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

• P-450 ENZYME INDUCTION• P-450 ENZYME INHIBITION• GI ABSORPTION• GI DRUG BINDING• DRUG EXCRETION• PROTEIN BINDING COMPETITION

P-450 ENZYME INDUCTION

• 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 THEP-450 ENZYME SYSTEM

• 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 BINDINGDISPLACEMENT

• 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)