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DRUG INTERACTIONS IN EMERGENCY MEDICINE: AN OVERVIEW

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Title: DRUG INTERACTIONS IN EMERGENCY MEDICINE: AN OVERVIEW


1
DRUG INTERACTIONS IN EMERGENCY MEDICINE AN
OVERVIEW SCOTT LINSCOTT, MD UNIVERSITY OF UTAH
SCHOOL OF MEDICINE
2
DRUG INTERACTIONS
  • PREVALANCE
  • MECHANISMS
  • MOST COMMON
  • THOSE WITH HIGHEST MORBIDITY / MORTALITY
  • MOST ARE UNPREDICTABLE

3
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)

4
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 gt60

5
MECHANISMS
  • P-450 ENZYME INDUCTION
  • P-450 ENZYME INHIBITION
  • GI ABSORPTION
  • GI DRUG BINDING
  • DRUG EXCRETION
  • PROTEIN BINDING COMPETITION

6
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)

7
P-450 ENZYME INDUCTION
  • EFFECT TAKES SEVERAL DAYS ( gt7 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

8
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

9
P-450 ENZYME INHIBITION
  • DEGREE OF INHIBITION IS USUALLY DEPENDENT
    UPON THE DOSE OF THE INHIBITING DRUG
    (CIMETIDINE lt 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)

10
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)

11
INHIBIT THE P-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

12
COMPETITION FOR RENAL TUBULAR EXCRETION
  • DIGOXIN QUINIDINE
  • DIGOXIN AMIODARONE
  • DIGOXIN VERAPAMIL
  • NSAIDs - METHOTREXATE

13
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

14
GI DRUG BINDING
  • ANTACIDS CIPRO (CHELATION)
  • ANTACIDS TCN (CHELATION)
  • IRON TCN (CHELATION)
  • CHOLESTYRAMINE WARFARIN (RESIN BINDING)
  • MOST DRUGS ACTIVATED CHARCOAL (ADVANTAGEOUS IN
    OVERDOSES)

15
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)

16
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

17
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)
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