Doi:10.1016/j.ccc.2006.02.004

Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, 7-153 WDH, 308 Harvard Street SE, Minneapolis, MN 55455, USA The number of reports of drug interactions is so great as to be overwhelming to most clinicians. On average over the last decade there were 60 papers per yearcited in PubMed with ‘‘drug interaction’’ in the title, and 1420 papers had druginteraction as a MeSH Major Topic Most of these publications are not humantrials, and only a small number was conducted in specific patient populations.
Because of the wide therapeutic index of most marketed drugs, most druginteractions do not cause harm to patients, and some are even used therapeuti-cally. These drug interactions may be a result of physical and chemical inter-actions (alterations in pH, ionic complexation), competition for pharmacokineticprocesses (interference with membrane transport proteins and enzymatic pro-cesses involved with intestinal absorption, metabolism, and renal excretion), orthey may be pharmacodynamic in nature (competitive inhibition at receptor sites,augmenting receptor stimulation) This article focuses on the drug interactionsthat are likely to cause harm in critically ill patients and that are mediated throughthe cytochrome P450 enzyme system (CYP450). Critical care practitionersshould understand the mechanism that underlies the drug interactions that arelikely to occur with the medications that are used commonly in critical illness.
Also, critical care practitioners must have access to accurate and timely druginteraction resources in their work environment. Generally, such resources are acombination of computer programs, Internet sites, and compendia.
Drug interactions are a specific type of adverse drug effect that usually are predictable, if not preventable. The contribution of drug interactions to overall 0749-0704/06/$ – see front matter D 2006 Elsevier Inc. All rights reserved.
doi: adverse drug effects is significant in terms of incidence and financial cost.
The incidence of drug interactions may be increasing as a result of the in-creased use of medications in the elderly, increasingly complex treatment ap-proaches to common disease states, and increased awareness of adverse drugreactions. In addition to the elderly and patients who take multiple drugs, pa-tients who have renal or liver disease are at an increased risk for drug interac-tions The outcome of drug interactions has been reported rarely; most interactions are theoretic and only pose potential adverse effects. When outcomes have beenevaluated the cost and morbidity have been significant A recent costanalysis of decreasing the interaction between warfarin and nonsteroidal anti-inflammatory drugs (NSAIDs) through the use of cyclooxygenase (COX)-2–selective NSAIDs proposed an overall health care savings that was due to thedecrease in bleeding rate The impact of drug interactions on the phar-maceutical industry also is significant. Of the 548 drugs that were introducedbetween 1975 and 1999, 56 (10.2%) had new drug–drug interaction warnings intheir package inserts (or label), or were withdrawn from the market for thesereasons Half of those withdrawals occurred after the products had been on themarket for more than 7 years, and millions of patient exposures had occurred.
Between 1997 and 2000 four drugs (terfenadine, astemizole, cisapride, mibe-fradil) that are metabolized by the CYP450 system—and subject to drug–druginteractions that increased the likelihood of arrhythmias because of prolongationof the QT interval—were removed from the United States market. Given thetremendous cost of research and development to bring a new drug to market(~$802 million in 2000), the loss of such a product from the market is significantOne of the approaches that the industry has taken to decrease the like-lihood of having to drop a drug from development because of drug interactionsis to screen candidate drugs for CYP450 interactions at the preclinical stageThere are multiple problems in projecting the results of in vitro testing tothe clinical situation. Current drug interaction screening can only indicate that acompound’s likelihood of drug interaction is ‘‘highly possible’’ or ‘‘least likely’’ The US Food and Drug Administration (FDA) guidance for industry has been published for the conduct of in vitro and in vivo drug metabolism and druginteraction studies, and this information is now expected to be included in thepackage insert The number of in vivo drug interaction studies that wereconducted on new drug applications submitted to the FDA was increasing beforethe publication of the guidance document. During the period of 1987 to 1991,only 30% of new drug applications had an in vivo drug interaction study, whereasduring the period of 1992 to 1997 this percentage was 53% Most (62%) ofthe drug interaction studies that were conducted during this period suggested lessthan a 20% change in some measured pharmacokinetic parameter; 24% weredeemed not clinically significant and 14% resulted in a labeling change. Onepercent resulted in a recommendation for monitoring, and 4% resulted in alabeled contraindication.
Overview of cytochrome P450 isozymes in drug metabolism The CYP450 enzymes are a superfamily of heme-containing, microsomal drug-metabolizing enzymes that are important in the biosynthesis and degrada-tion of endogenous compounds, chemicals, toxins, and medications. More than2700 individual members of the CYP450 superfamily have been identified, and57 cytochrome P enzymes are recognized in man They perform a variety ofchemical processes that lead to the oxidation, reduction, and hydrolysis of sub-strates to make them more water soluble, which facilitates elimination. Drugs thathave undergone biotransformation by the CYP450 enzymes may be activatedfrom a prodrug, converted to an active metabolite, or metabolized to an inactiveform. During this phase 1 reaction process the drug substrate is transformedby addition of conversion of a functional group, such as a hydroxyl, amine, orsulfhydryl Products of the phase 1 reaction may be excreted or metabolizedfurther by synthetic and conjugation reactions (phase 2 reactions) that combineendogenous substances (eg, glucuronic acid, glutathione, sulfur, glycine) with thenew functional group Following phase 2 reactions, metabolites usually areextremely polar and are excreted readily in the urine. The same processes thatmetabolize exogenous drugs and toxins also synthesize or degrade endogenoussubstances, such as steroid hormones, cholesterol, eicosanoids, and bile acids.
Thus, there is a constant competition for the activity of these enzyme systemswhich can lead to drug–drug interactions, drug–disease interactions, drug–herbalinteractions, and drug–food interactions.
CYP3A4 is the CYP450 isozyme that is involved most frequently in drug metabolism. The nomenclature for these enzymes is as follows: CYP representsthe root symbol for all cytochrome P450 proteins; 3 denotes the gene family; Adesignates the subfamily; and 4 represents the individual gene. CYP450 proteinswith more than 40% amino acid sequence identity are included in the same family;mammalian sequences with greater than 55% identity are included in the samesubfamily. The gene families CYP1, CYP2, and CYP3 are involved largely inbiotransformation of drugs, whereas the remaining 15 families in humans performendogenous metabolic activities (CYP3A4 and CYP3A5 accountfor the metabolism of approximately 50% of marketed drugs, and they make upapproximately 60% of the total hepatic CYP450 enzyme content Themetabolism of more than 90% of the most clinically important medications can beaccounted for by seven cytochrome P (CYP) isozymes (3A4, 3A5, 1A2, 2C9,2C19, 2D6, and 2E1) The CYP2 family is the largest in humans and contains about one third of human CYP450 enzymes. The CYP2 family has multiple polymorphisms that canresult in decreased enzyme activity or enhanced enzyme activity, which lead topatients being categorized into three unique phenotypes: poor metabolizers, Table 1Cytochrome P450 subfamilies and functions in humans Arachidonic acid and fatty acid metabolism Bile acid biosynthesis and prostacyclin synthase Steroid biosynthesis (steroid 17-a-hydroxylase) Bile acid biosynthesis and vitamin D3 activation Data from Lewis DF. 57 varieties: the human cytochromes P450. Pharmacogenomics 2004;5:305–18;and Danielson PB. The cytochrome P450 superfamily: biochemistry, evolution and drug metabolismin humans. Curr Drug Metab 2002;3:561–97.
extensive metabolizers, and ultrarapid metabolizers The importance ofidentifying a patient’s phenotype is in its infancy, but a system is being marketedthat will determine the genotype of a patient’s CYP2D6 or CYP2C19 (AmpliChipCYP450; Roche Molecular Systems, Inc., Pleasanton, California) Whendrugs have a narrow therapeutic index and are metabolized primarily by a singleCYP isozyme they present a greater risk for problems in patients with poor orultrarapid metabolism phenotypes. Poor metabolizers have higher concentrationsof drug in their bodies, whereas ultrarapid metabolizers may have subtherapeuticconcentrations with normal dosing. There are ethnic differences in the frequency ofthese phenotypes in the population The CYP isozymes are under genetic control and can be expressed to a varying degree in each individual Multiple factors, such as smoking, ethanolconsumption, environmental factors, disease states, and genetic inheritance,influence the amount and the activity of an individual patient’s CYP isozymes(Patients who have cirrhotic liver disease primarily havedecreased drug metabolizing capability because of a decreased amount of livertissue, and all of the CYP isozymes are affected The degree to whichindividual CYPs are reduced is not uniform, however, because CYP1A, 2C, and3A are more affected than others CYPs also are down-regulated duringinflammation and infection, which may lead to these patients being more sus-ceptible to adverse effects and drug interactions Genetic polymorphism;nutrition; smoking; drugs;environmental xenobiotics Genetic polymorphism; drugs;environmental xenobiotics Genetic polymorphism; nutrition;alcohol; environmental xenobiotics Nutrition; drugs; environmentalxenobiotics The CYP450 enzymatic metabolism of a drug (or substrate) can be blocked or inhibited by another drug or it can be accelerated when the enzyme system isinduced. Inhibition can be temporary and concentration dependent or it can be theresult of a permanent interference with the enzyme; drugs that cause the inhi-bition are referred to as reversible and irreversible (mechanism-based or suicide)inhibitors The most common type of drug interaction is simple competitiveinhibition for the enzyme reactive site. With simple competitive inhibition thedosing intervals of the interacting drugs can be manipulated to decrease the extentof the interaction when coadministration is required. When irreversible inhibitionoccurs, a metabolic intermediate is formed by the permanent binding of theinhibiting drug with the P450 enzyme at the heme, the protein, or both. Irre-versible inhibitors are of particular importance because they can decrease the firstpass clearance and the functional catalytic activity of drugs that normally arecleared by CYP3A4 until new enzyme can be manufactured Examples ofcommonly used irreversible inhibitors of CYP3A4 are clarithromycin, eryth-romycin, isoniazid, carbamazepine, irinotecan, tamoxifen, ritonavir, verapamil,nicardipine, 17-a-ethynylestradiol, fluoxetine, midazolam, and products in grape-fruit juice (bergamottin, 6V7V-dihydroxybergamottin) Many drugs can be substrates for multiple cytochrome P isozymes as well as inducers or inhibitors of multiple cytochrome P isozymes containssome common drugs that are used in ICUs, and the cytochrome isozymes forwhich they are substrates, inhibitors, and inducers With more than 100,000 drug–drug interactions being documented, distin- guishing those of clinical importance is mandatory A drug interaction Table 3Frequent substrates, inhibitors, and inducers of P450 isozymes in critically ill patients can be significant because it results in some grievous consequence to the pa-tient or because of its common nature, many patients are exposed to possibleharm. Fortunately, most drug interactions do not fall into these two catego-ries. Nonetheless, most pharmacy computer drug interaction software is sensitiveto many interactions, regardless of severity. The pharmacist and other clinicianscan tend to become accustomed to the routine interaction alarms that are of littleclinical significance, and miss or ignore the truly significant alarms that signifyreal harm The difference between potential drug interactions and significant drug inter- actions is illustrated by a recent study from Denmark A total of 200 medicaland surgical patients who were discharged from a hospital were surveyed and visited to ascertain the medications that they had in their homes and how frequentlythey used them. This information was cross-referenced with a drug-interactiondatabase and with hospital records to clarify the impact of the possible interactions.
The average age of patients was 75 years; the median number of drugs used was 8(range, 1–24 drugs). Drug usage consisted of prescription medications (93% ofpatients), over-the-counter medications (91% of patients), and herbal medicationsor dietary supplements (63% of patients). A total of 476 potential drug interactionswas identified in 63% of the patients. None of the interactions represented absolutecontraindications to the use of the interacting drugs together. Only 21 (4.4%) wereclassified as relative contraindications As the number of medications that apatient was taking increased, the risk for potential drug interactions also increased.
Patients who were taking 3 to 5 drugs had a 29% risk for potential interaction, andpatients who were taking 11 or more drugs had a 96% risk for having a potentialdrug interaction. None of the potential drug interactions actually resulted in anadverse event based on a review of the patients’ charts. Although 65% of patientsknew the purpose for each medication that they were prescribed, only 1% ofpatients were aware of the potential for a drug–drug or drug–food interaction.
Previous reports showed that potential drug interactions actually translate toadverse events in 0% to 24% of patients To address the problems with identifying clinically significant drug inter- actions and reducing their occurrence, a Partnership to Prevent Drug-DrugInteractions (PP-DDI) was formed recently. PP-DDI performed an analysis ofcommonly occurring drug interactions in ambulatory patients, and narrowed thenumber of clinically important interactions to 25 through careful evaluation ofthe literature and ratings by an expert panel using a modified Delphi processThe correlation of four common drug interaction compendia on interactionor severity also was evaluated during the study Drug interactions were ratedon a scale of code 1: highly clinically significant; code 2: moderately clinicallysignificant; code 3: minimally clinically significant; and code 4: not clinicallysignificant. Ratings were based on potential harm to the patient, frequency andpredictability of occurrence, and degree and quality of documentation. A total of406 drug interactions were listed at the highest level of severity (code 1) by atleast one of the four references. Poor agreement between the references wasobserved. Only 9 (2.2%) interactions were rated as code 1 in all four compendia,and another 35 (8.6%) were rated code 1 by three of the compendia. Mostinteractions (71.7%) were listed as most severe in only one reference. Althoughnot yet studied, one would expect similar findings in hospitalized patients.
The frequency of occurrence for the 25 clinically significant drug interactions that were identified by the PP-DDI was studied using a large pharmacy benefitmanagement company (PBM) database The study found that 374,000 of46 million plan participants potentially were exposed to one of the 25 clinicallysignificant drug interactions over a 25-month period. Notification of these inter-actions were sent to the pharmacy where the prescription was being filled;however, in two thirds of the cases there was no change in the prescription. Theprescriptions were reversed (canceled) between 20% and 46% of the time. The interaction of warfarin with NSAIDs was the most common and occurred in127,684 cases. This represents an exposure of 242.7 patients per 1000 patientstaking warfarin and 15.9 patients per 1000 patients taking NSAIDs (Most potential interactions occurred in patients who were olderthan 50 years of age, and the exposure rate increased with increasing age.
Commonly prescribed drugs in critically ill patients What constitutes commonly used drugs in critically ill patients vary by nation, region, type of hospital, and even by individual ICUs within a hospital lists the 40 most commonly used drugs at the University of Minnesota-Fairview Medical Center in the surgical (SICU), medical (MICU) and pediatric(PICU) ICUs during the first quarter of 2005. There are 23 drugs among the top40 used in the MICU that are not in the top 40 of the PICU and 13 that are not inthe top 40 of the SICU. There are 8 drugs in the SICU top 40 that are not in thetop 40 of the MICU or PICU. Over time the drugs that are used commonly in anICU also change. Of the top 30 drugs in the author’s ICUs in 1990, only 12 in theSICU, 12 in the MICU, and 14 in the PICU are still in the top 40 for those unitstoday Variability is expected to increase in open admission ICUs, comparedwith closed ICUs. Common interacting drugs included macrolide antibiotics(not azithromycin), benzodiazepines (not lorazepam), HIV protease inhibitors,calcium channel blockers, and HMG CoA reductase inhibitors (not pravastatin),which are substrates for CYP3A4 and CYP3A5. b-Blockers, antidepressants, andantipsychotics are frequent substrates for CYP2D6. NSAIDs, oral hypoglyce-mics, and angiotensin II blockers (not candesartan or valsartan) are substrates forCYP2C9. The proton pump inhibitors and antiepileptics are primarily substratesfor CYP2C19 The most common approach to minor drug interactions is to avoid the com- bination if possible, adjust the dose of the object drug, alter the administrationtimes of the drugs to minimize the overlap, and closely monitor for early de-tection Another important step is to maintain current knowledge withrespect to drug labeling. A study of trends in drug interactions for pharma-ceutical products in Japan from January 2000 to December 2003 revealed astriking number of package insert changes were due to new information regardingdrug interactions Of the 476 new drug interactions revisions that werereported, many (45%) were explanations of metabolic pathways and identifica-tion of CYP isoforms that are involved in the metabolic process. CYP3A4 wasthe primary isozyme involved (48% of revised package inserts), followed byCYP1A2 (14%), CYP2D6 (8%), CYP2C19 (2%), and CYP2C9 (1%). The cyto-chrome P isoform was not identified in 25% of the label revisions for drug Table 5Top 40 dispensed medications in the University of Minnesota Medical Center-Fairview ICUs fromJanuary to March 2005 Abbreviations: IV, intravenous; SMZ, sulfamethoxazole; TMP, trimethoprim; TPN, parenteral nutrition.
interactions. Revisions identified drugs as substrates for metabolic enzymes(65%), inhibitors of metabolic pathways (30%), or inducers of enzymes (5%). Inmany cases (40%) the references for the revision were company reports; 37% ofreferences were published journals or books; and 24% of revisions did not cite anypublications. Disappointingly, the time from publication of the reference to therevision of the package insert was more than 5 years in 58% of the cases.
Drug interaction software in hospitals should be improved to assist the clinician in identifying important and likely drug interactions. Eight strategiestoward this end have been identified  Computer systems should interact so information on patient drug use from multiple pharmacy systems can be accessed in real time.
 Warnings in systems should be individualized so patient factors that increase the risk for a drug interaction (renal failure, liver failure, age) can beintegrated in the severity decision.
 Trivial drug interactions should be defined and eliminated.
 New findings should be included in the software promptly.
 Inappropriate class-specific warnings should be eliminated because not all drugs in a class may undergo the drug interaction (macrolide antibiotics,statins, selective serotonin reuptake inhibitors).
 Optional links to more information should be available directly on the computer or through an Internet link.
 Rational therapeutic alternatives should be presented.
 Serious drug interactions should be more difficult to override and at least require authorization by a clinician.
Drug interactions are a significant clinical problem throughout health care.
Critically ill patients are more vulnerable to drug interactions, including seriousoutcomes that may result. Many drug interactions result from the CYP450enzyme system. Understanding the metabolic pathway of a drug can enhanceone’s ability to predict a drug interaction. When drug interactions are predictedthe clinician has several therapeutic options, including adjusting drug dosages,substituting equivalent drugs with different pathways of elimination, temporarilydiscontinuing the interacting medication, and monitoring the patient for thepredicted interaction. References and drug interaction software are improving intheir ability to guide rational decision making when drug interaction potentialsexist. There is an increasing knowledge base being generated by industry andrequired by the government of the mechanisms of drug interactions, but recog-nition and management of drug interactions can be improved The assistance of Dr. John Pastor, Assistant Director of Pharmacy at the University of Minnesota Medical Center-Fairview in obtaining the informationon drug usage in the ICUs is gratefully acknowledged.
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