Current Treatment Options in Gastroenterology (2014) 12:292–309 DOI 10.1007/s11938-014-0024-9

Geriatrics (S Katz, Section Editor)

Common GI Drug Interactions in the Elderly Marina Kim, DO1 Aamir Dam, MD2,* Jesse Green, MD2 Address 1 Internal Medicine, Albany Medical Center, 47 New Scotland Ave, Albany, NY 12208, USA Email: [email protected] *,2 Gastroenterology, Albany Medical Center, 47 New Scotland Ave, NY 12208, USA Email: [email protected] Email: [email protected]

Published online: 18 July 2014 * Springer Science+Business Media, LLC 2014

Keywords Elderly I Drug interaction I Adverse events I Polyphamacy I Common gastrointestinal conditions I GERD I Peptic ulcer disease I Gastroparesis I Diarrhea I Constipation I Irritable bowel syndrome I Inflammatory bowel disease I Chronic liver disease I Cytochrome p450 I P-glycoprotein

Opinion statement The careful review of drug-drug interactions is vital to the safe prescribing of medications for chronic medical conditions. The elderly population suffers from multiple medical problems, and polypharmacy leads to further morbidity in this vulnerable group of patients. We discuss gastrointestinal conditions such as GERD, peptic ulcer disease, gastroparesis, diarrhea, constipation, irritable bowel syndrome, inflammatory bowel disease, chronic liver disease and the commonly used medications in these conditions. Treatment options must be individualized and tailored to accommodate the underlying pharmacokinetics and known drug-drug interactions. The indication for the use of a therapeutic agent in the elderly and the duration of use must be frequently readdressed to help prevent polypharmacy and adverse drug reactions. Medications should be started at a low dose with careful titration to achieve a clinical response to prevent toxicity. The aim of this article is to increase awareness of important drug-drug interactions of commonly prescribed gastrointestinal medications in the elderly.

Introduction Polypharmacy and drug-drug interactions remain constant problems in the geriatric population and are risk factors for adverse drug reactions. Drug interactions can lead to a change in drug

concentrations that may have devastating consequences in an elderly patient. Pharmacokinetic drug interactions can occur at the level of drug absorption, distribution, elimination, and metab-

Common GI Drug Interactions in the Elderly olism. Drug interactions can also occur further downstream and have an additive, synergistic, or antagonistic clinical effect [1•]. From a metabolic standpoint, many drugs share a common pathway utilizing the cytochrome p450 system and membrane transporters such as P-glycoprotein (P-gp). The induction and inhibition of these enzymes are a common mechanism leading to numerous drug interactions and clinically significant events

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especially in medications with a narrow therapeutic window [2•, 3]. Other factors that must be considered in the elderly population include multi-organ dysfunction, change in weight, diet, and genetic factors [1•]. The Lexi-Comp database [4•] and PubMed searches for literature were used to evaluate pharmacokinetics and identify important interactions between various medications.

GERD Gastroesophageal reflux disease (GERD) can be associated with complications including esophagitis, peptic strictures, and Barrett’s esophagus. The prevalence of Barrett’s esophagus increases with age, and patients are at increased risk for developing esophageal adenocarcinoma [5]. Elderly patients need to be closely screened for symptoms of GERD particularly based on atypical symptoms including anorexia, regurgitation, dysphagia, hoarseness, respiratory symptoms, dyspepsia, and chest pain [5, 6]. Proton pump inhibitors (PPIs) are the most common and effective medication prescribed for the treatment of GERD [7]. Other indications for PPI use include acid hypersecretory states, peptic ulcer disease (PUD), eradication of Helicobacter pylori (H.pylori), and prophylaxis in high-risk patients on anti-platelet agents, NSAIDs, and anticoagulants [8]. The duration of PPI use should be determined judiciously given the reported adverse effects with long-term PPI use. The best evidence supports an association between PPI use and increased risk of Clostridium difficile-associated diarrhea (CDAD) in susceptible patients [9, 10]. Other adverse effects include bone fractures, vitamin B12 deficiency, hypomagnesemia, interstitial nephritis, and respiratory infections, although the evidence remains limited [11–13]. The risk of cardiovascular events with clopidogrel and PPI co-prescription have been implicated, as they share a common CYP 450 pathway, specifically the CYP2C19 isoform. In pharmacokinetic studies, PPIs have been shown to blunt the antiplatelet effect of clopidogrel, with omeprazole and esomeprazole exhibiting the greatest effect [12, 14]. Observational studies have demonstrated an increased risk with combination therapy [15, 16], though results have been inconsistent. Larger clinical studies do not suggest a clinically significant cardiovascular interaction between PPIs and clopidogrel [17]. However, in certain subgroups, such as those with underlying impaired metabolism of clopidogrel, a clinically significant interaction cannot be excluded [18]. Based on the current available data, clinicians can continue to prescribe PPIs in conjunction with antiplatelet drugs when their use will provide an optimal balance of benefit and risk [18–20]. Because PPIs are predominantly metabolized in the liver by the CYP2C19 and CYP3A4 pathways, other important drug interactions in the elderly exist. Omeprazole has been demonstrated to decrease clearance of citalopram [21], potentially increasing the risk for QT prolongation, cardiac arrhythmias, and the serotonin syndrome. In addition, omeprazole can interact and reduce

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Geriatrics (S Katz, Section Editor) clearance of diazepam, warfarin, cilostazol, and phenytoin [8]. Interestingly, other PPIs in the same class, specifically lansoprazole and pantoprazole sodium have not been shown to have significant metabolic interactions with these particular medications [8]. Also, certain medications can induce the CYP450 system and will result in more rapid metabolism of PPIs. These medications include phenytoin, rifampin, carbamazepine, and St. John’s wort, which may decrease serum concentration of omeprazole, and concomitant use should generally be avoided [4•]. PPIs influence the intragastric milieu, thereby modifying the release and metabolism of certain drug formulations such as a reduction of the bioavailability of oral ketoconazole, itraconazole, and mycophenolic acid when co-administered with omeprazole [8]. Interestingly, these changes in bioavailability were not observed in small studies with coadminstration of pantoprazole sodium and enteric-coated mycophenolate sodium [22]. In patients with inflammatory bowel disease on mesalamine therapy, PPIs may cause premature release of sustained-release mesalamine products and diminish therapeutic effect [4•]. PPIs should be used with caution in patients on certain immunosuppressants. Specifically, PPIs have been shown to decrease oral tarcrolimus clearance, thereby increasing blood tacrolimus concentrations [23]. Lastly, patients taking omeprazole who are also taking furosemide, hydrochlorothiazide, and spironolactone have an increased risk of developing hypomagnesemia [24]. For patients who do not tolerate PPIs, second-line therapy for GERD include histamine2 receptor antagonists (H2RA), which are less effective than PPIs and have limited efficacy in patients with severe erosive esophagitis [25]. H2RAs also influence the gastric pH, and can effect levels of medications such as mesalamine and ketoconazole [4•]. A common H2RA is famotidine, which has minimal drug interactions. However, caution should be taken with the use of cimetidine, as it is a substrate of P-gp and moderate inhibitor of multiple CYP450 isoforms [6]. Importantly, H2RAs are listed on the 2012 Beers criteria list for potentially inappropriate medications for older adults, as they have shown to increase the risk of drowsiness and falls in patients who are 65 years and older [26, 27•].

Peptic Ulcer Disease (PUD) Epidemiologic studies indicate that the incidence of both gastric ulcers and duodenal ulcers increase with age [28], and underlying comorbidity is associated with increased mortality in patients with peptic ulcer bleeding [29]. The most common causes of peptic ulcer disease (PUD) are H. pylori and NSAID use, and there is a high prevalence of both of these risk factors in the elderly population [30]. Use of concomitant medications, including antiplatelet/anticoagulation therapy, can synergistically increase the risk of complications from PUD. The mainstay for treatment and reduction of ulcer relapses is accomplished by the use of PPIs and the eradication of H. pylori if detected. The first-line treatment regimen against H. pylori is termed triple therapy, and

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commonly includes a PPI in combination with clarithromycin and amoxicillin for a minimum of 7 days [28]. Clarithromycin is a potent inhibitor of CYP3A4, resulting in numerous drug interactions. Clarithromycin can increase concentrations of alprazolam, midazolam, oxycodone, and fentanyl, thereby increasing risk of CNS depression, respiratory depression, and psychomotor impairment [4•]. In addition, it can increase levels of apixaban, rivaroxaban, calcium channel blockers, and statins, and predispose elderly patients to increased bleeding, hypotension, and rhabdomyolysis [4•, 31, 32]. A recent study showed that among older adults taking a calcium-channel blocker, concurrent use of clarithromycin compared with azithromycin was associated with a small but statistically significant, greater 30-day risk of hospitalization with acute kidney injury. The finding was most pronounced when clarithromycin was coprescribed with nifedipine [33•]. Other important considerations with concomitant clarithromycin use are increased levels of colchicine, budesonide, methylprednisolone, carbamazepine, quetiapine, buspirone, quinidine, ranolazine, sildenafil, salmeterol, theophylline, cilostazol, tacrolimus, cyclosporine, and saxagliptin [4•]. All these interactions are mediated by the inhibition of the CYP3A4 system. NSAID use is widespread in the elderly population for the treatment of chronic pain and osteoarthritis. NSAIDs can exert their effect topically and through systemic inhibition of prostaglandins, impairing local protective mechanisms to the gastric mucosa [34]. NSAIDS should be used with caution in older people and the lowest dose should be given for the shortest duration [35]. Patients at high-risk for NSAID-induced ulcers are those over the age 65, on higher doses of NSAIDs, taking concomitant corticosteroids or anticoagulants, those that have a concomitant H. pylori infection, or patients with a history of peptic ulcer or gastrointestinal hemorrhage [28]. Proton pump inhibitors (PPI) are recommended in the prevention of NSAID-induced gastric and duodenal ulcers [34, 36]. Misoprostol is an alternative agent for the prophylaxis of peptic ulcer formation [36]. However, it requires multiple daily dosages and is associated with adverse effects such as diarrhea, dyspepsia, and abdominal pain [28]. Given the increased incidence of diarrhea with misoprostol, it is recommended to avoid concomitant use with magnesium-containing antacids [4•].

Gastroparesis Gastroparesis is a motility disorder of the stomach and is most often idiopathic, diabetic, or postsurgical in nature [37]. Other causes relevant to the elderly population include radiation therapy, radiofrequency ablation of atrial arrhythmias, paraneoplatic phenomena, connective tissue disease, neurologic disorders, hypothyroidism, and hyperparathyroidism. Exogenous causes include medications, total parenteral nutrition, and chemotherapy agents [37]. The most frequent symptoms include nausea, vomiting, early satiety, bloating, and abdominal pain [38]. Diagnosis is established by evaluation of gastric retention time with scintigraphy [37]. Treatments are limited and include dietary measures, medications, psychological therapies, and surgical options [39].

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Geriatrics (S Katz, Section Editor) Prokinetic agents are employed to improve gastric emptying, but their use is often limited by side effects. Metoclopramide is the only FDA-approved medication for this condition. It is a dopamine D2 receptor antagonist, but stimulates 5-hydroxytryptamine 4 (5-HT4) receptors, increasing acetylcholine in the gut wall [40]. Metoclopramide can cross the blood–brain barrier, and may result in extrapyramidal movement disorders, including acute dystonic reactions, Parkinsonism, tardive dyskinesia, and akathisia. In addition, metoclopramide can cause drowsiness, fatigue, lethargy, and worsen underlying depression [38]. Given its effect on dopaminergic activity, use with antipsychotic agents can exacerbate extrapyramidal symptoms and increase the risk for neuroleptic malignant syndrome and serotonin syndrome. This risk is increased with concomitant use of promethazine, tricyclic antidepressants (TCAs), and selective serotonin reuptake inhibitors (SSRIs) [4•]. Given these serious adverse events, an evaluation of the risk/benefit profile and informed consent with the patient and family members should take place prior to initiation of therapy. Erythromycin, a macrolide antibiotic with prokinetic properties, has also been shown to improve symptoms in patients with gastroparesis, although patients can develop tolerance over time [38]. Erythromycin is metabolized primarily by the hepatic CYP3A4 system and has a similar drug interaction profile as clarithromycin, with numerous drugdrug interactions [4•].

Diarrhea Drug-induced diarrhea in the elderly can occur by a variety of mechanisms. Secretagogues such as misoprostol challenge fluid absorption, whereas drugs such as colchicine and digoxin work on the sodiumpotassium exchange pump. Mechanisms of diarrhea are often classified as osmotic, secretory, inflammatory, and fatty, and there is considerable overlap between these classifications [41]. In patients with acute diarrhea, physicians often consider the empiric use of fluoroquinolones to treat enteric infections. Importantly, fluoroquinolones have many adverse effects as well as pharmacodynamic drug interactions. Adverse effects include increased risk of tendonitis and tendon rupture, and this risk is potentiated in conjunction with corticosteroids. Fluoroquinolones can also cause QT prolongation and should be used with caution with certain antiarrhythmic, antibiotics, antidepressants, neuroleptics, and prokinetic agents. This interaction is especially significant in elderly patients with pre-existing heart disease, electrolyte imbalances, and/or hepatic impairment, as it can lead to life-threatening arrhythmias [42]. Coadministration of fluoroquinolones and warfarin predispose to an increase in international normalized ratio (INR). The elderly are also at particular risk for CDAD infection. Increased nosocomial exposure and frequent antibiotic courses are common risk factors. In addition, age is an independent risk factor for CDAD [43]. The first-line agent for uncomplicated CDAD is metronidazole, and severe disease is treated with oral vancomycin therapy [44]. The use of alcohol is contraindicated during therapy with metronidazole and for

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three days after discontinuation [45]. Metronidazole is a weak inhibitor of CYP2C9 and should be used with caution with vitamin K antagonists, as it may increase serum concentrations of warfarin and pose a risk of increasing the INR and associated bleeding [46]. Oral vancomycin has minimal systemic absorption, and drug-drug interactions are minimal [47]. For patients with acute and/or chronic diarrhea, symptomatic therapy can sometimes be achieved with the use of antimotility agents. Lomotil, an oral antidiarrheal agent, is a combination of diphenoxylate hydrocholoride and atropine. Diphenoxylate has local and central opiate effects. Concurrent administration with other CNS depressants such as barbiturates, benzodiazepines, opiates, and alcohol can potentiate the effect of diphenoxylate. Atropine has anticholinergic properties that can cause significant consequences in the elderly with increased risk of falls, acute delirium, cognitive impairment, constipation, xerostomia, diplopia, urinary retention, and dizziness. See Table 1 for a list of common medications with anticholinergic properties [48]. Loperamide, another anti-diarrheal agent, acts on the opiate receptor on circular and longitudinal intestinal smooth muscle and interferes with intestinal peristalsis and motility. Loperamide is a more preferable agent in the elderly, although it does have anticholinergic properties and similar caution needs to be taken [49]. In addition, loperamide is a substrate and inhibitor of the P-glycoprotein transporter, which plays a large role in the distribution and elimination of many drugs. Some examples of P-gp inhibitors include amiodorone, atorvastatin, carvedilol, cyclosporine, clarithromycin, erythromycin, ketoconazole, propranolol, tacrolimus, telaprevir, and verapamil. Quinidine, also an inhibitor of Pgp, has been shown to result in respiratory depression after administration with loperamide, possibly from increased penetration of loperamide in the central nervous system [50]. Other non-pharmacologic inhibitors of P-gp are garlic, green tea, grapefruit juice, and quercetin [51].

Constipation Studies have reported that the prevalence of constipation in the older adult ranges from 15 to 20 % in the community-dwelling elderly

Table 1. Common medications with anticholinergic properties used in the elderly Hyoscyamine Dicyclomine Diphenhydramine Ipratropium Antipsychotics Tricyclic Antidepressents Lomotil Loperamide Benzodiazepines Selective serotonin reuptake inhibitors Adapted from [48]

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Geriatrics (S Katz, Section Editor) population and up to 50 % among nursing home residents [52]. Laxatives are used daily in up to 74 % of nursing home residents. In addition to age, risk factors for chronic constipation include female gender, physical inactivity, low education and income, concurrent medication use, and depression. Constipation can result from primary colorectal dysfunction such as slow transit, dyssynergic defecation, or irritable bowel syndrome [53]. Alternatively, constipation may be a result of medications, neurologic disorders, or endocrine and metabolic disorders. The first step in the treatment of constipation is lifestyle and dietary modifications, as well as identifying and stopping any offending agents. If patients do not respond to lifestyle and dietary modifications, bulk laxatives such as psyllium and methylcellulose are recommended. Bulk laxatives are relatively safe. A minor interaction exists between psyllium and digoxin where psyllium may impact the absorption of digoxin [4•]. In patients who do not respond to bulk laxatives it is appropriate to try osmotic laxatives such as polyethylene glycol, which has minimal drug interactions. The next step may be adding stimulant laxatives. Bisacodyl effectively relieves constipation by stimulating peristaltic movement in the colon [54]. Bisacodyl should not be used together with antacids, as the increase in pH in the stomach causes the delayed formulation bisacodyl tablets to release the drug prematurely, which can cause gastric irritation and abdominal cramping [4•]. Phosphate enemas, although effective, can be very dangerous in individuals with significant comorbidities and impaired renal function, and can lead to severe hyperphosphatemia, hypocalcemia, hypo- and hyperkalemia, metabolic acidosis, and arrhythmias [55]. Phosphate enemas should not be used in individuals taking ACE inhibitors, Angiotensin II receptor blockers, or NSAIDs, as these may enhance the nephrotoxic effects and, specifically, the risk of acute phosphate nephropathy [4•]. These agents should generally be avoided in the elderly patient.

Irritable Bowel Syndrome (IBS) Irritable Bowel Syndrome (IBS) is one the most common reasons for visits to primary care providers and gastroenterologists [56]. The prevalence of this condition is lower in the elderly population, however, older patients with this condition have an overall poorer quality of life [57]. The Rome III criteria for IBS requires the presence of chronic abdominal pain and/or discomfort associated with a change in stool frequency, stool appearance, and relief with defecation [57]. IBS can be subtyped clinically into IBS with constipation, IBS with diarrhea, and mixed IBS [56, 58]. Treatment options are usually directed at the IBS subtype and involve a multidisciplinary approach with patient education, dietary modification, and pharmacologic therapy [59, 60]. The various categories of medications include antispasmodics, antidiarrheals, laxatives, bulking agents, receptor-targeted drugs, psychiatric, probiotics, and antibiotics. Over two million prescriptions are written for symptoms of IBS yearly,

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and physicians must weigh the benefits of symptom control with the many unacceptable side effects, especially in the elderly patient. Antispasmodics block muscarinic receptors and calcium channels resulting in gut smooth muscle relaxation [59]. In a meta-analysis, smooth muscle relaxants were efficacious in patients with pain-predominant IBS [61]. Hyoscyamine and dicyclomine are commonly prescribed anticholinergic agents in the USA. These agents should be used with caution in the geriatric population, especially in conjunction with other agents with anticholinergic properties [27•]. TCAs and SSRIs appear to be efficacious in chronic refractory symptoms and reduce global IBS symptoms compared to placebo [62]. Patients with comorbid depression or anxiety disorders also benefit from these agents. In elderly patients, TCAs must be used judiciously given the significant adverse effect profile and multiple drug interactions. Commonly used TCAs include amitriptyline, nortriptyline, desipramine, and imipramine. Drugs that commonly produce interactions that can increase TCA levels via strong inhibition of the CYP2D6 metabolic pathway include buproprion, fluoxetine, paroxetine, cinacalcet, and quinidine. Also, use with other QT prolongation agents can lead to significant cardiac arrhythmias [4•]. Another important consideration is the risk of serotonin syndrome when used in conjunction with SSRIs, MAO inhibitors, linezolid, lithium, metoclopramide, and St. John’s wart. In addition, concomitant use with medications that have anticholinergic or sympathomimetic properties should be avoided [4•]. SSRIs may be considered a safer alternative to TCAs in elderly patients, although further studies are needed to determine their effectiveness in IBS and significant drug interactions still need to be considered with these agents. Receptor-targeted drugs are emerging for the treatment of IBS. Lubiprostone acts locally in the small intestinal lumen, stimulating fluid secretion via activation of chloride channels on the intestinal membrane [63]. Non-clinical studies have shown diphenylheptane opioids (e.g., methadone) to reduce activation of chloride channels by lubiprostone, which may diminish therapeutic effect in the gastrointestinal tract [4•]. Most recently, linaclotide, an agonist of guanylate cyclase, was marketed for the treatment of chronic idiopathic constipation and IBS-C. At this time, no significant drug interactions have been reported. Thus far, results are encouraging for the use of lubiprostone and linaclotide in the treatment of IBS [63, 64], although additional studies evaluating efficacy and safety in the elderly population are required.

Inflammatory Bowel Disease (IBD) The incidence rates of ulcerative colitis (UC) and Crohn’s disease (CD) have increased worldwide, and with the aging population, the rate of elderly onset IBD is also expected to increase. Approximately 10–15 % of patients with IBD are diagnosed after the age of 60 [65]. Treating elderly patients with IBD is more challenging due to their multiple comorbidi-

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Geriatrics (S Katz, Section Editor) ties, impaired functional status, and polypharmacy. In addition, there is a lack of safety and efficacy data on immunosuppressive agents in older patients. Oral aminosalicylates (mesalamine) are the most commonly prescribed drugs for the treatment of patients with mild or moderately active IBD, and drug-drug interactions do exist with this class of medication [66]. As mentioned above, concurrent use with antacids can decrease the effectiveness of mesalamine therapy. Separating times of administration may help prevent this interaction from occurring [67]. In patients on warfarin therapy, INR levels should be monitored closely if using mesalamine, as it may enhance or decrease the anticoagulant effects of warfarin [68, 69]. Although the risk of renal disease is rare with aminosalicylates, NSAIDs may enhance the nephrotoxic effects of aminosalicylate derivatives and cause interstitial nephritis. Thus, renal function should also be regularly monitored in patients taking mesalamine along with other nephrotoxic drugs [70]. Moderate to severe UC or CD is treated with glucocorticoids, immunomodulators, and biologic agents. Immunomodulators include the thiopurines (6-mercaptopurine and azathioprine) and have lesser efficacy in UC than in CD. Azathioprine is a prodrug that is converted to 6-mercaptopurine (6-MP), which is further transformed to active thiopurine metabolites. The enzyme thiopurine methyltransferase (TPMT) converts 6-MP to 6-methlymercaptopurine (6-MMP). If the TPMT enzymatic activity is diminished, then the dose of azathioprine should be reduced or stopped [71]. Therefore, TMPT screening is recommended before starting azathioprine/6-MP therapy. Some patients may have an altered metabolism and exhibit a high 6-MMP/6-TGN ratio, which places them at risk for hepatoxicity and therapeutic failure. The enyme xanthine oxidase also plays a role in the metabolism of 6-MP to its inactive product [72, 73]. Allopurinol is a xanthine oxidase inhibitor and reduces the inactivation of 6-MP [74]. Studies have suggested that long-term co-administration of allopurinol and low-dose thiopurines is an effective and well-tolerated treatment in certain groups of IBD patients with an altered thiopurine metabolism [75]. Interestingly, aminosalicylates have been shown to inhibit TPMT, increasing the risk for myelosupression, and further studies are needed to establish their use as an adjunctive therapeutic modality [76]. Ace inhibitors, when used together with thiopurines, also increase the risk of leukopenia and anemia, as they have an additive effect with the 6TGN metabolite [77]. Conventional glucocorticoids such as prednisone are substrates of Pgp, and its active metabolite, prednisolone, is a substrate of CYP3A4. Therefore, inhibitors of CYP3A4 can potentially increase levels of prednisolone. Budesonide is also metabolized by CYP3A4, and potent inhibitors and inducers can influence drug levels. Regardless of drug interactions, long-term glucocorticoid use should be avoided, given the adverse effects that include osteopenia, avascular necrosis, opportunistic infections, and cataract formation [78, 79]. Lastly, biologic therapies such as infliximab and adalimumab should not be used together with any other monoclonal antibodies or biologics

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for fear of enhanced immunosuppressive effects and increased risk of infections [4•]. Elderly patients are at increased risk for serious infections and malignancy while on immonumodulator and biologic therapy. Currently, no consensus guidelines exist specific to elderly patients with IBD.

Hepatitis C In the US, 2–5 million are chronically infected with hepatitis C and the numbers are almost 170 million worldwide [80]. The emergence of new and novel treatments for chronic hepatitis C signifies a major change in the standard of care. In the last decade, the standard of care mainly included a combination of pegylated interferon plus ribavirin. This regimen is limited by its numerous adverse effects, including neutropenia, hemolytic anemia, and flu-like symptoms. In 2011, the FDA approved two serine protease inhibitors, telaprevir and boceprevir, for use in combination with pegylated interferon plus ribavirin for genotype 1. Both can also result in anemia, and telaprevir can cause a rash and anorectal discomfort. Boceprevir and telaprevir are metabolized by and inhibit the hepatic CYP3A4 system, and are also substrates of the transporter P-gp [1•]. Given these properties, they have a significant number of drug-drug interactions, similar to clarithromycin [1•]. Alpha-1 antagonists (doxazosin, tamsulosin), ergot derivatives, cisapride, lovastatin, simvastatin, phosphodiesterase inhibitors (sildenafil), midazolam, cyclosporine, and tacrolimus should be avoided, as they can reach toxic levels when used with these direct-acting antiviral agents (DAAs) [4•]. Many other drug interactions exist and are primarily mediated by the CYP3A4 and P-glycoprotein pathways [81]. Please see Table 2 for medications commonly metabolized through the P-gp and the CYP450 metabolic pathways. Most recently, sofosbuvir, an NS5B polymerase inhibitor, has been approved, which has a more favorable side effect profile and less drugdrug interactions [1•]. Sofosbuvir does not effect CYP enzymes, although is a substrate of P-gp [82]. Rifampin, phenobarbital, phenytoin, carbamazepine, dexamethasone, and St. John’s wort are inducers of CYP3A4 and intestinal P-gp, and may decrease concentrations of boceprevir, telaprevir, and sofosbuvir, leading to loss of virologic response. Therefore, co-administration should be avoided [4•, 82]. Numerous other novel DAAs currently are being studied in clinical trials. Therefore, health-care providers treating Hepatitis C will need to understand the pharmacokinetics properties of DAAs. A resourceful, evidence-based website, www.hep-druginteractions.org/, can be a useful tool when prescribing these agents [81].

Cirrhosis Currently, chronic liver disease and cirrhosis represent the 12th leading cause of mortality in the USA [83]. Cirrhosis is the final common pathway of chronic liver disease and involves the replacement of nor-

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Table 2. Common medications metabolized by the cytochrome P450 system and P-glycoprotein transporter Important inhibitors of cytochromes P450

Important substrates for cytochrome P450

Amiodorone (2A6, 2C9, 2D6) Boceprevir (3A4) Bupropion (2D6)

Alprazolam (3A4)

Important inhibitors/ substrates of P-glycoprotein Amiodorone

Amiodorone (3A4) Amitryptiline (2D6)

Apixaban Atorvastatin

Clarithromycin (3A4)

Apixiban (3A4)

Boceprevir

Cimetidine (1A2, 2C19, 2D6, 3A4) Cinacalcet (2D6) Ciprofloxacin (1A2) Clopidogrel (2B6) Cyclosporine (3A4) Erythromycin (3A4) Fluoxetine (2D6, 2C19) Isoniazid (2A6, 2C19, 2D6, 2E1) Ketoconazole (3A4, 2C19, 2C9, 2D6) Omeprazole (2C19) Paroxetine (2D6, 2B6) Quinidine (2D6) Telaprevir (3A4) Verapamil (3A4) Clopidogrel (2B6)

Atorvastatin (3A4)

Carvedilol

Budesonide (3A4) Buspirone (3A4) Carvedilol (2D6) Cilostazol (2C19) Citalopram (2C19, 3A4) Clopidogrel (2C19) Colchicine (3A4)

Cimetidine Ciprofloxacin Clarithromycin Cyclosporine Dabigatran Erythromycin Ketoconazole

Diazepam (3A4)

Loperamide

Doxazosin (3A4) Fentanyl (3A4) Midazolam (3A4) Nifedipine (3A4) Oxycodone (3A4) Propranolol (1A2, 2D6) Quetiapine (3A4) Quinidine (3A4) Ranolazine (3A4) Rivaroxaban (3A4) Saxagliptin (3A4) Saxagliptin (3A4) Sildenafil (3A4) Simvastatin (3A4) Tacrolimus (3A4) Tamsulosin (3A4) Theophylline (3A4, 2E1) Warfarin (2C9)

Propranolol Quinidine Ranolazine Rivaroxaban Sofosbuvir Tacrolimus Telaprevir Verapamil

Important inducers of cytochromes P450/ P -glycoprotein Carbamazepine (1A2, 2B6, 2C19, 2C8, 2C9, 3A4) Dexamethasone (3A4) Phenobarbital (1A2, 3A4, 2A6, 2B6, 2C8, 2C9) Phenytoin (2C19, 3A4, 2B6, 2C9, 2C8) Rifampin (1A2, 2A6, 2B6, 2C19, 2C8, 2C9, 3A4)

Adapted from [4•]

mal liver architecture with fibrosis and scarring [84]. This end-stage process leads to liver dysfunction and complications secondary to portal hypertension [85]. Therefore, these patients are more prone to polypharmacy and adverse drug reactions due to potential changes in drug metabolism with liver dysfunction and multiple drug-drug interactions [86, 87].

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Ascites is the most common complication of decompensated liver cirrhosis. The initial approach to management is restriction of dietary sodium and diuretic therapy [88]. In elderly patients, monitoring for volume depletion, hypotension, electrolyte abnormalities, delirium, arrythmias, and renal dysfunction is critical while on diuretic therapy. Furosemide and spironolactone are commonly used medications and important drug interactions must be considered. A common adverse effect with spironolactone is a dose-related increase in serum potassium levels and physicians should be cognizant of other agents that can result in hyperkalemia [89]. Some of these agents include amiloride, cyclosporine, tacrolimus, NSAIDs, and triamterene [4•]. Lasix, on the other hand, can result in hypokalemia and significant volume depletion. Another important adverse effect to consider is ototoxicity, particularly in combination with known ototoxic drugs such as aminoglycosides [4•]. In addition, case reports of ototoxicity have been described with concomitant use of sildenafil with furosemide [90]. Interestingly, bile acid sequestrants can bind to furosemide in the gastrointestinal tract and decrease its therapeutic effect, therefore separating the time of administration that may otherwise reduce the risk of this interaction [4•]. NSAIDs can also alter the therapeutic value of loop diuretics by inhibiting prostaglandins and influencing renal hemodynamics [86, 91]. Hepatic encephalopathy is a reversible neuropsychiatric complication of liver cirrhosis [85]. Identifying and addressing precipitants including offending medications, volume depletion, infection, and gastrointestinal bleeding are the most important aspects of managing this condition. Pharmacologic therapies include lactulose, a nonabsorbable disaccharide, and rifaximin, a nonabsorbable antibiotic, aimed at eliminating ammonia production from gut bacteria [84]. In-vitro studies show rifaximin inducing the CYP3A4 enzymes. Thus far, there is one case report that describes an interaction between warfarin and rifaximin in a patient with small intestinal bacterial overgrowth [92]. Further studies are needed to confirm these results. Propranolol and nadolol, are non-selective beta blockers that are indicated for primary prophylaxis for patients with large esophageal varices and secondary prevention for variceal hemorrhage [93]. A theoretical concern with propranolol is its use in diabetic patients on insulin or oral hypoglycemic therapy because it can potentiate hypoglycemia and eliminate signs of hypoglycemia (e.g., sweating, tachycardia) [94]. Another important concern is hypotension with concomitant use of anti-hypertensive and alpha-1 blocking agents used to treat genitourinary conditions [4•]. Lastly, CYP1A2 inducers (e.g., carbamazepine, rifampin, phenobarbital) and inhibitors (e.g., ciprofloxacin, fluvoxamine) can affect serum concentrations of propranolol [4•]. Nadolol has a similar interaction profile. In addition, it is a substrate of the P-gp system. In general, these medications can be prescribed to elderly patients, albeit with careful scrutiny for potential drug-drug interactions and should be started at a low dose with careful titration upward to achieve a clinical response (Table 3).

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Table 3. Commonly prescribed medication in the elderly interacting with common agents prescribed for gastrointestinal conditions Cirrhosis

HepC

Variceal prophylaxis

HE treatment

Diuretics

propranolol

Lactulose Rifaximin Furosemide Sprinolactone Sofosbuvir Boceprevir Telaprevir

infliximab

Antiviral agents

Biologics

Receptortargeted

Immunomodulators

Glucocorticoids

Aminosalicylate TCA’s

Antispasmodic

Phosphate

x

IBD

IBS

6-Mercaptopurine Azathioprine Budesonide Prednisolone Mesalamine Amitriptyline Lubiprostone Linaclotide Dicyclomine Hyoscyamine

Enema

Metocopramide

Stimulant Bulk Laxatives

Prokinetics

Cimetidine

Clarithromycin x

Antimotility

H2R blocker

Antimicrobials

Omeparazole Analgesics: Fentanyl Methadone NSAID’s Oxycodone Antiarrhythmic: Amiodarone Anticoagulants: Apixaban Clopidogrel Rivaroxaban Warfarin Anticonvulsants and mood stabilizers: Carbamezapine Lithium Phenobarbital Phenytoin Antidepressants: SSRI – eg. citalopram TCA –eg. Nortiptyline Anti-Gout: Allopurinol Colchicine Antihistamines: promethazine Antihypertensives: Nifedipine Verapamil Carvedilol Propranolol ACE-inhibitors Amiloride Anti-inflammatory: Budesonide Dexamthasone Methylprednisolone Prednisone Antimicrobials: Aminoglycosides ciprofloxacin Ketoconazole Rifampin Antipsychotics: Quetiapine

Constip ation

Diarrhea

Bisacodyl Psyllium Lomotil Loperamide Metronidazole Fluoroquinolone Erythromycin

Gastr opare sis

Antimicrobials

P U D

PPI

GERD

x x x

x

x

x x

x

x

x

x

x x

x x

x x

x x

x

x

x

x

x x x

x

x x

x x x x

x x

x x

x x x x

x x x x

x

x x x x x

x x x

x x

x x x x x x x x x

x x x x x

x x x

x

x

x

x

x x x

x x x x

x

x

x x x x x

x

x x

x x

x x x x

x

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Table 3. (continued) Anxiolytics: Alprazolam Midazolam Buspirone Cardiovascular: Cilostaol Digoxin Furosemide Hydrochlorthiazide Ranolazine Spironolactone Cholesterol: Atorvastatin Bile-Acid sequestrants Lovastatin Simvastatin Diabetes: Insulin Oral hypoglycemics Gastrointestinal: Aminosalicylates Antacids Cisapride Metoclopramide Immunosuppressants: Tacrolimus cyclosporine Mycophenolic acid Miscellaneous: Alcohol Cinacalcet Ergot derivatives Quinidine Non-Pharmacologic: Garlic Green Tea Grapefruit juice St.John’s wort Quercetin Respiratory: Salmeterol Theophylline Urologic: Doxazosin Tamsulosin Sildenafil

x x

x x x

x x x

x

x

x

x x

x x x x

x x

x x

x x x

x

x

x

x

x x

x x

x

x

x x x x x

x x x x

x x

x x x x

x

x x

x x

x x x x

x

x x

x x

x x

x x x x

x

x x

x

x

x x x x

x

x x x

x

x x x x x x

x

Conclusion The geriatric population is burdened with polypharmacy. Understanding the principles of drug-drug interactions can prevent serious adverse effects and lead to more appropriate co-prescribing in appropriate circumstances. It is important to be aware of the basic modes of drug metabolism including the cytochrome P450 system along with the Pglycoprotein transporter. In addition, many useful resources are available

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Geriatrics (S Katz, Section Editor) online and consultation with a pharmacist may provide additional help in treating this challenging population.

Compliance with Ethics Guidelines Conflict of Interest Marina Kim and Aamir Dam declare that they have no conflicts of interest. Jesse Green attended an Abbvie Immunology dinner meeting in October 2013. Equities and options held in professionally managed investment and retirement accounts (Pfizer, Eli Lilly, Bristol Myers Squibb, Procter & Gamble, Johnson & Johnson). Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: • Of importance 1.•

Kiser JJ, Burton Jr JR, Everson GT. Drug-drug interactions during antiviral therapy for chronic hepatitis C. Nat Rev Gastroenterol Hepatol. 2013;10(10):596–606. A comprehensive review that highlights the pinciples of drug-drug interactions and provides an overview of the direct-acting antiviral agents used to treat hepatitis C. 2.• Prandota J. Advances of molecular clinical pharmacology in gastroenterology and hepatology. Am J Ther. 2010;17(5):e137–62. This article outlines specific metabolic pathways for commonly prescribed gastrointestinal medications including medications influenced by the cytochrome p450 system and P-glycoprotein transporter. 3. Egan LJ. Drug interactions in gastroenterology: mechanisms, consequences, and how to avoid. Clin Gastroenterol Hepatol. 2004;2(9):725–30. 4.• Lexi-Comp OnlineTM, , Hudson, Ohio: Lexi-Comp, Inc. 2014. An easy-to-use and comprehensive drug information database with current evidence-based drug interactions and fully referenced discussion of the available literature. 5. D’Souza AL. Ageing and the gut. Postgrad Med J. 2007;83(975):44–53. 6. Poh CH, Navarro-Rodriguez T, Fass R. Review: treatment of gastroesophageal reflux disease in the elderly. Am J Med. 2010;123(6):496–501. 7. Boeckxstaens G, El-Serag HB, Smout AJPM, Kahrilas PJ. Symptomatic reflux disease: the present, the past and the future. Gut. 2014. doi:10.1136/gutjnl-2013-306393.

8.

9.

10.

11. 12.

13. 14.

15.

Wedemeyer RS, Blume H. Pharmacokinetic drug interaction profiles of proton pump inhibitors: an update. Drug Saf. 2014;37(4):201–11. Kwok CS et al. Risk of Clostridium difficile infection with acid suppressing drugs and antibiotics: meta-analysis. Am J Gastroenterol. 2012;107(7):1011–9. Janarthanan S et al. Clostridium difficile-associated diarrhea and proton pump inhibitor therapy: a meta-analysis. Am J Gastroenterol. 2012;107(7):1001–10. Reimer C. Safety of long-term PPI therapy. Best Pract Res Clin Gastroenterol. 2013;27(3):443–54. Abraham NS. Proton pump inhibitors: potential adverse effects. Curr Opin Gastroenterol. 2012;28(6):615–20. Yang YX, Metz DC. Safety of proton pump inhibitor exposure. Gastroenterology. 2010;139(4):1115–27. Frelinger 3rd AL et al. A randomized, 2-period, crossover design study to assess the effects of dexlansoprazole, lansoprazole, esomeprazole, and omeprazole on the steady-state pharmacokinetics and pharmacodynamics of clopidogrel in healthy volunteers. J Am Coll Cardiol. 2012;59(14):1304– 11. Ho PM et al. Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome. JAMA. 2009;301(9):937–44.

Common GI Drug Interactions in the Elderly 16.

Juurlink DN et al. A population-based study of the drug interaction between proton pump inhibitors and clopidogrel. CMAJ. 2009;180(7):713–8. 17. Bhatt DL et al. Clopidogrel with or without omeprazole in coronary artery disease. N Engl J Med. 2010;363(20):1909–17. 18. Abraham NS et al. ACCF/ACG/AHA 2010 expert consensus document on the concomitant use of proton pump inhibitors and thienopyridines: a focused update of the ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use. Am J Gastroenterol. 2010;105(12):2533–49. 19. Chen J et al. Pharmacodynamic impacts of proton pump inhibitors on the efficacy of clopidogrel in vivo–a systematic review. Clin Cardiol. 2013;36(4):184–9. 20. Gerson LB. Proton pump inhibitors and potential interactions with clopidogrel: an update. Curr Gastroenterol Rep. 2013;15(6):329. 21. Rocha A et al. Omeprazole preferentially inhibits the metabolism of (+)-(S)-citalopram in healthy volunteers. Br J Clin Pharmacol. 2010;70(1):43–51. 22. Kofler S et al. The proton pump inhibitor pantoprazole and its interaction with enteric-coated mycophenolate sodium in transplant recipients. J Heart Lung Transplant. 2011;30(5):565–71. 23. Itagaki F et al. Effect of lansoprazole and rabeprazole on tacrolimus pharmacokinetics in healthy volunteers with CYP2C19 mutations. J Pharm Pharmacol. 2004;56(8):1055–9. 24. Singh M et al. Gastrointestinal drug interactions affecting the elderly. Clin Geriatr Med. 2014;30(1):1–15. 25. Parasa S, Sharma P. Complications of gastro-oesophageal reflux disease. Best Pract Res Clin Gastroenterol. 2013;27(3):433–42. 26. Hart AM. Evidence-based recommendations for GERD treatment. Nurse Pract. 2013;38(8):26–34. quiz 34-5. 27.• American Geriatrics Society Beers Criteria Update Expert, P. American Geriatrics Society updated Beers Criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc. 2012;60(4):616–31. An updated set of guidelines to be used by health-care providers that discusses the challenges of treating older adults and recommendations for drugs to be avoided in the elderly. 28. Pilotto A et al. Optimal management of peptic ulcer disease in the elderly. Drugs Aging. 2010;27(7):545–58. 29. Leontiadis GI et al. Effect of comorbidity on mortality in patients with peptic ulcer bleeding: systematic review and meta-analysis. Am J Gastroenterol. 2013;108(3):331–45. quiz 346. 30. Pilotto A. Aging and upper gastrointestinal disorders. Best Pract Res Clin Gastroenterol. 2004;18(Suppl):73–81.

31.

Kim et al.

307

Mueck W, Kubitza D, Becka M. Co-administration of rivaroxaban with drugs that share its elimination pathways: pharmacokinetic effects in healthy subjects. Br J Clin Pharmacol. 2013;76(3):455–66. 32. Mueck W, Schwers S, Stampfuss J. Rivaroxaban and other novel oral anticoagulants: pharmacokinetics in healthy subjects, specific patient populations and relevance of coagulation monitoring. Thromb J. 2013;11(1):10. 33.• Gandhi S et al. Calcium-channel blockerclarithromycin drug interactions and acute kidney injury. JAMA. 2013;310(23):2544–53. A recent study that supports safety warnings regarding the concurrent use of CYP3A4 inhibitors and calcium-channel blockers. 34. Sostres C, Gargallo C, Lanas A. Drug-related damage of the ageing gastrointestinal tract. Best Pract Res Clin Gastroenterol. 2009;23(6):849–60. 35. Abdulla A et al. Guidance on the management of pain in older people. Age Ageing. 2013;42 Suppl 1:i1–57. 36. Lanza FL et al. Guidelines for prevention of NSAIDrelated ulcer complications. Am J Gastroenterol. 2009;104(3):728–38. 37. Hasler WL. Gastroparesis. Curr Opin Gastroenterol. 2012;28(6):621–8. 38. Lee A. Gastroparesis: what is the current state-of-the-art for evaluation and medical management? What are the results? J Gastrointest Surg. 2013;17(9):1553–6. 39. Camilleri M, Bharucha AE, Farrugia G. Epidemiology, mechanisms, and management of diabetic gastroparesis. Clin Gastroenterol Hepatol. 2011;9(1):5–12. quiz e7. 40. Lee A, Kuo B. Metoclopramide in the treatment of diabetic gastroparesis. Expert Rev Endocrinol Metab. 2010;5(5):653–62. 41. Thomson AB. Small intestinal disorders in the elderly. Best Pract Res Clin Gastroenterol. 2009;23(6):861–74. 42. Yap YG, Camm AJ. Drug induced QT prolongation and torsades de pointes. Heart. 2003;89(11):1363–72. 43. Khanna S, Pardi DS. Clostridium difficile infection: new insights into management. Mayo Clin Proc. 2012;87(11):1106–17. 44. Surawicz CM et al. Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections. Am J Gastroenterol. 2013;108(4):478–98. quiz 499. 45. Immonen S, Valvanne J, Pitkala KH. The prevalence of potential alcohol-drug interactions in older adults. Scand J Prim Health Care. 2013;31(2):73–8. 46. Howard-Thompson A et al. Intracerebral hemorrhage secondary to a warfarin-metronidazole interaction. Am J Geriatr Pharmacother. 2008;6(1):33–6. 47. Rao S et al. Systemic absorption of oral vancomycin in patients with Clostridium difficile infection. Scand J Infect Dis. 2011;43(5):386–8.

308 48.

49.

50.

51.

52.

53. 54.

55.

56. 57. 58.

59.

60. 61.

62.

63.

64.

Geriatrics (S Katz, Section Editor) Chew ML et al. Anticholinergic activity of 107 medications commonly used by older adults. J Am Geriatr Soc. 2008;56(7):1333–41. Rudolph JL et al. The anticholinergic risk scale and anticholinergic adverse effects in older persons. Arch Intern Med. 2008;168(5):508–13. Sadeque AJ et al. Increased drug delivery to the brain by P-glycoprotein inhibition. Clin Pharmacol Ther. 2000;68(3):231–7. Kahn JH, Magauran BG, Olshaker JS (2014). Pharmacology in the Elderly. Geriatric emergency medicine: principles and practice. Cambridge University: Cambridge, United Kingdom. Bosshard W et al. The treatment of chronic constipation in elderly people: an update. Drugs Aging. 2004;21(14):911–30. Gallegos-Orozco JF et al. Chronic constipation in the elderly. Am J Gastroenterol. 2012;107(1):18–25. quiz 26. Manabe N et al. Effects of bisacodyl on ascending colon emptying and overall colonic transit in healthy volunteers. Aliment Pharmacol Ther. 2009;30(9):930–6. Mendoza J et al. Systematic review: the adverse effects of sodium phosphate enema. Aliment Pharmacol Ther. 2007;26(1):9–20. Ford AC, Talley NJ. Irritable bowel syndrome. BMJ. 2012;345:e5836. Canavan C, West J, Card T. The epidemiology of irritable bowel syndrome. Clin Epidemiol. 2014;6:71–80. Heading R et al. Systematic review: the safety and tolerability of pharmacological agents for treatment of irritable bowel syndrome–a European perspective. Aliment Pharmacol Ther. 2006;24(2):207–36. Chang FY. Irritable bowel syndrome: the evolution of multi-dimensional looking and multidisciplinary treatments. World J Gastroenterol. 2014;20(10):2499–514. Trinkley KE, Nahata MC. Treatment of irritable bowel syndrome. J Clin Pharm Ther. 2011;36(3):275–82. Jailwala J, Imperiale TF, Kroenke K. Pharmacologic treatment of the irritable bowel syndrome: a systematic review of randomized, controlled trials. Ann Intern Med. 2000;133(2):136–47. Ruepert L et al. Bulking agents, antispasmodics and antidepressants for the treatment of irritable bowel syndrome. Cochrane Database Syst Rev. 2011;8, CD003460. Gras-Miralles B, Cremonini F. A critical appraisal of lubiprostone in the treatment of chronic constipation in the elderly. Clin Interv Aging. 2013;8:191–200. Videlock EJ, Cheng V, Cremonini F. Effects of linaclotide in patients with irritable bowel syndrome with constipation or chronic constipation: a metaanalysis. Clin Gastroenterol Hepatol. 2013;11(9):1084–1092 e3. quiz e68.

65.

66.

67.

68.

69.

70.

71.

72.

73.

74.

75.

76.

77.

78.

79.

Ha CY, Katz S. Clinical outcomes and management of inflammatory bowel disease in the older patient. Curr Gastroenterol Rep. 2013;15(2):310. Feagan BG, Chande N, MacDonald JK. Are there any differences in the efficacy and safety of different formulations of Oral 5-ASA used for induction and maintenance of remission in ulcerative colitis? Evidence from cochrane reviews. Inflamm Bowel Dis. 2013;19(9):2031–40. Ng SC, Kamm MA. Therapeutic strategies for the management of ulcerative colitis. Inflamm Bowel Dis. 2009;15(6):935–50. Hall S, Rindone JP. A case of sulphasalazine potentiating the hypoprothombinemic effect of warfarin resulting in bleeding. J Clin Pharm Ther. 2011;36(2):246–8. Carty E, MacEy M, Rampton DS. Inhibition of platelet activation by 5-aminosalicylic acid in inflammatory bowel disease. Aliment Pharmacol Ther. 2000;14(9):1169–79. Firwana BM et al. Nephrotic syndrome after treatment of Crohn’s disease with mesalamine: case report and literature review. Avicenna J Med. 2012;2(1):9–11. Sahasranaman S, Howard D, Roy S. Clinical pharmacology and pharmacogenetics of thiopurines. Eur J Clin Pharmacol. 2008;64(8):753–67. Clunie GP, Lennard L. Relevance of thiopurine methyltransferase status in rheumatology patients receiving azathioprine. Rheumatology (Oxford). 2004;43(1):13–8. Hoentjen F, Sakuraba A, Hanauer S. Update on the management of ulcerative colitis. Curr Gastroenterol Rep. 2011;13(5):475–85. Min MX, Weinberg DI, McCabe RP. Allopurinol enhanced thiopurine treatment for inflammatory bowel disease: safety considerations and guidelines for use. J Clin Pharm Ther. 2014;39(2):107–11. Hoentjen F et al. Safety and effectiveness of longterm allopurinol-thiopurine maintenance treatment in inflammatory bowel disease. Inflamm Bowel Dis. 2013;19(2):363–9. de Graaf P et al. Influence of 5-aminosalicylic acid on 6thioguanosine phosphate metabolite levels: a prospective study in patients under steady thiopurine therapy. Br J Pharmacol. 2010;160(5):1083–91. Irving PM, Shanahan F, Rampton DS. Drug interactions in inflammatory bowel disease. Am J Gastroenterol. 2008;103(1):207–19. quiz 206, 220. Seguro LP, Rosario C, Shoenfeld Y. Long-term complications of past glucocorticoid use. Autoimmun Rev. 2013;12(5):629–32. Suh SY et al. Systemic steroid-induced cataracts in children: long-term changes in morphology and visual acuity. J AAPOS. 2013;17(4):371–3.

Common GI Drug Interactions in the Elderly 80.

81.

82.

83.

84. 85.

86.

87.

Hajarizadeh B, Grebely J, Dore GJ. Epidemiology and natural history of HCV infection. Nat Rev Gastroenterol Hepatol. 2013;10(9):553–62. Back D, Else L. The importance of drug-drug interactions in the DAA era. Dig Liver Dis. 2013;45 Suppl 5:S343–8. Abraham GM, Spooner LM. Sofosbuvir in the Treatment of Chronic Hepatitis C: New Dog, New Tricks. Clin Infect Dis. 2014. doi:10.1093/cid/ciu265 Asrani SK et al. Underestimation of liver-related mortality in the United States. Gastroenterology. 2013;145(2):375–82 e1-2. Liou IW. Management of end-stage liver disease. Med Clin N Am. 2014;98(1):119–52. Rahimi RS, Rockey DC. End-stage liver disease complications. Curr Opin Gastroenterol. 2013;29(3):257–63. Franz CC et al. Potential drug-drug interactions and adverse drug reactions in patients with liver cirrhosis. Eur J Clin Pharmacol. 2012;68(2):179– 88. Lewis JH, Stine JG. Review article: prescribing medications in patients with cirrhosis - a practical guide. Aliment Pharmacol Ther. 2013;37(12):1132–56.

88.

89.

90.

91.

92.

93.

94.

Kim et al.

309

Runyon BA, Committee APG. Management of adult patients with ascites due to cirrhosis: an update. Hepatology. 2009;49(6):2087–107. Sica DA. Pharmacokinetics and pharmacodynamics of mineralocorticoid blocking agents and their effects on potassium homeostasis. Heart Fail Rev. 2005;10(1):23–9. Skeith L et al. Sildenafil and furosemide associated ototoxicity: consideration of drug-drug interactions, synergy, and broader clinical relevance. J Popul Ther Clin Pharmacol. 2013;20(2):e128–31. Paterson CA et al. Randomized, open-label, 5-way crossover study to evaluate the pharmacokinetic/ pharmacodynamic interaction between furosemide and the non-steroidal anti-inflammatory drugs diclofenac and ibuprofen in healthy volunteers. Int J Clin Pharmacol Ther. 2011;49(8):477–90. Hoffman JT et al. Probable interaction between warfarin and rifaximin in a patient treated for small intestine bacterial overgrowth. Ann Pharmacother. 2011;45(5):e25. Garcia-Tsao G et al. Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis. Hepatology. 2007;46(3):922–38. Hartshorn EA. Interactions of cardiac drugs. Ann Pharmacother. 2006;40(6):1181–4.