David Juurlink SMACC Chicago talk 'Drug Interactions That Can Kill (and How to Avoid Them)’ takes us on a journey of drug interactions, case studies, and avoidance strategies. Juurlink starts by educating us on the two different drug-drug interactions (DDI) - effects of one drug altered by the use of another . First of which is Pharmacokinetic where by one drug alters the level of another, the second Pharmacodynamic being no change in drug levels, and uses this as a basis for his following case studies. Juurlink speaks of the dreadful literature that is available on the thousands of drug interaction per year, stating that most information comes from case reports and volunteer studies, and suggests that majority of these interaction are avoidable. Juurlink goes on to discuss the findings of 4 case studies involving the following Drug-Drug Interactions and their effects on the patients. SMX/TMP + sulfonylureas Macrolides + digoxin APAP + warfarin SMX/TMP + ACEI/ARB Juurlink provides us with a short list of trigger drugs that we should be aware of, a list of meds that warrant extra caution and list of possible safer alternatives. He also suggests that it is of the up most importance to have a good pharmacist to turn to as they are given more information on drugs interactions then physicians. And, to utilise resources such as pharmacy times - where you can get information on drug interactions at a push of the button. Juurlink also suggests that an Informed patient is a very useful safety mechanism.

1. Lethal Drug Interactions
And How 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 Mostly Bad News
Bad news:
 Thousands of them
 Literature: Awful
 Terminology: Worse
 Can be fatal
Good news:
 Avoidable

5. Case 1
 72 y.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
 Day 5:
 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 Short List
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-fold risk of hypoglycemia
JAMA 2003

10. Case 2
 82 y.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)
 Membrane glycoprotein
 first identified in chemo-
resistant cancer cells

13. P-glycoprotein (P-gp)
 Membrane glycoprotein
 first identified in chemo-
resistant cancer cells
 Expressed in
 gut
 kidney
 bile canaliculi
 BBB

14. P-glycoprotein (P-gp)
 Membrane glycoprotein
 first identified in chemo-
resistant cancer cells
 Expressed in
 gut
 kidney
 bile canaliculi
 BBB
 P-gp:
 “natural defense mechanism”

15. What happened?

16. Macrolides and Digoxin
Gomes et al CP&T 2009

17. The P-gp short list
Substrates Inhibitors Inducers
digoxin macrolides rifampin
diltiazem amiodarone dexamethasone
cyclosporine antifungals St. John’s wort
dabigatran etexilate verapamil

18. Case 3
 42 y.o. woman

recurrent idiopathic VTE

INR consistently 2.0 to 3.0
 LRTI

Rx levofloxacin
 1 week later

Painless hematuria

INR 9.2

19. What happened?

20. Acetaminophen and Warfarin?

21. Acetaminophen & Warfarin
What’s going on?
II, VII, IX, X IIa, VIIa, IXa, Xa
γ-carboxylase
Vit K
hydroquinone
Vit K
epoxide
warfarin
X
NAPQIΘ

22. DDIs with Warfarin:
The 5 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
 83 y.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 this happen?
 Meds
 ramipril
 rofecoxib
 spironolactone
 trimethoprim
 Disease
 diabetes
 renal insufficiency

28. Hyperkalemia:
The Usual Suspects
Renal disease ACE Inhibitors ARBs K+
supplements
Spironolactone
Amiloride
Triamterene

29. The Unusual Suspects
NSAIDsDiabetes β-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 How to Not Kill People)

34. 1. Keep a short list of “triggers”
 antibiotics
 verapamil, diltiazem
 amiodarone
 CNS depressants

35. 2. Some meds warrant extra caution
 anticoagulants
 digoxin
 sulfonylureas
 opioids
 miscellaneous

anticonvulsants

lithium

immunosuppressants

36. 3. Is there a safer alternative?
 Maybe
 macrolides -> azithro
 SMX/TMP -> almost anything else
 β-lactams
 pravastatin, rosuvastatin
 citalopram, venlafaxine

37. 4. Have some resources
 #1: A good pharmacist

39. 5. Arm the patient

40. Recap
 DDIs
 Types and challenges
 Cases
 SMX/TMP + sulfonylureas
 Macrolides + digoxin
 APAP + warfarin
 SMX/TMP + ACEI/ARB
 Avoidance strategies

41. Thanks