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![Frontmatter
Drug-drug interaction (DDI):
Effect of one drug altered by use of another
Two types
Pharmacokinetic
One drug alters the level of another time ->
Drug B
[DrugA]](https://image.slidesharecdn.com/1050djuurlink-160523235953/75/David-Juurlink-Drug-Interactions-That-Can-Kill-and-How-to-Avoid-Them-2-2048.jpg)
![Frontmatter
Drug-drug interaction (DDI):
Effect of one drug altered by use of another
Two types
Pharmacokinetic
One drug alters the level of another
Pharmacodynamic
No change in drug levels
time ->
time ->[DrugA]
Drug B
Drug B
[DrugA]](https://image.slidesharecdn.com/1050djuurlink-160523235953/75/David-Juurlink-Drug-Interactions-That-Can-Kill-and-How-to-Avoid-Them-3-2048.jpg)
![[digoxin] 5.1 nmol/L (3.6 ng/mL)](https://image.slidesharecdn.com/1050djuurlink-160523235953/75/David-Juurlink-Drug-Interactions-That-Can-Kill-and-How-to-Avoid-Them-11-2048.jpg)
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David Juurlink - Drug Interactions That Can Kill (and How to Avoid Them)
The document discusses lethal drug-drug interactions (DDIs) and how to avoid them, emphasizing both pharmacokinetic and pharmacodynamic types. It presents several case studies illustrating the dangers of specific combinations, particularly involving common medications and the cytochrome P450 system. To mitigate risk, the document recommends maintaining awareness of high-risk drug combinations and suggests consulting pharmacists for safer alternatives.
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David Juurlink - Drug Interactions That Can Kill (and How to Avoid Them)
- 1. Lethal Drug Interactions AndHow to Avoid Them June 24th , 2015 Dave Juurlink Toronto @davidjuurlink
- 2. Frontmatter Drug-drug interaction(DDI): Effect of one drug altered by use of another Two types Pharmacokinetic One drug alters the level of another time -> Drug B [DrugA]
- 3. Frontmatter Drug-drug interaction(DDI): Effect of one drug altered by use of another Two types Pharmacokinetic One drug alters the level of another Pharmacodynamic No change in drug levels time -> time ->[DrugA] Drug B Drug B [DrugA]
- 4. DDIs - It’s MostlyBad News Bad news: Thousands of them Literature: Awful Terminology: Worse Can be fatal Good news: Avoidable
- 5. Case 1 72y.o. woman Type 2 DM, hypertension Metformin, glimepiride, chlorthalidone, ramipril Symptoms of UTI Rx: SMX/TMP (Bactrim, Septra) One DS tablet B.I.D. x 7 days
- 6. Case 1 Day5: Confused GTC seizure EMS: Capillary glucose low What happened?
- 7. The Cytochrome (CYP)P450 System A group of enzymes What they do: Modify some drugs Substrates Can be turned off Inhibitors Can be revved up Inducers % of drugs metabolized by various CYPs CYP3A4 CYP2D6 CYP2C9 CYP1A2 other
- 8. The CYP2C9 ShortList CYP 2C9 Substrates CYP 2C9 Inhibitors sulfonylureas SMX/TMP (S)-warfarin metronidazole fluvoxamine, fluoxetine fluconazole amiodarone Glimepiride SMX/TMP Time
- 9. SMX/TMP + Sulfonylureas: 6-foldrisk of hypoglycemia JAMA 2003
- 10. Case 2 82y.o. woman Independent, lives alone PHx: atrial fibrillation, penicillin allergy On pravastatin, digoxin, warfarin, HCTZ Cellulitis Rx clarithromycin 500 mg BID
- 11. [digoxin] 5.1 nmol/L(3.6 ng/mL)
- 12. P-glycoprotein (P-gp) Membraneglycoprotein first identified in chemo- resistant cancer cells
- 13. P-glycoprotein (P-gp) Membraneglycoprotein first identified in chemo- resistant cancer cells Expressed in gut kidney bile canaliculi BBB
- 14. P-glycoprotein (P-gp) Membraneglycoprotein first identified in chemo- resistant cancer cells Expressed in gut kidney bile canaliculi BBB P-gp: “natural defense mechanism”
- 15.
- 16. Macrolides and Digoxin Gomeset al CP&T 2009
- 17. The P-gp shortlist Substrates Inhibitors Inducers digoxin macrolides rifampin diltiazem amiodarone dexamethasone cyclosporine antifungals St. John’s wort dabigatran etexilate verapamil
- 18. Case 3 42y.o. woman recurrent idiopathic VTE INR consistently 2.0 to 3.0 LRTI Rx levofloxacin 1 week later Painless hematuria INR 9.2
- 19.
- 20.
- 21. Acetaminophen & Warfarin What’sgoing on? II, VII, IX, X IIa, VIIa, IXa, Xa γ-carboxylase Vit K hydroquinone Vit K epoxide warfarin X NAPQIΘ
- 22. DDIs with Warfarin: The5 A’s Amiodarone Antimicrobials sulfamethoxazole / trimethoprim metronidazole fluconazole Antidepressants Analgesics NSAIDs acetaminophen Antiplatelets
- 23. Warfarin and Antiplatelets NNH/ year 34 10 8
- 24. Case 4 83y.o. woman PMH: CAD, HTN, GERD, OA, DM2, CKD Meds Metoprolol 50 mg BID Aspirin 325 mg OD Lisinopril 20 mg OD Spironolactone 25 OD Rofecoxib 12.5 mg OD SMX/TMP DS 1 BID (recent UTI) CC: NFW x 3 days
- 27. Why did thishappen? Meds ramipril rofecoxib spironolactone trimethoprim Disease diabetes renal insufficiency
- 28. Hyperkalemia: The Usual Suspects Renaldisease ACE Inhibitors ARBs K+ supplements Spironolactone Amiloride Triamterene
- 29. The Unusual Suspects NSAIDsDiabetesβ-blockers Septra Salt substitutes
- 30. Trimethoprim Amiloride Antibiotic Admission for↑K+ O.R. & 95% CI Co-trimoxazole 6.7 (4.5 to 10.0) Norfloxacin 0.8 (0.4 to 1.5) Ciprofloxacin 1.4 (0.9 to 2.2) Nitrofurantoin 1.1 (0.6 to 2.0) Amoxicillin (reference) 1.0 Antoniou et al. Arch Int Med 2010 Co-trimoxazole and ↑K+
- 33. Avoiding DDIs (a.k.a Howto Not Kill People)
- 34. 1. Keep ashort list of “triggers” antibiotics verapamil, diltiazem amiodarone CNS depressants
- 35. 2. Some medswarrant extra caution anticoagulants digoxin sulfonylureas opioids miscellaneous anticonvulsants lithium immunosuppressants
- 36. 3. Is therea safer alternative? Maybe macrolides -> azithro SMX/TMP -> almost anything else β-lactams pravastatin, rosuvastatin citalopram, venlafaxine
- 37. 4. Have someresources #1: A good pharmacist
- 39. 5. Arm thepatient
- 40. Recap DDIs Typesand challenges Cases SMX/TMP + sulfonylureas Macrolides + digoxin APAP + warfarin SMX/TMP + ACEI/ARB Avoidance strategies
- 41.
Editor's Notes
- #3 I underscore that although we think about pharmacokinetic DDIs most often, this is only one type of DDI and that pharmacodynamic DDIs are also s msjor concern. And probably even more common.
- #4 I underscore that although we think about pharmacokinetic DDIs most often, this is only one type of DDI and that pharmacodynamic DDIs are also s msjor concern. And probably even more common.
- #9 The lists are longer, but shorter is manageable Pretty much all SUs Only (S) warfarin is 2C9 (R is 3a4) but S is where the money is Phenytoin is complex but has some 2C9 and it should probably be under warfarin
- #10 An example of a real world study, from my thesis. I often tell people The translation of this is that IF you have an older patient on glyburide and you Rx Septra, their risk of hospital admission FOR hypoglycemia in the next 7 days is about 5 to 6 times higher with Septra than with Amox
- #12 Surely someone will guess this
- #18 You might want to shorten this list / lose the HIV stuff. Up to you
- #19 I made this case up. Maybe you want to tweak it
- #21 Clearly doe s not happen to some people (many) Expression varies I have seen several instances of INR > 6 with APAP < 4 g per day Maybe influences by GSH, 2e1 activity, Gilbert’s disease, who knows But bottom line is that it is wrong and dangerous to assume APAP is safe in a patient on warf
- #22 Clearly doe s not happen to some people (many) Expression varies I have seen several instances of INR > 6 with APAP < 4 g per day Maybe influences by GSH, 2e1 activity, Gilbert’s disease, who knows But bottom line is that it is wrong and dangerous to assume APAP is safe in a patient on warf
- #23 Amio – 2C9 Abx - any, by virtue of gut vitamin K (you can make a case for closer INR monitoring in anybody starting Abx while on warf) - Septra and Flagyl have dual issue of 2C9 inhib - Paper not yet submitted looks at RR of UGI bleed in patients on warf Septra ~ 4 fold risk Other UTI drugs zero to minimal increae risk The APAP interaction should make people sit up and listen
- #25 I think Septra was the last straw here
- #28 Cartoon makes a joke about Drug A x Drug B. The reality is that patients often have multiple drugs and diseases that conspire together
- #35 Short list for ER docs should be antibiotic heavy.
- #36 Short list for ER docs should be antibiotic heavy.
- #37 Short list for ER docs should be antibiotic heavy.