santé d) e) f) g) h) 2) Based on pharmacokinetics and drug metabolism algorithms a) Intermed-Rx.ca ( b) GeneMedRx ( c)
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27 Clinical Case #2 A patient complains of arthritis pain and her doctor prescribes celecoxib/celebrex 200 mg die. Her pharmacological fil shows : Metformine/Glucophage 500 mg tid Glyburide/Diabeta 2.5 mg bid Omeprazole/Losec 20 mg die Amitriptyline/Elavil 10 mg HS Conjugated oestrogens/premarin mg die Calcium 500 mg bid Upon her next visit to your pharmacy, the patient complains about flushing, weaknesses and drowsiness since few days. She is convinced nced that her hormonal drug has to be reviewed but she also mentioned that on occasion, her glycemia seems lower than previously. What pertinent drug-drug interaction can be unmasked?
28 Interactions médicamenteusesm
29 Interactions médicamenteusesm InterMed-Rx.ca propriété du Laboratoire Dr Jacques Turgeon inc.
30 Interactions médicamenteusesm Clinical Case #3 A patient aged 41 years old a chronic pain since several years. She is followed by a chronic pain clinic and in psychiatry. For her pain control, she receives : Baclofen/Lioresal 10 mg 4 co/day Gabapentin/Neurontin 300mg 15 caps/day Mexiletine 100 mg 6 caps/day Methadone 17.5 mg bid For her mood, she receives : Bupropion/Wellbutrin SR 100 mg 3 co/day Carbamazepine/Tegretol 200 mg 3 co HS Paroxetine/Paxil 20 mg 2 co die Clonazepam/Rivotril 2 mg tid prn What can be sais about drug-drug interactions in this patient?
31 Interactions médicamenteusesm
32 Intersubject variability in drug response Conclusions Clinical consensus and the availability of new classes of drugs are factors that contribute to the emergence of polypharmacy. Drug-drug interactions are no longer of the academic world. They can be understood, they can be predicted and they can be managed with tools that can support clinicians by providing new information.
33 References Hansten PD et Horn JR. The top 100 Drug interactions edition.. H&H Publications. rx.ca Drug interaction facts PubMed
THE NEED FOR ADVANCED CLINICAL DECISION SUPPORT SYSTEMS FOR THE MANAGEMENT OF PATIENTS WITH POLYPHARMACY
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I NSAID MHRA...p.1 MHRA...p.2 NSAID EU EMEA...p.5 Health Canada...p.5 Paroxetine pimozide QT Health Canada...p.6 Australian Adverse Drug Reactions Bulletin Vol.24 No.4 TGA SSRI...p.7 Ezetimibe...p.9 Cabergoline...p.10
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