DRUG INTERACTIONS IN
EMERGENCY MEDICINE:
AN OVERVIEW
SCOTT LINSCOTT, MD
UNIVERSITY OF UTAH SCHOOL OF MEDICINE
DRUG INTERACTIONS
• PREVALANCE
• MECHANISMS
• MOST COMMON
• THOSE WITH HIGHEST
MORBIDITY / MORTALITY
• MOST ARE UNPREDICTABLE
PREVALANCE
• HERR, LINSCOTT, ET AL - 1992
• 340 CONSECUTIVE PATIENTS IN THE ED:
FOUND 135 POTENTIAL DRUG
INTERACTIONS
• 20 CLINICALLY RELEVANT DI IN 15 PTS
• INCIDENCE HIGHER AMONG DRUGS PTS ON
CURRENTLY THAN MEDS PRESCRIBED IN
THE ED (9.7% VS 3.1%)
PREVALANCE
• 10 PTS: PRESENTING SYMPTOMS
WERE DUE TO DRUG-DRUG INTERACTIONS
• ONE FATALITY: PATIENT ON COUMADIN, PUT
ON CIPRO – INR WAS 15 AND THE PATIENT
HAD A FATAL GI HEMORRHAGE
• ONLY PREDICTOR OF CLINICAL RELEVANCE
WAS AGE >60
MECHANISMS
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P-450 ENZYME INDUCTION
P-450 ENZYME INHIBITION
GI ABSORPTION
GI DRUG BINDING
DRUG EXCRETION
PROTEIN BINDING COMPETITION
P-450 ENZYME
INDUCTION
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CAUSES DECREASED EFFECT OF OBJECT DRUG:
WARFARIN, TCA, DISOPYRAMIDE, QUINIDINE,
THEOPHYLLINE
DRUGS WHICH MAY INDUCE P450 ENZYMES:
• PROTEASE INHIBITORS AND NNRTIs (RITONAVIR)
• BARBITURATES, PRIMIDONE (MYSOLINE)
• CARBAMAZEPINE (TEGRETOL)
• PHENYTOIN (DILANTIN)
• RIFAMPIN
• SMOKING (THEOPHYLLINE)
P-450 ENZYME
INDUCTION
• EFFECT TAKES SEVERAL DAYS ( >7 DAYS) TO
BECOME CLINICALLY SIGNIFICANT
• MAY NEED TO INCREASE DOSE OF OBJECT
DRUG TO OBTAIN DESIRED EFFECT
• IF STOP THE INDUCING DRUG, MAY DEVELOP
SIGNIFICANT TOXICITY OF OBJECT DRUG
• BEST TO DECREASE THE DOSE OF OBJECT
DRUG BEFORE STOPPING INDUCING DRUG
P-450 ENZYME
INHIBITION
• MOST DRUGS ARE METABOLIZED BY MIXED
FUNCTION OXIDASES (CYTOCHROME P450 ISOENZYMES IA2, IIC9, IID6, & IIIA4)
• DRUGS WHICH COMPETITIVELY INHIBIT THE
P450 SYSTEM MAY DECREASE METABOLISM OF
THE OBJECT DRUG AND LEAD TO TOXICITY
• UNLIKE ENZYME INDUCTION, THIS EFFECT
OCCURS VERY SOON (WITHIN 24 HRS) OF
STARTING THE INHIBITING DRUG
P-450 ENZYME
INHIBITION
• DEGREE OF INHIBITION IS USUALLY
DEPENDENT UPON THE DOSE OF THE
INHIBITING DRUG (CIMETIDINE < 400 mg DAILY
IS UNLIKELY TO SIGNIFICANTLY INHIBIT THE
P450 ENZYME SYSTEM AND CAUSE OBJECT
DRUG TOXICITY)
• USE PEPSID-AC RATHER THAN TAGAMET-HB
• TOXICITY OF OBJECT DRUG DEPENDS ON ITS
INITIAL LEVEL (IF HIGH INITIALLY, MORE
LIKELY TO CAUSE TOXICITY, ie INITIALLY HIGH
INR - CIPRO)
P-450 ENZYME
INHIBITION
• MOST COMMON MECHANISM OF DRUG
INTERACTIONS
• MOST COMMON CAUSE OF MORTALITY AND
SEVERE MORBIDITY AMONG DIs
• ALL NEW DRUGS WHICH ARE METABOLIZED BY
THE LIVER MUST BE TESTED WITH CIMETIDINE
(OTC)
INHIBIT THE
P-450 ENZYME
SYSTEM
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CIMETIDINE
AMIODARONE
FLUOXETINE, PAROXETINE, FLUVOXAMINE
VERAPAMIL
OMEPRAZOLE
PROTEASE INHIBITORS AND NNRTIs (RITONAVIR)
QUINIDINE
ERYTHROMYCIN, CLARITHROMYCIN
INH
TMP-SMZ
CIPROFLOXACIN (ESP. COUMADIN)
KETOCONAZOLE
GRAPEFRUIT JUICE
COMPETITION FOR
RENAL TUBULAR
EXCRETION
• DIGOXIN – QUINIDINE
• DIGOXIN – AMIODARONE
• DIGOXIN – VERAPAMIL
• NSAIDs - METHOTREXATE
GI ABSORPTION
• ALTERATIONS IN MOTILITY: ACETAMINOPHEN
ABSORPTION IS INCREASED BY REGLAN &
ERYTHROMYCIN AND DECREASED BY
PROBANTHINE
• ALTERATIONS IN pH: KETOCONAZOLE
REQUIRES A LOW GASTRIC pH TO
DISSOLVE ADEQUATELY FOR ABSORPTION.
H2 BLOCKERS, PPIs, AND ANTACIDS
DECREASE ITS BIOAVAILABILITY
GI – DRUG BINDING
• ANTACIDS + CIPRO (CHELATION)
• ANTACIDS + TCN (CHELATION)
• IRON + TCN (CHELATION)
• CHOLESTYRAMINE + WARFARIN (RESIN
BINDING)
• MOST DRUGS + ACTIVATED CHARCOAL
(ADVANTAGEOUS IN OVERDOSES)
PROTEIN BINDING
DISPLACEMENT
• PREVIOUSLY FELT TO BE A COMMON AND
IMPORTANT DRUG INTERACTION
• ONLY CLINICALLY IMPORTANT IF OBJECT DRUG
IS HIGHLY PROTEIN BOUND (WARFARIN)
• WHEN OBJECT DRUG IS DISPLACED, MORE OF IT
ENTERS THE TISSUES AND ITS METABOLISM
INCREASES → DECREASED FREE DRUG
• THEREFORE, THE EFFECT IS VERY TRANSIENT
AND ONLY IMPORTANT IF INTIAL LEVEL OF
OBJECT DRUG IS HIGH (EXCESS PROTHROMBIN
TIME/INR)
MISCELLANEOUS
• TCA + EPINEPHRINE = HYPERADRENERGIC STATE
(USE 0.05 - 0.1 mg SQ)
• TCA + FLUOXETINE (PROZAC), PAROXETINE
(PAXIL), FLUVOXAMINE (LUVOX) = TCA TOXICITY
(DUE TO P450 INHIBITION) - NOT A PROBLEM
WITH SERTRALINE (ZOLOFT)
• AMINOGLYCOSIDE + ETHACRYNIC ACID =
OTOTOXIC
• ACEI + K+ SPARING DIURETICS / K+ / NSAIDs =
HYPERKALEMIA
SUMMARY
• Most are uncommon and unpredictable
• A few are associated with significant morbidity
and mortality, esp. warfarin
• Best book: Hansten and Horn: Managing
Clinically Important Drug Interactions (2003)
(www.drugfacts.com)
• Computer programs (online and CD-ROM):
• Drug-Reax (Micromedex:
www.micromedex.com)
• Drug Interaction Facts (www.drugfacts.com)
• PDA based programs:
• Lexi-Interact (www.lexi-comp.com)
• iFacts and DrugIx (www.skyscape.com)