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 >60

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 ( >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

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 < 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. H 2 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)www.drugfacts.com Computer programs (online and CD-ROM): Drug-Reax (Micromedex: www.micromedex.com) www.micromedex.com Drug Interaction Facts (www.drugfacts.com)www.drugfacts.com PDA based programs: Lexi-Interact (www.lexi-comp.com)www.lexi-comp.com iFacts and DrugIx (www.skyscape.com)