KDA Today

KDA Today

For Immediate Release

Date: Sep 12th, 2016
Contact: Dr. Demetra Antimisiaris
Phone: 800-292-1855
Email: info@kyda.org

Polypharmacy: A Geriatric Syndrome with Serious Implications for Oral Health

Background:

Modern medicine has made living with multiple chronic diseases possible, but now faces the difficult balance of improving quality of life, and managing the means by which this is achieved. Today, we are able to extend life expectancy due to improvements in sanitation, living conditions and medical technology, including the use of various pharmaceutical products. Polypharmacy, the use of multiple medications at the same time is considered a geriatric syndrome, and is a side effect of modern medicine. Geriatric syndromes are conditions that are multifactorial health conditions occurring due to accumulated effects of impairments in multiple systems, but are not necessarily specific organic disease processes, such as incontinence, dizziness, cognitive impairment, falls, delirium and frailty.

In 1900, those aged 65 years and older constituted four percent of the population, which had a life expectancy of 46 years. Today, those over 65 represent 13-16 percent of the population, which enjoys a life expectancy of 75 years for men and 80 years for women (1). By 2030 elders will constitute 22 percent of the population with the percent over 80 years of age set to quadruple (2). Elders are most vulnerable to medication problems, and suffer increased exposure to medication. They are frailer and lack the physiological reserve to survive interventions and medical events.

The PDR in 1969 contained 1,415 pages, inclusive of Over the Counter (OTC) products. In 2008, the PDR held 3,482 pages of prescription products with a separate OTC and dietary supplements book. In addition to the supervised use of medications, there is an unprecedented level of self-medication due to direct to consumer marketing and more prescription items going over the counter, annually. Surveys of mean daily OTC drug use in people over 65-years-old range from 31-96 percent of the population, with a 70 percent average (3). A 2004 Boston College survey reports that 42 percent of all adults take vitamins, daily, and 19 percent take herbals and supplements, daily. In any given week, 82 percent of U.S. adults take at least one medication (prescription or nonprescription drug, vitamin/mineral, herbal/natural supplement), while 30 percent take at least five (4).

The use of multiple medications is accompanied by significant risk due to anything from drug-drug and drug-disease interactions to a patient's own cognitive ability to manage his or her medications. A linear relationship exists between the number of medications taken and the risk of adverse reactions. The same linear relationship has been seen with the number of medications used and mortality, even after adjusting for disease severity (5, 6). At particular risk are the elderly. Eighty-eight percent of people over 65 live with chronic health problems. Adults over 65 years of age currently account for just 13 percent of the general population, but constitute 40 percent of all hospitalizations and 50 percent of hospital days. Approximately one third of hospital admissions in the elderly result from medication related problems (7, 8). With increasing pressure on primary care physicians to manage complex medical problems in less time, it is not surprising that adverse events occur. Similarly, sub-specialists adhering to practice guidelines may excessively treat an older, frail adult, with negative consequences.

If medication-related problems were a disease, it would rank fifth of the top ten with regard to the economic impact of diseases affecting Americans 65 years of age and older (9). That places medication-related problems behind diabetes and in front of osteoarthritis. The state of Kentucky leads the country for expenditure on antidiabetics, antihypertensives, GI medications and analgesics/anti- inflammatory meds, and antidepressants. Kentucky also leads the overall scripts per capita statistics for the United States; ahead of West Virginia, Alabama, Mississippi, Louisiana, and Arkansas (10). With such unusually high medication, OTC, herbal and supplement use in Kentucky, all stake holders are obligated to consider the implications and risks.

Considerations in caring for older adults with high medication use burdens:

Frailty and Physiological Reserve
The majority of the medications that are used in the elderly were brought to market based on safety and efficacy studies performed in either younger or healthier subjects than those actually taking the medications. To participate in a safety and efficacy drug trial, the exclusion criteria eliminate frailest patients with multiple co morbidities. Additionally, the frailest of the frail cannot even make their way to clinic to participate in studies. Be cautious using medications new to the market. Rofecoxib (Vioxx®) was introduced with claims of improved safety, but was found in post marketing data to cause adverse cardiac effects and increased mortality.

Impaired physiology is important to take into account when prescribing for elders. Current science pertaining to our understanding of the physiology of aging is changing daily, thus our understanding of how drugs behave in elders is also changing rapidly. Hepatic metabolism slows with age resulting in impaired first pass effect. Renal function is impaired with age in all persons. With every decade of age over 40-years-old, a person loses 1 ml/min of creatinine clearance of renal function per year (and at 40 years of age, typical CrCl-100ml/min). This renal slowing occurs regardless of renal insults such as environmental toxicity, diabetes and the like. Renal dose adjustment is often overlooked leading to adverse medication events. Many drugs such as memantine, and levofloxacin require renal dosage adjustment, or are contraindicated in elders with moderate to severe renal impairment such as bisphosphonates. As a class of drugs, antibiotics have many which require renal dose adjustment, and NSAIDs (non-steroidal anti-inflammatory drugs) are acceptable for most patients in treating transient pain and inflammation, but might not be in those with severe renal impairment, high blood pressure and concomitant use of anticoagulants.

A deceiving feature of elderly patients is that their serum creatinine level may seem normal despite marked renal impairment. Most labs do report Glomerular Filtration Rate, however they calculate using the MDRD, which has not been validated in elderly subjects. The Cockcroft-Gault Equation is recommended because it has better validation in elders and is the FDA renal dose adjustment standard.

The use of medications in older adults requires consideration of their diminished physiological reserve and altered pharmacokinetics; resulting in a decreased ability to adjust to neurotransmitter alterations, changes in blood pressure, glucose and other parameters influenced by medications and disease states. These cardiovascular, renal, neural hormonal, endocrine and other changes, result in the elderly patients being less able to recover from challenges such as hypoglycemia, hypotension, confusion and delirium.

It is useful to recognize that the goals of care may be quite different in elders. Tight glucose control may not be the goal of treatment in elders due to their increased risk of falls, decreased ability to survive hypoglycemic events and decreased need to prevent end organ damage with respect to their expected survivability. (11) A relaxed approach is useful also with respect to blood pressure control in elders. The JNC 8 blood pressure guidelines markedly relaxed blood pressure goals for the elderly in acknowledgement of the fact that elders have different long term goals than younger persons and less reserve to tolerate aggressive medication management of blood pressure.

As healthcare providers for older adults, it is advisable to be as conservative as possible with medication use and other interventions because of their lack of physiological reserve. Individualization is important regarding the care of older adults because age is just a surrogate marker of frailty. We all know older adults who seem far more robust than their age and vice versa. So a 70-year-old who is very active may tolerate medical interventions (including medications) just as a middle-aged adult could. Conversely, a 60-year-old, living with high disease burden and frailty may require more conservative management.

Adverse drug outcomes in dental practice
Xerostomia: The most common adverse drug reaction effecting oral health are those causing xerostomia. In particular, anticholinergic drug effects. But, other medication causes of xerostomia are often present, including dehydration due to diuretic use, decongestants, pain medications, muscle relaxants, antidepressants, anti-seizure medications and more. Estimates range from 300-500 prescription and over the counter medications are linked to xerostomia. The risk of xerostomia compounded by polypharmacy is highest in patients who live with multi-morbidity and take multiple medications. Additionally, with the aging of the population, cancer is increasingly being considered a chronic disease (thanks to treatment successes and the ability for people to live with cancer longer), thus chemotherapy and radiation therapy are significant irreversible causes of xerostomia. Nerve damage, and chronic disease, including diabetes, HIV, Sjogren’s Syndrome, and others layer on top of polypharmacy leading to significant xerostomia prevalence in older adults.

Sometimes less anticholinergic and xerostomia chronic disease medication choices can be made such as managing hypertension without a “water pill”, or choosing a sertraline over amitriptyline for depression therapy. But, chances are, the xerostomia an older patient experiences is to some degree a chronic condition. In that case, encouraging the use of products to treat xerostomia would be appropriate.

Lichenoid Reaction: A common inflammatory condition is lichen planus (LP). LP is an immune mediated process where T-cells mediate the destruction of basal cells of the epithelium. Many medications are linked to cutaneous lichenoid hypersensitivity reactions (LHR), and they are often difficult to distinguish from idiopathic reactions. The postulation is that active thiol groups in the chemical structure of multiple medications can trigger LP reactions. Two classes often linked to LP are nonsteroidal anti-inflammatory agents, and antihypertensive agents such as beta blockers, ACE inhibitors, and diuretics (hydrochlorothiazide). Antidiabetic medications, including sulfonylureas (glipizide), anticonvulsants, sulfasalazine, allopurinol and lithium have all been reported to cause LR. (13)

Aphthous-like Ulcers: another oral problem that has been linked to a multitude of drug classes. The mechanism of ulceration is beyond this discussion, however, the drugs linked to aphthous ulcers and aphthous-like ulcers are diverse and reflect the collections of medications not uncommon to the older adult.

Osteonecrosis of the Jaws (ONJ): dental professionals are well versed in the risks associated with bisphosphonate use and ONJ. We often associate ONJ with bisphosphonate use, but with the introduction of denosumab to the market (Prolia®, Xgeva®), we have to also know that although these are not bisphosphonates (they are monoclonal antibodies or “mabs”), they do work through the mechanism of bone density. They have only been on the market approximately seven years, and initially didn’t claim any ONJ results in their FDA safety and efficacy trials (of course, because there were not enough subjects for a long enough time to have that adverse effect surface), but there have been a few case reports, and eight cases in the FREEDOM trial, as would be expected with any antiresorptive drug. (15, 16)

Given that this type of antiresorptive drug is reported in studies to be very effective in avoiding skeletal complications of metastatic bone disease, future use is expected to rise. As for bisphosphonates, patients who are elderly and have received bisphosphonate therapy for osteoporosis (not bone metastasis) might consider discontinuation of therapy if they have received many years of therapy and begin a drug holiday, as bisphosphonates have a very long t½, and the FIT/FLEX trial demonstrated protection from fracture up to five years post discontinuation of use when used for five years, minimum. (17) In other words, bisphosphonates incorporate into the bone matrix and take a long time to come out. These bisphosphonate patients have to be monitored closely and urged to continue high level oral health care beyond the stop date of bisphosphonate use. As for the denosumab patients after discontinuation of therapy, the need to monitor is not as clear. It appears that the drug clears the body swiftly, but consider that there are atypical fractures associated with denosumab use (meaning that there is some rearrangement of bone architecture as with bisphosphonates), and many of patients receiving denosumab have received bisphosphonates, previously. The risk of ONJ post discontinuation of denosumab is yet to be seen.

Medications have been linked to many oral problems ranging from LP to pigmentation, fibrovascular hyperplasia, keratosis/epithelial hyperplasia, dysesthesias and osteonecrosis of the jaws. (14) Again, the review of polypharmacy involvement in these conditions is beyond the scope of this discussion.

Anticoagulation: mindfulness regarding bleeding risk is always at the forefront of dental practice due to the invasive nature of procedures and routine office dental care. There are the well-known anticoagulants such as warfarin, aspirin, ibuprofen, naproxen, and the new novel oral anticoagulants such as dabigatran, rivaroxaban, apixaban and edoxaban. There are the low molecular weight injectables, such as dalteparin, tinzaparin and enoxaparin that you might run across if treating nursing home patients or patients who are bed or chair bound and high clot risk patients.

The hidden anticoagulation threats are the herbals, supplements and some antidepressants. (Did you know platelets have serotonin receptors?) When assessing your patient for anticoagulation risk, it would be prudent to use a database such as Lexicomp®, Epocrates®, Micromedex®, Drugs.com®, Drugs Facts and Comparisons® or others, and run an interaction checker, not just for drug anticoagulant synergy, but in general.

Conclusion
In addition to medication-induced problems, it is important for the health care provider to appreciate the barriers to and difficulty in implementation of care in older adults who are taking complex medication regimens. There are cognitive and physical problems which can impair successful treatment and follow up. These impairments may, themselves, be medication induced.

Healthcare providers of all disciplines should keep medication-induced problems high on the differential diagnosis list. Remember, at minimum, to do an interaction checker listing all prescriptions, OTC products, supplements and herbs. Also keep in mind that what may look like a physiological or organic problem might actually be a medication-induced problem, particularly in older medically complex adults. A well-respected scholar from U Mass, Jerry Gurwitz MD, once said, “Whenever an elderly patient experiences a status change, medication-related problems have to be ruled out”.

References
1. US Census Data accessed July 2015
2. AGS: Underrepresentation of Older Adults in Clinical Trials. http://www.americangeriatrics.org/policy/clinical_trials.shtml
3. Hanlon JT, et al. Epidemiology of over-the-counter drug use in community dwelling elderly: United States perspective. Drugs Aging. 2001;18:123-131
4. Slone Survey, Boston College. Patterns of Medication Use in the United States. http://www.bu.edu/slone/files/2012/11/SloneSurveyReport2005.pdf
5. Denham MJ, Adverse Drug Reactions. Brit Med Bull 1990 (46): 53-62
6. Bath, PA et al. Identification of Risk Factors for 15-year Mortality Among Community-Dwelling Older People Using Cox Regression and a Genetic Algorithm. Journal of Gerontology, 2005. (60A) 8, 1052-1058.
7. Woodford H, Walker R. Emergency hospital admissions in idiopathic Parkinson's disease. Mov Disord. 2005; 20:1104-1108.
8. Hanlon JT, Schmader KE, Ruby CM, Weinberger M. Suboptimal prescribing in older inpatients and outpatients. J Am Geriatr Soc. 2001; 49:200-209.
9. Alzheimer’s Disease Foundation and Referral Center, National Cancer Institute, Am Diabetes Assoc, Arthritis Foundation, National Center for Health Statistics, National Parkinsons Foundation, National Stroke Foundation.
10. Kaiser Foundation Scripts per Capita http://kff.org/other/state-indicator/retail-rx-drugs-per-capita/
11. The Action to Control Cardiovascular Risk in Diabetes Study Group (ACCORD) Effects of Intensive Glucose Lowering in Type 2 Diabetes NEJM 358;24 www.nejm.org June 12, 2008
12. James, P, Oparil S, Carter B, et al. 2014 Evidence-Based Guideline for the Management of High Blood Pressure in Adults. A report from the panel members appointed to the Eight Joint National Committee (JNC8). JAMA Feb 5, 2014. Vol 311, No. 5: 507-520.
13. Schlosser B. Lichen planus and lichenoid reactions of the oral mucosa: case report. Dermatol. Ther. 2010; 23:251-267.
14. Yuan A, Woo S. Adverse drug events in the oral cavity. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. 2015; 119: 35-47.
15. Uyanne J, Calhoun C, Le A. Antiresorptive drug-related osteonecrosis of the jaw. Dent. Clin. North. Am. 2014 Apr, 58(2): 369-84.
16. Papadopoulos S, Lippuner K, Roux C, et al. The effect of 8 or 5 years of denosumab treatment in postmenopausal women with osteoporosis: results from the FREEDOM Extension study. Osteoporosis Int. 2015 Dec; 26 (12): 2773-83.
17. Black D, Schwartz A, Ensrud K. Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension: a randomized trial. JAMA. 2006 Dec 27; 296 (24): 2927-38.

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