david juurlink - drug interactions that can kill (and how to avoid them)

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