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Introduction

How many of us in clinical practice have heard the question: “Doctor, will this drug interact with any of my other medications?” This common question has been challenging to answer, often leading to using laborious drug interaction computer programs, smartphone-based programs, or a call to the pharmacist. The purpose of this chapter is to help address this question, assess the likelihood of a drug-drug interaction, and advise the patient on what to expect should they experience an adverse drug effect.

This chapter will discuss serotonin syndrome and other toxicity syndromes, adverse drug events (ADEs), drug-drug interactions (DDIs) , the P450 enzymatic system, and the multiple inhibitors and inducers of drug metabolism. It will also address genetic variability of drug metabolism within certain populations and ethnic groups. Finally, we will develop a system for evaluating DDIs that includes a pocket-sized guide that can be used in the office or bedside to determine whether a patient may be at risk for a DDI.

Case Study

A 93-year-old woman presents with a 6-week history of recurrent syncopal events . She had been previously high functioning, living alone in her own home. One morning upon getting out of bed, she fell forward when bending for her slippers, falling to the floor without injury. She denied vertigo or loss of consciousness but felt “top heavy.” Two weeks later, she had a second event while on the commode, felt suddenly unwell, and then fell off the commode, fracturing the left ankle. In the hospital, a carotid US showed a 90% stenosis of the left internal carotid artery. She underwent urgent endarterectomy and was discharged to short-term rehab. While there, she had a third event of dizziness, light-headedness, and loss of consciousness while on the commode, falling to the floor with confusion and slurred speech, lasting several minutes.

In the hospital, she had no orthostatic hypotension, and Dix-Hallpike testing was normal. She was found to have hypokalemia, hypocalcemia, and hypomagnesemia.

It was noted on her medication that she takes metoprolol. When asked, she admitted to taking nightly acetaminophen with diphenhydramine (Tylenol PM) for sleep.

Diphenhydramine , an antihistamine, is a common over-the-counter sleep aid. It is a substrate and an inhibitor of the P450 enzyme 2D6 , which metabolizes 25% of all commercially available medications [1]. Metoprolol is also a substrate of 2D6. Coadministration of a substrate (metoprolol) and an inhibitor (diphenhydramine) of the same enzyme may increase serum concentrations of the substrate. In the case of metoprolol, an already active parent compound, this may lead to toxicity, resulting in bradycardia and hypotension [2]. It is suspected that the patient may have had syncope due to the interaction of diphenhydramine with metoprolol [3].

The converse is true in the case of a prodrug such as hydrocodone , which must be converted to its active metabolite, hydromorphone. When codeine cannot be converted to morphine due to P450 enzyme inhibition, the patient may have inadequate analgesia [4].

Pharmacogenomic differences may also contribute to drug-drug interactions. Five to 10% of Caucasians are poor metabolizers of CYP2D6, meaning they have fewer than two copies of the gene for the enzyme [5]. Metabolically active parent compounds like diphenhydramine and metoprolol will have higher concentrations in poor metabolizers, increasing the risk of toxicity [1]. Prodrugs such as hydrocodone and clopidogrel, metabolized by 2D6 and 2C19, respectively, lose efficacy in poor metabolizers, due to an inability to convert to the active metabolite [4].

The Impact of Libby Zion on Resident Education

In 1984, an 18-year-old college freshman died in New York Hospital. Few events have had as great an impact on medical resident education [6]. Libby Zion was admitted for agitation, confusion, and muscular twitching. She had a history of depression and was taking phenelzine, an MAO inhibitor . The house officers assigned to her care prescribed meperidine and haloperidol for sedation and placed restraints to prevent self-harm. By the following morning, she had a fever of 107F and died from a cardiac arrest. Her father Sidney Zion, a prominent journalist, brought charges against the hospital and the physicians, indicting the medical training system for excessive work hours and poor supervision that, he argued, contributed to poor judgment and medical negligence [6, 7].

In 1995, the jury in the Zion v. New York Hospital trial returned a mixed verdict, finding that the doctors were partially responsible for Libby’s death but that Libby was also responsible based on autopsy samples positive for cocaine metabolites. Later, the New York Supreme Court threw out the cocaine evidence. They upheld the damages against the doctors and found the hospital not guilty of negligent trainee supervision given the training standards of the time [6, 7].

As a result of Libby’s death, and her father Sidney Zion’s considerable influence, the Bell Commission was convened in New York to address the issue of residency work hours [8]. In 2003, the ACGME adopted most of the Bell Commission’s recommendations, restricting residency work hours at all US training programs to 80 h per week [9].

But would the current work hour restrictions have saved Libby Zion? Would a well-rested resident have recognized the signs and symptoms of serotonin syndrome that Libby Zion exhibited, namely, confusion, agitation, and muscular hyperactivity? Would the doctor have known that meperidine is associated with significant drug interactions that might worsen serotonin syndrome? Libby Zion’s death was more likely due to a knowledge deficit than a sleep deficit.

An important lesson from Libby Zion’s death is that drug-drug interactions (DDIs) and adverse drug events (ADEs) are common and under-recognized. Prescribers are often unaware of the potential for harm in many commonly prescribed medications.

Scope of the Problem

Adverse drug events (ADEs) are common. In an ambulatory setting , the rate of ADEs is 50 per 1000 person-years, of which 28% are considered preventable. Cardiovascular medications were the most common cause, followed by diuretics, nonopioid analgesics, hypoglycemics, and anticoagulants [10].

Almost 6.5% of all hospitalized patients are admitted due to ADEs, with a fatality rate of 0.15% [12]. Fear of receiving the wrong medication while in hospital is a common concern of patients [12]. High rates of hospitalization have been confirmed in multiple studies, of which two thirds are considered preventable [11, 13, 14].

Drug-drug interactions (DDIs) are a fraction of all ADEs [15]. However, most potential drug-drug interactions do not actually occur [16]. Despite the frequency of theoretically dangerous medication combinations, actual harm is relatively infrequent. Using a computerized interaction tool , Marino found 12,578 potential drug-drug interactions among 3473 emergency department patients, with 9% actually having the expected interaction [17].

Electronic medical records frequently flag potential drug interactions, but the relative infrequency of DDI may cause busy clinicians to ignore repetitive notifications when ordering medications, something known as alert fatigue [18].

Despite the emphasis on detection and prevention of DDIs, the advent of computerized order entry has not substantially reduced the frequency of these events [19].

The adverse drug events reporting system of the FDA estimate roughly 15,000 deaths per year can be attributed to medication effects [20]. ADEs account for up to 6.5% of hospital admissions [11]. In 2011, there were an estimated 100,000 emergency visits for ADEs, 48% occurring over age 80 and two thirds due to unintentional overdose [21]. The most common medications were warfarin, insulin, antiplatelets, and oral hypoglycemic agents. Only 1.2% were due to a high-risk medication as listed in Beers list [22] (Table 10.1).

Table 10.1 High Risk medications for side effects and interactions [22]
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One third of all ED visits for ADRs involved just three medications: warfarin (17.3%), insulin (13.0%), and digoxin (3.2%) [21, 23].

It is no wonder that ADEs are so common. In 2006, the Slone Survey reported 82% of adults and 56% of children in the USA take at least one prescription or nonprescription medication or dietary supplement. Over age 65, 17% take ten or more medications in a given week [24].

Risk factors for ADEs and DDIs include age greater than 65, multiple medications and OTCs, genetic variability in drug metabolism, and medical comorbidity [13, 15]. Drug-drug interactions represented 3–5% of all in-hospital medication errors [16]. A lack of awareness of drug interactions by physicians also contributes to the problem [25].

Adverse drug reactions may occur by a variety of mechanisms as listed in Table 10.2 [26].

Table 10.2 Types of adverse drug events
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Clinical Syndromes of Drug Toxicity

There are many clinical syndromes relevant to neurologic practice that result from drug toxicity (Table 10.3).

Table 10.3 Clinical syndromes related to medication toxicity
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Several are associated with acute confusional states, a common reason for neurologic consultation. Many of these agents are present on the Beers list of potentially inappropriate medications (Table 10.1).

A number of commonly prescribed medications may induce neurotoxicity including confusion, myoclonus, asterixis, and increased risk of falls in patients with low creatinine clearance (<60 ml/min). The most common is gabapentin but also duloxetine, levetiracetam, pregabalin, and tramadol [22]. Gabapentin is a common cause of neurotoxicity in patients with low creatinine clearance [37, 38]. Patients may develop confusion, myoclonus, asterixis, and obtundation [30, 39].They may present as recurrent falls due to asterixis of the legs, inducing unexpected knee buckling [40, 41].

The term serotonin syndrome was first coined by Sternbach in 1991 [42]. It is a potential complication of serotonergic drugs, especially when used in combination [43, 44].The incidence is unclear, since most cases are probably unrecognized. On occasion, cases are overestimated. An FDA alert warning of the risk of serotonin syndrome with the combination of SSRI and triptans was likely unwarranted based on poor documentation [45]. Toxicity occurs in 27% and deaths in 0.3% of patients overdosing on SSRIs [46]. For nefazodone, the incidence is 0.4 cases per 1000 patient-months [47].

Patients present with a clinical triad of mental status changes, autonomic instability, and motor hyperexcitability, usually within 24 h of a change in medication [43]. Most patients recover within 1–2 days after drug withdrawal; however some may develop respiratory failure, seizures, rhabdomyolysis, and cardiac arrest (Table 10.4). Mortality from serotonin syndrome was associated with use of MAO inhibitors but now is quite rare in recent series [27].

Table 10.4 Clinical features of serotonin syndrome [48]
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Some overlap of symptoms and signs exist for serotonin syndrome, neuroleptic malignant syndrome, and anticholinergic toxicity. They can generally be distinguished by the motor hyperexcitability, rapidity of onset, and recent addition or increase of a serotonergic medication [43].

Serotonergic drugs may act by increasing serotonin synthesis (tryptophan), decreasing serotonin metabolism (phenelzine, selegiline), increasing serotonin release (amphetamines, cocaine), and inhibiting reuptake (SSRIs, SNRIs, TCAs, meperidine, dextromethorphan). Some act directly on serotonin receptors (buspirone, triptans).

The treatment of serotonin syndrome is supportive care, with no randomized trials of any specific therapy. Most respond to withdrawal of the offending agent, intravenous fluids, benzodiazepines for agitation and myoclonus, anticonvulsants for seizures, critical care monitoring for autonomic instability, and airway protection. Cyproheptadine , a nonspecific serotonin receptor blocker, may be used in doses of 4–24 mg/day administered by nasogastric tube. Other agents have been tried anecdotally including dantrolene, propranolol, mirtazapine, and atypical antipsychotics. Bromocriptine, an agent commonly used for neuroleptic malignant syndrome, may exacerbate serotonin syndrome due to its indirect effect on serotonin metabolism and should be avoided [43].

P450 Metabolism

Over 95% of commercially available drugs are metabolized by the P450 system. Most are metabolized by just five enzymes: CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4.

The p450 enzyme system is an important determinant of drug interactions. With the exception of renal failure, alterations in protein binding are less clinically relevant than the P450 system [49, 50]. Even highly protein-bound drugs such as phenytoin and warfarin quickly alter binding ratios when coadministered and achieve a new steady state. Less well appreciated by practicing physicians is that medications may compete with, inhibit, or induce the metabolism of other drugs. Further, some of these enzymes are subject to genetic variation, making affected patients susceptible to toxicity at lower than expected doses [5, 51].

Drugs undergo phase I, II, and III metabolism. Phase I is carried out by the P450 system, primarily in the liver, and includes oxidation, hydroxylation, acetylation, and methylation [52].

Monamine oxidation , also phase I, is not part of the P450 system.

Phase II prepares the drug for elimination. Glucuronidation and sulfation increase water solubility, enhancing elimination in the urine or stool. Important drug interactions occur during phase II metabolism, such as the interaction of lamotrigine with valproate leading to Stevens-Johnson syndrome [53]. Further discussion of phase II metabolism may be found in Sirot et al. [26].

Phase III refers to the action of P-glycoprotein and other intracellular transporters. They account for the blood-brain barrier. Inhibitors of P-glycoprotein increase the permeability of the blood-brain barrier, allowing certain compounds to penetrate the CNS. An example is the combination of quinidine, a P-glycoprotein inhibitor, with loperamide, a peripherally acting opioid used for diarrhea. Patients on both may experience a central narcotic effect of loperamide in the presence of quinidine [54, 55].

P450 Enzyme System (Fig. 10.1)

These enzymes are located primarily in the liver, kidney, intestine, lungs, and brain. Six enzymes metabolize over 80% of all medications [2, 52]. They are CYP1A2, 2B6, 2C9, 2C19, 2D6, and 3A4.

Fig. 10.1
figure 1

P450 enzymes and some examples of representative drugs

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CYP2D6, 2C19, and 2C9 are especially prone to genetic variability. Depending upon the number of gene copies of a particular allele, patients may be poor metabolizers (no functioning alleles), intermediate metabolizers (1 copy), extensive metabolizers (2 copies – the normal state), or ultrametabolizers (3–13 copies).

Substrates/Inducers/Inhibitors

Drugs may be substrates (requiring the enzyme for its metabolism/activation), inhibitors (preventing the metabolism of other substrates of the enzyme), or inducers of enzymatic activity, leading to accelerated metabolism/activation of another drug. Some drugs such as fluoxetine may be both a substrate of 2D6 at low concentrations and an inhibitor at higher concentrations [2]. The pharmacokinetic mechanism of drug interactions may be enzyme competition from two substrates [4], enzyme inhibition of a substrate by an inhibitor [4, 56], or enzyme hyper- or hypometabolism of a substrate medication due to pharmacogenetic variants of P450 enzymes [5, 57, 58].

Genetic Variants and Pharmacogenomics

Pharmacogenomics is the study of the variability in drug metabolism in individuals. Most P450 enzymes have two gene copies. However, an individual may have none, one, or more than two copies, thus increasing or reducing the rate of metabolism of the substrate medication. The multiple variants of the enzymes are termed polymorphisms. Screening tests are available from commercial laboratories that assess the likelihood of genetic susceptibility to drug interaction. Phillips reviewed 18 studies of ADEs related to genetic variations of CYP enzymes. Two thirds of the 27 drugs most commonly identified are metabolized by an enzyme with genetic variants [59].

Although 2D6 polymorphisms are present in 7% of the population, 14% of hospitalized psychiatric patients have 2D6 variants, suggesting a far greater risk of adverse drug events requiring hospitalization [60] (Table 10.5).

Table 10.5 Genetic polymorphisms and clinical relevance [26]
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Prodrugs

Some agents like hydrocodone and clopidogrel are prodrugs . They must be converted by 2D6 or 2C19, respectively, to the active compound. Other agents like metoprolol are metabolically active prior to 2D6 metabolism. Therefore coadministration of codeine and an inhibitor of 2D6 such as diphenhydramine or paroxetine may lead to inadequate analgesia due to lack of conversion of codeine to its active metabolite, morphine. Conversely, coadministration of metoprolol with an inhibitor of 2D6 such as amiodarone may lead to metoprolol toxicity with hypotension and bradycardia [4, 56].

P450 Enzyme Subtypes

CYP1A2 metabolizes 15% of all drugs, including caffeine, benzodiazepines, SSRIs, haloperidol, and clozapine [61]. Activity of metabolism is induced by tobacco [62] and inhibited by fluvoxamine, quinolones, and cimetidine. There is mild genetic variability.

CYP2C9 metabolizes 20% of the most commonly prescribed drugs, most importantly warfarin. Other “substrates ” include phenytoin, tolbutamide, glipizide, losartan, fluvastatin, and NSAIDs. It is inhibited by fluconazole and induced by phenobarbital and rifampin. Up to 10% of Caucasians may be 2C9 deficient and may develop bleeding on usual doses of warfarin due to an inability to metabolize the drug. An FDA alert encourages physicians to consider genetic screening in patients whose anticoagulation is difficult to manage [63].

CYP2C19 metabolizes citalopram, diazepam, and omeprazole. It is inhibited by fluoxetine, fluvoxamine, omeprazole, and certain HIV drugs. It is induced by phenobarbital and rifampin. Up to 20% of Asians may be 2C19 poor metabolizers and are susceptible to toxicity on standard doses of diazepam [52, 63].

CYP2D6 is responsible for 25% of P450 drug metabolism, particularly the SSRIs, TCAs, phenothiazines, risperidone, and codeine. It is inhibited by amiodarone, fluoxetine, paroxetine, cimetidine, and quinidine. It may be induced by dexamethasone. 2D6 has significant polymorphisms. One in 10–14 Caucasians and 4% of African Americans are poor metabolizers. Because codeine must be converted to morphine to have an analgesic effect, these patients experience no analgesia with codeine. A small percentage are ultrametabolizers (1–7% of Caucasians, 25% of Ethiopians), leading to excessive narcosis on standard doses of codeine [51]. Conversely, patients deficient in 2D6 may develop toxicity on standard doses of active compounds such as haloperidol, due to inability to convert to inactive metabolites [64, 65].

CYP3A4 metabolizes 60% of currently available medications, including calcium channel blockers, HIV drugs, statins, cyclosporin, antihistamines, and cisapride. It is present in the intestinal mucosa and liver and accounts for the majority of first-pass metabolism. The enzyme lining the intestine is strongly inhibited by grapefruit juice [66]. The furanocoumarins in the fruit inactivate the enzyme in the gut, reducing first-pass metabolism, and allows for higher concentrations of drug leading to toxicity [52]. Other inhibitors include ketoconazole, metronidazole, AZT, omeprazole, erythromycin, and verapamil. The enzyme is induced by Hypericum (St John’s-wort), carbamazepine, phenobarbital, and phenytoin [67].

Substrates/Inducers/Inhibitors

The majority of clinically useful medications are P450 substrates , meaning that they are metabolized by one or more P450 enzymes [52]. Medications may also be inhibitors or inducers (activators) of enzyme metabolism. Inducers are medications that increase the activity of enzyme. Inhibitors reduce enzyme activity. An agent may be both a substrate at low concentrations, and an inhibitor at higher levels, thus providing a potential check on toxicity. Some medications may be metabolized preferentially by one P450 enzyme at lower concentrations and by one or more others enzymes at higher concentrations. An example is codeine , a prodrug , which is a substrate of 2D6 but also 3A4 [51] (Table 10.6).

Table 10.6 Significant P450 enzymes and clinically relevant drug-drug interactions [2]
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Prodrugs

Tamoxifen , a common antihormonal agent for the treatment of breast cancer, is a substrate of both 3A4 and 2D6. If taken with potent inhibitors of 2D6 metabolism such as fluoxetine, duloxetine, or diphenhydramine , tamoxifen is unable to be converted to its active form endoxifen, rendering it ineffective (Table 10.7).

Table 10.7 Common prodrugs
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A Top Ten List of DDIs: Table 10.8

A Top Ten list would include commonly prescribed medications in combination with known P450 enzyme inhibitors or inducers or enzymes with marked pharmacogenomic variation. That list might include combinations of diphenhydramine , metoprolol , fluoxetine, SSRIs, first-generation anticonvulsants, oral contraceptives, meperidine and other opioids, amiodarone, fluoroquinolone, omeprazole, theophylline, antifungals, and clopidogrel.

Table 10.8 A top ten list of potential DDIs
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Combining risperidone with carbamazepine, commonly used as a mood stabilizer, may lead to reduced therapeutic levels of risperidone due to enzyme induction [69]

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Prevention/Recognition (Table 10.9)

Prevention of DDIs begins with a careful assessment of the patients medications and dietary supplements. A mnemonic such as AVOID MISTAKES serves as a helpful reminder of risk factors for drug interactions.

Table 10.9 A stepwise approach to drug-drug interactions
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DDI Card

Patients frequently want to know whether the medication we are about to prescribe is likely to interact with others on their list. The tables listed below may be reprinted for use in the patient exam rooms and serve as a guide when counselling on potential drug interactions.

The most common mechanism of DDI is the coadministration of a substrate with an inhibitor or inducer of the same P450 enzyme. The tables below list common and clinically relevant drugs likely to interact.

First, determine whether there are any inhibitors on the patient’s medication list. Next, identify any substrates of the inhibited or induced enzyme in question. Finally, discuss the symptoms and warning signs of possible interactions and whether the drug should be abruptly discontinued or weaned in the event of an interaction.

Cytochrome P450 drug interactions

CYP1A2

Substrates

Acetaminophen

Frovatriptan

Quinine

Amitriptyline

Haloperidol

Ranitidine

Bupropion

Imipramine

Rasagiline

Caffeine

Melatonin

 

Clomipramine

Metoclopramide

Theophylline

Clozapine

Mexiletine

Tizanidine

 

Mirtazapine

R-warfarin

Cyclobenzaprine

Naproxen

 

Doxepin

Olanzapine

Zolmitriptan

Duloxetine

  
 

Propranolol

 

Fluvoxamine

  

Inhibitors

Amiodarone

Fluphenazine

Paroxetine

Amlodipine

Fluoxetine

Perphenazine

Caffeine

Fluvoxamine

Refecoxib

Cimetidine

Levofloxacin

Sertraline

 

Lidocaine

 
 

Mexiletine

Verapamil

Ciprofloxacin

Nifedipine

 

Diclofenac

Norfloxacin

Herbal tea

Duloxetine

 

Peppermint, Chamomile Teas

 

Olanzapine

 
 

Oral contraceptives

 

Inducers

Brussels sprouts

Phenobarbital

 

Cruciferous veggies

Rifampin

 

Carbamazepine

Tobacco smoke

Marijuana

Char-grilled meats

St. John’s Wort

 
 

Paclitaxol

 

Key- bold= common drug interactions, or dominant pathway

MAO, Phase II and Phase III ( P-glycoprotein) drug interactions are not included

Important Prodrugs*

Codeine

 

Tramadol

Clopidogrel

Tamoxifen

Azathioprine

Midodrine

 

Mycophenolate

CYP3A4

Substrates

Alprazolam

Doxepin

Methadone

Quetiapine

Amiodarone

 

Midazolam

Quinidine

Amlodipine

Erythromycin

Mirtazapine

 
 

Esomeprazole

Marijuana

Sildenafil

Atorvastatin

 

Modafinil

Simvastatin

Bromocriptine

Ethosuximide

Nefazodone

Tacrolimus

Bupropion

Felbamate

Nicardipine

Tamoxifen

Buspirone

Felodipine

  

Caffeine

 

Omeprazole

Tiagabine

Carbamazepine

Fentanyl

Ondansetron

 
 

Fluconazole

Oral contraceptives

Ttramadol

Clarithromycin

Fluvoxamine

Oxcarbazepine

 

Cocaine

Haloperidol

 

Trazodone

Cyclophosphamide

  

Venlafaxine

Cyclosporine

Hydrocortisone

Pravastatin

Verapamil

 

Ketoconazole

  

Dexamethasone

Lansoprazole

Prednisone

Warfarin

Diazepam

Lidocaine

Progesterone

 

Diltiazem

Losartan

 

Zolpidem

 

Lovastatin

  

Inhibitors

Amiodarone

Fentanyl

Ketoconazole

 

Atorvastatin

Fluconazole

Lovastatin

Saquinavir

Cimetidine

Fluoxetine

Nicardipine

Simvastatin

Ciprofloxacin

Fluvoxamine

  

Clarithromycin

 

Nifedipine

Sertraline

Cyclosporine

Grapefruit juice (functional inducer)

Nefazodone

Tacrolimus

Diltiazem

   

Erythromycin

 

Omeprazole

Valproic acid

 

Isoniazid

  
  

Paroxetine

Verapamil

  

Quinidine

Voriconazole

Inducers

Carbamazepine

Oxcarbazepine

Prednisone

St. John’s Wort

Dexamethasone

Phenobarbital

Primidone

Topiramate (>200 mg)

Modafinil

Phenytoin

Rifampin

 
  1. Important notice: These tables are not all-inclusive. New information is continually identified

CYP2D6

Substrates

Poor metabolizers- 7–10% of Caucasians, 4% African Americans

Ultrarapid metabolizers-1–7% Caucasians, 25% of Ethiopians

Amitriptyline

Duloxetine

Nortriptyline

Bupropion

Fluoxetine

Oxycodone

Carvedilol

Fluphenazine

Paroxetine

Codeine*

Fluvoxamine

Propafenone

Desipramine

Haloperidol

Propranolol

Dextromethorphan

Hydrocodone

Risperidone

Donepezil

Imipramine

Sertraline

Doxepin

Lidocaine

Tamoxifen*

Doxorubicin

Methadone

Thioridazine

 

Metoclopramide

Timolol

 

Metoprolol

Tramadol*

 

Mexiletine

Venlafaxine

 

Mirtazapine

 

Inhibitors

Amiodarone

Duloxetine

Nortriptyline

Amitriptyline

Fluoxetine

Paroxetine

Atorvastatin

Fluvoxamine

Pimozide

Bupropion

Haloperidol

Pioglitazone

Celecoxib

Isoniazid

Quinidine

Clozapine

Lansoprazole

Risperidone

Cocaine

Methadone

Ritonavir

Desipramine

 

Sertraline

Diclofenac

 

Thioridazine

Diphenhydramine

 

Trazodone

  

Venlafaxine

Inducers

Probably none

CYP2C9

Substrates

2C9 Impaired in 1–10% Caucasians

Bupropion

Glipizide

Naproxen

Valproic acid

Carvedilol

Ibuprofen

Phenobarbital

Voriconazole

Celecoxib

Indomethacin

Phenytoin

S-warfarin

Cyclophosphamide

Irbesartan

Piroxicam

Marijuana

Dapsone

Losartan*

Sildenafil

 

Diclofenac

Meloxicam

SMX/TMP

 

Fluoxetine

Methadone

Tamoxifen

 

Inhibitors

Amiodarone

Fluvoxamine

Metronidazole nicardipine

Sertraline

Cimetidine

Ginkgo Biloba

Pantoprazole

Simvastatin

Fluconazole

Ibuprofen

Paroxetine

Valproic acid

Fluoxetine

Indomethacin

Piroxicam

Zafirlukast

Fluvastatin

Ketoconazole

Quinine

 
 

Losartan

Ritonavir

 

Inducers

Carbamazepine

Phenobarbital

Primidone

Ritonavir

Dexamethasone

Phenytoin

Rifampin

St. John’s Wort

Oxcarbazepine

   

CYP2C19

Substrates

2C19 impaired in 15–30% of Asians

Amitriptyline

Diazepam

Omeprazole

Progesterone

Carisoprodol

Esomeprazole

Pantoprazole

Sertraline

Clomipramine

Fluoxetine

Phenobarbital

Voriconazole

Citalopram

Imipramine

Phenytoin

Warfarin

Clopidogrel*

Indomethacin

  

Cyclophosphamide

Lansoprazole

  

Dapsone

Methadone

  

Inhibitors

Amiodarone

Fluoxetine

Isoniazid

Oral contraceptive paroxetine

Amitriptyline

Fluvoxamine

Ketoconazole

Sertraline

Cimetidine

Imipramine

Lansoprazole

Topiramate

Felbamate

Indomethacin

Modafinil

Valproic acid

Fluconazole

 

Nicardipine

 
  

Omeprazole

 

Inducers

Carbamazepine

Pentobarbital

Rifampin

St. John’s Wort

Oxcarbazepine

Phenytoin

 

Glucocorticoids

Prevention/Recognition

An effective means of preventing adverse drug reactions and drug-drug interactions is rounding with a hospital-based clinical pharmacist. Rivkin found that rounding with a pharmacist who screened ICU patients for potential drug interactions reduced ADEs by 65% and reduced length of stay and mortality [70]

DDI Websites

http://medicine.iupui.edu/CLINPHARM/DDIS

https://www.drugs.com/drug_interactions.html

www.themedicalletter.com [17]

www.druginteractioninfo.org

www.pharmvar.org

www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionslabeling/ucm080499.htm