1000 Drug Interactions That You Didnt Know You KnewPaul Starr, M.D.Department of Family MedicineLouisiana State University

IntroductionDrug interactions were once thought to represent an insidious threat to public health. Although initial estimates predicted huge numbers of dangerous drug interactions, in practice they do not appear to be as menacing as they once appeared

EpidemiologyUnknown incidenceStill a preventable cause of morbidity

Pivot TableAspirinCimetidineDigoxinErythromycinFluconazoleIronNifedipinePhenytoinPropranololTerfenadineTetracyclineWarfarin

war tet ter pro phe nif iro flu ery dig cim asp

Pivot TableAspirinCimetidineDigoxinErythromycinFluconazoleIronNifedipinePhenytoinPropranololTerfenadineTetracyclineWarfarin

war tet ter pro phe nif iro flu ery dig cim asp

Pivot TableAspirinCimetidineDigoxinErythromycinFluconazoleIronNifedipinePhenytoinPropranololTerfenadineTetracycline

war tet ter pro phe nif iro flu ery dig cim(Dont forget to turn the corner!)

Learning objectives for improving awareness of drug interactionsA. Evaluate medications B. Famous interactions C. Group medications D. Hear your patient

Medications for this lectureAspirinCimetidineDigoxinErythromycinFluconazoleIron

NifedipinePhenytoinPropranololTerfenadineTetracyclineWarfarin

Consider the Medications passage through the body

Consider the Medications passage through the body

Absorptiona. Chelation : Divalent cations such as calcium or iron can bind to certain medications and prevent their absorptionI. iron with tetracycline (H.C. Heinrich and KH Oppitz, Tetracycline inhibits iron absorption in man. Naturwissenschaften, 60:524, 1973)

Absorptionb. Absorption pH: Weak acids need to be absorbed at a low pH. Raising the pH with antacid medication considerably hinders absorption.I. iron with cimetidine (R Esposito, Cimetidine and iron-deficiency anaemia. Lancet, 2:1132, 1977)II. cimetidine with aspirin (W Khoury, et.al., The effect of cimetidine on aspirin absorption. Gastroenterology, 76:1169, 1979.

AbsorptionDrug Absorption @ pH=1 @ pH=8Acids: Salicylic Acid 61% 13% Thiopental 46% 34%Bases: Aniline 6% 56% Quinine 0% 18%

Pivot TableAspirinCimetidineDigoxinErythromycinFluconazoleIronNifedipinePhenytoinPropranololTerfenadineTetracycline

war tet ter pro phe nif iro flu ery dig cimAAA

Phase 1 (usually inactivated) CYP EnzymesOxidationReductionDealkylationHydrolysis Phase 2 (ear-marked for destruction)ConjugationGlucuronidationSulfationMethylationAcetylationProtein Binding

CYP Enzymes in drug metabolismSubstrates Inhibitors InducersCyp1A2Coumadin Cimetidine PhenytoinCyp2B6Bupropion Thiotepa RifampinCyp2C9Phenytoin Isoniazid RifampinCyp2C19Diazepam Ketoconazole N/ACyp2D6Metoprolol Cimetidine N/ACyp2E1Ethanol Disulfiram INHCyp3A4,5,7Terfenadine Erythromycin Phenytoin (and everything!)

CYP Enzyme Table

Three Kinds of Metabolic InteractionsSubstrate (a cyp enzyme simply performs a reaction on a medicationInhibition (a medication binds so strongly to a cyp enzyme that it prevents the enzyme from metabolizing other medications)Induction (the medication interacts with the enzyme in a way that leads to new production of the enzyme; this takes time!)

MetabolismAmitriptylline is metabolized by CYP1A2Cimetidine inhibits CYP1A2Coadministration results in elevated Amitriptylline levels

Michaelis-Menten ModelE + SESE + PEnzymePlusSubstrateEnzyme-SubstrateComplexEnzymePlusProductK1K2K-1K1= forward reactionK2= completed reactionK-1= aborted reaction(Pertinent to Substrate and Inhibition)

Michaelis-Menten ModelE + SESE + PEnzymePlusSubstrateEnzyme-SubstrateComplexEnzymePlusProductK1K2K-1K1= forward reactionK2= completed reactionK-1= aborted reactionKmA derivation that describes the completed reactionKiA derivation that describes an inhibited reaction(Pertinent to Substrate and Inhibition)

KiKi = _[Inhibitor]_Km,obs- 1.0KmKm=(k2+k-1)k1

InhibitionSubstrates Inhibitors Inducers Cyp1A2Warfarin Cimetidine Phenytoin Cyp2B6Bupropion Thiotepa Rifampin Cyp2C9Phenytoin Isoniazid Rifampin Cyp2C19Diazepam Ketoconazole N/A Cyp2D6Metoprolol Cimetidine N/A Cyp2E1Ethanol Disulfiram INHCyp3A4,5,7Terfenadine Erythromycin Phenytoin (and everything!)

InductionEndoplasmic ReticulumNucleusCYP1AAhRActivationArnt+Up-regulation

InductionSubstratesInhibitorsInducersCyp1A2WarfarinCimetidine PhenytoinCyp2B6BupropionThiotepa RifampinCyp2C9PhenytoinIsoniazid RifampinCyp2C19DiazepamKetoconazole N/ACyp2D6MetoprololCimetidineN/ACyp2E1EthanolDisulfiramINHCyp3A4,5,7TerfenadineErythromycin Phenytoin (and everything!)

MetabolismAmitriptylline is metabolized by CYP1A2Cimetidine inhibits CYP1A2Coadministration results in elevated Amitriptylline levelsRanitidine inhibits CYP1A2 BUT to a much lesser degree (lower Ki)

MetabolismAspirinCimetidineDigoxinErythromycinFluconazoleIronNifedipinePhenytoinPropranololTerfenadineTetracycline

war tet ter pro phe nif iro flu ery dig cimAAAMMMM

Target1. If two medications make it past the hepatic enzymes, there is potential for interaction at the site of action, or at sites of major side effects.Propranolol with nifedipine (A-V conduction disturbances and sinus bradycardia U Elkayam et al, Effects of nifedipine on hemodynamics and cardiac function in patients with normal left ventricular ejection fraction already treated with propranolol. Am J Cardiol, 58:536, 1986Warfarin with aspirin (RA OReilly et al, Impact of aspirin and chlorthalidone on the pharmacodynamics of oral anticoagulants in man. Ann NY Acad Sci, 179:173, 1971.)

TargetAspirinCimetidineDigoxinErythromycinFluconazoleIronNifedipinePhenytoinPropranololTerfenadineTetracycline

war tet ter pro phe nif iro flu ery dig cimAAAMMMMTT

EliminationCertain medications can compete for excretionDigoxin with erythromycin (H Wakasugi et al, Effect of clarithromycin on renal excretion of digoxin; interaction with P-glycoprotein. Clin Pharmacol Ther, 64:123, 1998) Although this report was regarding clarithromycin, the caution was extended to all macrolides. Interestingly, there are other digoxin/macrolide interactions including hepatic metabolism, and a unique mechanism in which gut flora which inactivate digoxin can be eliminated with oral antibiotics!

EliminationAspirinCimetidineDigoxinErythromycinFluconazoleIronNifedipinePhenytoinPropranololTerfenadineTetracycline

war tet ter pro phe nif iro flu ery dig cimAAAMMMMTTE

Famous InteractionsAspirinCimetidineDigoxinErythromycinFluconazoleIronNifedipinePhenytoinPropranololTerfenadineTetracycline

war tet ter pro phe nif iro flu ery dig cimAAAMMMMTTE

Famous InteractionsAspirinCimetidineDigoxinErythromycinFluconazoleIronNifedipinePhenytoinPropranololTerfenadineTetracycline

war tet ter pro phe nif iro flu ery dig cimAAAMM MMTTEMM?AMMMMMM?M??MM?M?

Grouping MedicationsMetabolic effectsChemical familyHaving memorized the above famous interactions, you can expand your knowledge dramatically by remembering a few rules regarding the drug families to which the medications belong. They can be grouped by:

Potent InhibitorsFluoroquinolones (ie: ciprofloxacin)H2Blockers (ie: most notably cimetidine)Imidazoles (ie fluconazole)INHRitonavir

Mnemonic: cip, cim, con, INH, and rit

Potent InducersNeuroleptics:CarbamazepinePhenobarbitalPhenytoinAND:Rifampin

Mnemonic: carb, barb, pheny, and rif

H1 BlockersAspirinCimetidineDigoxinErythromycinFluconazoleIronNifedipinePhenytoinPropranololTerfenadineAstemizoleLoratadineTetracycline

war tet ter ast lor pro phe nif iro flu ery dig cimAAAMM MTTEMM?AMMMMMM??MM??MMMMM

Divalent CationsAspirinCimetidineDigoxinErythromycinFluconazoleIronCalciumMagnesiumNifedipinePhenytoinPropranololTerfenadineTetracycline

war tet ter pro phe nif iro ca ma flu ery dig cimAMM MMTTEMM?AMMMMMM?M??MM?M?AA

H2 BlockersH2Blockers follow the same rules as H1Blockers; Cimetidine is the most potent inhibitor, ranitidine to a lesser degree, and famotidine slightly lesser. Mnemonic: cim>ran>fam

Beta BlockersBetaBlockers knowing that propranolol contributes significantly to heart block in the presence of nifedipine, it is interesting to note that metoprolol and atenolol appear to be relatively safe. Mnemonic: pro>aten>meto

MacrolidesMacrolide antibiotics are aggressively metabolized by cyp3A4 with the exception of azithromycin which is metabolized by a different mechanism. Clarithromycin is one of the most potent utilizers of Cyp3A4 and entertains vast potential for competitive inhibition with many other medications. Mnemonic: clar>ery>azith

AntifungalsAntifungals of the imidazole class are metabolized with varying affinities for the cyp enzymes. Fluconazole turns out to be one of the more benign medications whereas ketoconazole is a very potent inhibitor of cyp3A4. Mnemonic: keto>itra>flu

Calcium Channel BlockersCalcium channel blockers like betablockers vary in their ability to cause heart block. Mnemonic: ver>nif>car

ConclusionExamining medications encourages careful review of medications Famous interactions should be memorized and form the basis of a broader understanding of drug interactions in generalGrouping medications allows one to extrapolate known data to a certain extent across a drug groupsHearing patients complaints can help alert the physician to identifying previously unreported reactions

EpidemiologyIn a recent study from Ontario, Dr. Juurlink performed a retrospective analysis on hospital admissions and determined the odds of elderly patients requiring hospital admission after experiencing known (and therefore preventable) drug interactions. Juurlink DN, Mamdani M, Kopp A, Laupacis A, Redelmeier DA. Drug-drug interactions among elderly patients hospitalized for drug toxicity. JAMA 2003 Apr 2;289(13):1652-8 The frequency of significant beneficial or adverse drug interactions is unknown. Surveys that include data obtained in vitro, in animals, and in case reports tend to predict a frequency of interactions that is higher than actually occurs. Estimates of the incidence of clinical drug-drug interactions range from 3% to 5% in patients taking a few drugs to 20% in patients who are receiving 10-20 drugs.\(Goodman and Gilmans The Pharmacological Basis of Therapeutics, Joel G. Hardman, et.al., editors, McGraw-Hill 10th edition, 2001, pg. 54.) Potential risk factors for and the preventability of drug-induced threats to life were studied. Case reports of adverse drug events (ADEs) published in Clin-Alert during 1977-97 were the source of information on drug-induced life threats. Patient, drug, and event variables were identified, and the causality, predictability, and preventability of each case were assessed. Data were entered into a relational database for analysis. The data indicated 846 drug-induced life threats. Seventy-four percent of the cases were assessed as definite or probable. Patients received usual or below-usual dosages in 89% of the cases. Patients tended to be middle-aged and only moderately ill. The drug categories most frequently associated with life threats were antimicrobials and central-nervous-system agents. Plasma drug level monitoring should have been performed in 127 cases but occurred only in 31 cases (24%). Event types were distributed as adverse drug reactions (50%), allergic reactions (35%), drug interactions (11%), and medication errors (4%). A commercial reference classified almost half of the drug interactions associated with a life threat as posing minimal or no potential risk to the patient. Half of the life-threatening events were judged to have been preventable; about half of these could have been prevented by a pharmacist. Litigation was reported for only 1% of the cases of drug-induced threats to life; judgments and settlements averaged $1.2 million. A review of published case reports of ADEs for 1977-97 yielded information on possible risk factors for drug-induced life threats and on which events may have been preventable.Marcellino K, Kelly WN. Potential risks and prevention, Part 3: Drug-induced threats to life. Am J Health Syst Pharm 2001 Aug 1;58(15):1399-405

The frightening thing about drug interactions is the daunting number of potential interactions. This is most readily confronted by looking at a pivot table. Constructing a pivot table can present a daunting variety of potential drug interactions. A pivot table is like the mileage chart that appears in the corner of some roadmaps. Medications are listed AtoZ on the y axis, and ZtoA on the x axis. Fortunately since an interaction between drug A and drug B is the same as the interaction between drug B and drug A, the table can be cut diagonally in half. Next, one eliminates the overdose line the diagonal that represents a drug interacting with itself, and one is left with a neat chart of boxes which can contain potential drug interactions. Although there is frequently more than one kind of drug interaction between any two given drugs, there is usually one interaction that predominates. (On a practical note: when scanning a pivot table which has been cut diagonally dont forget to turn the corner when you get to the end of a row..you may miss most of the interactions!)

A. Evaluate medications (develop a short list of most commonly used medications, review their basic pharmacology, construct small pivot table). For the purposes of this lecture well consider 12 medications.B. Famous interactions (the 12 medications considered were chosen because they have some rather archetypal interactions!)C. Group medications (branching out from the 12 closely studied medications inferences can be drawn regarding similar medications)D. Hear your patient (because of the vast number of potential drug interactions new ones are being discovered every day..but only if one listens carefully to patients descriptions of adverse reactions that they have experienced after adding a new drug to their regimen.)

There are basically four sites at which drug interactions most commonly occur. (For simplicitys sake, Ive omitted protein-binding interactions which are relatively few, and which I group with metabolic interactions in a larger lecture.)Metabolism refers to the processing of medications after they are absorbed. Most of these interactions inactivate medications and prepare them for elimination. Most of these occur in the liver. Most of the metabolic interactions are mediated by the CYP enzymes.

For a thorough list of clinically relevant medications and their cyp enzymes please consult the excellent website provided by the University of Illinois at http://medicine.iupui.edu/flockhart/clinlist.html

Of the hundreds of cyp enzymes in nature only about 9 seem to be relevant to drug interactions. Many other enzymes are present in man such as the enzymes involved in the steroid pathway enzymes ie: 17 alpha hydroxylase, etc. There is an excellent searchable database at http://www.gentest.com/human_p450_database/index.html in which one can look up specific research documents regarding specific drug interactions. There is also the P450 Homepage maintained by Dr. David Nelson http://drnelson.utmem.edu/CytochromeP450.html which provides extensive links regarding the basic science of p450 systems.Dont attempt to read this slide! It is a copy of the typical CYP table which lists the cyp enzymes and the medications that interact with them either as substrates, inhibitors, or inducers. The reason that this diagram is not terribly useful is that the assignment to substrate or inhibitor category is somewhat arbitrary! Some substrates bind more readily than others, causing a competitive inhibition! This can only be predicted by looking more closely at the enzyme kinetics.CYP enzymes bind medications (ie: substrates). Recalling regular biochemistry, the reaction can proceed and the enzyme releases the product (usually an inactivated metabolite). The likelihood for the reaction to go to completion is described by a coefficient Km. Sometimes an enzyme has such a high affinity for a substrate that it binds strongly to the substrate and is reluctant to let it go. This is described by the coefficient Ki (the lower the coefficient, the more likely it is to inhibit the enzyme). Enzymes with a low Ki for a substrate are considered inhibitors. Sometimes the enzyme releases the substrate without completing the reaction (K-1). Some substrates will bind an enzyme more strongly than other substrates. This is termed competitive inhibition. Finally, some medications induce new transcription of new enzymes. This process typically takes a few days Ki seems to be a quite useful value. If Km describes the likelihood for a reaction proceed forward, then Ki can help predict competitive inhibition. The higher the Ki, the greater the inhibition. The Ki values for isoniazid, fluconazole, and diltiazem are 73, 15, and 2 respectively. This might lead one to expect that a patient taking diltiazem for high blood pressure might experience hypotensive episodes when initiating isoniazid therapy since isoniazid has a higher Ki, binds more readily and prevents the metabolism of diltiazem, thus raising its levels.

Inhibition:Cimetidine with coumadin (I Niopas et al, Further insight into the stereoselective interaction between warfarin and cimetidine in man. Br J Clin Pharmacol, 32:508, 1991)Terfenadine with erythromycin (KE Biglin, Drug-induced torsades de pointes: a possible interaction of terfenadine and erythromycin. Drug Invest, 7:148, 1994) This famous report led to the eventual removal of terfenadine from the US market!

Unlike substrates and inhibitors, inducers are not directly affected by Michaelis-menten pharmacodynamics, but rather involve translation of new proteins. This process takes more time.Induction:Phenytoin with erythromycin (K Bachman et al, Single dose phenytoin clearance during erythromycin treatment. Res Commun Chem Pathol Pharmacol, 46:207, 1984) This report underscores the fact that the induction process takes some time; therefore single dose therapy seems to be permissible!)Cimetidine with fluconazole (surprise! Although one would predict an interesting interaction because of the cyp enzymology since they are both potent inhibitors of Cyp2C9, the predominant interaction is because of absorption! RA Blum et al, Increased gastric pH and the bioavailability of fluconazole and ketoconazole. Ann Intern Med, 114:755, 1991)

There are better examples of medications that compete for excretion, but for the purposes of this lecture I used dig and erthromycin because of their extensive interactions with other medications! The classic elimination interaction is penicillin with probenecid which enables prolonged effects from single doses of penicillin.The famous interactions listed above establish the rules by which most drug interactions occur. Memorizing just these ten interactions lays the groundwork for remembering LARGE amounts of interactions!

Knowing the mechanisms of the famous interactions, it isnt that difficult to predict how medications are going to interact. Phenytoin has potent metabolic consequences for many medications. The same is true for cimetidine. Note the number of empty boxes, and the number of question marks; the question marks represent either single case reports or an apparent interaction the mechanism of which cannot be established. Also, having filled in as many of the known or even possible drug interactions, there are still many question marks, and many blanks!The Medical Letter text on drug interactions often groups medications by chemical family. The good side is that they group together similar medications so that it can remind you to be careful when using similar medications. The bad side is that in looking up the medication you may not realize that cimetidine is listed under H2 blockers; when you dont see cimetidine specifically, you might be misled into believing it to be safe.H1Blockers are surprisingly toxic when their metabolism is inhibited. And they are usually inhibited by medications that seem relatively benign; antibiotics, etc. Terfenadine and astemizole were so bad that they were removed from the market! Loratadine fortunately turns out to be relatively benign Mnemonic: ter>ast>lorDivalent cations (such as calcium, iron, and magnesium) all bind numerous medications (notably tetracycline, digoxin and ciprofloxacin). The way to avoid the interaction with calcium is to dose the medications at different times. Although interactions with calcium and magnesium have not been documented, it would be wise to anticipate this interaction and avoid dosing these medications together