Drug Interactions—A Review
`Shannon F. Manzi, PharmD,*y Michael Shannon, MD, MPHz§
`
`The incidence and severity of drug interactions are on the rise as more medications are
`brought to market. Following the absorption, distribution, metabolism, and excretion model
`of pharmacokinetics, this review will provide an overview of the varied mechanisms of
`drug-drug, drug-herb, and drug-food interactions with emphasis placed on the interactions
`most likely to cause harm. This information is intended to assist the pediatric emergency
`physician in recognizing drug interactions to identify and remove the offending agent when
`appropriate. Understanding the mechanisms of drug interactions will assist all clinicians in
`avoiding these serious, often preventable, events.
`Clin Ped Emerg Med 6:93-102 ª 2005 Elsevier Inc. All rights reserved.
`
`KEYWORDS cytochrome P450, P-glycoprotein, monoamine oxidase inhibitors,
`drug interactions
`
`As pharmaceutical technology continues to expand at a
`
`phenomenal rate, so does the incidence of drug
`interactions. A regimen of 2 or more drugs, admission to a
`critical care unit, and increasing age are risk factors for
`experiencing a drug interaction [1,2]. These interactions
`can range in severity from theoretical
`to clinically
`significant,
`including prolonged morbidity and even
`death. The emergency department (ED) is a particularly
`unique setting where drug interactions may occur because
`of the lack of information about a patient’s current drug
`regimen and preexisting drug interactions, the addition of
`short-term treatments to chronic disease states, and the
`need for follow-up outside the ED. One study examining
`the risk of drug interactions demonstrated a 25%
`incidence of a preexisting drug interaction and a 5%
`interaction rate for those who received a medication while
`
`*Emergency Department Clinical Pharmacist, Children’s Hospital
`Boston, Boston, MA 02115, USA.
`yNortheastern University, Boston, MA 02115, USA.
`zDivision of Emergency Medicine, Children’s Hospital Boston,
`Boston, MA 02115, USA.
`§Harvard Medical School, Boston, MA 02115, USA.
`Reprint requests and correspondence: Shannon F. Manzi, PharmD,
`Department of Pharmacy, Children’s Hospital Boston, 300 Long-
`wood Ave, Boston, MA 02115.
`
`1522-8401/$ - see front matter ª 2005 Elsevier Inc. All rights reserved.
`doi:10.1016/j.cpem.2005.04.006
`
`in the ED [3]. Pediatric emergency physicians, like all
`emergency care providers, must be knowledgeable about
`drug interactions and the mechanisms involved to avoid
`these events and recognize them when they occur.
`Drug interactions occur not only with other medica-
`tions, but also with herbal preparations, dietary supple-
`ments, and foods. In this review, we will provide an
`overview of the varied mechanisms of drug-drug, drug-
`herb, and drug-food interactions with emphasis placed on
`the interactions most likely to cause harm (Table 1).
`Following the absorption, distribution, metabolism, and
`excretion model of pharmacokinetic properties, we will
`attempt to organize the interactions by process.
`
`Administration/Absorption
`Administration of 2 medications at or around the same
`time can result in clinically significant drug interactions.
`It has been well documented that some antibiotics such as
`the fluoroquinolones and tetracyclines will bind to iron,
`calcium, calcium-fortified foods, and antacids if given
`simultaneously [4-8]. The resulting compound will be
`excreted with little or no systemic absorption of the
`antibiotic. This can result
`in treatment
`failures and
`emergence of resistant organisms. Phenytoin may also
`bind to iron, calcium, and magnesium in antacids, as well
`as continuous tube feedings [9-14]. Low phenytoin serum
`
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`S.F. Manzi, M. Shannon
`
`levels and subsequent loss of seizure control may result if
`the interactions are not recognized. To avoid these drug
`interactions, the iron, calcium, and antacids must be
`given either 2 hours before or 2 hours after the dose of
`the interacting drug.
`It
`is also recommended that
`continuous tube feedings be turned off for 2 hours before
`and after phenytoin administration.
`Sucralfate and cholestyramine will also physically bind
`other medications such as chlorothiazide, ciprofloxacin,
`cyclosporine, digoxin, ketoconazole, phenytoin, valproic
`acid, and warfarin. In some cases, administering the drug
`2 hours before sucralfate or cholestyramine and monitor-
`ing for effects will be adequate. In other cases, the
`combination may need to be avoided altogether, such as
`with warfarin and cholestyramine.
`Several
`factors are responsible in determining the
`amount of drug that is absorbed by the body, including
`age, hydrochloric acid secretion, gastric emptying time,
`intestinal motility, and bile acid secretion. The primary
`mechanism of absorption is passive diffusion of non-
`ionized drug molecules via the lipophilic gastrointestinal
`(GI) mucosa. Therefore, drugs that change the pH, gastric
`emptying time, or GI motility will
`interact with the
`absorption of other agents.
`More recently, induction and inhibition of intestinal
`P-glycoprotein drug efflux pump have been described in
`significant drug interactions, particularly involving cyclo-
`sporine. P-glycoprotein is genetically encoded and widely
`distributed among the body cells [15]. The primary role
`of P-glycoprotein is the expulsion of toxins and drugs
`from the cells. If the expression of P-glycoprotein is
`enhanced, especially in the intestine, the substrate drugs
`have reduced bioavailability. Supratherapeutic levels and
`toxicity can occur if the P-glycoprotein expression is
`decreased [15]. Of note, orange juice may inhibit the
`P-glycoprotein intestinal
`transport and absorption of
`levofloxacin [4].
`Erythromycin, a macrolide antibiotic, is also known to
`increase gut motility and,
`in recent years, has been
`exploited for this property as an alternative to cisapride.
`Cisapride was removed from the market secondary to life-
`threatening arrhythmias and torsades de pointes that
`occurred when combined with other drugs that inhibited
`cytochrome P3A4 isoenzyme, depleted electrolytes, or
`prolonged the QT interval [16]. Drugs that delay gastric
`emptying will usually slow the transition of drug into the
`small intestine, thus delaying and decreasing absorption.
`Warfarin is known to interact with many foods, herbal
`supplements, and medications [17]. Diets high in
`vitamin K such as those with a high quantity of green
`leafy vegetables (Table 2) can decrease or even reverse
`the anticoagulation effect. In addition, supplements of
`vitamin A, E, or C may alter the prothrombin time.
`Other interactions can be exploited to enhance
`absorption of the drug. Didanosine liquid is prepared
`with antacid suspension to ensure adequate pH for
`
`optimum stability. Ferrous sulfate is converted to the
`ferric state in the presence of vitamin C, resulting in
`enhanced absorption. Many drugs should be taken with
`food to ensure absorption, whereas other drugs should be
`given on an empty stomach (Table 3). Often,
`the
`presence of
`food will delay the absorption but not
`decrease the overall bioavailability of the drug. Consis-
`tency, either with or without food, should be stressed for
`medications with the potential to have fluctuation of
`serum levels and resultant toxicities such as phenytoin,
`propranolol, and warfarin.
`Drug interactions occurring during the administration
`phase are not only limited to the oral route. Intravenous
`aminoglycoside antibiotics can be inactivated if given
`within 30 minutes of a penicillin derivative. Postexposure
`prophylaxis that requires both passive (immune globulin)
`and active (vaccine) immunizations should be given at
`separate intramuscular injection sites and different
`extremity to avoid decreasing the immune response to
`the vaccine.
`Much like the enteral drug interactions that are
`sometimes used to enhance the effect of a drug, injectable
`drug interactions can also be useful. Small amounts of
`epinephrine can be added to local anesthetic injections
`during laceration treatment. Epinephrine is a potent local
`vasoconstrictor and will decrease blood flow to the area,
`creating a more visible working environment and
`enhancing the effect by decreasing the removal of the
`local anesthetic.
`It is well known that alcohol-containing beverages
`can potentiate the sedative effects of anxiolytics and
`opioids. However, alcohol can be involved in other
`types of interactions as well. Metronidazole in combi-
`nation with alcohol, even a small amount such as that
`found in mouthwash, can cause severe nausea and
`
`Table 1
`Drugs frequently involved in serious drug
`interactions.
`
`Cyclosporine
`Erythromycin
`Fluconazole
`HMG-CoA reductase inhibitors
`Itraconazole
`Ketoconazole
`Linezolid
`MAOIs
`Meperidine
`Neuroleptics
`Phenytoin
`Protease inhibitors (especially ritonavir)
`Rifampin
`SSRIs
`Theophylline
`Warfarin
`
`HMG-CoA indicates 3-hydroxy-3-methylglutaryl coenzyme A.
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`Drug interactions—a review
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`95
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`Table 2
`
`Foods that interact with warfarin.
`
`Vegetables
`Alfalfa
`Asparagus
`Broccoli
`Brussel sprouts
`Cabbage
`Cauliflower
`Kale
`Lettuce
`Onions
`Spinach
`Turnip greens
`Watercress
`Herbal products
`Ginseng
`Green teas
`Melilot
`Tonka beans
`Woodruff
`Miscellaneous
`Avocado
`Fish oils
`Liver
`Soybeans
`Papain
`
`vomiting — the bdisulfiramQ effect. Often overlooked is
`the amount of alcohol in other medications. Ranitidine
`(Zantac) syrup contains 7.5% ethanol and can be
`responsible for unexplained nausea and vomiting in a
`patient who is also receiving metronidazole.
`Antidotal
`therapy is the ultimate use of a drug
`interaction for positive outcomes. Administration of
`calcium may treat calcium channel blocker overdose by
`overcoming the blockade. Naloxone and nalmefene
`selectively antagonize opioid receptors, reversing respi-
`ratory and mental status depression secondary to opioid
`intoxication. Flumazenil reverses benzodiazepine intox-
`ication via competitive binding to the benzodiazepine
`receptor. Activated charcoal adsorbs many drugs and
`toxins and is used successfully for GI decontamination
`after toxic ingestions.
`
`Distribution
`Distribution of medications depends on total body water,
`extracellular fluid, percentage of adipose tissue, and
`capacity to bind to plasma proteins. Albumin and a-1
`glycoprotein are the primary circulating plasma proteins
`to which drugs bind. Some drug interactions occur
`because of competition for the binding sites on these
`proteins. In effect, one drug bknocksQ the other off the
`binding site or, alternatively, occupies the site, not
`allowing the other drug to bind. Drugs that are highly
`protein bound are listed in Table 4 [18]. For an
`
`interaction to become clinically significant, the involved
`drugs must be highly ( N 95%) protein bound or have a
`very narrow therapeutic window. For example, phenytoin
`is not only involved in several cytochrome P450
`(CYP450) interactions to be discussed later and the
`physical binding interactions discussed previously, but
`also is between 89% and 93% protein bound with a very
`narrow therapeutic window. When phenytoin is given
`concurrently with valproic acid or salicylates, the free
`fraction of phenytoin increases because of competition
`for the same binding sites by the other drugs. The free
`fraction of phenytoin is usually 10% to 20% of the total
`serum concentration (10 -20 lg/mL). When the free
`fraction of phenytoin rises above 2 mcg/mL, toxicity is
`generally seen, consisting of ataxia, nystagmus, increased
`seizure activity, and, if high enough, coma.
`
`Metabolism
`Drug metabolism is divided into 2 categories, phase I and
`phase II transformation reactions. Phase I reactions
`include oxidation, hydrolysis, and reduction, resulting
`in a compound that is generally less toxic and more
`hydrophilic, allowing for easy excretion. In some cases,
`metabolism of a parent compound may lead to the
`formation of active metabolites (eg, acetaminophen,
`methanol, and ethylene glycol). Phase II reactions
`primarily result in the termination of biologic activity of
`the drug. Phase II transformation reactions include
`glucuronidation, sulfation, acetylation, and methylation.
`Although there are several routes of drug metabolism as
`
`Table 3
`Partial list of drugs that should be taken with food
`or on an empty stomach.
`
`Take With Food
`
`Albendazole
`Atovaquone
`Carbamazepine
`Griseofulvina
`Lithiumb
`Nelfinavir
`Ritonavir
`Trazodoneb
`
`Take on Empty
`Stomach
`
`Ampicillin
`Didanosine
`Efavirenz
`Erythromycin
`Furosemide
`Glipizidec
`Indinavir
`Iron
`Isoniazid
`Itraconazole
`Loracarbef
`Mercaptopurine
`Metforminc
`Minocycline
`Penicillamine
`Rifampin
`Tetracycline
`
`a Take with high-fat meals.
`b Take immediately after eating.
`c Administer 30 minutes before eating.
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`96
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`S.F. Manzi, M. Shannon
`
`described above, this review will focus on the phase I
`CYP450 enzymes and acetylation.
`A rapidly expanding wealth of knowledge has become
`available since the late 1980s with regard to CYP450
`interactions. In fact, most drug interactions occurring
`during metabolism are the result of CYP450 enzyme
`inhibition or induction. The CYP450 enzymes are unique
`isoenzymes found primarily in the liver and are respon-
`sible for the metabolism of many drugs and toxins. These
`enzymes may inactivate a drug by creating a metabolite
`or, alternatively, activate the drug. The enzymes are so
`named because of the absorption of light at a wavelength
`of 450 nm [19]. The CYP450 enzymes are grouped into
`families 1, 2, and 3 and divided into subfamilies A to E.
`The individual member enzymes are further designated
`by a number (eg, 3A4, 2D6).
`The CYP450 enzymes are genetically encoded. Inter-
`patient variability in CYP450 enzyme activity makes it
`difficult to adequately predict who will experience an
`adverse reaction or an exaggerated drug interaction. Age-
`related development of CYP450 enzymes matures and
`even surpasses adult capacity during the first year of life
`[20]. As pharmacogenomics develops, a source of reliable
`and rapid information targeted at the individual capa-
`bility to metabolize medications will be available for more
`routine use [21].
`Induction of CYP450 enzymes occurs when a drug
`stimulates the synthesis of more enzyme protein, enhanc-
`ing the enzyme’s metabolizing capacity. Ginseng may
`induce the enzyme that metabolizes warfarin, decreasing
`warfarin effectiveness. St John’s wort is a potent inducer
`
`Table 4
`
`Drug
`
`Drugs that are highly protein bound ( NNNNNNNN 95%).
`
`Protein Bound (%)
`
`Amitriptyline
`Chlorpromazine
`Clofibrate
`Diazepam
`Dicloxacillin
`Diphenhydramine
`Furosemide
`Glyburide
`Ibuprofen
`Imipramine
`Indomethacin
`Ketoconazole
`Mebendazole
`Naproxen
`Nifedipine
`Nortriptyline
`Oxazepam
`Phenytoin*
`Thyroxine
`Valproic acid*
`Warfarin
`
`* Narrow therapeutic window.
`
`96
`96
`95
`97
`96
`98
`99
`95
`99
`96
`97
`99
`95
`99
`98
`95
`96
`89-93
`99
`90
`99.5
`
`of CYP3A4 and is involved in the most severe drug-herb
`interactions noted to date (see Table 5 for drugs metab-
`olized by CYP3A4). The protease inhibitors, cyclosporine,
`warfarin, digoxin, oral contraceptives, and many other
`medications can be rendered ineffective with concomitant
`use of St John’s wort [22-31]. Patients and families must be
`asked directly about their herbal and dietary supplement
`use, as many do not consider these products as drugs or
`even as over-the-counter drugs because they are touted as
`ball naturalQ [32-34]. In fact, a study examining herbal
`therapy use in a pediatric ED reported that 77% of
`caregivers did not believe or were not sure that herbal
`products had any side effects and 66% did not believe or
`were not sure that herbal products interacted with other
`medications [33].
`Inhibition of CYP450 enzymes may occur secondary
`to competitive binding between 2 drugs or to perma-
`nent inactivation [19]. Generally, inhibition begins after
`the first dose of
`the inhibitor and the length of
`inhibition correlates with the half-life of
`the drug.
`Discontinuation of the inhibitor will usually cause the
`serum concentrations of other drugs metabolized by
`that enzyme to decrease, whereas discontinuation of an
`inducer will result in an increased serum concentration
`and risk of toxicity.
`The enzymes responsible for most drug metabolism
`and interactions are listed in more detail.
`
`Cytochrome P1A2
`Approximately 15% of medications used today are
`metabolized by cytochrome P1A2 (CYP1A2), including
`caffeine, theophylline, tricyclic antidepressants (TCAs),
`and warfarin. Activity of CYP1A2 can be induced by
`cigarette smoke, charbroiled foods, and cruciferous
`vegetables (eg, broccoli and cabbage). Several medica-
`tions also affect CYP1A2 activity. Carbamazepine, phe-
`nobarbital, and rifampin induce CYP1A2 as well as
`several other enzymes, leading to clinically significant
`drug interactions. Omeprazole and ritonavir simultane-
`ously induce CYP1A2 and inhibit 1 or more other
`enzymes. Inhibitors of CYP1A2 include erythromycin,
`ciprofloxacin, fluvoxamine, and grapefruit juice.
`
`Cytochrome P2C9
`Cytochrome P2C9 (CYP2C9) is responsible for the
`metabolism of several common medications including
`ibuprofen, phenytoin, and warfarin. Rifampin and rifa-
`butin are powerful inducers of CYP2C9 activity and will
`therefore decrease serum concentrations of the above
`substrates. Other inducers include carbamazepine, etha-
`nol, and phenobarbital. Amiodarone,
`fluoxetine, and
`fluconazole are among several drugs known to inhibit
`CYP2C9 activity. Genetic polymorphisms occur in 1% to
`3% of whites, contributing to abnormally decreased
`enzyme activity in these individuals (poor metabolizers).
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`97
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`Cytochrome P2C19
`Medications metabolized by cytochrome P 2C19
`(CYP2C19) include several benzodiazepines, citalopram,
`TCAs, omeprazole, and lansoprazole. Rifampin induces
`CYP2C19 activity, whereas fluvoxamine, fluoxetine, and
`ticlopidine inhibit this enzyme. Genetic polymorphisms
`are responsible for interpatient variability in CYP2C19
`activity. The enzyme is absent in 13% to 23% of Asians
`and 3% of whites [35].
`
`Cytochrome P2D6
`Cytochrome P2D6 (CYP2D6) comprises a relatively small
`percentage (2%-6%) of the total CYP450 in the liver but is
`involved in the metabolism of many medications (up to
`25%). Multiple TCAs, b-blockers, haloperidol, sertraline,
`and thioridazine are metabolized by CYP2D6. The
`conversion of codeine to the active form, morphine, is
`catalyzed by CYP2D6, and patients with low activity
`demonstrate a poor analgesic response [19]. Unlike other
`CYP450 enzymes, there are no known inducers of this
`activity except pregnancy. Several medications inhibit
`CYP2D6, the most potent include cimetidine, fluoxetine,
`haloperidol, paroxetine, and codeine. Genetic polymor-
`phisms play a significant role in determining CYP2D6
`activity, as with CYP2C19. Approximately 1% to 3% of
`African American and Asian patients and 5% to 10% of
`whites lack this enzyme, placing them at risk for
`increased toxicity from medications that are metabolized
`by CYP2D6 [35].
`
`Cytochrome P2E1
`Although cytochrome P2E1 (CYP2E1) metabolizes a
`relatively small fraction of clinically used medications,
`this enzyme plays a significant role in the activation and
`inactivation of toxins. Cytochrome P2E1 metabolizes
`primarily small organic molecules (eg, ethanol, carbon
`tetrachloride) as well as acetaminophen and dapsone.
`Although only a small percentage of acetaminophen is
`metabolized by CYP2E1, this hydroxylation produces
`N-acetyl-p-benzoquinoneimine, a hepatotoxin. Chronic
`ethanol use can induce CYP2E1 activity leading to a
`greater percentage of acetaminophen metabolized to
`increasing the risk of
`N-acetyl-p-benzoquinoneimine,
`hepatotoxicity from acetaminophen. The use of inhibitors
`such as disulfiram to prevent toxicity associated with
`compounds that form toxic metabolites when metabo-
`lized via CYP2E1 is currently being investigated [36].
`
`Cytochrome P3A3/4
`Cytochrome P3A (CYP3A) is both the most abundant and
`clinically significant family of CYP450 enzymes. The
`CYP3A family is composed of 4 major enzymes: CYP3A3,
`CYP3A4, CYP3A5, and CYP3A7. Cytochrome P3A4 is the
`most common and is implicated in most drug interactions.
`
`However, because these enzymes are so closely related
`(most are 97% similar), they are often referred to collec-
`tively by the subfamily name, CYP3A. Up to 60% of the
`liver’s total CYP450 is CYP3A, and nearly 50% of all cli-
`nically relevant medications are metabolized by CYP3A.
`The presence of CYP3A in the small intestine results in
`decreased bioavailability of many drugs. Cytochrome P3A
`inducers include the glucocorticoids, rifampin, carbama-
`zepine, phenobarbital, and phenytoin. Among the many
`significant CYP3A inhibitors are grapefruit juice, eryth-
`romycin, ketoconazole, clarithromycin, and verapamil.
`
`N-acetyltransferase
`Acetylation is a unique, non-CYP pathway of drug
`metabolism. Dapsone, hydralazine, isoniazid, procaina-
`mide, and sulfonamides are examples of drugs metabolized
`via acetylation. Acetylation polymorphisms are well
`described. Variants in the alleles coding for the conjugat-
`ing N-acetyltransferase enzymes occur in 50% of Ameri-
`cans, white and black, resulting in slow acetylators. Slow
`acetylator phenotypes occur in 60% to 70% of Northern
`Europeans and 5% to 10% of Asians [35]. These slow acet-
`ylators demonstrate enhanced toxicity, but longer drug
`effectiveness. The fast acetylator phenotypes may not dem-
`onstrate the desired therapeutic response to treatment.
`
`Excretion\Elimination
`Excretion and elimination of drugs occur primarily via
`the kidneys. Biliary secretion, plasma esterases, and other
`minor pathways are important routes, albeit less common
`than renal elimination. As with absorption in the GI tract,
`renal elimination is dependent on multiple factors. These
`include glomerular filtration rate, tubular secretion, and
`tubular reabsorption.
`Urinary alkalinization and acidification by some drugs
`can cause others to be more (or less) readily excreted
`(Table 6). Other agents can inhibit renal tubular secretion
`and assist in maintaining a higher serum concentration
`than the body would normally allow. A classic example is
`the use of probenecid and penicillin, secondary to
`probenecid blocking tubular secretion of b-lactams. More
`recently, probenecid has become an integral part of the
`regimen for decreasing the nephrotoxic effects of cidofo-
`vir by limiting the exposure of renal proximal tubular
`cells to the drug. Alternatively, probenecid should not be
`used with sulfonamides, ketorolac, or methotrexate
`because of increased serum concentrations and half-life,
`resulting in increased toxicity [37]. Quinidine may
`undergo increased renal tubular reabsorption in alkali-
`nized urine. Sodium bicarbonate–containing infusions
`are used to alkalinize the urine to enhance excretion of
`aspirin in the overdose setting.
`In other instances, this interaction can be potentially
`detrimental as in the case of methotrexate and the proton
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`Table 5
`
`Cytochrome P450 substrates, inducers, and inhibitors.
`
`1A2
`
`Substrates
`Acetaminophen
`Amitriptyline
`Caffeine
`Clomipramine
`Clozapine
`
`Cyclobenzaprine
`Estradiol
`Fluvoxamine
`Haloperidol
`Imipramine
`Mexiletine
`Naproxen
`
`Olanzapine
`Ondansetron
`Pentazocine
`Propranolol
`Ropivacaine
`Tacrine
`Theophylline
`TCAs
`Verapamil
`R-Warfarin*
`Zileuton
`Zolmitriptan
`
`2C9
`
`2C19
`
`2D6
`
`2E1
`
`3A3/4
`
`Amitriptyline
`Celecoxib
`Diclofenac
`Fluoxetine
`Flurbiprofen
`
`Fluvastatin
`Glipizide
`Glyburide
`Ibuprofen
`Irbesartan
`Losartan
`Naproxen
`
`Phenytoin
`Piroxicam
`Rosglitazone
`Sulfamethoxazole
`Tamoxifen
`Torsemide
`Tolbutamide
`S-Warfarin*
`
`Amitriptyline
`Carisoprodol
`Citalopram
`Clomipramine
`Cyclophos
`phamide
`Diazepam
`Fluoxetine
`Imipramine
`Indomethacin
`Lansoprazole
`Nelfinavir
`Omeprazole
`
`Pantoprazole
`Phenytoin
`Primidone
`Progesterone
`Proguanil
`Propranolol
`Teniposide
`TCAs
`R-Warfarin*
`
`Amitriptyline
`Amphetamine
`Atomoxetine
`Carvedilol
`Chlorpheniramine
`
`Chlorpromazine
`Clomipramine
`Clozapine
`Codeine
`Desipramine
`Dextromethorphan
`Encainide
`
`Flecainide
`Fluoxetine
`Fluvoxamine
`Haloperidol
`Imipramine
`Lidocaine
`Methadone
`Metoclopramide
`Metoprolol
`Mexiletine
`Nortriptyline
`Olanzapine
`Ondansetron
`Oxycodone
`Paroxetine
`Perphenazine
`Propafenone
`Propranolol
`Risperidone
`
`Acetaminophen
`Benzene
`Caffeine
`Chlorzoxazone
`Dapsone
`
`Dextromethorphan
`Ethanol
`Enflurane
`Halothane
`Isoflurane
`Isoniazid
`Sevoflurane
`
`Theophylline
`Venlafaxine
`
`Alfentanil
`Alprazolam
`Amiodarone
`Amitriptyline
`Amlodipine
`
`Atorvastatin
`Bromocriptine
`Budesonide
`Bupropion
`Buspirone
`Caffeine
`Calcium
`channel blockers
`Carbamazepine
`Cisapride
`Clomipramine
`Clonazepam
`Cocaine
`Codeine
`Cyclosporine
`Dapsone
`Dexamethasone
`Dextromethorphan
`Diazepam
`Diltiazem
`Disopyramide
`Doxycycline
`Ergotamine
`Erythromycin
`Ethinyl estradiol
`Ethosuximide
`Etoposide
`
`Lidocaine
`Loratadine
`Lovastatin
`(Not pravastatin)
`Methadone
`
`Midazolam
`Nefazodone
`Nicardipine
`Nifedipine
`Nimodipine
`Omeprazole
`Ondansetron
`
`Paclitaxel
`Paroxetine
`Pimozide
`Progesterone
`Protease inhibitors
`Quetiapine
`Quinidine
`Quinine
`Rifabutin
`Rifampin
`Ritonavir
`Salmeterol
`Saquinavir
`Sertraline
`Sildenafil
`Simvastatin
`Tacrolimus
`Tamoxifen
`Theophylline
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`
`Drug interactions—a review
`
`99
`
`Trazodone
`Triazolam
`TCAs
`Venlafaxine
`Verapamil
`Vinca alkaloids
`Warfarin
`Zolpidem
`
`Fentanyl
`Finasteride
`Fluconazole
`Fluoxetine
`Haloperidol
`Ifosfamide
`Imipramine
`Indinavir
`Isradipine
`Itraconazole
`Ketoconazole
`Lansoprazole
`
`Amiodarone
`Cimetidine
`Ciprofloxacin
`Clarithromycin
`Diltiazem
`Erythromycin
`Fluconazole
`Fluoxetine
`Fluvoxamine
`Grapefruit juice
`Itraconazole
`Ketoconazole
`Nefazodone
`Nifedipine
`Omeprazole
`Propoxyphene
`
`Protease inhibitors
`Verapamil
`
`(continued on next page)
`
`Disulfiram
`Methylpyrazole
`
`Sertraline
`Tamoxifen
`Thioridazine
`Timolol
`Tramadol
`Trazodone
`TCAs
`Venlafaxine
`
`Amiodarone
`Bupropion
`Celecoxib
`Chloroquine
`Chlorpheniramine
`Chlorpromazine
`Cimetidine
`Citalopram
`Clemastine
`Clomipramine
`Cocaine
`Diphenhydramine
`Doxorubicin
`Escitalopram
`Fluoxetine
`Haloperidol
`
`Hydroxyzine
`Indinavir
`Methadone
`Metoclopramide
`
`Inhibitors
`Amiodarone
`Cimetidine
`Ciprofloxacin
`Clarithromycin
`Erythromycin
`Fluoxetine
`Fluvoxamine
`Gatifloxacin
`Grapefruit juice
`Interferon
`Levofloxacin
`Mexiletine
`Ofloxacin
`Nefazodone
`Ticlopidine
`
`Cimetidine
`Felbamate
`Fluoxetine
`Fluvoxamine
`Indomethacin
`Ketoconazole
`Lansoprazole
`Omeprazole
`Paroxetine
`Ritonavir
`Ticlopidine
`Topiramate
`
`Amiodarone
`Cimetidine
`Clopidogrel
`Fluconazole
`Fluoxetine
`Fluvastatin
`Fluvoxamine
`Isoniazid
`Lovastatin
`Metronidazole
`Paroxetine
`Phenylbutazone
`Probenecid
`Ritonavir
`Sertraline
`Sulfamethoxazole-
`trimoprim
`Teniposide
`Zafirlukast
`
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`
`100
`
`S.F. Manzi, M. Shannon
`
`Table 5 continued
`
`1A2
`
`2C9
`
`2C19
`
`2D6
`
`2E1
`
`3A3/4
`
`Paroxetine
`Perphenazine
`Propoxyphene
`Quinidine
`Ranitidine
`Ritonavir
`Sertraline
`Terbinafine
`Thioridazine
`Ticlopidine
`
`Pregnancy
`
`Chronic ethanol
`Isoniazid
`Ritonavir
`Tobacco
`
`Carbamazepine
`Dexamethasone
`Efavirenz
`Griseofulvin
`Nevirapine
`Phenobarbital
`Phenytoin
`Prednisone
`Rifabutin
`Rifampin
`Ritonavir
`St John’s wort
`Sulfinpyrazone
`Troglitazone
`
`Carbamazepine
`Norethindrone
`Prednisone
`Rifampin
`
`Carbamazepine
`Ethanol
`Phenobarbital
`Phenytoin
`Primidone
`Rifabutin
`Rifampin
`Secobarbital
`
`Inducers
`Broccoli
`Brussel sprouts
`Carbamazepine
`Charbroiled food
`Cigarette smoke
`Modafinil
`Naficillin
`Omeprazole
`Phenobarbital
`Phenytoin
`Rifampin
`Ritonavir
`Tobacco
`
`Data from http://medicine.iupui.edu/flockhart/table.htm; [19] Shannon M. Pediatr Emerg Care 1997;13(5):350 -3; Taketomo CK, Hodding JH, Kraus DM. Pediatric Dosage
`Handbook. 10th ed. Cleveland: Lexicomp Inc, 2003 - 2004.
`* S-Warfarin isomer has 2 to 5 times more anticoagulant activity than R-warfarin isomer. Therefore, 2C9 interactions most significantly affect warfarin activity.
`
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`Drug interactions—a review
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`101
`
`pump inhibitor omeprazole. By inhibiting hydrogen ions
`(protons) in the renal tubules, omeprazole may also
`inhibit methotrexate elimination as it is actively secreted
`in the distal tubules with hydrogen ions [38,39]. This can
`result
`in prolonged elevated serum concentrations,
`particularly concerning after treatment with a high-dose
`regimen for cancer therapy.
`Another concerning interaction involves the use of
`potassium-sparing diuretics such as spironolactone with
`drugs or herbal supplements that can increase serum
`potassium levels. In this case, serum potassium rises
`secondary to a drug-induced impairment of the renin-
`angiotensin-aldosterone system that regulates potassium
`excretion. After the abrupt publication of the Randomized
`Aldosterone Evaluation Study (RALES) in which the
`mortality rate was significantly decreased in participants
`who received spironolactone vs placebo for advanced heart
`failure, a number of fatalities due to hyperkalemia were
`reported [40]. Impaired renal function and the addition of
`b-blockers are thought to compound the retention of
`potassium. When combined with spironolactone, the
`following agents can increase potassium, possibly leading
`to hyperkalemia and cardiac arrest if not intercepted:
`nonsteroidal anti-inflammatory drugs, COX-2 inhibitors,
`angiotensin-converting enzyme inhibitors, angiotensin II
`receptor antagonists. b-blockers, cyclosporine, tacroli-
`mus, heparin, ketoconazole, trimethoprim, pentamidine,
`and noni juice [40 - 45]. Aggressive monitoring of renal
`function and potassium levels in patients who are receiving
`these medications with spironolactone is warranted.
`
`Duplication of Pharmacologic
`Effect
`A notable food-drug interaction includes the monoamine
`oxidase inhibitors (MAOIs) and foods containing tyr-
`amine, an exogenous monoamine, such as pepperoni and
`aged cheese. Monoamine oxidase is responsible for
`regulating the degradation of catecholamines and seroto-
`nin in both the central nervous system and periphery [46].
`Thus, inhibition of the degradation of these neurotrans-
`mitters plus the exogenous tyramine results in an
`interaction typically presenting as a hypertensive crisis
`in which patients develop uncontrollable hypertension,
`headache, and fever. Other drugs that may potentiate this
`interaction with MAOIs include meperidine, dopamine,
`and over-the-counter sympathomimetics such as pseu-
`doephedrine [47]. Monoamine oxidase inhibitors irrever-
`sibly bind the enzyme, resulting in inhibition lasting for
`up to 2 weeks after discontinuation of the drug. For this
`reason, an appropriate b washoutQ period must pass before
`starting another agent known to interact with MAOIs.
`Classic MAOIs such as phenelzine, selegiline, and
`tranylcypromine are used infrequently today. However,
`the relatively new antibiotic, linezolid, is a weak MAOI
`
`Table 6
`
`Drugs that change urinary pH.
`
`Increase pH
`
`Citrate salts
`(eg, Bicitra)
`Furosemide
`Sodium bicarbonate
`Sodium lactate
`
`Decrease pH
`
`Ascorbic acid
`
`Lithium
`Topiramate
`
`and several cases of serotonin syndrome have been
`reported when linezolid is combined with selective
`serotonin reuptake inhibitors (SSRIs) [48 -52]. Serotonin
`syndrome is a constellation of symptoms presenting with
`hyperthermia, rigidity, myoclonus, agitation, shivering,
`and seizures caused by excessive serotonin availability at
`the receptors. Use of SSRIs with amphetamines, dextro-
`methorphan, meperidine, MAOIs, TCAs, linezolid, suma-
`triptan, St John’s wort, trazadone, and venlafaxine can
`potentially result in serotonin syndrome [53,54].
`Tardive dyskinesia is a permanent extrapyramidal
`movement disorder that may result from combination
`treatment with neuroleptics and antiparkinson agents, as
`well as with high-dose therapy of neuroleptics and
`metoclopramide [55].
`
`Summary
`The mechanisms of drug interactions are varied and may
`include herbal supplements and foods, as well as other
`drugs. As the number of drug interactions increase, it is
`important to have on-hand drug interaction resources
`available to ensure patient safety. Several current com-
`prehensive references include Lexi-Interact (published by
`Lexicomp), DRUG–REAX (published by Micromedex),
`the Natural Medicines Comprehensive Database
`(published by the Pharmacists’ Letter and Physician’s
`Letter), and the cyp450 resource http://medicine.iupui.
`edu/flockhart/table.htm. Many of these references are
`available in online or PDA versions. Being informed about
`the potential for drug interactions is the best way to
`prevent them from occurring. Moreover, the ED physician
`must be able to recognize drug interactions to identify and
`remove the offending agent. Understanding the mecha-
`nisms of drug interactions will as