The Tablet | December 2015

In This Issue

Geriatric pharmacotherapy

This article is a guide to prescribing psychotropic medication for the geriatric population.

By Joseph E. Comaty, PhD

Although individuals 65 years of age or older comprise 14.5 percent of the U.S. population (U.S. Census Bureau, 2014), they are reported to be the largest per capita consumers of prescription medications (Qato, Alexander, Conti, Johnson, Schumm, & Tessler, 2008); and within this population, 29 percent take five or more prescription medications; 42 percent take at least one over-the-counter medication; and 42 percent take at least one dietary supplement. The CDC reports that individuals 65 years of age or older receive 14 different prescriptions per year (American Society of Consultant Pharmacists, 2006). To effectively treat the elderly requires an understanding of the special circumstances associated with this population. The first areas to understand are the pharmacokinetic and pharmacodynamic changes that occur as we age.

Pharmacokinetics and Pharmacodynamics of the Elderly

There are four components of pharmacokinetics: absorption, distribution, metabolism and elimination . As a person ages, changes in bowel size and decrease in pH slow the rate of absorption, while the total amount of drug absorbed remains the same. This increases the risk for drug-drug competition and drug-food interactions to occur (Carlo & Alpert, 2015). The volume of distribution (Vd) for fat-soluble drugs increases with age, because lean muscle mass shrinks while fat tissue increases. Conversely, Vd for water-soluble drugs decreases, because of decreases in total body fluid. This affects drug half-life (t1/2). In addition, albumin decreases with aging, resulting in a larger free fraction of drug in blood, meaning more drug is available to reach target receptors (Carlo & Alpert, 2015). Metabolic deficiencies result from decreased liver mass, decreased liver blood flow and decreased CYP enzyme activity with age. The result is decreased metabolism of many psychotropic medications, prolonging their effect and increasing the probability of drug-drug interactions, especially considering that the elderly are treated with multiple medications (Carlo & Alpert, 2015). Many psychotropic medications are eliminated in urine via the kidney. In the elderly, there is a decrease in renal activity (i.e., decrease in the GFR) which slows drug elimination, resulting in reabsorption and recirculation, thus extending t1/2. Rising blood levels may result in toxicity or other adverse events (Carlo & Alpert, 2015).

On the pharmacodynamic side, decreased receptor affinity and receptor numbers may reduce drug effectiveness at the receptor site. Changes in G-protein function may affect postsynaptic receptor function and RNA translation. Comorbid chronic illnesses may potentiate these actions, causing decreased drug effects in the elderly (Carlo & Alpert, 2015).

Medication Effects and Risks

Although there are few well designed controlled studies of psychotropic drugs in the elderly, and no FDA clinical trials, these drugs are used frequently in this population. Often, drugs are used preferentially over other, nonpharmacological, approaches such as evidence based psychotherapy; bright light treatment for depression; and nondrug treatments for the neuropsychiatric symptoms of dementia such as caregiver education, behavioral interventions, problem-solving training, music therapy and aroma therapy (Rothenberg & Wiechers, 2015).

When psychotropic medications are used in the elderly, sufficient attention should be paid to critical issues such as the indication (i.e., what is being treated); what class of drug is to be used; what dose is to be used; what is the research evidence showing that the selected drug has efficacy for the indication; what is the expected benefit; and what are the expected risks/adverse events? A partnership between the American Geriatrics Society (AGS) and the American Psychiatric Association (APA) and other professional organizations called Choosing Wisely is intended to promote conversations between clinicians and patients by helping patients choose care that is supported by evidence, not duplicative of other tests or procedures already received, free from harm and truly necessary.

Antipsychotic medications (APs). Antipsychotics are used in the elderly to treat aggressive behaviors, agitation, delusions, hallucinations and sleep disorders, that may be part of the presentation of dementia. This is despite the FDA black box warning about using APs to treat agitation/aggressive behavior related to dementia. The use of APs may not be effective and are likely to produce various adverse events to which the elderly are more sensitive. The adverse effects include sedation (which will affect cognition and increase risk for falls); anticholinergic effects (blurred vision, dry mouth, urinary retention, constipation, dizziness, cognitive impairment); and cardiovascular effects (hypo- or hypertension, tachycardia, QTc changes); and metabolic disorders. The elderly patient may already have many of these conditions as part of normal aging or another chronic medical condition, so these drugs will only exacerbate them. APs also carry neurological risks for the elderly like extrapyramidal symptoms (EPS), akathesia and tardive dyskinesia (TD). The elderly are more susceptible to these adverse neurological events compared to adults. And all APs pose a risk for neuroleptic malignant syndrome (NMS). In fact, elderly patients have several risk factors, which would increase their susceptibility to NMS including having dementia, being malnourished and dehydrated, and being on multiple psychotropic medications. Noting that a large number of elderly in nursing facilities were being treated with APs in the absence of a diagnosis that would justify their use, the Centers for Medicare and Medicaid Services (CMS) started a program in 2011 to reduce the use of APs in nursing facilities. This “National Partnership to Improve Dementia Care in Nursing Homes” involved adding indicators to facility surveys that tracked the use of APs within the facility. These indicators then linked to a facility's five-star quality rating. Following implementation, AP use in nursing facilities was reduced by 19 percent. They have extended the program and set a new goal of reducing AP use in nursing facilities by 30 percent by 2016 (CMS, 2015).

Antidepressants (ADs). For the elderly, the most significant risks include anticholinergic, sedative, cognitive, cardiovascular (blood pressure and conduction), falls and increased bleeding (made worse for the elderly already receiving anticoagulant medication).

Benzodiazepines (BDZs). Although these drugs have a wide variety of adverse effects, especially when used in the elderly, they are some of the most frequently used medications in this population. In fact, according to a study funded by the NIMH, benzodiazepines, especially long-acting versions, are used more frequently the older a person gets. Additional findings from this study indicated that prescriptions for benzodiazepines were less likely to be issued by psychiatrists in the older age groups; and that females are more likely than males to be treated with these drugs (Olfson, King, & Schoenbaum, 2014). The problems with using benzodiazepines in the elderly include a reduced capacity to metabolize the drugs in the elderly (increasing their t1/2 and increasing the risk for toxicity); active metabolites in some of the medications (essentially creating an extended release function); the side effects of cognitive (executive function), memory and attentional deficits (functions which may already be impaired in the elderly); decreased reaction time; and increased risk for falls. Add to this that benzodiazepines may cause paradoxical reactions (i.e., increase agitation) in the elderly; can produce carryover effects next day; and can produce tolerance, dependence and respiratory depression. Also, once started, benzodiazepines are notoriously difficult to withdraw. Finally, a recent study has indicated that the long-term use (i.e., > three months) of benzodiazepines can increase the risk for later dementia (Billioti de Gage et al., 2014).

“Z” drugs (zolpidem, zaleplon, eszopliclone). Their adverse effects include drowsiness (risk of falls), dizziness (falls), nausea, carryover effects next day, blackouts and sleep walking, eating, driving and other complex behaviors. Due to these concerns, the FDA recently advised reducing the bedtime dose of these agents by half for all persons using these medications. Safer alternatives to benzodiazepines or the “Z” drugs as hypnotic agents for the elderly might be ramelteon (melatonin receptor agonist) or suvorexant (orexin receptor antagonist). Keep in mind that the elderly may also be using OTC drugs like diphenhydramine or herbals to help them get to sleep which increases the probability of drug-drug interactions with prescribed medications.

The American Academy of Sleep Medicine (AASM) and the American Medical Directors Association (AMDA) have made the following recommendations to treat sleep disorders in the elderly: (1) First use psychological or behavioral interventions (sleep hygiene techniques; psychotherapy to treat underlying psychiatric disorders that disturb sleep); (2) if medication treatment is necessary then treat for a period of two to four weeks and then re-evaluate; (3) preferentially use short to intermediate acting ‘“Z” drugs or ramelteon; (4) avoid long-term use (i.e., > one month) of any long-acting benzodiazepine; and (5) avoid prolonged use (i.e., > one week) of antihistamines.

Cholinesterase inhibitors (CIs). Currently, there are four cholinesterase inhibitors (tacrine, donepezil, rivastigmine and galantamine) used to treat dementia. Tacrine is little used due to need for multiple doses and its risk of liver toxicity. Concerns about the use of these drugs include the window for efficacy is limited (around six months to one year); usefulness in moderate to severe dementia is limited; none of these agents will affect the disease course nor prevent the eventual outcome; and they are not effective for any other form of dementia (i.e., vascular dementia). Adverse effects of the drugs include diarrhea, nausea, vomiting, dyspepsia, bradycardia, dizziness, headache and weight loss. A recent review summarized the state of the literature for cholinesterase inhibitors as indicating that they may be useful in the treatment of mild cases of Alzheimer's dementia; but, the changes noted in cognitive functioning were minimal and not necessarily clinically relevant; they do not produce changes in functional ability; they do not change the course of the disease; their adverse effects and cost may outweigh any benefit; they are not useful for other types of dementia; and they have no effect on preventing the progression from mild cognitive impairment (MCI) to dementia (Buckley & Salpeter, 2015).

Memantine. This drug is an NMDA receptor antagonist. The same limitations as seen with CIs applies to memantine. Memantine also has many of the same adverse effects including diarrhea, constipation, nausea, vomiting, dyspepsia, dizziness, headache, weight gain, somnolence, depression, anxiety, hallucinations, incontinence and a risk for Stevens-Johnson-Syndrome (SJS). Memantine may be useful in moderate to severe ALZ; but not in mild dementia; effect sizes are small; there is little change in functional ability; memantine does not change disease progression; adverse effects may outweigh cost/benefit; and, it is not useful in other forms of dementia (Buckley & Salpeter, 2015). There is some evidence to suggest that the combination of a CI with memantine may be helpful in moderate to severe Alzheimer's dementia (Gauthiera & Molinuevo, 2013), but this has not been supported by other studies (Howard et al., 2012).

Beers Criteria. The Beers Criteria are published by the American Geriatrics Society (AGS) and updated periodically. The latest version was just published in October 2015. These criteria provide information on medications that are either ineffective or high risk when used to treat elderly patients. The data are divided into two domains: (1) potentially inappropriate use of medications based on their class and (2) potentially inappropriate use of medications based on the patient's disease or condition. The new additions to the 2015 edition include (1) a list of drugs for which dose adjustment is required based on kidney function and (2) drug–drug interactions. The intentions of the criteria are to “improve medication selection; educate clinicians and patients; reduce adverse drug events; and serve as a tool for evaluating quality of care, cost, and patterns of drug use of older adults” (p. 2; American Geriatrics Society, Beers Criteria Expert Update Panel, 2015).

In summary, the clinical pearls for treating elderly individuals include “start low and go slow,” medications for the elderly need to be initiated at doses lower than those for adults; and when dose increases are necessary, they should be lower in dose and slower in rate than for adults; psychological/psychiatric disorders such as depression, anxiety and substance abuse should be evaluated in the elderly and if present, properly treated. Evaluations of the elderly should include a comprehensive review of all drugs being taken, including those that are prescribed, those taken OTC and herbals. Finally, decreasing doses of or eliminating medications can be more effective than increasing doses or adding medication when treating the elderly.

Web Resources

References

American Geriatrics Society Beers Criteria Expert Update Panel. (2015, October). Early view. Retrieved October 13, 2015, from Journal of the American Geriatric Society: http://onlinelibrary.wiley.com/journal/10.1111/(ISSN)1532-5415/earlyview

American Society of Consultant Pharmacists. (2006). ASCP fact sheet. (Center for Disease Control) Retrieved October 7, 2015, from American Society of Consultant Pharmacists Web site: https://www.ascp.com/articles/about-ascp/ascp-fact-sheet

Billioti de Gage, S., Moride, Y., Ducruet, T., Kurth, T., Verdoux, H., Tournier, M., et al. (2014). Benzodiazepine use and risk of Alzheimer's disease: Case-control study. BMJ, 1-10.

Briesacher, B., Tjia, J., Field, T., Peterson, D., & Gurwitz, J. (2013). Antipsychotic use among nursing home residents. JAMA, 440-442.

Buckley, J., & Salpeter, S. (2015). A risk-benefit assessment of dementia medications: Systematic review of the evidence. Drugs and Aging, 32, 453–467.

Carlo, A., & Alpert, J. (2015). Geriatric psychopharmacology: Pharmacokinetic and pharmacodynamic considerations. Psychiatric Annals, 45 (7), 336-341.

CMS. (2015, April 14). National partnership to improve demenitia care in nursing homes. Retrieved October 11, 2015, from CMS.gov: https://www.cms.gov/Medicare/Provider-Enrollment-and-Certification/SurveyCertificationGenInfo/National-Partnership-to-Improve-Dementia-Care-in-Nursing-Homes.html

Gauthiera, S., & Molinuevo, J. (2013). Benefits of combined cholinesterase inhibitor and memantine treatment in moderate–severe Alzheimer's disease. Alzheimer's and Dementia, 9, 326–331.

Howard, R., McShane, R., Lindesay, J., Ritchie, C., Baldwin, A., Barber, R., et al. (2012). Donepezil and memantine for moderate-to-severe Alzheimer's disease. The New England Journal of Medicine, 366, 893-903.

Huybrechts, K., Gerhard, T., Crystal, S., Olfson, M., Avorn, J., Levin, R., et al. (2012). Differential risk of death in older residents in nursing homes prescribed specific antipsychotic drugs: Population based cohort study. BMJ, 344 (e977), 1-12.

Olfson, M., King, M., & Schoenbaum, M. (2014, December). Benzodiazepine use in the United States. JAMA Psychiatry, E1-E7.

Qato, D., Alexander, G. C., Conti, R., Johnson, M., Schumm, P., & Tessler, S. (2008). Use of prescription and over-the-counter medications and dietary supplements among older adults in the United States. JAMA, 2867-2878.

Rothenberg, K., & Wiechers, I. (2015). Antipsychotics for neuropsychiatric symptoms of dementia—Safety and efficacy in the context of informed consent. Psychiatric Annals, 45 (7), 348-353.

U.S. Census Bureau. (2014, July 1). Quick facts. Retrieved October 7, 2015, from U.S. Census Bureau Website: http://www.census.gov/quickfacts/table/PST045214/00