WARFARIN & SULFONAMIDES This interaction is one of the most well supported in the literature. The scenario is that a patient presents with signs and symptoms of UTI and the drug of choice appears to be Septra or Bactrim DS (sulfamethoxazole / trimethoprim). However, the sulfa antibiotic is known to displace warfarin from protein binding sites where more than 90% of warfarin is bound, affecting the clotting cascade. It is recommended to use an alternative antibiotic, or test INR soon after the sulfa antibiotic is started. The question then comes as to when to test. We recently experienced that scenario where the INR was tested 4 days after the start of the sulfa antibiotic, and there was a slight dose adjustment downward of the warfarin based on a higher, but not remarkably higher, INR. Several days later the INR was 7.7. The moral of the story: alternative drug therapy may be the safest approach.

WARFARIN & AMIODARONE Warfarin can also interact with amiodarone, (a serious interaction), so when starting amiodarone on someone receiving warfarin, frequent INR monitoring is warranted.

LITERATURE REVIEW An excellent review by Juurlink, DN and Redelmeier, DA, et al in 2003, studied hospital admissions likely due to drug interactions. Most  significant were:

• Those admitted for severe hypoglycemia and taking glyburide were 6 times more likely to have been started on a sulfa antibiotic in the last 7 days.

• Those admitted with digoxin toxicity were 12 times more likely to have been treated with clarithromycin (similar to azithromycin) in the previous week.

• Those admitted for hyperkalemia and treated with an ACE inhibitor were 20 times more likely to have been treated with spironolactone or other potassium-sparing diuretic in the previous week.

The above three suggest either alternative drug therapies, or frequent monitoring with patient education as to what symptoms to look for.

NSAIDs & SSRIs We know that NSAIDs are associated with increased risk of GI bleeding, with odds ratios from 1.5 to about 7.0, depending upon the drug. SSRI’s are also associated with a modest increase in risk for GI bleeding (odds ratio of 1.5-3.0). Of particular concern is that the combination of any NSAID with an SSRI results in a significantly elevated, disproportionate risk for GI bleeding with odds ratios as high as 15.6. The increase in risk is even seen with low-dose aspirin (odds ratio of 7.2).

With upper GI bleeding being a serious ADE leading to harm and hospitalization in older adults, this warrants a review of such combination therapy. It also begs the question, should we be using NSAIDs on a routine basis in older adults?

According to the American Geriatric Association (AGS) Pain Management Guidelines from 2009, chronic use of NSAIDs should be avoided in the older adult population whenever possible. If use is required, then mitigation of that risk, in part, should occur with the use of a proton pump inhibitor.

OTHER INTERACTIONS

• ACE inhibitors plus sulfonamides leading to hyperkalemia

• Warfarin and NSAIDs causing bleeding

• Warfarin and dicloxacillin leading to DECREASED INR

• ACEs or ARBs plus potassium supplements causing hyperkalemia

• Trimethoprim can increase serum digoxin levels by up to 75%

• Opiates (primarily Oxycontin or oxycodone) and SSRIs (Prozac, Zoloft, Lexapro, Celexa, etc) or SNRIs (Effexor) resulting in serotonin syndrome, may be more likely in older adults. Look for this in short-term rehab patients who start on relatively high doses of opiates to control pain from joint replacement surgery.

In closing, you now have a list of some of the most significant drug interactions that lead to ADEs in older adults. However, there are many that are not listed here which can be equally impacting to the lives of older adults. My recommendation is to use a drug interaction screening tool at the point-of-prescribing, or ensure that you encourage your patient to ask the pharmacist to ensure they have checked for all possible interactions. ADE avoidance is the best approach to safety.

http://www.goldenliving.com/healthcare-news-events/gl-press-releases/press.aspx?assetId=bf1f968b-74d4-41eb-8262-04ec546b9e0a

In another study in long term care residents, Dr. Garfinkel was able to apply the same algorithm and discontinue 332 drugs in 119 disabled residents. What was observed was a lower one-year mortality rate than in the control group, 21% vs. 45%, and a lower rate of referrals to acute care facilities, 11.8% vs. 30% in the control group. This study also measured a substantial decrease in medication costs.

Reducing medication use in the old-old population makes perfect sense since many older adults will suffer from duplicate therapy and resultant toxicity; serious drug-drug interactions; lack of monitoring that leads to drug toxicity; cumulative anticholinergic drug burden with functional and cognitive decline; yet many of these drugs are used with lacking evidence of benefit in this population. It may be that we see a major shift, in a relatively short period of time, in how medications are used in long term care facilities, and the extended impact may be a significant reduction in hospitalizations thereby improving quality of life and helping save the Medicare system. You can find Dr. Garfinkel’s work referenced on his home page at: http://www.dr-g.co.il/.

It may prove fruitful for organizations involved in ACOs to strongly consider utilizing the assistance of those who understand the nuances of medication use in this population to take advantage of an opportunity that pays big dividends. A well thought out approach and launch of a formal program in LTC facilities can lead to a significant lowering of hospitalization rates.

Some of the more specific findings from the studies were: patient and healthcare professional reports are of similar quality; there was some evidence that different ADRs are reported; new ADRs are reported; reported symptoms to SSRI antidepressants, e.g. Zoloft, Celexa, Lexapro, Prozac, are not found in health care professional reports, implying a reluctance to report unusual psychiatric symptoms to physicians; some evidence that patients report ADR symptoms quicker; no evidence that reports result in distraction from signal detection, meaning they do not distract from ADR “flags” and overload the ADR reporting system.

In all, patient-reporting of ADRs is a reliable method for detecting probable ADRs which can lead to mitigating them and improving quality of life, and avoid unnecessary utilization of health care resources, in addition to lessening the risk for patient harms. However, in my experience, if people are not educated on what side-effects to monitor for, and if physicians do not acknowledge that ADRs are possibly occurring, especially some of the more unusual ADRs, then a large percentage are not addressed and lead to negative outcomes. Several other studies have validated this finding. Lastly, specific questions asked of the patient that may elucidate if an ADR is occurring should be included in every medication review and office visit. The reliability of this technique is greater than what one might think.

Looking deeper at the possible causes, Dr. Hines ascribes lack of medication reconciliation as one cause, where medications are not reconciled in detail which leads to duplicate drug therapies and drug interactions, thought to cause adverse drug events in about 26% of all ADE cases. He also states that patients may not ascribe adverse effects to medications and will not ask for changes in drug therapy. Yet a well-educated patient is more likely to recognize symptoms as an adverse event, implying that patient education upon discharge is critical. One possible solution is to create a comprehensive medication plan that travels with the patient after discharge so critical lab monitoring occurs, along with key educational points on how to properly take medication, in addition to a list of key symptoms that can be likened to the medication therapies the person is taking. Lastly, designing a drug regimen that the patient can adhere to is also important, especially for people discharged after an episode for congestive heart failure. Poor adherence is strongly associated with readmission to the hospital in those with congestive heart failure.

In summary, medications play a key role in mitigating risk and improving survival and function, but when not well managed they can lead to adverse drug events that cause harm and lead to readmission to the hospital. Some data suggest that the adverse events will show up about 14 to 21 days after hospital discharge implying that a well-designed medication plan can prevent a large number of readmissions.

Here are some other links that refer to adverse drug events after discharge from hospitals.

http://bennet.senate.gov/newsroom/press/release/?id=3d5c9532-be2a-4a3f-baa9-3f9196d394aa

http://hospitalmedicine.ucsf.edu/improve/literature/discharge_committee_literature/reengineering_systems/role_of_pharmacist_counseling_in_prevent_ade_after_hosp_schnipper_ama.pdf

http://psnet.ahrq.gov/primer.aspx?primerID=11

http://www.caretransitions.org/documents/Promoting%20effective%20transitions%20of%20care%20-%20JHM.pdf

http://www.ncbi.nlm.nih.gov/pubmed/15903284

These findings are consistent with a large body of literature that the greater the number of medications we take, the greater the risk or likelihood we will experience an adverse drug reaction that causes us to seek medical attention. Using the number of medications a person takes as a screening tool should prompt all parties involved to review a persons medications to: ensure they are needed, that the doses are appropriate,that monitoring is in place, are free from significant drug interactions, and taken properly, since all of these contribute to the risk for an adverse drug reaction.

In the discussion section, the authors go on to talk about the concept of medication-minimization and how this approach might lead to a lower rate of adverse drug events, albeit how it can be a challenging task to pare down a complicated drug regimen. However, there is a growing body of evidence that suggests how we can pare down the drug regimens of an older adults without causing harm, and in many instances improve how they function. This is an area that will gain greater clarity in everyday practice and drastically change medication utilization in older adults, all for the greater good.

http://www.askapatient.com/viewrating.asp?drug=21366&name=CRESTOR

• Starting a bladder health drug such as Detrol (tolterodine), Ditropan (oxybutynin), Vesicare (solifenacin) or other,  in someone who develops urinary incontinence from Aricept (donepezil), Exelon (rivastigmine) or Razadyne (galantamine). In one study it was shown that people who used this class of memory health drugs were 1.5 times more likely to be prescribed a bladder health agent. The bladder health agent may also lessen the beneficial effects of the memory health drug.
• NSAIDs such as ibuprofen, naproxen, among many others, causing high blood pressure from the effects of the NSAID on the kidneys. What can follow is the addition of a medication for high blood pressure.
• The addition of a diuretic due to the development of fluid retention from a medication for high blood pressure such as amlodipine (Norvasc).
• The development of joint pain from a bone health drug such as Fosamax (alendronate), Actonel (risedronate) or Boniva (ibandronate), and then an analgesic or pain medication is added, which can then lead to side-effects depending upon the type of pain medication started. This prescribing cascade was validated by FDA and alerts were posted in 2008 and 2009.
• One last example is the use of Reglan (metoclopramide) for nausea, which then leads to the side-effect of movement disorders that mimic Parkinson’s disease. Those that present with this Parkinson’s-like side-effect are more likely to be misdiagnosed with Parkinson’s disease and treated with more medications to manage the tremors or slowness in movement that are the side-effects from the metoclopramide.

A key point to keep in mind is that you should always look back to when a medication was started to see if the side-effect, which is being treated as a condition or disease, followed not long after the addition of the primary drug. This is trying to develop a “temporal association” or an association related to the time of starting a new drug and the appearance of a side-effect. This leads to the primary principle in geriatric pharmacy management and that is “Always suspect the drug until proven otherwise”. If you can spot prescribing cascades it may be possible to reduce unnecessary medications that lead to adverse effects. Check with your doctor of pharmacist if you suspect a side-effect from a drug that may be treated with another drug. There is a good article that lists other prescribing cascades and speaks to the concepts more in depth at: http://www.australianprescriber.com/magazine/34/6/162/6

What I see as critical is that we still have a huge gap between the prescribing of useful and necessary medications in older adults and the achievement of positive outcomes in which ADEs are minimized. If we can define the continuum whereby the MD prescribes, the pharmacist ensures proper monitoring and the patient becomes the person who is engaged and at the center of their health, then we may make some progress.  But as it stands, nothing has changed to imply that under the current model that we will avoid the bulk of preventable ADEs. More specifically a suggested plan is to: 1) Educate MDs on ADE risk, proper drug selection and how to design a monitoring plan in partnership with pharmacists and their patients, 2) Educate pharmacists on ADE detection, proper drug administration and monitoring so they can be wholly integrated into this continuum thereby achieving real results, and 3) Last but not least, educate and engage the “patient”, or shall I say the person, to also monitor their medication regimen and report any changes in how they feel as a possible adverse effect from a medication.

http://www.oas.samhsa.gov/2k11/DAWN013/AdverseReactionsOlderAdults_HTML.pdf

In this study the most frequently reported symptoms were: gastrointestinal problems, fatigue, dizziness, problems with balance, rash or itching, which all accounted for 55% of reported symptoms. But what did the researchers miss because they were not knowledgeable about the unexpected adverse effects of some medications? Just about any complaint that an older adult has can be medication-related. Think of all the adverse effects I’ve discussed on this site such as: urinary incontinence, muscle aches, memory loss, poor balance and falls, insomnia, among many others, all assumed to be age-related complaints. In summary, if you are experiencing what you think to be medication-related symptoms, have your medications reviewed in order to determine if a medication is affecting your function or quality of life so you can avoid unnecessary discomfort or harm.