Lethal Drug InteractionsAnd How to Avoid Them
June 24th, 2015Dave Juurlink
Toronto
@davidjuurlink
Frontmatter
Drug-drug interaction (DDI): Effect of one drug altered by use of another
Two types Pharmacokinetic
One drug alters the level of anothertime ->
Drug B
[Dru
g A]
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 -> [D
rug
A]
Drug B
Drug B
[Dru
g A]
DDIs -It’s Mostly Bad News
Bad news: Thousands of them Literature: Awful Terminology: Worse Can be fatal
Good news: Avoidable
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
Case 1
Day 5: Confused GTC seizure EMS: Capillary glucose low
What happened?
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
CYP3A4CYP2D6
CYP2C9
CYP1A2 other
The CYP2C9 Short List
CYP 2C9Substrates
CYP 2C9Inhibitors
sulfonylureas SMX/TMP(S)-warfarin metronidazole
fluvoxamine, fluoxetinefluconazoleamiodarone
Glim
epiri
de
SMX/TMP
Time
SMX/TMP + Sulfonylureas:6-fold risk of hypoglycemia
JAMA 2003
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
[digoxin] 5.1 nmol/L (3.6 ng/mL)
P-glycoprotein (P-gp)
Membrane glycoprotein first identified in chemo-
resistant cancer cells
P-glycoprotein (P-gp)
Membrane glycoprotein first identified in chemo-
resistant cancer cells Expressed in
gut kidney bile canaliculi BBB
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”
What happened?
Macrolides and DigoxinGomes et al CP&T 2009
The P-gp short list
Substrates Inhibitors Inducers
digoxin macrolides rifampindiltiazem amiodarone dexamethasone
cyclosporine antifungals St. John’s wortdabigatran etexilate verapamil
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
What happened?
Acetaminophen and Warfarin?
Acetaminophen & WarfarinWhat’s going on?
II, VII, IX, X IIa, VIIa, IXa, Xa-carboxylase
Vit Khydroquinone
Vit Kepoxide
warfarin
X
NAPQIΘ
DDIs with Warfarin:The 5 A’s
Amiodarone Antimicrobials
sulfamethoxazole / trimethoprim metronidazole fluconazole
Antidepressants Analgesics
NSAIDs acetaminophen
Antiplatelets
Warfarin and Antiplatelets
NNH / year34108
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
Why did this happen?
Meds ramipril rofecoxib spironolactone trimethoprim
Disease diabetes renal insufficiency
Hyperkalemia:The Usual Suspects
Renal disease ACE Inhibitors ARBs K+ supplements Spironolactone
Amiloride Triamterene
The Unusual Suspects
NSAIDsDiabetes -blockersSeptra Salt
substitutes
Trimethoprim Amiloride
AntibioticAdmission 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+
Avoiding DDIs (a.k.a How to Not Kill People)
1. Keep a short list of “triggers”
antibiotics verapamil, diltiazem amiodarone CNS depressants
2. Some meds warrant extra caution
anticoagulants digoxin sulfonylureas opioids miscellaneous
anticonvulsants lithium immunosuppressants
3. Is there a safer alternative?
Maybe macrolides -> azithro SMX/TMP -> almost anything else -lactams pravastatin, rosuvastatin citalopram, venlafaxine
4. Have some resources
#1: A good pharmacist
5. Arm the patient
Recap
DDIs Types and challenges
Cases SMX/TMP + sulfonylureas Macrolides + digoxin APAP + warfarin SMX/TMP + ACEI/ARB
Avoidance strategies
Thanks